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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
2
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
5/15/2012
3
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
5/15/2012
4
Foucar. Am J Clin Pathol 2009;132:281-9
MDS/MPNunclassified
5q-/JAK2(+) Atypical MDS/MPN
Orazi & Germing. Leukemia 2008;22:1308-19
5/15/2012
5
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)
5/15/2012
6
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
5/15/2012
7
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
5/15/2012
9
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
5/15/2012
10
Distinct Mutation Pattern in JMML than CMML
Perez et al. BJH 2010;151:460-8
5/15/2012
11
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
5/15/2012
12
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
5/15/2012
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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
5/15/2012
14
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
5/15/2012
15
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
5/15/2012
16
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
5/15/2012
17
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
5/15/2012
18
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
5/15/2012
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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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20
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
5/15/2012
21
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