1. Biology of MDS/MPN overlap syndromes (except CMML)
Andreas Reiter
Haematology and Oncology
University Medical Center Mannheim
Ruprecht-Karls-University Heidelberg
Germany

2. WHO 2008: Myeloid Neoplasms
AML
MDS
Myeloid
neoplasms
MDS/MPN
MPN
MLN-eo
aCML
CML
PMF
CEL
PDGFRA
MDS/MPNu PV
CNL
MCD
PDGFRB
( RARS-T ) ET
MPNu
FGFR1
CMML
JMML

3. Diagnostic algorithm of MDS/MPN
WBC >13x109/l or platelets >450x109/l
At least one cytopenia:
Hb <13/<12g/dl (m/f)
Platelets <140x109/l
WBC <1.8x109/l
Dysplasia >10% in at least one lineage
MDS/MPN
Platelets >450x109/l
Anemia and
>15% ring sideroblasts
WBC >13x109/l
Dysplastic granulopoiesis >10%
Myeloid precursors >10%
RARS-T
Atypical CML
Monocytosis >1x109/l (and >10%)
Dysplasia in at least one lineage or
Cytogenetic or molecular aberration
CMML

4. Median survival (months)
Survival in MDS/MPN
Median survival (months)
aCML
25 (22-77)
RARS-T
46 (39-82)
MDS/MPNu <5% blasts >5% blasts
CMML CMML-1
CMML-2
14 (10-32) 19 13
Orazi A and Germing U, Leukemia, 2008
Breccia et al, Haematologica, 2006
Sekeres M, ASCO Annual Meeting, 2013

5. AML-free and overall survival in atypical CML and MDS/MPNu
Wang et al, Blood, in press

6. MDS/MPN-U: natural history and clinical outcome by treatment strategy
MDS/MPN-U without RARS-T (n=85)
Median age 70 years (22-90), 90% >60 years
JAK2 V617F positive (17/56, 30%)
No treatment regimen significantly improved response Hypomethylating agents (n=36, 42%) Immunomodulatory drugs (n=13, 15%) Allogeneic stem cell transplant (n=5, 6%)
Median OS 12.4 months (0.3–138.7)
MDS-IPSS and MDA global score provided statistical significance in univariate analysis, only thrombocytosis (52.5 vs months, p<0.001) was prognostic in multivariate analysis
Ongoing clinical trial incorporating the combination of ruxolitinib and azacitidine
DiNardo et al., Leukemia 28, 961-4, 2014

7. Mutations and prognosis in RARS/RARS-T
JAK2 V617F mutation ~60%
SF3B1 mutation >80%
MPL W515 mutation ~ 5%
High-risk: Age >80 years
SF3B1 wt
JAK2 wt
Broséus et al, Leukemia 2013

8. Molecular genetics of RARS/RARS-T
Somatic mutation SF3B1 (60-80%): mitochondrial iron overload, ineffective erythropoiesis, anemia
Somatic mutation in JAK2 or MPL (70-80%):
thrombocytosis
Hematopoietic
stem cell
Ring sideroblasts and ineffective erythropoiesis (myelodysplastic features of RARS)
Ring sideroblasts and thrombocytosis (myelodysplastic & myeloproliferative features of RARS-T)
Cazzola et al. Blood 121, 260-9, 2013 8

9. Molecular genetics of atypical CML
SETBP1 mutations
in ≈25% of aCML
SETBP1
Piazza R et al, Nat Genetics, 2013
Makishima H et al, Nat Genetics, 2013

10. SETBP1 mutation in atypical CML
WBC (p=0.008)
Hb (p=0.44)
Platelets (p=0.16)
SETBP1- = 77 months
SETBP1+ = 22 months
p=0.01, HR=2,27
Piazza et al, Nat Genetics, 2013

11. Diagnostic algorithm of MDS/MPN
WBC >13x109/l or platelets >450x109/l
At least one cytopenia:
Hb <13/<12g/dl (m/f)
Platelets <140x109/l
WBC <1.8x109/l
Dysplasia >10% in at least one lineage
WBC >25x109/l
Mature neutrophils and bands
Leukocytes appear toxic
No precursors
No dysgranulopoiesis
MDS/MPN
CNL
Platelets >450x109/l
Anemia and
>15% ring sideroblasts
WBC >13x109/l
Dysplastic granulopoiesis >10%
Myeloid precursors >10%
RARS-T
Atypical CML
Monocytosis >1x109/l (and >10%)
Dysplasia in at least one lineage or
Cytogenetic or molecular aberration
CMML

