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CMML from biology to
treatment
Pierre Fenaux
Hocircpital St Louis
Paris 7 UniversityFrance
GFM
ASH 2015
Disclosure
I have the following financial
relationships
Consultant and Contracted
Research for
Boehringer Ingelheim Celgene Corporation
Janssen Pharmaceuticals Inc Novartis
An update on CMML
bull Definition epidemiology
bull Characteristics
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
1 Persistent PB monocytosis (gt1 x109L)
bull gt 3 months
bull (gt 10 of WBC)
bull No impact of BM monocyte
2 No Phi- or BCR-ABL fusion gene
bull No eosinophilia no PDGFRAB rearrangement
3 lt20 myeloblasts or monoblasts in PB or BM
bull Including promonocytes
4 Evidence of dysplasia in one or more lineages
bull If lacking acquired clonal cytogenetic abnormality
bull or persistent monocytosis gt 3 months with exclusion of all other causes of monocytosis
bull CMML-1 lt5 PB blasts and lt10 BM blasts
bull CMML-2 5ndash19 PB blasts and 10ndash19 BM blastsVardiman Blood 2009
WHO-2008 criteria for CMML
Goasguen Haematologica 2009
Promonocytes in CMML
Epidemiology
bull Elderly patients (median age 75)
bull Male predominance (2 to 31)
bull Incidence About 20 of MDS (05 to
1100000year)
bull About 10 are therapy related
bull About 20 associated with immunological
disorders
bull 358 CMML patients of whom 39 (11) had t-CMML
bull median latency to develop t-CMML 6 years
time from outside diagnosis to MDACC referral was 15 months (range
0-80) Of thosepatients 39 (11) had prior exposureto chemotherapy andor
radiation therapy and were defined as t-CMML Clinical data of the studied
patientswereobtained at the timeof referral to MDACC Therapies that were
given to the patients were categorized into 4 groups (1) best supportive care
or cytoreductive therapy using hydroxyurea or oral etoposide (BSCCR) (2)
hypomethylating agents (HMA) such as 5-azacitidinendashbased or decitabine-
based regimens (3) AML-like induction therapy and (4) other therapies
including immunomodulatory drugs(thalidomideor lenalidomide) or tyrosine
kinase inhibitors (iMiDsTKIs) Cytogenetics and mutational analyses of
Figure 1 Survival estimate for t-CMML and de novo CMML Differences in OS duration (A) and LFS duration (B) between 319 patients with de novo CMML and 39 patients with t-CMML
BLOOD 17 OCTOBER 2013 x VOLUME 122 NUMBER 16 THERAPY-RELATED CHRONIC MYELOMONOCYTIC LEUKEMIA 2809
Original Paper
A Close Association of Autoimmune-Mediated Processes and Autoimmune Disorders with Chronic Myelomonocytic Leukemia Observation from a Single Institution
Introduction
Key Words
Abstract
Do
wnlo
ad
ed b
y
INS
ER
M D
ISC
IS
T
19
81
43
431
- 1
12
32
015
85
00
9 P
M
123 CMML 195 had at least one immune-mediated
disorder most commonly ITP gout and psoriasis
Association between CMML and vasculitis
An update on CMML
bull Definition epidemiology
bull Characteristics
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML in the adult a report of 60 cases with special reference to prognostic
factorsBr J Haematol 198765101-6
bull MF 33
bull median age 73 years
bull Splenomegaly in 32 of cases
bull hyperleucocytosis in 52 of cases
bull mean blood monocytosis 43 X 10(9)l
bull marrow blasts gt=5 57 of the cases
bull median survival was 28 months
hematological characteristics
ndash MDS
bull cytopenias
bull excess of marrow blasts
bull marrow dysplasia
bull abnormal karyotype (-7+8 rarely complex)
ndash MPN
bull Splenomegaly
bull Extra hematological disease (serous effusions cutaneous
lesions)
bull increased WBC counts
bull monocytosis (gt1000mm3)
bull immature myeloid cells in the blood (myelocytes
metamyelocytes)
laquo dysplastic raquo CMML WBC lt 13GL
laquo proliferative raquo CMML WBC gt 13Gl
Haematologica 2011
Flow Cytometry as diagnostic tool
Selimoglu-Buet et al Blood 2015
CD1
4
MO1 CD14+CD16-
Classical monocytes
CD14lowCD16high
non-classical
monocytes
MO3
Healthy
donors
MO1 lt 94
MO2 + MO3
gt 6 C
D16
Peripheral blood human monocyte subsets
MO2 CD14+CD16+
Intermediate
monocytes
Age-matched controls CMML reactive monocytosis
CMML monocytosis is made mostly of classical (MO1)
monocytes
CD14
CD16
CMML MDS MDS MPN
Before AZA After AZA
CD14
CD
16
0 3 6 9 12 15 1875
80
85
90
95
100Threshold
94
MO
1 (
o
f to
tal
mo
no
cyte
s)
AZA
Response to hypomethylating agents
includes a decrease in MO1 subset
Respond
ers (N=7)
Molecular abnormalities in 80 CMML
RAS
CBL JAK
2
Signal
transduction
EZH2
TET2
Epigenetic
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing e
ZRSR2
U2AF1
SRSF2
SF3B1
Frequency of mutations (Itzykson JCO
2013)
Gene Ndeg pts studied Mutation
TET2 262 151 (58)
SRSF2 220 101 (46)
ASXL1 312 125 (40)
RUNX1 263 39 (15)
NRAS 263 29 (11)
CBL 264 27 (10)
JAK2 263 21 (8)
KRAS 263 20 (8)
ZRSF2 189 15 (8)
IDH2 229 13 (6)
SF3B1 220 13 (6)
U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Disclosure
I have the following financial
relationships
Consultant and Contracted
Research for
Boehringer Ingelheim Celgene Corporation
Janssen Pharmaceuticals Inc Novartis
An update on CMML
bull Definition epidemiology
bull Characteristics
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
1 Persistent PB monocytosis (gt1 x109L)
bull gt 3 months
bull (gt 10 of WBC)
bull No impact of BM monocyte
2 No Phi- or BCR-ABL fusion gene
bull No eosinophilia no PDGFRAB rearrangement
3 lt20 myeloblasts or monoblasts in PB or BM
bull Including promonocytes
4 Evidence of dysplasia in one or more lineages
bull If lacking acquired clonal cytogenetic abnormality
bull or persistent monocytosis gt 3 months with exclusion of all other causes of monocytosis
bull CMML-1 lt5 PB blasts and lt10 BM blasts
bull CMML-2 5ndash19 PB blasts and 10ndash19 BM blastsVardiman Blood 2009
WHO-2008 criteria for CMML
Goasguen Haematologica 2009
Promonocytes in CMML
Epidemiology
bull Elderly patients (median age 75)
bull Male predominance (2 to 31)
bull Incidence About 20 of MDS (05 to
1100000year)
bull About 10 are therapy related
bull About 20 associated with immunological
disorders
bull 358 CMML patients of whom 39 (11) had t-CMML
bull median latency to develop t-CMML 6 years
time from outside diagnosis to MDACC referral was 15 months (range
0-80) Of thosepatients 39 (11) had prior exposureto chemotherapy andor
radiation therapy and were defined as t-CMML Clinical data of the studied
patientswereobtained at the timeof referral to MDACC Therapies that were
given to the patients were categorized into 4 groups (1) best supportive care
or cytoreductive therapy using hydroxyurea or oral etoposide (BSCCR) (2)
hypomethylating agents (HMA) such as 5-azacitidinendashbased or decitabine-
based regimens (3) AML-like induction therapy and (4) other therapies
including immunomodulatory drugs(thalidomideor lenalidomide) or tyrosine
kinase inhibitors (iMiDsTKIs) Cytogenetics and mutational analyses of
Figure 1 Survival estimate for t-CMML and de novo CMML Differences in OS duration (A) and LFS duration (B) between 319 patients with de novo CMML and 39 patients with t-CMML
BLOOD 17 OCTOBER 2013 x VOLUME 122 NUMBER 16 THERAPY-RELATED CHRONIC MYELOMONOCYTIC LEUKEMIA 2809
Original Paper
A Close Association of Autoimmune-Mediated Processes and Autoimmune Disorders with Chronic Myelomonocytic Leukemia Observation from a Single Institution
Introduction
Key Words
Abstract
Do
wnlo
ad
ed b
y
INS
ER
M D
ISC
IS
T
19
81
43
431
- 1
12
32
015
85
00
9 P
M
123 CMML 195 had at least one immune-mediated
disorder most commonly ITP gout and psoriasis
Association between CMML and vasculitis
An update on CMML
bull Definition epidemiology
