Sessione 1: Approccio terapeutico

alle sindromi mielodisplastiche e alla

leucemia mieloide cronica

La leucemia

mielomonociticamielomonocitica

cronica

Francesco Onida

Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico

Università Degli Studi di Milano

2008 WHO classification of the

Myelodysplastic/Myeloproliferative

Neoplasms (MDS/MPNs)

• Chronic Myelomonocytic Leukemia (CMML)

• Atypical Chronic Myeloid Leukemia (aCML)

• Juvenile Myelomonocytic Leukemia (JMML)

• MDS/MPN, Unclassifiable (MDS/MPN-U), including

refractory anemia with ring sideroblasts and thrombocytosis

(RARS-T) as a provisional entity

Vardiman et al., Blood 2009;114:937-951

Diagnostic criteria for CMML

1. Persistent peripheral blood monocytosis >1x109/L

2. No Philadelphia chromosome or BCR-ABL1 fusion gene

3. No rearrangement of PDGFRB (cases with eosinophilia and PDGFRBabnormalities should be classified as “myeloid neoplasm witheosinophilia associated with PDGFRB rearrangement”)

4. Fewer than 20% blasts* in the blood and in the bone marrow4. Fewer than 20% blasts* in the blood and in the bone marrow

5. Dysplasia in one or more myeloid lineages.

If myelodysplasia is absent or minimal, the diagnosis of CMML may still bemade if the other requirements are met, and:

• an acquired, clonal cytogenetic or molecular genetic abnormality is presentin the haemopoietic cells, or

• the monocytosis has persisted for at least 3 months and

• all other causes of monocytosis have been excluded

*Blasts include myeloblasts, monoblasts and promonocytes.

Orazi A et al. Myelodysplastic/Myeloproliferative Neoplasms, Chapter 4, in WHO Classification of Tumours of Haematopoietic

and Lymphoid Tissues, 4° Edition, IARC Press, 2008, pp. 76-86.

CMML

• Well-defined diagnostic criteria

• Heterogeneity of clinical features• Heterogeneity of clinical features

• Extreme heterogeneity of natural course

Subclassification of CMML

1994 (FAB):

− Myelodysplastic (MD)-CMML WBC ≤13x109/L

− Myeloproliferative (MP)-CMML WBC >13x109/L− Myeloproliferative (MP)-CMML WBC >13x109/L

2001-2008 (WHO):

− CMML-1 PB-blasts <5% BM-blasts <10%

− CMML-2 PB-blasts 5-19% BM-blasts 10-19%

or Auer rods or Auer rods

Life expectation in CMML(127 pts)

Onida F - Unpublished data

Management recommendations for CMML:consensus statements from the SIE, SIES,

GITMO groups

� Because life expectancy in CMML is highly heterogeneous,

risk assessment is recommended for clinical decision

making in individual patients

Prognosis and risk classification

making in individual patients

� CMML-1 and CMML-2 WHO classification is recommended

for prognostic implications but it should not be considered

sufficient on its own to discriminate between low- and high-

risk patients.

Haematologica. 2013 Sep;98(9):1344-52

� Although not included in the WHO classification, the distinction

between MD- and MP-CMML is highly recommended due to its

clinical implications

Management recommendations for CMML:consensus statements from the SIE, SIES,

GITMO groups

Prognosis and risk classification

clinical implications

� The use of CMML specific risk-oriented systems* for individual

patient risk assessment is recommended, in particular for

patients who are candidates for allogeneic HSCT or enrolled in

clinical trials

Haematologica. 2013 Sep;98(9):1344-52

* At present, there is no universally used validated CMML-specific risk classification

system

Prognostic Scoring Systems

Cytogenetic risk stratification in CMML

Abnormal karyotype: 110/414 (27%)• Trisomy 8 (n=30; 27%)

• -Y (n=18; 16%)

• Complex (n=12; 11%)

• Monosomy 7 (n=6; 5%)

Low risk:

• normal or –Y (single)IPSS CGsCMML-specific

Overall Survival

Such et al. Haematologica 2011; 96(3): 375

High risk:

• abn chr 7, complex, +8

Intermediate risk:

• all others

IPSS CGsCMML-specific

CMML-specific prognostic scoring system (CPSS)

Training cohort: 558 pts (Spanish Group of Myelodysplastic Syndromes)

Validation cohort: 274 pts (Düsseldorf, Pavia)

Such et al. Blood 2013; 121(15): 3005-3015

Risk Groups:

Low = 0 Interm-1 = 1 Interm-2 = 2-3 High = 4-5

CMML-specific prognostic scoring system (CPSS)