12. aCML vs. CNL
aCML
CNL

13. Molecular characteristics of aCML and CNL
CSF3R
SETBP1
Reference
CNL
aCML
Maxson et al, NEJM, 2013;
Gotlib et al, Blood, 2013
8/9
(89%)
8/20
(40%)
5/9
(56%)
3/20
(15%)
Pardanani et al, Leukemia, 2013
10/12
(83%)
0/19
(0%)
4/12
(33%)
Meggendorfer et al, ASH 2013
7/20
(35%)
2/60
(3%)
2/19
(11%)
19/60
(32%)
Piazza et al, ASH 2013
N/A
8/65
(12%)
18/65
(28%)
Piazza et al, Nature Genetics, 2013
17/70
(24%)
Courtesy of J. Gotlib

14. Molecular characteristics of aCML and CNL
ASXL1
SETBP1
CSF3R
SRSF2
aCML
64%
32% 3%
40%
CNL
73%
11%
35%
21%
CMML
44% 5% 1%
48%
Meggendorfer et al., Abstract 105, ASH 2013

15. MDS/MPN with CBL mutations%
Myeloproliferative features
Leukocytosis (>10x109/l)
11/13
85%
Myeloid precursors >10%
12/13
92%
Increased BM cellularity
11/12
BM fibrosis (no grade III)
10/13
77%
Splenomegaly
Myelodysplastic features
Anemia (<13g/dl)
13/13
100%
Thrombocytopenia (<150x109/l)
8/13
62%
Monocytosis (>1x109/l)
Dysplasia in BM and PB
10/12
83%
Prior diagnosis (n=13)
CMML (n=6)
MDS/MPNu (n=4)
aCML (n=2)
PMF (n=1)
5 patients positive for mutations in EZH2 (n=3) and TET2 (n=2)
Allogeneic SCT (n=2)
Three-year survival rate was 27%
Schwaab et al., Annals of Haematology 91; 2012: 1713

16. No abnormality defines specific disease entities except BCR-ABL
Classes of somatically acquired driver mutation in MPN, MDS/MPN and MDS
SIGNAL-LING
EPIGE-NETIC
mRNA
SPLICING
TRAN-SCRIPTION
COHESIN
CYTO
TK fusions
JAK2
MPL
CBL
NF1
NRAS
KRAS
CSF3R
RIT1
PTPN11
FLT3
KIT
SETBP1
CALR
TET2
DNMT3A
IDH1/2
EZH2
ASXL1
PHF6
CREBP
EP300
SF3B1
SRSF2
U2AF1
ZRSR2
LUC7L2
PPRF8
RUNX1
TP53
ETV6
BCOR
CUX1
STAG2
SMC1A
SMC3
RAD21
5q-
-7/7q +8
+19
i(17q)
del(11q)
del(12p)
del(20q)
inv(3q)
t(3;3)
No abnormality defines specific disease entities except BCR-ABL

17. Molecular heterogeneity in MDS/MPN and MPN
Molecular aberrations
initiating
modifying
transforming
cooperating
no functional role
RAS
RUNX1
TP53
...
Genetic
predisposition
Genotype in mice
Familial MPN
Haplotype 46/1
JAK2 V617F
JAK2 exon 12
CALR
MPL
KIT D816V
Phenotype
Progression
SF3B1
SETBP1
SRSF2
ASXL1
CSF3R
TET2
EZH2
...

18. Biology of MDS/MPN: conclusion
Diagnosis
Challenging
Overlap of morphologic findings
Pathogenesis
Mutations in various genes
Molecular heterogeneity
Some of them rather disease-specific
Prognostic relevance
Prognosis
Poor
Thrombocytosis is a favourable risk factor
Increasing importance of the mutational profile
Treatment
No targeted treatment
Allogeneic SCT is rarely performed
Current strategies do not affect progression or survival