bull Characteristics
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML in the adult a report of 60 cases with special reference to prognostic
factorsBr J Haematol 198765101-6
bull MF 33
bull median age 73 years
bull Splenomegaly in 32 of cases
bull hyperleucocytosis in 52 of cases
bull mean blood monocytosis 43 X 10(9)l
bull marrow blasts gt=5 57 of the cases
bull median survival was 28 months
hematological characteristics
ndash MDS
bull cytopenias
bull excess of marrow blasts
bull marrow dysplasia
bull abnormal karyotype (-7+8 rarely complex)
ndash MPN
bull Splenomegaly
bull Extra hematological disease (serous effusions cutaneous
lesions)
bull increased WBC counts
bull monocytosis (gt1000mm3)
bull immature myeloid cells in the blood (myelocytes
metamyelocytes)
laquo dysplastic raquo CMML WBC lt 13GL
laquo proliferative raquo CMML WBC gt 13Gl
Haematologica 2011
Flow Cytometry as diagnostic tool
Selimoglu-Buet et al Blood 2015
CD1
4
MO1 CD14+CD16-
Classical monocytes
CD14lowCD16high
non-classical
monocytes
MO3
Healthy
donors
MO1 lt 94
MO2 + MO3
gt 6 C
D16
Peripheral blood human monocyte subsets
MO2 CD14+CD16+
Intermediate
monocytes
Age-matched controls CMML reactive monocytosis
CMML monocytosis is made mostly of classical (MO1)
monocytes
CD14
CD16
CMML MDS MDS MPN
Before AZA After AZA
CD14
CD
16
0 3 6 9 12 15 1875
80
85
90
95
100Threshold
94
MO
1 (
o
f to
tal
mo
no
cyte
s)
AZA
Response to hypomethylating agents
includes a decrease in MO1 subset
Respond
ers (N=7)
Molecular abnormalities in 80 CMML
RAS
CBL JAK
2
Signal
transduction
EZH2
TET2
Epigenetic
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing e
ZRSR2
U2AF1
SRSF2
SF3B1
Frequency of mutations (Itzykson JCO
2013)
Gene Ndeg pts studied Mutation
TET2 262 151 (58)
SRSF2 220 101 (46)
ASXL1 312 125 (40)
RUNX1 263 39 (15)
NRAS 263 29 (11)
CBL 264 27 (10)
JAK2 263 21 (8)
KRAS 263 20 (8)
ZRSF2 189 15 (8)
IDH2 229 13 (6)
SF3B1 220 13 (6)
U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
An update on CMML
bull Definition epidemiology
bull Characteristics
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
1 Persistent PB monocytosis (gt1 x109L)
bull gt 3 months
bull (gt 10 of WBC)
bull No impact of BM monocyte
2 No Phi- or BCR-ABL fusion gene
bull No eosinophilia no PDGFRAB rearrangement
3 lt20 myeloblasts or monoblasts in PB or BM
bull Including promonocytes
4 Evidence of dysplasia in one or more lineages
bull If lacking acquired clonal cytogenetic abnormality
bull or persistent monocytosis gt 3 months with exclusion of all other causes of monocytosis
bull CMML-1 lt5 PB blasts and lt10 BM blasts
bull CMML-2 5ndash19 PB blasts and 10ndash19 BM blastsVardiman Blood 2009
WHO-2008 criteria for CMML
Goasguen Haematologica 2009
Promonocytes in CMML
Epidemiology
bull Elderly patients (median age 75)
bull Male predominance (2 to 31)
bull Incidence About 20 of MDS (05 to
1100000year)
bull About 10 are therapy related
bull About 20 associated with immunological
disorders
bull 358 CMML patients of whom 39 (11) had t-CMML
bull median latency to develop t-CMML 6 years
time from outside diagnosis to MDACC referral was 15 months (range
0-80) Of thosepatients 39 (11) had prior exposureto chemotherapy andor
radiation therapy and were defined as t-CMML Clinical data of the studied
patientswereobtained at the timeof referral to MDACC Therapies that were
given to the patients were categorized into 4 groups (1) best supportive care
or cytoreductive therapy using hydroxyurea or oral etoposide (BSCCR) (2)
hypomethylating agents (HMA) such as 5-azacitidinendashbased or decitabine-
based regimens (3) AML-like induction therapy and (4) other therapies
including immunomodulatory drugs(thalidomideor lenalidomide) or tyrosine
kinase inhibitors (iMiDsTKIs) Cytogenetics and mutational analyses of
Figure 1 Survival estimate for t-CMML and de novo CMML Differences in OS duration (A) and LFS duration (B) between 319 patients with de novo CMML and 39 patients with t-CMML
BLOOD 17 OCTOBER 2013 x VOLUME 122 NUMBER 16 THERAPY-RELATED CHRONIC MYELOMONOCYTIC LEUKEMIA 2809
Original Paper
A Close Association of Autoimmune-Mediated Processes and Autoimmune Disorders with Chronic Myelomonocytic Leukemia Observation from a Single Institution
Introduction
Key Words
Abstract
Do
wnlo
ad
ed b
y
INS
ER
M D
ISC
IS
T
19
81
43
431
- 1
12
32
015
85
00
9 P
M
123 CMML 195 had at least one immune-mediated
disorder most commonly ITP gout and psoriasis
Association between CMML and vasculitis
An update on CMML
bull Definition epidemiology
bull Characteristics
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML in the adult a report of 60 cases with special reference to prognostic
factorsBr J Haematol 198765101-6
bull MF 33
bull median age 73 years
bull Splenomegaly in 32 of cases
bull hyperleucocytosis in 52 of cases
bull mean blood monocytosis 43 X 10(9)l
bull marrow blasts gt=5 57 of the cases
bull median survival was 28 months
hematological characteristics
ndash MDS
bull cytopenias
bull excess of marrow blasts
bull marrow dysplasia
bull abnormal karyotype (-7+8 rarely complex)
ndash MPN
bull Splenomegaly
bull Extra hematological disease (serous effusions cutaneous
lesions)
bull increased WBC counts
bull monocytosis (gt1000mm3)
bull immature myeloid cells in the blood (myelocytes
metamyelocytes)
laquo dysplastic raquo CMML WBC lt 13GL
laquo proliferative raquo CMML WBC gt 13Gl
Haematologica 2011
Flow Cytometry as diagnostic tool
Selimoglu-Buet et al Blood 2015
CD1
4
MO1 CD14+CD16-
Classical monocytes
CD14lowCD16high
non-classical
monocytes
MO3
Healthy
donors
MO1 lt 94
MO2 + MO3
gt 6 C
D16
Peripheral blood human monocyte subsets
MO2 CD14+CD16+
Intermediate
monocytes
Age-matched controls CMML reactive monocytosis
CMML monocytosis is made mostly of classical (MO1)
monocytes
CD14
CD16
CMML MDS MDS MPN
Before AZA After AZA
CD14
CD
16
0 3 6 9 12 15 1875
80
85
90
95
100Threshold
94
MO
1 (
o
f to
tal
mo
no
cyte
s)
AZA
Response to hypomethylating agents
includes a decrease in MO1 subset
Respond
ers (N=7)
Molecular abnormalities in 80 CMML
RAS
CBL JAK
2
Signal
transduction
EZH2
TET2
Epigenetic
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing e
ZRSR2
U2AF1
SRSF2
SF3B1
Frequency of mutations (Itzykson JCO
2013)
Gene Ndeg pts studied Mutation
TET2 262 151 (58)
SRSF2 220 101 (46)
ASXL1 312 125 (40)
RUNX1 263 39 (15)
NRAS 263 29 (11)
CBL 264 27 (10)
JAK2 263 21 (8)
KRAS 263 20 (8)
ZRSF2 189 15 (8)
IDH2 229 13 (6)
SF3B1 220 13 (6)
U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
An update on CMML
bull Definition epidemiology
bull Characteristics
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
1 Persistent PB monocytosis (gt1 x109L)
bull gt 3 months
bull (gt 10 of WBC)
bull No impact of BM monocyte
2 No Phi- or BCR-ABL fusion gene
bull No eosinophilia no PDGFRAB rearrangement
3 lt20 myeloblasts or monoblasts in PB or BM
bull Including promonocytes
4 Evidence of dysplasia in one or more lineages
bull If lacking acquired clonal cytogenetic abnormality
bull or persistent monocytosis gt 3 months with exclusion of all other causes of monocytosis
bull CMML-1 lt5 PB blasts and lt10 BM blasts
bull CMML-2 5ndash19 PB blasts and 10ndash19 BM blastsVardiman Blood 2009
WHO-2008 criteria for CMML
Goasguen Haematologica 2009
Promonocytes in CMML
Epidemiology
bull Elderly patients (median age 75)
bull Male predominance (2 to 31)
bull Incidence About 20 of MDS (05 to
1100000year)
bull About 10 are therapy related
bull About 20 associated with immunological
disorders
bull 358 CMML patients of whom 39 (11) had t-CMML
