5/15/2012

1

European Focus on Myeloproliferative Neoplams and Myelodysplastic Syndromes 2012

4-5 May, Lisbon, Portugal

MDS/MPN Overlap Syndromes

Evangelos Terpos, MD, PhDUniversity of Athens School of Medicine, Athens, Greece

Diagnostic Criteria for MDS/MPN subtypes –WHO 2008

Vardiman et al. Blood 2009;114:937-51Foucar. Am J Clin Pathol 2009;132:281-9

5/15/2012

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MDS/MPN: Main Characteristics

Orazi & Germing. Leukemia 2008;22:1308-19

CMMLM/F 2:1median 70 yearsMonocytes > 1000/µl Absence of t(9;22)

or bcr/ablD splasia in 1 2 linesDysplasia in 1-2 lines<20% blasts

Foucar. Am J Clin Pathol 2009;132:281-9Orazi & Germing. Leukemia 2008;22:1308-19

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aCML

Foucar. Am J Clin Pathol 2009;132:281-9Orazi & Germing. Leukemia 2008;22:1308-19

RARS--T

Foucar. Am J Clin Pathol 2009;132:281-9

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Foucar. Am J Clin Pathol 2009;132:281-9

MDS/MPNunclassified

5q-/JAK2(+) Atypical MDS/MPN

Orazi & Germing. Leukemia 2008;22:1308-19

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Atypical MDS/MPN associated with Isochromosome 17q

Orazi & Germing. Leukemia 2008;22:1308-19

MDS/MPN – Pathogenesis

«»I know one thing, that I do not know anything

Socrates (470 - 399 BC)

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Recurrent Gene Mutations in MDS/MPN

Graubert & Walter. Hematology (ASH Education Program) 2011:543-9

Epigenetic Pathways and MDS/MPN

Graubert & Walter. Hematology (ASH Education Program) 2011:543-9

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Schematic representation of the localization of molecular mutations at the protein level in CMML and CMML-derived AML patients

missense (black

triangles)triangles)

nonsense (green

triangles)

frameshift mutations

(red

Jankowska A M et al. Blood 2011;118:3932-41

(triangles)

new splice variants

(blue triangles)

TET-2 Mutations

Smith et al. Blood 2010;116:3923-32Ko &, Rao. Blood 2011;118:4501-3

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TET-2 Mutations in MDS/MPN

Jankowska et al. Blood 2009;113:6403-10

TET-2 in CMML

Kosmider et al. Blood 2009;114:3285-91Smith et al. Blood 2010;116:3923-32

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JAK-2 Mutations in MDS/MPN (n=179)

Dunlap et al. Am J Clin Pathol 2011;135:709-19

Nat Genet. 2010 Aug;42(8):722-6

12% in patients with MDS/MPD (273) & IMF (30) Loss of function of H3K27 methyltransferase EZH2 in MDS = oncosuppressor gene

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Distinct Mutation Pattern in JMML than CMML

Perez et al. BJH 2010;151:460-8

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CD14+/CD24‐Macrophage

Monocytes

Microenvironment & CMML

CD14+/CD24

‐defensins mRNA expression

CD163

0

200

400

600

800

1000

1200

1400

M‐CSF + HNP3 (mM)

0     0    0.5  1  2.5  5 

CMML

CD14‐/CD24+

?

Droin et al. Blood 2012;115:78-88

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CMML I: PB < 5% blasts+promonocytes

• BM 0-9% blasts+promonocytes

CMML – Sub-Groups

CMML II: PB 5-19% blasts+promonocytes

BM 10-19% blasts+promonocytes

presence of Auer rods irrespective of

blast/promononocyte counts

CMML with Eosinophils: > 1500/µl Eos

CMML with Mast Cells (SM-AHNMD)

CMML: Clinical Features

Germing et al. Haematologica 2007;92:974-77

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CMML – Multiparameter Flow Cytometry

Expression of myelomonocytic antigens CD33 and CD13

Variable expression of CD68 and CD64

Frequently decreased expression of CD14

Overexpression of CD56

Aberrant expression of CD2

Decreased expression of HLA-DR, CD13, CD15, CD64, CD36or CD36

Increase of CD34 + cells with aberrant phenotype may be associated with early transformation to acute myeloid leukaemia

