pathogenesis and management of cmmlicksh.org/2018/data/eha-ksh01-03_raphael_itzykson.pdf · 2019....
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![Page 1: Pathogenesis and management of CMMLicksh.org/2018/data/EHA-KSH01-03_Raphael_Itzykson.pdf · 2019. 11. 4. · 1. Persistent PB monocytosis (≥1 x109/L and ≥ 10% of WBC) • No impact](https://reader033.vdocuments.mx/reader033/viewer/2022060720/60800f85e5869a14d65a7c15/html5/thumbnails/1.jpg)
Pathogenesis and management of CMML
Raphaël Itzykson, Hôpital Saint-Louis, Paris
International Conference of the Korean Society of Hematology March 29th 2018
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대한혈액학회 Korean Society of Hematology
COI disclosure
Name of author : Raphael Itzykson
I currently have, or I have had in the past two years, an affiliation or financial
interest with business corporation(s):
(1) Consulting fees, patent royalties, licensing fees : No
(2) Research fundings: Yes, Janssen, Novartis
(3) Others No
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Clinical presentation of CMML
Monocytosis Hyperleukocytosis Tumor symptoms
Dysplasia Anemia Thrombocytopenia
Myeloproliferation
Myelodysplasia
Granulomonocytic Hyperplasia
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Somatic mutations in CMML
Whole genome 475 mutations
Exome
15 mutations
Recurrent Oncogenes 2 mutations
Nat Commun. 2016;7:10767. J Clin Oncol. 2013;31(19):2428-36.
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Three families of recurrent mutations in CMML
RAS
CBL
JAK2
Signaling
EZH2
TET2
Epigenetics
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing
ZRSR2
U2AF1
SRSF2
SF3B1
At least one of those in 95% of patients None is specific of CMML
~90% ~75% ~60%
TET2
IDH2
IDH1
CBL
NRAS
KRAS
JAK2
FLT3
KIT
SRSF2
U2AF35
SF3B1
ZRSR2
J Clin Oncol. 2013;31(19):2428-36.
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HSC
MPP
CMP
MEP GMP
Two mechanisms for the granulomonocytic hyperplasia in CMML
Platelets RBC PN Monocytes
GM-CSF Hypersensitivity?
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JAK2
Grb2
Sos Ras
Ras GTP Nf1
Raf
MEK
ERK
Cbl
AP1
GM-CSF
GM-CSF hypersensitivity in MDS/MPN
Shc
Shp2
PI3K
Akt
JMML : ~100%
Mutations
control
JMML
GM-CSF
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JAK2
Grb2
Sos Ras
Ras GTP Nf1
Raf
MEK
ERK
Cbl
AP1
CMML: ~60 %
JMML: ~100%
Mutations
GM-CSF
GM-CSF hypersensitivity in MDS/MPN
Shc
Shp2
PI3K
Akt
control
JMML
GM-CSF
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GM-CSF hypersensitivity in MDS/MPN
restricted to GM-CSF restricted to CMML with
Signaling mutation
(RAS, CBL, JAK2)
Blood. 2013;121(25):5068-77.
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HSC
MPP
CMP
Erythro Granulo Mono
A model for the pathogenesis of CMML
GM-CSF Hypersensitivity
Enhanced Self-renewal
Epigenetic hits (TET2) Splice hit (SRSF2)
Differentiation bias
MD-CMML
Signaling mutations
MP-CMML
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1. Persistent PB monocytosis (≥1 x109/L and ≥ 10% of WBC)
• No impact of BM monocyte %
2. Not meeting criteria for BCR-ABL CML, PMF, PV, or ET
3. If eosinophilia: No evidence of PDGFRA, PDGFRB, or FGFR1 rearrangement or PCM1-JAK2
4. <20% myeloblasts or monoblasts in PB or BM
• Including promonocytes
5. Evidence of dysplasia in one or more lineages
• If lacking: acquired, clonal cytogenetic or genetic abnormality
6. or persistent monocytosis > 3 months, with exclusion of all other causes
• CMML-0: <2% PB blasts and <5% BM blasts
• CMML-1: 2-4% PB blasts and 5-9% BM blasts
• CMML-2: 5–19% PB blasts and 10–19% BM blasts
Arber, Blood 2016
WHO-2016 criteria for CMML
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Molecular biology as diagnostic tool?