bull median latency to develop t-CMML 6 years
time from outside diagnosis to MDACC referral was 15 months (range
0-80) Of thosepatients 39 (11) had prior exposureto chemotherapy andor
radiation therapy and were defined as t-CMML Clinical data of the studied
patientswereobtained at the timeof referral to MDACC Therapies that were
given to the patients were categorized into 4 groups (1) best supportive care
or cytoreductive therapy using hydroxyurea or oral etoposide (BSCCR) (2)
hypomethylating agents (HMA) such as 5-azacitidinendashbased or decitabine-
based regimens (3) AML-like induction therapy and (4) other therapies
including immunomodulatory drugs(thalidomideor lenalidomide) or tyrosine
kinase inhibitors (iMiDsTKIs) Cytogenetics and mutational analyses of
Figure 1 Survival estimate for t-CMML and de novo CMML Differences in OS duration (A) and LFS duration (B) between 319 patients with de novo CMML and 39 patients with t-CMML
BLOOD 17 OCTOBER 2013 x VOLUME 122 NUMBER 16 THERAPY-RELATED CHRONIC MYELOMONOCYTIC LEUKEMIA 2809
Original Paper
A Close Association of Autoimmune-Mediated Processes and Autoimmune Disorders with Chronic Myelomonocytic Leukemia Observation from a Single Institution
Introduction
Key Words
Abstract
Do
wnlo
ad
ed b
y
INS
ER
M D
ISC
IS
T
19
81
43
431
- 1
12
32
015
85
00
9 P
M
123 CMML 195 had at least one immune-mediated
disorder most commonly ITP gout and psoriasis
Association between CMML and vasculitis
An update on CMML
bull Definition epidemiology
bull Characteristics
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML in the adult a report of 60 cases with special reference to prognostic
factorsBr J Haematol 198765101-6
bull MF 33
bull median age 73 years
bull Splenomegaly in 32 of cases
bull hyperleucocytosis in 52 of cases
bull mean blood monocytosis 43 X 10(9)l
bull marrow blasts gt=5 57 of the cases
bull median survival was 28 months
hematological characteristics
ndash MDS
bull cytopenias
bull excess of marrow blasts
bull marrow dysplasia
bull abnormal karyotype (-7+8 rarely complex)
ndash MPN
bull Splenomegaly
bull Extra hematological disease (serous effusions cutaneous
lesions)
bull increased WBC counts
bull monocytosis (gt1000mm3)
bull immature myeloid cells in the blood (myelocytes
metamyelocytes)
laquo dysplastic raquo CMML WBC lt 13GL
laquo proliferative raquo CMML WBC gt 13Gl
Haematologica 2011
Flow Cytometry as diagnostic tool
Selimoglu-Buet et al Blood 2015
CD1
4
MO1 CD14+CD16-
Classical monocytes
CD14lowCD16high
non-classical
monocytes
MO3
Healthy
donors
MO1 lt 94
MO2 + MO3
gt 6 C
D16
Peripheral blood human monocyte subsets
MO2 CD14+CD16+
Intermediate
monocytes
Age-matched controls CMML reactive monocytosis
CMML monocytosis is made mostly of classical (MO1)
monocytes
CD14
CD16
CMML MDS MDS MPN
Before AZA After AZA
CD14
CD
16
0 3 6 9 12 15 1875
80
85
90
95
100Threshold
94
MO
1 (
o
f to
tal
mo
no
cyte
s)
AZA
Response to hypomethylating agents
includes a decrease in MO1 subset
Respond
ers (N=7)
Molecular abnormalities in 80 CMML
RAS
CBL JAK
2
Signal
transduction
EZH2
TET2
Epigenetic
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing e
ZRSR2
U2AF1
SRSF2
SF3B1
Frequency of mutations (Itzykson JCO
2013)
Gene Ndeg pts studied Mutation
TET2 262 151 (58)
SRSF2 220 101 (46)
ASXL1 312 125 (40)
RUNX1 263 39 (15)
NRAS 263 29 (11)
CBL 264 27 (10)
JAK2 263 21 (8)
KRAS 263 20 (8)
ZRSF2 189 15 (8)
IDH2 229 13 (6)
SF3B1 220 13 (6)
U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
1 Persistent PB monocytosis (gt1 x109L)
bull gt 3 months
bull (gt 10 of WBC)
bull No impact of BM monocyte
2 No Phi- or BCR-ABL fusion gene
bull No eosinophilia no PDGFRAB rearrangement
3 lt20 myeloblasts or monoblasts in PB or BM
bull Including promonocytes
4 Evidence of dysplasia in one or more lineages
bull If lacking acquired clonal cytogenetic abnormality
bull or persistent monocytosis gt 3 months with exclusion of all other causes of monocytosis
bull CMML-1 lt5 PB blasts and lt10 BM blasts
bull CMML-2 5ndash19 PB blasts and 10ndash19 BM blastsVardiman Blood 2009
WHO-2008 criteria for CMML
Goasguen Haematologica 2009
Promonocytes in CMML
Epidemiology
bull Elderly patients (median age 75)
bull Male predominance (2 to 31)
bull Incidence About 20 of MDS (05 to
1100000year)
bull About 10 are therapy related
bull About 20 associated with immunological
disorders
bull 358 CMML patients of whom 39 (11) had t-CMML
bull median latency to develop t-CMML 6 years
time from outside diagnosis to MDACC referral was 15 months (range
0-80) Of thosepatients 39 (11) had prior exposureto chemotherapy andor
radiation therapy and were defined as t-CMML Clinical data of the studied
patientswereobtained at the timeof referral to MDACC Therapies that were
given to the patients were categorized into 4 groups (1) best supportive care
or cytoreductive therapy using hydroxyurea or oral etoposide (BSCCR) (2)
hypomethylating agents (HMA) such as 5-azacitidinendashbased or decitabine-
based regimens (3) AML-like induction therapy and (4) other therapies
including immunomodulatory drugs(thalidomideor lenalidomide) or tyrosine
kinase inhibitors (iMiDsTKIs) Cytogenetics and mutational analyses of
Figure 1 Survival estimate for t-CMML and de novo CMML Differences in OS duration (A) and LFS duration (B) between 319 patients with de novo CMML and 39 patients with t-CMML
BLOOD 17 OCTOBER 2013 x VOLUME 122 NUMBER 16 THERAPY-RELATED CHRONIC MYELOMONOCYTIC LEUKEMIA 2809
Original Paper
A Close Association of Autoimmune-Mediated Processes and Autoimmune Disorders with Chronic Myelomonocytic Leukemia Observation from a Single Institution
Introduction
Key Words
Abstract
Do
wnlo
ad
ed b
y
INS
ER
M D
ISC
IS
T
19
81
43
431
- 1
12
32
015
85
00
9 P
M
123 CMML 195 had at least one immune-mediated
disorder most commonly ITP gout and psoriasis
Association between CMML and vasculitis
An update on CMML
bull Definition epidemiology
bull Characteristics
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML in the adult a report of 60 cases with special reference to prognostic
factorsBr J Haematol 198765101-6
bull MF 33
bull median age 73 years
bull Splenomegaly in 32 of cases
bull hyperleucocytosis in 52 of cases
bull mean blood monocytosis 43 X 10(9)l
bull marrow blasts gt=5 57 of the cases
bull median survival was 28 months
hematological characteristics
ndash MDS
bull cytopenias
bull excess of marrow blasts
bull marrow dysplasia
bull abnormal karyotype (-7+8 rarely complex)
ndash MPN
bull Splenomegaly
bull Extra hematological disease (serous effusions cutaneous
lesions)
bull increased WBC counts
bull monocytosis (gt1000mm3)
bull immature myeloid cells in the blood (myelocytes
metamyelocytes)
laquo dysplastic raquo CMML WBC lt 13GL
laquo proliferative raquo CMML WBC gt 13Gl
Haematologica 2011
Flow Cytometry as diagnostic tool
Selimoglu-Buet et al Blood 2015
CD1
4
MO1 CD14+CD16-
Classical monocytes
CD14lowCD16high
non-classical
monocytes
MO3
Healthy
donors
MO1 lt 94
MO2 + MO3
gt 6 C
D16
Peripheral blood human monocyte subsets
MO2 CD14+CD16+
Intermediate
monocytes
Age-matched controls CMML reactive monocytosis
CMML monocytosis is made mostly of classical (MO1)
monocytes
CD14
CD16
CMML MDS MDS MPN
Before AZA After AZA
CD14
CD
16
0 3 6 9 12 15 1875
80
85
90
95
100Threshold
94
MO
1 (
o
f to
tal
mo
no
cyte
s)
AZA
Response to hypomethylating agents
includes a decrease in MO1 subset
Respond
ers (N=7)
Molecular abnormalities in 80 CMML
RAS
CBL JAK
2
Signal
transduction
EZH2
TET2
Epigenetic
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing e
ZRSR2
U2AF1
SRSF2
