Pathogenesis and management of CMMLicksh.org/2018/data/EHA-KSH01-03_Raphael_Itzykson.pdf · 2019....
Transcript of Pathogenesis and management of CMMLicksh.org/2018/data/EHA-KSH01-03_Raphael_Itzykson.pdf · 2019....
Pathogenesis and management of CMML
Raphaël Itzykson, Hôpital Saint-Louis, Paris
International Conference of the Korean Society of Hematology March 29th 2018
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
Clinical presentation of CMML
Monocytosis Hyperleukocytosis Tumor symptoms
Dysplasia Anemia Thrombocytopenia
Myeloproliferation
Myelodysplasia
Granulomonocytic Hyperplasia
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.
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.
HSC
MPP
CMP
MEP GMP
Two mechanisms for the granulomonocytic hyperplasia in CMML
Platelets RBC PN Monocytes
GM-CSF Hypersensitivity?
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
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
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.
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
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
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
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
* 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
‘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
Management of CMML
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
Wattel Blood 1996
Hydroxyurea in proliferative CMML
• HY versus VP16 in ‘advanced’ MP-CMML (N=105)
• Overall Response Rate: 60% (CR: 20%)
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?
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
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
Allogeneic SCT in CMML
NRM 35% Relapse 35%
Park et al Eur J Hematol 2013
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
• « 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
Retrospective, 174 patients, EU+US
Duchmann et al, ASH 2017
Genetic biomarkers in CMML treated with HMAs
Specific methylation signatures predict decitabine response in chronic myelomonocytic leukemia
Meldi J Clin Invest 2015
Epigenetic biomarkers in CMML treated with HMAs
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
Management of CMML
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