Training cohort Validation cohort

Such et al. Blood 2013; 121(15): 3005-3015

An alternative CPSS with Hb instead of RBC transfusion dependency offered identical

prognostic capacity

Prognostic score including gene mutations in CMML (GFM)

Training cohort: 312 pts (GFM)

Validation cohort: 165 pts (Munich Leukemia Laboratory cohort)

Itzykson R et al. J Clin Oncol. 2013 Jul 1;31(19):2428-36

Prognostic score including gene mutations in CMML (GFM)

• Age > 65 yrs = 2 points

• Anemia (M < 10 g/dL, F < 11 d/dL) = 2 points

• WBC > 15 x 109/L = 3 points

Itzykson R et al. J Clin Oncol. 2013 Jul 1;31(19):2428-36

Risk Groups:

Low = 0-4 Interm = 5-7 High ≥ 8

• Platelet < 100 x 109/L = 2 points

• ASXL1 status = 2 points

Training cohort Validation cohort

Prognostic score including gene mutations in CMML (GFM)

Itzykson R et al. J Clin Oncol. 2013 Jul 1;31(19):2428-36

International CMML Consortium

International CMML Consortium

International CMML Consortium

International CMML Consortium

Baseline characteristics

Padron E et al. ASH 2014

International CMML Consortium

Baseline characteristics - BM

Padron E et al. ASH 2014

International CMML Consortium

Baseline characteristics - blood

Padron E et al. ASH 2014

International CMML Consortium

Padron E et al. ASH 2014

International CMML Consortium

Padron E et al. ASH 2014

International CMML Consortium

Padron E et al. ASH 2014

Molecular analysis in CMML(42 pts)

Onida F - Unpublished data

73%

85%

60%

80%

100%

Patients with gene mutations

P = 0.41340%

20%

40%

60%

80%

100%

MD MP

SRSF2

87%

47%53%

8%

33%38%

0%

20%

40%

60%

80%

100%

MD MP

TET2

mut TET2 2 mut TET2 1 mut TET2

P = 0.0418

0%

20%

40%

MD MP

9%

45%

0%

20%

40%

60%

80%

100%

MD MP

ASXL1

P = 0.0123

9%

60%

0%

20%

40%

60%

80%

100%

MD MP

Proliferation-associated genes

P = 0.0296

Onida F - Unpublished data

Prognostic impact of gene mutation

Onida F - Unpublished data

Prognostic impact of gene mutation

Onida F - Unpublished data

Management recommendations for CMML:SIE, SIES, GITMO consensus statements

Determinants of therapeutic intervention

� Therapy should be started when the disease is

symptomatic or progressive, and, in particular, when one

of these events occurs:

• a) severe anemia (Hb less than 10 g/dL);

• b) percentage of blasts in peripheral blood >5%(including myeloblasts, monoblasts and promonocytes;)

• c) platelet count ≤ 50x109/L;

• d) WBC count ≥ 30x109/L;

• e) immature granulocytes ≥ 10% in peripheral blood;

• f) extramedullary manifestations of the disease

• g) symptomatic splenomegaly

Haematologica. 2013 Sep;98(9):1344-52

Response rate: 60% vs 36%Median Survival: 20 vs 9 months

Blood 1996, 88;7: 2480-2487

Intensive CT in CMMLIntensive CT in CMML

Topotecan 1.25 mg/m2 c.i. x 5 d + Ara-C 1 g/m2 x 5 d

Response rate: CR 12/27 (44%)

Response duration: median 33 wks

Beran et al. Blood 2001, 98:624a

Further intensification of treatment increases toxicity and mortality

and does not appear to significantly benefit response and survival.

Beran M at al. JCO 1999, 17: 2819-2830.

FTIs in CMMLFTIs in CMML

CRs: CMML-1 (1 of 8; 12.5%)

CMML-2 (2 of 9; 22.2%)

Median survival: 14.5 months

In CMML, tipifarnib and lonafarnib as single agents were associated with lowand short-lasting response rates independent of RAS mutational status andinhibition of farnesyltransferase.