SF3B1
Frequency of mutations (Itzykson JCO
2013)
Gene Ndeg pts studied Mutation
TET2 262 151 (58)
SRSF2 220 101 (46)
ASXL1 312 125 (40)
RUNX1 263 39 (15)
NRAS 263 29 (11)
CBL 264 27 (10)
JAK2 263 21 (8)
KRAS 263 20 (8)
ZRSF2 189 15 (8)
IDH2 229 13 (6)
SF3B1 220 13 (6)
U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Goasguen Haematologica 2009
Promonocytes in CMML
Epidemiology
bull Elderly patients (median age 75)
bull Male predominance (2 to 31)
bull Incidence About 20 of MDS (05 to
1100000year)
bull About 10 are therapy related
bull About 20 associated with immunological
disorders
bull 358 CMML patients of whom 39 (11) had t-CMML
bull median latency to develop t-CMML 6 years
time from outside diagnosis to MDACC referral was 15 months (range
0-80) Of thosepatients 39 (11) had prior exposureto chemotherapy andor
radiation therapy and were defined as t-CMML Clinical data of the studied
patientswereobtained at the timeof referral to MDACC Therapies that were
given to the patients were categorized into 4 groups (1) best supportive care
or cytoreductive therapy using hydroxyurea or oral etoposide (BSCCR) (2)
hypomethylating agents (HMA) such as 5-azacitidinendashbased or decitabine-
based regimens (3) AML-like induction therapy and (4) other therapies
including immunomodulatory drugs(thalidomideor lenalidomide) or tyrosine
kinase inhibitors (iMiDsTKIs) Cytogenetics and mutational analyses of
Figure 1 Survival estimate for t-CMML and de novo CMML Differences in OS duration (A) and LFS duration (B) between 319 patients with de novo CMML and 39 patients with t-CMML
BLOOD 17 OCTOBER 2013 x VOLUME 122 NUMBER 16 THERAPY-RELATED CHRONIC MYELOMONOCYTIC LEUKEMIA 2809
Original Paper
A Close Association of Autoimmune-Mediated Processes and Autoimmune Disorders with Chronic Myelomonocytic Leukemia Observation from a Single Institution
Introduction
Key Words
Abstract
Do
wnlo
ad
ed b
y
INS
ER
M D
ISC
IS
T
19
81
43
431
- 1
12
32
015
85
00
9 P
M
123 CMML 195 had at least one immune-mediated
disorder most commonly ITP gout and psoriasis
Association between CMML and vasculitis
An update on CMML
bull Definition epidemiology
bull Characteristics
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML in the adult a report of 60 cases with special reference to prognostic
factorsBr J Haematol 198765101-6
bull MF 33
bull median age 73 years
bull Splenomegaly in 32 of cases
bull hyperleucocytosis in 52 of cases
bull mean blood monocytosis 43 X 10(9)l
bull marrow blasts gt=5 57 of the cases
bull median survival was 28 months
hematological characteristics
ndash MDS
bull cytopenias
bull excess of marrow blasts
bull marrow dysplasia
bull abnormal karyotype (-7+8 rarely complex)
ndash MPN
bull Splenomegaly
bull Extra hematological disease (serous effusions cutaneous
lesions)
bull increased WBC counts
bull monocytosis (gt1000mm3)
bull immature myeloid cells in the blood (myelocytes
metamyelocytes)
laquo dysplastic raquo CMML WBC lt 13GL
laquo proliferative raquo CMML WBC gt 13Gl
Haematologica 2011
Flow Cytometry as diagnostic tool
Selimoglu-Buet et al Blood 2015
CD1
4
MO1 CD14+CD16-
Classical monocytes
CD14lowCD16high
non-classical
monocytes
MO3
Healthy
donors
MO1 lt 94
MO2 + MO3
gt 6 C
D16
Peripheral blood human monocyte subsets
MO2 CD14+CD16+
Intermediate
monocytes
Age-matched controls CMML reactive monocytosis
CMML monocytosis is made mostly of classical (MO1)
monocytes
CD14
CD16
CMML MDS MDS MPN
Before AZA After AZA
CD14
CD
16
0 3 6 9 12 15 1875
80
85
90
95
100Threshold
94
MO
1 (
o
f to
tal
mo
no
cyte
s)
AZA
Response to hypomethylating agents
includes a decrease in MO1 subset
Respond
ers (N=7)
Molecular abnormalities in 80 CMML
RAS
CBL JAK
2
Signal
transduction
EZH2
TET2
Epigenetic
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing e
ZRSR2
U2AF1
SRSF2
SF3B1
Frequency of mutations (Itzykson JCO
2013)
Gene Ndeg pts studied Mutation
TET2 262 151 (58)
SRSF2 220 101 (46)
ASXL1 312 125 (40)
RUNX1 263 39 (15)
NRAS 263 29 (11)
CBL 264 27 (10)
JAK2 263 21 (8)
KRAS 263 20 (8)
ZRSF2 189 15 (8)
IDH2 229 13 (6)
SF3B1 220 13 (6)
U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Epidemiology
bull Elderly patients (median age 75)
bull Male predominance (2 to 31)
bull Incidence About 20 of MDS (05 to
1100000year)
bull About 10 are therapy related
bull About 20 associated with immunological
disorders
bull 358 CMML patients of whom 39 (11) had t-CMML
bull median latency to develop t-CMML 6 years
time from outside diagnosis to MDACC referral was 15 months (range
0-80) Of thosepatients 39 (11) had prior exposureto chemotherapy andor
radiation therapy and were defined as t-CMML Clinical data of the studied
patientswereobtained at the timeof referral to MDACC Therapies that were
given to the patients were categorized into 4 groups (1) best supportive care
or cytoreductive therapy using hydroxyurea or oral etoposide (BSCCR) (2)
hypomethylating agents (HMA) such as 5-azacitidinendashbased or decitabine-
based regimens (3) AML-like induction therapy and (4) other therapies
including immunomodulatory drugs(thalidomideor lenalidomide) or tyrosine
kinase inhibitors (iMiDsTKIs) Cytogenetics and mutational analyses of
Figure 1 Survival estimate for t-CMML and de novo CMML Differences in OS duration (A) and LFS duration (B) between 319 patients with de novo CMML and 39 patients with t-CMML
BLOOD 17 OCTOBER 2013 x VOLUME 122 NUMBER 16 THERAPY-RELATED CHRONIC MYELOMONOCYTIC LEUKEMIA 2809
Original Paper
A Close Association of Autoimmune-Mediated Processes and Autoimmune Disorders with Chronic Myelomonocytic Leukemia Observation from a Single Institution
Introduction
Key Words
Abstract
Do
wnlo
ad
ed b
y
INS
ER
M D
ISC
IS
T
19
81
43
431
- 1
12
32
015
85
00
9 P
M
123 CMML 195 had at least one immune-mediated
disorder most commonly ITP gout and psoriasis
Association between CMML and vasculitis
An update on CMML
bull Definition epidemiology
bull Characteristics
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML in the adult a report of 60 cases with special reference to prognostic
factorsBr J Haematol 198765101-6
bull MF 33
bull median age 73 years
bull Splenomegaly in 32 of cases
bull hyperleucocytosis in 52 of cases
bull mean blood monocytosis 43 X 10(9)l
bull marrow blasts gt=5 57 of the cases
bull median survival was 28 months
hematological characteristics
ndash MDS
bull cytopenias
bull excess of marrow blasts
bull marrow dysplasia
bull abnormal karyotype (-7+8 rarely complex)
ndash MPN
bull Splenomegaly
bull Extra hematological disease (serous effusions cutaneous
lesions)
bull increased WBC counts
bull monocytosis (gt1000mm3)
bull immature myeloid cells in the blood (myelocytes
metamyelocytes)
laquo dysplastic raquo CMML WBC lt 13GL
laquo proliferative raquo CMML WBC gt 13Gl
Haematologica 2011
Flow Cytometry as diagnostic tool
Selimoglu-Buet et al Blood 2015
CD1
4
MO1 CD14+CD16-
Classical monocytes
CD14lowCD16high
non-classical
monocytes
MO3
Healthy
donors
MO1 lt 94
MO2 + MO3
gt 6 C
D16
Peripheral blood human monocyte subsets
MO2 CD14+CD16+
Intermediate
monocytes
Age-matched controls CMML reactive monocytosis
CMML monocytosis is made mostly of classical (MO1)
monocytes
CD14
CD16
CMML MDS MDS MPN
Before AZA After AZA
CD14
CD
16
0 3 6 9 12 15 1875
80
85
90
95
100Threshold
94
MO
1 (
o
f to
tal
mo
no
cyte
s)
AZA
Response to hypomethylating agents
includes a decrease in MO1 subset
Respond
ers (N=7)
Molecular abnormalities in 80 CMML
RAS
CBL JAK
2
Signal
transduction
EZH2
TET2
Epigenetic
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing e
ZRSR2
U2AF1
SRSF2
SF3B1
