Pathogenesis and management of CMML

Transcription

1 Pathogenesis and management of CMML Raphaël Itzykson, Hôpital Saint-Louis, Paris International Conference of the Korean Society of Hematology March 29th 2018

2 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

3 Clinical presentation of CMML Myeloproliferation Hyperleukocytosis Monocytosis Tumor symptoms Granulomonocytic Hyperplasia Dysplasia Anemia Thrombocytopenia Myelodysplasia

4 Somatic mutations in CMML Whole genome 475 mutations Exome 15 mutations Recurrent Oncogenes 2 mutations Nat Commun. 2016;7: J Clin Oncol. 2013;31(19):

5 Three families of recurrent mutations in CMML Signaling CBL JAK2 RAS ASXL1 EZH2 Epigenetics NH 2 N N O TET2 SRSF2 IDH DNMT3A ZRSR2 Splicing A Exon 2 U2AF1 SF3B1 ~60% ~90% ~75% At least one of those in 95% of patients None is specific of CMML CBL NRAS KRAS JAK2 FLT3 KIT TET2 IDH2 IDH1 SRSF2 U2AF35 SF3B1 ZRSR2 J Clin Oncol. 2013;31(19):

6 Two mechanisms for the granulomonocytic hyperplasia in CMML HSC MPP CMP MEP GMP GM-CSF Hypersensitivity? Platelets RBC PN Monocytes

7 GM-CSF hypersensitivity in MDS/MPN Mutations GM-CSF JMML : ~100% Akt Ras PI3K Sos Cbl Grb2 Shc Shp2 JAK2 GM-CSF Nf1 Ras GTP JMML Raf MEK control ERK AP1

8 GM-CSF hypersensitivity in MDS/MPN Mutations GM-CSF CMML: ~60 % JMML: ~100% Akt Ras PI3K Sos Cbl Grb2 Shc Shp2 JAK2 GM-CSF Nf1 Ras GTP JMML Raf MEK control ERK AP1

9 GM-CSF hypersensitivity in MDS/MPN restricted to GM-CSF restricted to CMML with Signaling mutation (RAS, CBL, JAK2) Blood. 2013;121(25):

10 A model for the pathogenesis of CMML Epigenetic hits (TET2) Splice hit (SRSF2) Enhanced Self-renewal HSC Signaling mutations Differentiation bias MPP CMP GM-CSF Hypersensitivity Erythro Granulo Mono MD-CMML MP-CMML

11 WHO-2016 criteria for CMML 1. Persistent PB monocytosis ( 1 x10 9 /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

12 Molecular biology as diagnostic tool? Itzykson JCO 2013, Busque Nat Genet 2011, Genovese NEJM 2014, Jaiswal NEJM 2014 CBL RAS ASXL1 EZH2 Signaling JAK2 Epigenetics NH 2 N N O DNMT3A TET2 IDH No single specific mutation Preferential combo: TET2/SRSF2 CHIP genes: TET2, DNMT3A, ASXL1 One mutation Low VAF (<20%) SRSF2 ZRSR2 Splicing A Exon 2 SF3B1 U2AF1

13 CD16 Flow cytometry as diagnostic tool Accumulation of classical monocytes (MO1) is a key feature of CMML Age-matched controls CMML Reactive monocytosis CD14 Selimoglu-Buet et al. Blood 2015

14 Prognostic Impact of Gene Mutations Cumulative Overall Survie Probability Globale Survival of (%) Survival (%) 0% 20% 40% 100% 60% 80% fav unfav TET2 SRSF2 ASXL1 RUNX1 NRAS CBL JAK2 KRAS ZRSR2 IDH2 SF3B1 U2AF1 * *** *** * * ** * HR (95% CI) * Overall Survival 18 months ASXL1 wildtype ASXL1 sauvage ASXL1 mutated muté 48 months jco$asxl1= jco$asxl1= N à risque Mois Months OS AMLFS * P < 0.05 ** P < 0.01 *** P < Itzykson, JCO 2013

15 Next-generation Prognostic scores in CMML Score CPSS GFM Mayo CPPS-mol Clinical Features Molecular Features Blasts WBC RBC-TD Cytogenetics Age WBC Hb Platelets Monocytes IMC Hb Platelets Blasts WBC RBC-TD Cytogenetics No ASXL1 No ASXL1 NRAS RUNX1 SETBP1 Risk groups mos (mths) Validation Yes Yes Yes Yes Reference Such Blood 2012 Itzykson JCO 2013 Patnaik Leukemia 2013 Elena Blood 2016

16 Management of CMML

17 Eltrombopag in CMML with thrombocytopenia Prospective multicentric GFM Phase II trial (n=19/30) Lower-risk CMML-0 with platelets < /mm3 IWG 2006 Response rate: 63% Median response duration: 8 mois RUNX1 mutations do not impair response achievement Itzykson et al ASH 2017

18 Hydroxyurea in proliferative CMML HY versus VP16 in advanced MP-CMML (N=105) Overall Response Rate: 60% (CR: 20%) Wattel Blood 1996

19 Ruxolitinib in CMML US Phase 1/2 trial Few hematological responses captured by IWG 2006 Spleen and general symptoms improvements Prolonged survival compared to historical control? Padron et al ASH 2017

20 Targeted therapy in proliferative CMML GM-CSF Akt PI3K Cbl Grb2 Shc Shp2 JAK2 Ras Sos Nf1 Ras GTP CMML Raf MEK ERK Mutations JMML AP1

21 Targeted therapy in proliferative CMML GM-CSF Akt PI3K Cbl Grb2 Shc Shp2 JAK2 Ras Sos Nf1 Ras GTP Raf MEK ERK Targets Lyubynska Science Transl Med 2012, Padron Blood 2013, Goodwin, Blood 2014, Kong, J Clin Invest 2014

22 Allogeneic SCT in CMML NRM 35% Relapse 35% Park et al Eur J Hematol 2013

23 Proportion of patients surviving AZA is licensed in CMML-2 with WBC < 12 G/L CMML: n= Azacitidine (n=179) 0.2 CMML: n=5 CCR (n=179) Time from randomisation (months) Lancet Oncol 2009;10:223 32

24 Hypomethylating agents in CMML «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

25 Genetic biomarkers in CMML treated with HMAs Retrospective, 174 patients, EU+US Duchmann et al, ASH 2017

26 Epigenetic biomarkers in CMML treated with HMAs Specific methylation signatures predict decitabine response in chronic myelomonocytic leukemia Meldi J Clin Invest 2015

27 DACOTA Trial A Randomized Phase III study of Decitabine with or without Hydroxyurea versus Hydroxyurea in patients with advanced proliferative Chronic Myelomonocytic Leukemia CMML WBC > 13 G/L Decitabine 20mg/m 2 /d x5d q.28d ± HY during the first 3 cycles N=168 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 EMSCO FISM

28 Management of CMML

29 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