Leukemia 2008;22:1707–1711;

Blood 2007;109:4158-4163

Azacitidine in CMML

Azacitidine in CMML

Pleyer L et al. Leukemia Research (2014) 38, 475-483

Azacitidine in CMML: A UK multi-centre phase 2

prospective controlled study

Drummond MW et al. Leukemia (2014) 28, 1570–1572

DecitabineDecitabine in CMMLin CMML

European trial: 66 high-risk MDS patients. 45 mg/m2/d for 3 dq 6 wks

9 CMML pts � 1 CR, 1 PR, 2 HI (overall RR of 44%)

Number of patients 19 CMML/95 MDS

WBC >12 x 109/L 13 (68%)

MDACC trial:

Wijermans P et al. J Clin Oncol 2000, 18:956–962

Aribi A et al. Cancer 2007. 109;13:713-717

WBC >12 x 109/L 13 (68%)

Schedule 20 mg/m2 i.v. x 5 d q28 16

20 mg/m2 s.c. x 5 d q28 1

10 mg/m2 i.v. x 10 d q28 2

Median number of courses 9 (range 1-18)

Complete response 11 (58%)

Hematologic improvement 2 (11%)

39 patients (Nov 2008 – Jun 2009) – 32/39 MP-CMML

• Inclusion criteria:

DecitabineDecitabine in CMML in CMML –– GFM TrialGFM Trial

- CMML dx according to WHO 2008, except BM blasts up to 29%

- Poor prognosis (Int-2/High in MD, additional criteria in MP)

• Treatment schedule: 20 mg/m2 i.v. x 5 d q28

Braun T et al. Blood 2011 118 (14) : 3824-3831

DecitabineDecitabine in CMML in CMML –– GFM TrialGFM Trial

• Median number of cycles = 10 (range 1-24)

• ORR 38% (15 pts)

• 10% CR (4 pts)

• 20% marrow CR (8 pts)

• 8% HI (3 pts)

RBC-transfusion independence in 36% (8/22)

• 46% SD (18 pts)

• 15% progression to AML (6 pts)• 15% progression to AML (6 pts)

Braun T et al. Blood 2011 118 (14) : 3824-3831

Titolo dello studio Studio clinico di fase II, aperto, multicentico che

valuta l’efficacia di decitabina nel trattamento della

leucemia mielomonocitica cronica nell’adulto

Tipo di studio Studio aperto multicentrico

Dose 6 cicli di decitabina 20 mg/m2 ev in infusione continua per

5 gg ogni 28 gg

Obiettivo principale Efficacia di decitabina : percentuale di risposta secondo

DecitabineDecitabine in CMML in CMML –– Italian TrialItalian Trial

Obiettivo principale Efficacia di decitabina : percentuale di risposta secondo

IWG 2000/2006

Obiettivi secondari Durata di risposta, sopravvivenza , Qualità di vita, studio

biologico (midollo e s. periferico) della metilazione e

espressione genica

Arruolamento 12 mesi , 43 pazienti

Durata dello studio 2 anni

By courtesy of V. Santini

1. Età > 18 anni

2. Diagnosi di LMMC secondo criteri WHO 2008

3. Se leucociti ≤ 12 000/mm3: IPSS alto o INT-2

Se leucociti > 12 000/mm3: almeno 2 dei criteri seguenti:

Italian Trial Italian Trial -- Criteri di inclusione

- Blasti midollari > 5 %

- Tutte le anomalie citogenetiche clonali, esclusa t(5;12) (q33; p13)

- Anemia < 10 g/dL

- Piastrinopenia < 100 x 109/L

- Splenomegalia > 5 cm sotto il margine costale

- Localizzazione extra midollare dimostrata

DecitabineDecitabine in CMML in CMML –– Risultati preliminari

• N ° pazienti arruolati = 44 (variante proliferativa > 80%)

• Età mediana = 72 anni (range 46-84)

• Mediana cicli somministrati = 14 (range 1-34)

• 2 pazienti ancora in trattamento (08/2014)• 2 pazienti ancora in trattamento (08/2014)

• Risposta completa = 36% (16/44).

• Buona tolleranza globale. Tossicità prevalentemente ematologica.

• Metiloma alla diagnosi � predittivo di risposta

V. Santini, comunicazione personale

LenalidomideLenalidomide//MelphalanMelphalan in CMMLin CMML

Buckstein R et al. Leukemia Research (2014) 38, 756-763

LenalidomideLenalidomide//MelphalanMelphalan in CMMLin CMML

CMML pts number = 12 (9 MP-CMML). Median age 73 (range 52-87)

Lenalidomide 10 mg + Melphalan 2 mg x 21 days (q28) up to 12 cycles

3 responses, all in MP-CMML: 1 CR (68 d), 1 HI-PLT (63 d), 1 HI-E (147 d)

Buckstein R et al. Leukemia Research (2014) 38, 756-763

Management recommendations for CMML:SIE, SIES, GITMO consensus statements

First-line therapy - 1

The treatment strategy should be decided first according to the

disease hematologic phenotype (MD vs MP) and to the number

of blasts

� Patients with MD-CMML and less than 10% blasts in BM

should be managed with supportive therapy aimed atshould be managed with supportive therapy aimed at

correcting cytopenias. Patients with severe anemia and with

serum EPO ≤ 500 mU/dL) should be treated with ESA.