Frequency of mutations (Itzykson JCO
2013)
Gene Ndeg pts studied Mutation
TET2 262 151 (58)
SRSF2 220 101 (46)
ASXL1 312 125 (40)
RUNX1 263 39 (15)
NRAS 263 29 (11)
CBL 264 27 (10)
JAK2 263 21 (8)
KRAS 263 20 (8)
ZRSF2 189 15 (8)
IDH2 229 13 (6)
SF3B1 220 13 (6)
U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
bull 358 CMML patients of whom 39 (11) had t-CMML
bull median latency to develop t-CMML 6 years
time from outside diagnosis to MDACC referral was 15 months (range
0-80) Of thosepatients 39 (11) had prior exposureto chemotherapy andor
radiation therapy and were defined as t-CMML Clinical data of the studied
patientswereobtained at the timeof referral to MDACC Therapies that were
given to the patients were categorized into 4 groups (1) best supportive care
or cytoreductive therapy using hydroxyurea or oral etoposide (BSCCR) (2)
hypomethylating agents (HMA) such as 5-azacitidinendashbased or decitabine-
based regimens (3) AML-like induction therapy and (4) other therapies
including immunomodulatory drugs(thalidomideor lenalidomide) or tyrosine
kinase inhibitors (iMiDsTKIs) Cytogenetics and mutational analyses of
Figure 1 Survival estimate for t-CMML and de novo CMML Differences in OS duration (A) and LFS duration (B) between 319 patients with de novo CMML and 39 patients with t-CMML
BLOOD 17 OCTOBER 2013 x VOLUME 122 NUMBER 16 THERAPY-RELATED CHRONIC MYELOMONOCYTIC LEUKEMIA 2809
Original Paper
A Close Association of Autoimmune-Mediated Processes and Autoimmune Disorders with Chronic Myelomonocytic Leukemia Observation from a Single Institution
Introduction
Key Words
Abstract
Do
wnlo
ad
ed b
y
INS
ER
M D
ISC
IS
T
19
81
43
431
- 1
12
32
015
85
00
9 P
M
123 CMML 195 had at least one immune-mediated
disorder most commonly ITP gout and psoriasis
Association between CMML and vasculitis
An update on CMML
bull Definition epidemiology
bull Characteristics
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML in the adult a report of 60 cases with special reference to prognostic
factorsBr J Haematol 198765101-6
bull MF 33
bull median age 73 years
bull Splenomegaly in 32 of cases
bull hyperleucocytosis in 52 of cases
bull mean blood monocytosis 43 X 10(9)l
bull marrow blasts gt=5 57 of the cases
bull median survival was 28 months
hematological characteristics
ndash MDS
bull cytopenias
bull excess of marrow blasts
bull marrow dysplasia
bull abnormal karyotype (-7+8 rarely complex)
ndash MPN
bull Splenomegaly
bull Extra hematological disease (serous effusions cutaneous
lesions)
bull increased WBC counts
bull monocytosis (gt1000mm3)
bull immature myeloid cells in the blood (myelocytes
metamyelocytes)
laquo dysplastic raquo CMML WBC lt 13GL
laquo proliferative raquo CMML WBC gt 13Gl
Haematologica 2011
Flow Cytometry as diagnostic tool
Selimoglu-Buet et al Blood 2015
CD1
4
MO1 CD14+CD16-
Classical monocytes
CD14lowCD16high
non-classical
monocytes
MO3
Healthy
donors
MO1 lt 94
MO2 + MO3
gt 6 C
D16
Peripheral blood human monocyte subsets
MO2 CD14+CD16+
Intermediate
monocytes
Age-matched controls CMML reactive monocytosis
CMML monocytosis is made mostly of classical (MO1)
monocytes
CD14
CD16
CMML MDS MDS MPN
Before AZA After AZA
CD14
CD
16
0 3 6 9 12 15 1875
80
85
90
95
100Threshold
94
MO
1 (
o
f to
tal
mo
no
cyte
s)
AZA
Response to hypomethylating agents
includes a decrease in MO1 subset
Respond
ers (N=7)
Molecular abnormalities in 80 CMML
RAS
CBL JAK
2
Signal
transduction
EZH2
TET2
Epigenetic
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing e
ZRSR2
U2AF1
SRSF2
SF3B1
Frequency of mutations (Itzykson JCO
2013)
Gene Ndeg pts studied Mutation
TET2 262 151 (58)
SRSF2 220 101 (46)
ASXL1 312 125 (40)
RUNX1 263 39 (15)
NRAS 263 29 (11)
CBL 264 27 (10)
JAK2 263 21 (8)
KRAS 263 20 (8)
ZRSF2 189 15 (8)
IDH2 229 13 (6)
SF3B1 220 13 (6)
U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Original Paper
A Close Association of Autoimmune-Mediated Processes and Autoimmune Disorders with Chronic Myelomonocytic Leukemia Observation from a Single Institution
Introduction
Key Words
Abstract
Do
wnlo
ad
ed b
y
INS
ER
M D
ISC
IS
T
19
81
43
431
- 1
12
32
015
85
00
9 P
M
123 CMML 195 had at least one immune-mediated
disorder most commonly ITP gout and psoriasis
Association between CMML and vasculitis
An update on CMML
bull Definition epidemiology
bull Characteristics
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML in the adult a report of 60 cases with special reference to prognostic
factorsBr J Haematol 198765101-6
bull MF 33
bull median age 73 years
bull Splenomegaly in 32 of cases
bull hyperleucocytosis in 52 of cases
bull mean blood monocytosis 43 X 10(9)l
bull marrow blasts gt=5 57 of the cases
bull median survival was 28 months
hematological characteristics
ndash MDS
bull cytopenias
bull excess of marrow blasts
bull marrow dysplasia
bull abnormal karyotype (-7+8 rarely complex)
ndash MPN
bull Splenomegaly
bull Extra hematological disease (serous effusions cutaneous
lesions)
bull increased WBC counts
bull monocytosis (gt1000mm3)
bull immature myeloid cells in the blood (myelocytes
metamyelocytes)
laquo dysplastic raquo CMML WBC lt 13GL
laquo proliferative raquo CMML WBC gt 13Gl
Haematologica 2011
Flow Cytometry as diagnostic tool
Selimoglu-Buet et al Blood 2015
CD1
4
MO1 CD14+CD16-
Classical monocytes
CD14lowCD16high
non-classical
monocytes
MO3
Healthy
donors
MO1 lt 94
MO2 + MO3
gt 6 C
D16
Peripheral blood human monocyte subsets
MO2 CD14+CD16+
Intermediate
monocytes
Age-matched controls CMML reactive monocytosis
CMML monocytosis is made mostly of classical (MO1)
monocytes
CD14
CD16
CMML MDS MDS MPN
Before AZA After AZA
CD14
CD
16
0 3 6 9 12 15 1875
80
85
90
95
100Threshold
94
MO
1 (
o
f to
tal
mo
no
cyte
s)
AZA
Response to hypomethylating agents
includes a decrease in MO1 subset
Respond
ers (N=7)
Molecular abnormalities in 80 CMML
RAS
CBL JAK
2
Signal
transduction
EZH2
TET2
Epigenetic
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing e
ZRSR2
U2AF1
SRSF2
SF3B1
Frequency of mutations (Itzykson JCO
2013)
Gene Ndeg pts studied Mutation
TET2 262 151 (58)
SRSF2 220 101 (46)
ASXL1 312 125 (40)
RUNX1 263 39 (15)
NRAS 263 29 (11)
CBL 264 27 (10)
JAK2 263 21 (8)
KRAS 263 20 (8)
ZRSF2 189 15 (8)
IDH2 229 13 (6)
SF3B1 220 13 (6)
U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
An update on CMML
bull Definition epidemiology
bull Characteristics
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML in the adult a report of 60 cases with special reference to prognostic
factorsBr J Haematol 198765101-6
bull MF 33
bull median age 73 years
bull Splenomegaly in 32 of cases
bull hyperleucocytosis in 52 of cases
bull mean blood monocytosis 43 X 10(9)l
bull marrow blasts gt=5 57 of the cases
bull median survival was 28 months
hematological characteristics
ndash MDS
bull cytopenias
bull excess of marrow blasts
bull marrow dysplasia
bull abnormal karyotype (-7+8 rarely complex)
ndash MPN
bull Splenomegaly
bull Extra hematological disease (serous effusions cutaneous
lesions)
bull increased WBC counts
bull monocytosis (gt1000mm3)
bull immature myeloid cells in the blood (myelocytes
metamyelocytes)
laquo dysplastic raquo CMML WBC lt 13GL
laquo proliferative raquo CMML WBC gt 13Gl
Haematologica 2011
Flow Cytometry as diagnostic tool
Selimoglu-Buet et al Blood 2015
CD1
4
MO1 CD14+CD16-
Classical monocytes
CD14lowCD16high
non-classical
monocytes
MO3
Healthy
donors
MO1 lt 94
MO2 + MO3
gt 6 C
D16
Peripheral blood human monocyte subsets
MO2 CD14+CD16+
Intermediate
monocytes
Age-matched controls CMML reactive monocytosis
CMML monocytosis is made mostly of classical (MO1)