Bacher et al. BJH 2012; epub ahead of print

CMML-Cytogenetic Abnormalities are Present in 20-35% of Patients at Diagnosis

Bacher et al. BJH 2012; epub ahead of print

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CMML: Diagnostic Algorithm

Bacher et al. BJH 2012; epub ahead of print

CMML - Prognosis

1,0

,8

p=0.005

mOS: CMML-1: 20 mmOS: CMML-2: 14 m

on

1,0

,8

p=0.001

CMML-1: 2-year 14%; 5-year 14%

CMML-2: 2-year 24%; 5-year 63 %

cum

. su

rviv

al

,6

,4

,2

CMML 1

CMML 2 cum

. ri

sk o

f A

ML

evo

lutio

,6

,4

,2

CMML 1

CMML 2

months

156

144

132

120

108

96

84

72

60

48

36

24

12

0

0,0

months

156

144

132

120

108

96

84

72

60

48

36

24

12

0

0,0

Germing et al. Haematologica 2007;92:974-77

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Prognostic Failure of IPSS in CMML

• Low frequency of karyotype anomalies• Low frequency of karyotype anomalies

• BM blast counts mainly between 5 and 20%

• ANC usually > 1800/ µl

• Anemia rare

IPSS criteria Cytogenetics, Cytopenias not of discriminative value

Prognostic Factors in CMMLSummary of studies using multivariate analyses

No. of studiesProven prognostic indicator

Unproven prognostic indicator

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1,0

,8

CMML: Impact of LDH

p=0.00005e

Sur

viva

l

,8

,6

,4

p

160136112967248240

Cum

ula

tive ,2

0,0

months

LDH normal, n= 121mOS: 31 months

LDH elevated, n= 167,mOS: 14 months

mOS, median overall survival; LDH, lactate dehydrogenase

M.D. Anderson Prognostic Score for CMML

1,0 p<0.00005

Score Variables:Hemoglobin < 12 g/dlIMP > 0%BM blasts > 10%Abs. Lymph < 2,500/µl

cum

. sur

viva

l

,8

,6

,4

,2

low

intermed. I

IMP, Immature Progenitors in BloodOnida et al. Blood 2002;99:840-9

months

15614413212010896847260483624120

,

0,0

intermed. IIhigh

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Cytogenetics & Prognosis in CMML

IPSS cytogenetic classification

Such et al. Haematologica 2011;96:375-83

Survival Differences Among MDS/MPN

Orazi & Germing. Leukemia 2008;22:1308-19

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RARS-T: Features of the Disease

Malcovati et al. Blood 2009;114:3538-45

GEP is Different in RARS-T than in RARS

Malcovati et al. Blood 2009;114:3538-45

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Treatment of MDS/MPN

• Hydroxyurea (Wattel et al. 1996)

• EPO (EPO i.S. <500)

• Lenalidomide

•Azacytidine

Demethylating Agents in CMML

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Azacitidine in CMML (n=38)

Costa et al. Cancer 2011;117:2690-6

Azacitidine was administered at a dose of 75 mg/m2/day for 7 days or 100 mg/m2/day for 5 days every 4 weeks.

Lenalidomide in CMML with del5q

15614160

180

200

14

16

18

Wbc

PLT

LDH

Blasts

Lenalidomide25 mg/d

startconditioning

53

115

75

6

7

4

7,55

10,3

60

80

100

120

140

PL

T a

nd

WB

C i

n G

PT

/l

4

6

8

10

12

LD

H i

n u

mo

l/l,

bla

st

in %

Blasts

3

25

4

2

2,3

1

0

20

40

-20 -15 -10 0 5 10 15 20 25 30day of treatment

0

2

4

Platzbecker et al. Leukemia 2007;21:2384-5

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Conclusions

• MDS/MPN consist a distinct group of myeloid malignancies with heterogeneous disordersmalignancies with heterogeneous disorders

• Differences in the pathophysiology of the diseases

• Mutations in genes that are implicated in epigenetic modifications seem to participate in the biology of these diseases

• Treatment remains unsatisfactoryTreatment remains unsatisfactory

• Studies including only patients with MDS/MPN are needed to reveal better management for these patients