G-CSF may be considered in febrile neutropenia.

� In MD-CMML with high number of blasts (≥10% in BM, ≥5%

in the blood), supportive therapy should be integrated with

the use of hypomethylating agents.

Haematologica. 2013 Sep;98(9):1344-52

Management recommendations for CMML:SIE, SIES, GITMO consensus statements

First-line therapy - 2

� In selected patients with MD-CMML, allo-SCT may be offered

within clinical trials

� Patients with MP-CMML with a low number of blasts should

be treated with cytoreductive therapy. HU is the drug ofbe treated with cytoreductive therapy. HU is the drug of

choice to control proliferative myelomonocytic cells and to

reduce organomegaly.

� Patients with MP-CMML and a high number of blasts should

receive blastolytic therapy with polychemotherapy followed,

when possible, by allo-SCT (within clinical trial).

Haematologica. 2013 Sep;98(9):1344-52

AlloAllo--SCT in CMMLSCT in CMML

FHCRC FHCRC (1990-2004)Pts number = 43. Median age 48 yrs (range 1-66)

MD-CMML 16 (37%) / MP-CMML 27 (63%)

WHO CMML-1: 32 /CMML-2: 11

Related donors in 21/ 22 UD

Various conditioning regimens

(mostly Bu-Cy or Bu-Cy-TBI)

RFS 41% at 4 yrs, Cum. relapse 21%, NRM 35%

Kerbauy et al. Biol BMT 11:713-720 (2005)

Pts number = 50. Median age 44 yrs (range 19-61)

Related donors in 43 / 7 MUD

Various conditioning regimens

RFS 18% at 5 yrs, Cum. relapse 49%, NRM 52%

Graft versus CMML effect?

EBMT (1988-2000)

Kröger et al. Br J Haematol 2002, 118:67–73.

AlloAllo--SCT in CMMLSCT in CMML

Pts number = 85 Median age 52 yrs (range 1-69)

CMML: de novo in 84%, secondary in 16%

Donors: related in 38 (45%); unrelated in 47 (55%)

Major causes of death: relapse and infections ± GvHD

Outcomes at 10 yrs:

• Progression-free Survival 38%

• Cumulative relapse 27% (correlated with MDAPS)

• Mortality associated with: lower Hct, HR CGs, High C.I., Older age

• Outcome not affected by WHO classification

Eissa H et al. BBMT 2010

AlloAllo--SCT in CMML (SFGMSCT in CMML (SFGM--TC)TC)

Pts number = 73 (1992-2009).

Median age 53 yrs (range 27-66)

MD-CMML 57 (78%) / MP-CMML 16 (22%)

WHO CMML-1: 24 /CMML-2: 26

Related donors in 41/ 32 UD

MAC 41%, RIC 59%

Park et al. Eur J Haematol. 2013 May;90(5):355-64

OS 42 % at 2 yrs, 32% at 3 yrs

RFS 29% at 3 yrs,

Cum. relapse 35% at 3 yrs,

NRM 36% at 3 yrs

Open questions

Criteri diagnostici:

Definizione di monocitosi. Relativa o assoluta?

• AMC >1000/mcL, >10%?

• WBC? Stable vs unstable count?

• IMC?

Eterogeneità clinica � sottoclassificazioni:

• MD- vs MP-CMML (what should be really considered MP?)

• CMML-1 vs CMML-2

• Different molecular aberrations/signature (pathways)

A proposal for a possible solution to the MD vs MP classification dilemma

A new MDS subcategory:

• RCUD/RCMD with monocytosis(monocyte >10%, WBC <10.000/mcL, IMC 0%, no splenomegaly)

Within the MDS/MPN:Within the MDS/MPN:

• CMML with WBC 10.000 to 20.000/mcL (monocyte >10%)

• CMML with WBC <10.000/mcL (monocyte >10%) if IMC >0% and/or splenomegaly and or organ infiltration (e.g. skin)

A new Ph-negative MPN subcategory:

• MP-CMML with WBC >20.000/mcL (monocyte >10%), or requiring cytoreductive treatment to maintain WBC <20.000/mcL

MDS

Myeloid Disorders

RCUD/RCMD with monocytosis

AMLMPN

MDS/MPN

MP-CMML

CMML