monocytes
CD14
CD16
CMML MDS MDS MPN
Before AZA After AZA
CD14
CD
16
0 3 6 9 12 15 1875
80
85
90
95
100Threshold
94
MO
1 (
o
f to
tal
mo
no
cyte
s)
AZA
Response to hypomethylating agents
includes a decrease in MO1 subset
Respond
ers (N=7)
Molecular abnormalities in 80 CMML
RAS
CBL JAK
2
Signal
transduction
EZH2
TET2
Epigenetic
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing e
ZRSR2
U2AF1
SRSF2
SF3B1
Frequency of mutations (Itzykson JCO
2013)
Gene Ndeg pts studied Mutation
TET2 262 151 (58)
SRSF2 220 101 (46)
ASXL1 312 125 (40)
RUNX1 263 39 (15)
NRAS 263 29 (11)
CBL 264 27 (10)
JAK2 263 21 (8)
KRAS 263 20 (8)
ZRSF2 189 15 (8)
IDH2 229 13 (6)
SF3B1 220 13 (6)
U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
CMML in the adult a report of 60 cases with special reference to prognostic
factorsBr J Haematol 198765101-6
bull MF 33
bull median age 73 years
bull Splenomegaly in 32 of cases
bull hyperleucocytosis in 52 of cases
bull mean blood monocytosis 43 X 10(9)l
bull marrow blasts gt=5 57 of the cases
bull median survival was 28 months
hematological characteristics
ndash MDS
bull cytopenias
bull excess of marrow blasts
bull marrow dysplasia
bull abnormal karyotype (-7+8 rarely complex)
ndash MPN
bull Splenomegaly
bull Extra hematological disease (serous effusions cutaneous
lesions)
bull increased WBC counts
bull monocytosis (gt1000mm3)
bull immature myeloid cells in the blood (myelocytes
metamyelocytes)
laquo dysplastic raquo CMML WBC lt 13GL
laquo proliferative raquo CMML WBC gt 13Gl
Haematologica 2011
Flow Cytometry as diagnostic tool
Selimoglu-Buet et al Blood 2015
CD1
4
MO1 CD14+CD16-
Classical monocytes
CD14lowCD16high
non-classical
monocytes
MO3
Healthy
donors
MO1 lt 94
MO2 + MO3
gt 6 C
D16
Peripheral blood human monocyte subsets
MO2 CD14+CD16+
Intermediate
monocytes
Age-matched controls CMML reactive monocytosis
CMML monocytosis is made mostly of classical (MO1)
monocytes
CD14
CD16
CMML MDS MDS MPN
Before AZA After AZA
CD14
CD
16
0 3 6 9 12 15 1875
80
85
90
95
100Threshold
94
MO
1 (
o
f to
tal
mo
no
cyte
s)
AZA
Response to hypomethylating agents
includes a decrease in MO1 subset
Respond
ers (N=7)
Molecular abnormalities in 80 CMML
RAS
CBL JAK
2
Signal
transduction
EZH2
TET2
Epigenetic
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing e
ZRSR2
U2AF1
SRSF2
SF3B1
Frequency of mutations (Itzykson JCO
2013)
Gene Ndeg pts studied Mutation
TET2 262 151 (58)
SRSF2 220 101 (46)
ASXL1 312 125 (40)
RUNX1 263 39 (15)
NRAS 263 29 (11)
CBL 264 27 (10)
JAK2 263 21 (8)
KRAS 263 20 (8)
ZRSF2 189 15 (8)
IDH2 229 13 (6)
SF3B1 220 13 (6)
U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
hematological characteristics
ndash MDS
bull cytopenias
bull excess of marrow blasts
bull marrow dysplasia
bull abnormal karyotype (-7+8 rarely complex)
ndash MPN
bull Splenomegaly
bull Extra hematological disease (serous effusions cutaneous
lesions)
bull increased WBC counts
bull monocytosis (gt1000mm3)
bull immature myeloid cells in the blood (myelocytes
metamyelocytes)
laquo dysplastic raquo CMML WBC lt 13GL
laquo proliferative raquo CMML WBC gt 13Gl
Haematologica 2011
Flow Cytometry as diagnostic tool
Selimoglu-Buet et al Blood 2015
CD1
4
MO1 CD14+CD16-
Classical monocytes
CD14lowCD16high
non-classical
monocytes
MO3
Healthy
donors
MO1 lt 94
MO2 + MO3
gt 6 C
D16
Peripheral blood human monocyte subsets
MO2 CD14+CD16+
Intermediate
monocytes
Age-matched controls CMML reactive monocytosis
CMML monocytosis is made mostly of classical (MO1)
monocytes
CD14
CD16
CMML MDS MDS MPN
Before AZA After AZA
CD14
CD
16
0 3 6 9 12 15 1875
80
85
90
95
100Threshold
94
MO
1 (
o
f to
tal
mo
no
cyte
s)
AZA
Response to hypomethylating agents
includes a decrease in MO1 subset
Respond
ers (N=7)
Molecular abnormalities in 80 CMML
RAS
CBL JAK
2
Signal
transduction
EZH2
TET2
Epigenetic
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing e
ZRSR2
U2AF1
SRSF2
SF3B1
Frequency of mutations (Itzykson JCO
2013)
Gene Ndeg pts studied Mutation
TET2 262 151 (58)
SRSF2 220 101 (46)
ASXL1 312 125 (40)
RUNX1 263 39 (15)
NRAS 263 29 (11)
CBL 264 27 (10)
JAK2 263 21 (8)
KRAS 263 20 (8)
ZRSF2 189 15 (8)
IDH2 229 13 (6)
SF3B1 220 13 (6)
U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Haematologica 2011
Flow Cytometry as diagnostic tool
Selimoglu-Buet et al Blood 2015
CD1
4
MO1 CD14+CD16-
Classical monocytes
CD14lowCD16high
non-classical
monocytes
MO3
Healthy
donors
MO1 lt 94
MO2 + MO3
gt 6 C
D16
Peripheral blood human monocyte subsets
MO2 CD14+CD16+
Intermediate
monocytes
Age-matched controls CMML reactive monocytosis
CMML monocytosis is made mostly of classical (MO1)
monocytes
CD14
CD16
CMML MDS MDS MPN
Before AZA After AZA
CD14
CD
16
0 3 6 9 12 15 1875
80
85
90
95
100Threshold
94
MO
1 (
o
f to
tal
mo
no
cyte
s)
AZA
Response to hypomethylating agents
includes a decrease in MO1 subset
Respond
ers (N=7)
Molecular abnormalities in 80 CMML
RAS
CBL JAK
2
Signal
transduction
EZH2
TET2
Epigenetic
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing e
ZRSR2
U2AF1
SRSF2
SF3B1
Frequency of mutations (Itzykson JCO
2013)
Gene Ndeg pts studied Mutation
TET2 262 151 (58)
SRSF2 220 101 (46)
ASXL1 312 125 (40)
RUNX1 263 39 (15)
NRAS 263 29 (11)
CBL 264 27 (10)
JAK2 263 21 (8)
KRAS 263 20 (8)
ZRSF2 189 15 (8)
IDH2 229 13 (6)
SF3B1 220 13 (6)
U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Flow Cytometry as diagnostic tool
Selimoglu-Buet et al Blood 2015
CD1
4
MO1 CD14+CD16-
Classical monocytes
CD14lowCD16high
non-classical
monocytes
MO3
Healthy
donors
MO1 lt 94
MO2 + MO3
gt 6 C
D16
Peripheral blood human monocyte subsets
MO2 CD14+CD16+
Intermediate
monocytes
Age-matched controls CMML reactive monocytosis
CMML monocytosis is made mostly of classical (MO1)
monocytes
CD14
CD16
CMML MDS MDS MPN
Before AZA After AZA
CD14
CD
16
0 3 6 9 12 15 1875
80
85
90
95
100Threshold
94
MO
1 (
o
f to
tal
mo
no
cyte
s)
AZA
Response to hypomethylating agents
includes a decrease in MO1 subset
Respond
ers (N=7)
Molecular abnormalities in 80 CMML
RAS
CBL JAK
2
Signal
transduction
EZH2
TET2
Epigenetic
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing e
ZRSR2
U2AF1
SRSF2
SF3B1
Frequency of mutations (Itzykson JCO
2013)
Gene Ndeg pts studied Mutation
TET2 262 151 (58)
SRSF2 220 101 (46)
ASXL1 312 125 (40)
RUNX1 263 39 (15)
NRAS 263 29 (11)
CBL 264 27 (10)
JAK2 263 21 (8)
KRAS 263 20 (8)
ZRSF2 189 15 (8)
IDH2 229 13 (6)
SF3B1 220 13 (6)
U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Age-matched controls CMML reactive monocytosis
CMML monocytosis is made mostly of classical (MO1)
monocytes
CD14
CD16
CMML MDS MDS MPN
Before AZA After AZA
CD14
CD
16
0 3 6 9 12 15 1875
80
85
90
95
100Threshold
94
MO
1 (
o
f to
tal
mo
no
cyte
s)
AZA
Response to hypomethylating agents
includes a decrease in MO1 subset
Respond
ers (N=7)
Molecular abnormalities in 80 CMML
RAS
CBL JAK
2
Signal
transduction
EZH2
TET2
Epigenetic
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing e
ZRSR2
U2AF1
SRSF2
SF3B1
Frequency of mutations (Itzykson JCO
2013)
Gene Ndeg pts studied Mutation
TET2 262 151 (58)
SRSF2 220 101 (46)
ASXL1 312 125 (40)
RUNX1 263 39 (15)
NRAS 263 29 (11)
CBL 264 27 (10)
JAK2 263 21 (8)
KRAS 263 20 (8)
ZRSF2 189 15 (8)
IDH2 229 13 (6)
SF3B1 220 13 (6)
U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
CMML MDS MDS MPN
Before AZA After AZA
CD14
CD
16
0 3 6 9 12 15 1875
80
85
90
95
100Threshold
94
MO
1 (
o
f to
tal
mo
no
cyte
s)
AZA
Response to hypomethylating agents
includes a decrease in MO1 subset
Respond
ers (N=7)
Molecular abnormalities in 80 CMML
RAS
CBL JAK
2