RAS
CBL
JAK2
Signaling
EZH2
TET2
Epigenetics
N
NH2
N O
ASXL1
IDH
DNMT3A
A Exon 2
Splicing
ZRSR2
U2AF1
SRSF2
SF3B1
• No single specific mutation • Preferential combo: TET2/SRSF2 • CHIP genes:
• TET2, DNMT3A, ASXL1 • One mutation • Low VAF (<20%)
Itzykson JCO 2013, Busque Nat Genet 2011, Genovese NEJM 2014, Jaiswal NEJM 2014
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Age-matched controls CMML Reactive monocytosis
Accumulation of ‘classical’ monocytes (MO1) is a key feature of CMML
CD14
CD
16
Flow cytometry as diagnostic tool
Selimoglu-Buet et al. Blood 2015
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* P < 0.05 ** P < 0.01 *** P < 0.001
OS
AMLFS
fav unfav
*
*** ***
*
*
* **
*
*
0.1 1.0 10.0
U2AF1
SF3B1
IDH2
ZRSR2
KRAS
JAK2
CBL
NRAS
RUNX1
ASXL1
SRSF2
TET2
HR (95% CI)
Itzykson, JCO 2013
Prognostic Impact of Gene Mutations
120 3624 48 60
0%
20
%4
0%
10
0%
60
%8
0%
Months
Cu
mu
lativ
e P
rob
ab
ility
of S
urv
iva
l
0 6 12 18 24 30 36 42 48 54 60
0.0
0.2
0.4
0.6
0.8
1.0
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 à risque Mois
Su
rvie
Glo
ba
le (
%)
ASXL1 sauvage
ASXL1 muté
Overall Survival
ASXL1 wildtype
ASXL1 mutated
Ove
rall
Surv
ival
(%
)
Months
48 months
18 months
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‘Next-generation’ Prognostic scores in CMML
Score CPSS GFM Mayo CPPS-mol
Clinical Features
Blasts WBC
RBC-TD Cytogenetics
Age WBC Hb
Platelets
Monocytes IMC Hb
Platelets
Blasts WBC
RBC-TD Cytogenetics
Molecular Features
No ASXL1 No ASXL1 NRAS
RUNX1 SETBP1
Risk groups 4 3 3 4
mOS (mths) 5 - 72 14-60 10-32 17 - 70
Validation Yes Yes Yes Yes
Reference Such Blood 2012
Itzykson JCO 2013
Patnaik Leukemia 2013
Elena Blood 2016
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Management of CMML
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Eltrombopag in CMML with thrombocytopenia
• Prospective multicentric GFM Phase II trial (n=19/30)
• Lower-risk CMML-0 with platelets < 50 000/mm3
• IWG 2006 Response rate: 63%
• Median response duration: 8 mois
• RUNX1 mutations do not impair response achievement
Itzykson et al ASH 2017
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Wattel Blood 1996
Hydroxyurea in proliferative CMML
• HY versus VP16 in ‘advanced’ MP-CMML (N=105)
• Overall Response Rate: 60% (CR: 20%)
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Ruxolitinib in CMML
Padron et al ASH 2017
• US Phase 1/2 trial
• Few hematological responses captured by IWG 2006
• Spleen and general symptoms improvements
• Prolonged survival compared to historical control?
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JAK2
Grb2
Sos Ras
Ras GTP Nf1
Raf
MEK
ERK
Cbl
AP1
CMML
JMML
Mutations
GM-CSF
Targeted therapy in proliferative CMML
Shc
Shp2
PI3K
Akt
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JAK2
Grb2
Sos Ras
Ras GTP Nf1
Raf
MEK
Cbl
GM-CSF
Targeted therapy in proliferative CMML
Shc
Shp2
PI3K
Akt
Targets Lyubynska Science Transl Med 2012, Padron Blood 2013, Goodwin, Blood 2014, Kong, J Clin Invest 2014
ERK
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Allogeneic SCT in CMML
NRM 35% Relapse 35%
Park et al Eur J Hematol 2013
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Time from randomisation (months)
Pro
po
rtio
n o
f p
ati
en
ts s
urv
ivin
g
CCR (n=179)
Azacitidine (n=179)
0 5 10 15 20 25 30 35 40
0
0.2
0.4
0.6
0.8
1.0
Lancet Oncol 2009;10:223–32
CMML: n=11
CMML: n=5
AZA is licensed in CMML-2 with WBC < 12 G/L
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• « meta-analysis » of 17 studies
• Overall Response Rate: 50%
• Complete Response Rate: 25%
• Regression of myeloproliferative features (poorly captured)
• MP-CMML retains adverse prognosis
• No difference between azacitidine and decitabine • PSM models Alfonso, Am J Hematol 2017 ; Duchmann, submitted
Hypomethylating agents in CMML
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Retrospective, 174 patients, EU+US
Duchmann et al, ASH 2017
Genetic biomarkers in CMML treated with HMAs
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Specific methylation signatures predict decitabine response in chronic myelomonocytic leukemia
Meldi J Clin Invest 2015
Epigenetic biomarkers in CMML treated with HMAs
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DACOTA Trial
A Randomized Phase III study of Decitabine
with or without Hydroxyurea versus Hydroxyurea
in patients with advanced proliferative Chronic Myelomonocytic Leukemia
EMSCO FISM
Decitabine 20mg/m2/d x5d q.28d
± HY during the first 3 cycles
CMML
WBC > 13 G/L
≥ 2 criteria:
Marrow blasts ≥5 %
Abnormal K (except –Y)
ANC > 16 G/l
Hb < 10 g/dL
Platelets < 100 G/L
Splenomegaly > 5 cm
Or Extramedullary localization
HY
Primary Endpoint: Event-free Survival
- Death
- Transformation to AML
- Progression of myeloproliferation
N=168
N=168
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Management of CMML
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MDS/MPN in the GFM
• Academic and Industry Trials
• Patients registry
• Academic EU trials through EMSCO
• Academic Int’l trials through MDS/MPN IWG
• Cell bank and research focusing on CMML • INSERM U1170, Pr. E. Solary