Signal
transduction
EZH2
TET2
Epigenetic
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing e
ZRSR2
U2AF1
SRSF2
SF3B1
Frequency of mutations (Itzykson JCO
2013)
Gene Ndeg pts studied Mutation
TET2 262 151 (58)
SRSF2 220 101 (46)
ASXL1 312 125 (40)
RUNX1 263 39 (15)
NRAS 263 29 (11)
CBL 264 27 (10)
JAK2 263 21 (8)
KRAS 263 20 (8)
ZRSF2 189 15 (8)
IDH2 229 13 (6)
SF3B1 220 13 (6)
U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Before AZA After AZA
CD14
CD
16
0 3 6 9 12 15 1875
80
85
90
95
100Threshold
94
MO
1 (
o
f to
tal
mo
no
cyte
s)
AZA
Response to hypomethylating agents
includes a decrease in MO1 subset
Respond
ers (N=7)
Molecular abnormalities in 80 CMML
RAS
CBL JAK
2
Signal
transduction
EZH2
TET2
Epigenetic
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing e
ZRSR2
U2AF1
SRSF2
SF3B1
Frequency of mutations (Itzykson JCO
2013)
Gene Ndeg pts studied Mutation
TET2 262 151 (58)
SRSF2 220 101 (46)
ASXL1 312 125 (40)
RUNX1 263 39 (15)
NRAS 263 29 (11)
CBL 264 27 (10)
JAK2 263 21 (8)
KRAS 263 20 (8)
ZRSF2 189 15 (8)
IDH2 229 13 (6)
SF3B1 220 13 (6)
U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Molecular abnormalities in 80 CMML
RAS
CBL JAK
2
Signal
transduction
EZH2
TET2
Epigenetic
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing e
ZRSR2
U2AF1
SRSF2
SF3B1
Frequency of mutations (Itzykson JCO
2013)
Gene Ndeg pts studied Mutation
TET2 262 151 (58)
SRSF2 220 101 (46)
ASXL1 312 125 (40)
RUNX1 263 39 (15)
NRAS 263 29 (11)
CBL 264 27 (10)
JAK2 263 21 (8)
KRAS 263 20 (8)
ZRSF2 189 15 (8)
IDH2 229 13 (6)
SF3B1 220 13 (6)
U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Frequency of mutations (Itzykson JCO
2013)
Gene Ndeg pts studied Mutation
TET2 262 151 (58)
SRSF2 220 101 (46)
ASXL1 312 125 (40)
RUNX1 263 39 (15)
NRAS 263 29 (11)
CBL 264 27 (10)
JAK2 263 21 (8)
KRAS 263 20 (8)
ZRSF2 189 15 (8)
IDH2 229 13 (6)
SF3B1 220 13 (6)
U2AF1 EZH2 FLT3 DNMT3A NPM1 IDH1 KIT TP53 mutations le 5
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
genotype phenotype Correlations(Itzykson JCO 2013)
bull Lower Hb values associated with ASXL1 (P 1113089= 03) and SF3B1 (P= 1113089 004) mutations
bull lower platelets with TET2 (P 1113089= 0001) and RUNX1 (P= 1113089 003) mutations
bull ASXL1 (P= 1113089 03) and NRAS (P= 1113089 0001) mutations associated with higher WBC
bull extramedullary disease more frequent mutations in CBL (P 1113089 0001) NRAS (P= 1113089 002) KRAS (P= 1113089 001) or ASXL1 (P =1113089 006)
bull IDH2 and U2AF1 mutations associated with CMML-2 (both P= 1113089 04)
bull TET2 mutations correlated with low-risk cytogenetics(P= 1113089 0001)
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
CMML clonal architecture
1 ndash Early clonal dominance
2 - Linear acquisition of mutations
3 - Growth advantage to the more mutated cells with differentiation
TET2 SRSF2 KRAS
Itzykson R et al Blood 2013
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
CMML clonal architecture
4 - Some branching events mostly due to
mitotic recombination
Itzykson R et al Blood 2013
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Padron Blood 2014
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Grb2
SosRas
Ras
GTP
Nf1Raf
MEK
ERK
Cbl
AP1
GM-CSF
Shc
Shp2
GM-CSF hypersensitivity in CMML
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
GM-CSF hypersensitivity is present in only some
CMML cases
Controcircles LMMC
0
20
40
60
80
No
mb
re
de
co
lon
ies
Serum-free medium
GM-CSF 10 ngmL
90
29
P=001
Controls CMM
L
Nu
mb
er
of
co
lon
ies
RIT1
40
60
Itzykson et al Blood 2013
Median WBC
P=001
281 x109L
126 x109L
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Blood 2013
bull GM-CSFndashdependent STAT5 hypersensitivity in 90 of CMML samples and is enhanced by signaling mutations
bull Treatment with a GM-CSFndashneutralizingantibody and JAK2 inhibitors revealstherapeutic potential
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Part of the leukemic clone in the PB made of immature dysplastic granulocytes with a CD141113089CD241113089 phenotype
bull CD141113089CD241113089 CMML cells synthesize and secrete large amounts of alpha- defensin 1-3 (HNP1-3)
bull Recombinant HNPs inhibit M-CSFndashdriven differentiation of human PB monocytes into macrophages
a population of immature dysplastic granulocytes contributesto the CMML phenotype through production of alpha-defensins HNP1-3 that suppress the dif- ferentiationcapabilities of monocytes
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
JCI 2011
bull Loss of Tif1g in mouse HSCs favoredndash the expansion of the GMP compartment
ndash appearance of a cell-autonomous MPD that recapitulatescharacteristics of human CMML
bull TIF1γ undetectable in leukemic cells of 35 of CMML patientsndash Downregulation related to hypermethylation of CpG
sequences and specific histone modifications in the genepromoter
bull A demethylating agent restored the normal epigenetic status of the TIF1G promoter in humancells correlating with reestablishment of TIF1γ expression
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
CMML differential diagnosis
bull Reactive monocytosis (infectionshellip)
bull Very rare MPN with PDGF-R A and B rearrangements (eosinophilia t(512)hellip
bull MDS evolving to CMML
bull Monocytosis during transition from MPN or MDS to M4 or M5 AML
bull Other MDSMPN
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Goasguen Haematologica 2009
Promonocytes in CMML
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
CMML 2 or M4 or M5 AML
bull Clinical findings ndash Cutaneous involvement
ndash Gingival hypertrophy
bull Coagulopathy (DIC)
bull WBC gt 100Gl
bull Auer rods
bull Mutationsndash FLT3 ITD
ndash NPM1
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Prognostic factors in adult CMML an analysis of 107 cases J Clin Oncol 1988
bull Median survival 30 months (range 1 to 81 months) bull 17 AML progressionbull main poor prognostic factors
ndash ldquoMDS ldquolike excess of marrow blasts anemia thrombocytopeniapresence of PB blasts abnormal karyotype
ndash ldquoMPNrdquo like high PB monocytosis hyperleukocytosis presence of PB immature granulocytes splenomegaly
bull Multivariate analysisndash Survival at 1 year predicted by BM blasts and Hb with
82 accuracyndash Longer term survival (at 42 months) predicted by initial
PB leukocyte count
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
CMML laquo Scores raquo
bull laquo dysplastic raquo CMML (WBClt13000mm3) vs laquo proliferative raquo CMML (WBC gt 13000mm3)
bull CMML 1 (blasts lt10) vs CMML 2 (blasts gt 20)bull Modified Bournemouth score (BJH 1985)
bull GFM score (JCO 1988)
bull IPSS
bull MD Anderson score (Blood 2002)
bull Italian ndashSpanish score (CPSS) (Blood 2012)
bull Mayo clinic scorebull New GFM score (with mutations) (JCO 2013)
bull R-IPSSbull Recent cooperative efforts
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Prognostic value of mutations univariate analysis (Itzykson JCO 2013)
120 3624 48 60
0
20
4
0
10
0
60
8
0
Months
Cu
mu
lative
Pro
ba
bility o
f S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
00
02
04
06
08
10
187 167 134 106 84 65 50 33 19 11 5 jco$asxl1=0
125 95 68 44 29 17 10 8 6 4 1 jco$asxl1=1
187
125
134
68
84
29
50
10
19
6
5
1
N agrave risque Mois
Su
rvie
Glo
ba
le (
)
ASXL1 sauvage
ASXL1 muteacute
OS
P lt 00001
P lt 005 P lt 001 P lt 0001
OS
LFS
(CI 95)
favorableunfavorable
01 10 100
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95 CI)
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Prognostic score including gene
mutations
Age gt 65 2 ptsAnemia (lt10 grdl Flt11grdl M) 2 ptsWBC gt 15 Gl 3 ptsThrombocytopenia lt100 Gl 2 ptsASXL1 mutated 2 pts
Itzykson et al JCO 2013
0-4 low5-7 int8-11 high
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
bull N=1832 8 centers
bull 80 CMML 1
bull 75 marrow blasts better cut off than 10
bull All prognostic scores valid
bull prognostic significance of ASXL1 (P = 00001) CBL (P = 00001) and RUNX1 (P = 00001)
bull After correction for Hb ndash circulating blasts
ndash Plts
ndash Karyotype
ndash ASXL1 (P = 00114)
ndash CBL (P = 0003) mutations as independently prognostic
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
bull N=261 CMML aged lt65 years
bull In multivariable analysis
ndash lower HB (P = 001)
ndash higher circulating blast (P = 0002)
ndash ASXL1 (P = 00007)
ndash SRSF2 mutations (P = 0008)
ndash Mayo-French cytogenetic stratification (P = 004)
negatively impacted survival
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
An update on CMML
bull Definition epidemiology
bull Characteristics classification
bull Pathophysiology
bull Differential diagnosis
bull Prognostic factors
bull Response criteria
bull treatment
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Treatment of CMML
bull Treatment of symptomatic disorders
ndash Myeloproliferation
ndash Cytopenias
bull laquo disease modifying raquo drugs
ndash Chemotherapy
ndash Hypomethylating agents (HMAs)
bull Allogeneic SCT
bull laquo targeted drugs raquo
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
bull N=94 (Spanish and Dusseldorf registries)
bull Erythroid response (ER) in 64 and RBC-TI in 31
bull median duration 7 months (range 0ndash88)
bull CPSS and EPO level significantly associated with ER (P = 0003)
bull In CPSS low- or int 1-risk
ndash absence of RBC TD
ndash EPO level
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Treatment of thrombocytopenia
bull Peripheral thrombocytopenia
bull Hypomethylating agents
bull TPO agonist receptors
ndash Eltrombopag in laquo low risk raquo CMML with plateletslt50Gl (R Itzykson)
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Treatment of proliferative CMML
CMML with poor prognostic factors (Wattel Blood 1996)
1)If WBC le13 Gl
- IPSS int-2 or high
2) If gt13 Gl
at least 2 of the following criteria
-BM blasts ge5
-karyotype abnormal
-Hb lt 10 grdl
-Thrombocytopenia lt100 Gl
-Splenomegaly (SMG)
OR
-Extramedullary lesions (EML)
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
A randomized trial of hydroxyurea
versus VP16 in adult advanced CMMLWattelBlood 1996
bullN= 105
bullHydroxyurea yields 60 RR (1 CR) but
mainly minor responses vs 35 RR for
etoposide
Hydroxyurea is considered as ldquo standardrdquo for proliferative CMML
Median survival 20 vs 12 months
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
HMAs in CMML
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
-n= 76
-55 CMML1 and 45 CMML2
-46 WBC count gt13 times 109 L (MPN-CMML) and 32 palpable splenomegaly
-44 patients had neithersplenomegaly nor WBC gt 13 times109 L 32 patients had one of those features and 23 had both
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
bull 33 (43) responses including 13 CR ()
bull Median survival 29 months
bull Prognostic factors for OS ndash Univariate analysisndash palpable splenomegaly p = 002) ndash WBC gt 13 times 109 L (p = 0039)ndash IPSS in patients with WBC lt 13 GL (p = 0006)
ndash marrow blasts gt10 (p = 005)
bull By multivariate analysis marrow blasts gt10 and palpable splenomegaly had prognosticimpact on survival
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
bullbull
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Matched-pair analyses
-trend for higher 2Y OS for azacitidinecompared to HY (62 vs 41 p = 0067)
-longer OS for azacitidine first- line
vs HY first-line
(median 277 vs 62
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Decitabine in advanced CMML a phase 2 trialT Braun Blood 2011
bull Inclusion criteria
(1) age gt 18
(2) CMML (WHO 2008 criteria)
(3) poor prognostic criteriandash if WBC lt 13 gL IPSS int 2 or high
ndash if WBC gt 13 gL 2 of the following criteriabull marrow blasts gt 5
bull Hb lt10gdL
bull platelets lt 100000mm3
bull abnormal cytogenetics
bull SMG gt5 cm below costal margin
bull Extra medullary disease
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Decitabine in advanced CMML a phase 2
trialT Braun Blood 2011
bull 39 advanced CMML
bull Median number of cycles 10
bull Overall response rate 38 ( 10 CR 21
marrow CR 8 stable with HI)
bull OS 48 at 2 years
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
bull 79 pts treated wih AZA (n= 46) or DAC (n= 33)
bull Median OS 275 months
two-gene classifier (ASXL1SRSF2) stratifying
patients with 3y-OS estimates of 808 441 and 236 in ptswith neither either or both ASXL1SRSF2 mutated plt00001)
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
bull 167 differentially methylated regions
(DMRs) of DNA at baseline distinguished
responders from nonresponders using
NGS
These DMRs were primarily localized to
nonpromoter regions and overlapped with
distal regulatory enhancers
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
DACOTA phase III trial DAC vs HY in advanced CMML
bull Inclusion criteria as for the phase II trialbull Primary endpoint progression free survivalbull About 160 patients plannedbull Biological correlates
ndash Gene mutationsndash Gene expressionndash Gene methylation
bull 3 countries ndash France (R Itzykson P Fenaux)ndash Germany (U Platzbecker)ndash Italy (V Santini)
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Allogeneic SCT in CMML
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
bull 73 patients transplanted between 1992 and 2009median age 53 yrs
bull 36 palpable splenomegaly
bull 61 CMML-1 39 CMML-2
bull 48 13 and 9 good int and poor riskkaryotype
bull 43 RIC
bull 3-year OS NRMEFS and CIR 32 36 29 and 35
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Year of transplant lt2004 and
palpable splenomegaly
unfavorable
prognostic factors
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
BJH 2015
bull N=513 median age 53 allo before 2010
bull Conditioning standard (n = 249) RIC (n = 226)
bull Donors related (n = 285) or unrelated (n = 228)
bull Disease status at transplantation CR (122 patients) no CR (344)
bull 4-year NRM 41 relapse 32 RFS 27 OS 33
bull CR at transplantation associated with better
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
bull N=83 from 1991 to 2013
bull 41 received CT 37 HMA beforeallo SCT
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
laquo Targeted raquo treatments in CMML
bull Farnesyl transferase inhibitors
ndash Tipifarnib (15 CR) (Blood 2007)
ndash Lonafarnib (30 responses)( Feldman Leukemia 2008)
bull JAK2JAK1 inhibitors
bull Anti GM-CSF antibodies (KB 003)
bull MEK inhibitors
bull IDH 1 IDH2 targeted drugs
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Cooperative efforts on CMML
bull MDSMPN group of the International MDS Foundation
bull EHA and ELN recommendations for the diagnosis classification and treatment of CMML
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
Groupe Francophone
des Myeacutelodysplasies
bull Activates clinical trials in MDS (35 centers in France and Belgium + Switzerland)
bull Biological groups M Fontenay C Preudhomme
E Solary O Bernard
bull Website www gfmgrouporg
bull Online registry of French MDS cases
bull Close cooperation with - a patient support group- the International MDS Foundation- the European Leukemia Net
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