Chronic Myelomonocytic Leukemias Raphal Itzykson, Hpital - PowerPoint PPT Presentation

Chronic Myelomonocytic Leukemias Raphaël Itzykson, Hôpital Saint-Louis, Paris MDS, Chaos and Order, Meldola, Oct 26 th 2018

Co Conf nflicts of of In Interest o Research Funding: Janssen, Novartis, Oncoethix (now Merck) o Honoraria: Sanofi, BMS, Celgene o Consulting: Novartis, Otsuka Pharma, Jazz Pharmaceuticals, Karyopharm

MDS/MP MD MPN in ad adults CMML-0 CMML-1 CMML-2 aCML CNL MDS/MPN-U RARS-T Criterion Monocytes ( 10 9 /L ) > 1 (>10%) <10% < 1 Neutrophils ≥ 80% <10% IMC >10% <10% WBC (x 10 9 /L) > 13 ≥ 25 > 13* Platelets (10 9 /L) > 450* > 450 Basophils <2% <1% Peripheral Blasts <2% 3-5% 5-19% <20% <1% <1% BM Blasts <5% 5-10% 10-19% <20% < 5% < 5% No RS >15% No Yes One or+ Dysplasia DysG No Yes No t(9;22) / BCR-ABL1 No No No No No PDGFRA/B No No No No 1/100 000 Incidence Arber, Blood 2016

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

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 Splicing Signaling Epigenetics NH 2 ASXL1 SRSF2 TET2 A N Exon 2 EZH2 3’OH O CBL N IDH Exon 1 U2AF1 JAK2 RAS DNMT3A SF3B1 ZRSR2 ~75% ~60% ~90% At least one of those in 95% of patients None is specific of CMML CBL SRSF2 NRAS TET2 U2AF35 KRAS IDH2 SF3B1 JAK2 IDH1 ZRSR2 FLT3 KIT J Clin Oncol . 2013;31(19):2428-36.

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

GM-CSF hypersensitivity in MDS/MPN Mutations GM-CSF JMML : ~100% JAK2 PI3K Cbl Shc Akt Grb2 Shp2 GDP GM-CS GM CSF Sos Ras STAT5 JMML JM GTP Ras Nf1 Raf co cont ntrol MEK ERK AP1

GM-CSF hypersensitivity in MDS/MPN Mutations CMML: ~60 % GM-CSF JMML: ~100% JAK2 PI3K Cbl Shc Akt Grb2 Shp2 GDP GM-CS GM CSF Sos Ras STAT5 JM JMML GTP Ras Nf1 Raf co cont ntrol MEK ERK AP1

GM-CSF hypersensitivity in MDS/MPN restricted to CMML with restricted to GM-CSF Signaling mutation ( RAS , CBL , JAK2 ) présente absente Blood . 2013;121(25):5068-77.

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

WHO-20 WH 2016 6 cr criter eria fo 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-ABL11 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

Pr Promonocy cytes sh should be be co coun unted ed as as blas asts in CMML Goasguen Haematologica 2009

CM CMML L Cy Cytogene netics • Normal in 60-70% cases • No specific alteration: +8, -Y, -7/7q-, 20q-, +21, der(3q) • Prognosis of trisomy 8 debated • Two CMML-specific classifications CPSS Definition Freq Median OS Mayo Definition Freq Median OS high +8, chr.7, cplex 12% 11 months high cplex, monoso. 3% 3 months int autre 9% 18 months int autre 19% 20 months low NK, -Y 79% 37 months low NK, -Y, der(3q) 78% 41 months Such Haematologica 2011, Wassie Am J Hematol 2014, Tang Am J Hematol 2014

Mo Molecular bi biology gy as as diag agnostic to tool? Signaling • No single specific mutation • Preferential combo: TET2 / SRSF2 • CHIP genes: CBL • TET2, DNMT3A, ASXL1 JAK2 • One mutation RAS • Low VAF (<20%) Epigenetics Splicing NH 2 ASXL1 TET2 SRSF2 N A Exon 2 EZH2 3’OH O N IDH Exon 1 U2AF1 DNMT3A SF3B1 ZRSR2 Itzykson JCO 2013, Busque Nat Genet 2011, Genovese NEJM 2014, Jaiswal NEJM 2014

Flow cy Fl cytometry as as diag agnostic to tool Ac Accumulation of ‘cl classi ssica cal’ ’ monocytes (MO1) is is a k a key y fe feature of of CMML Age-matched controls CMML Reactive monocytosis CD16 CD14 Selimoglu-Buet et al. Blood 2015

Prognostic Impact of Gene Mutations fav unfav TET2 Overall Survival * SRSF2 * *** ASXL1 100% *** ASXL1 wildtype ASXL1 sauvage RUNX1 * 80% ASXL1 mutated ASXL1 muté Overall Survival (%) NRAS * Survie Globale (%) CBL ** 60% * JAK2 48 months 40% KRAS 18 months ZRSR2 20% * IDH2 0% SF3B1 U2AF1 0 12 24 36 48 60 N à risque Months Mois 0.1 1.0 10.0 187 134 84 50 19 5 HR (95% CI) 125 68 29 10 6 1 * P < 0.05 OS ** P < 0.01 AMLFS *** P < 0.001 Itzykson, JCO 2013

‘Next-generation’ Prognostic scores in CMML Score CPSS GFM Mayo CPPS-mol Clinical Blasts Age Monocytes Blasts Features WBC WBC IMC WBC RBC-TD Hb Hb RBC-TD Cytogenetics Platelets Platelets Cytogenetics Molecular No ASXL1 No ASXL1 Features 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 Itzykson Patnaik Elena Blood 2012 JCO 2013 Leukemia 2013 Blood 2016

Management of CMML

El Eltrombopag in in C CMML wi with th thrombocytopenia • Prospective multicentric GFM Phase II trial • Interim analysis n=19 • Lower-risk CMML-0 with platelets < 50 000/mm3 • IWG 2006 Response rate: 63% • Median response duration: 8 mois • 1-Year Cumulative Incidence of transformation to AML: 19% Historical control: 10% – • RUNX1 mutations do not impair response achievement Itzykson et al ASH 2017

Targeting pr Ta proliferative CM CMML GM-CSF JAK2 PI3K Cbl Shc Akt Grb2 Shp2 GDP Sos Ras STAT5 GTP Ras CMML Nf1 Raf Mutations MEK JMML ERK AP1

Ta Targeting pr proliferative CM CMML GM-CSF JAK2 PI3K Cbl Shc Akt Grb2 Shp2 GDP Sos Ras STAT5 GTP Ras Nf1 Raf MEK ERK Targets Lyubynska Science Transl Med 2012, Padron Blood 2013, Goodwin, Blood 2014, Kong, J Clin Invest 2014

Ru Ruxolitin litinib ib in 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

AZA is licensed in CMML-2 with WBC < 12 G/L 1.0 0.8 Proportion of patients surviving 0.6 CMML: n=11 0.4 Azacitidine (n=179) CCR (n=179) 0.2 CMML: n=5 0 5 15 35 40 0 30 10 20 25 Time from randomisation (months) Lancet Oncol 2009;10:223–32

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

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, unpublished

Molecular biomarkers for HMA - CMML N=174, retrospective SRSF2mut ASXL1mut TET2mut NRASmut RUNX1mut CBLmut U2AF1mut TET2mut/ASXL1wt Duchmann Ebiomedicine 2018

Specific molecular signatures predict decitabine response in chronic myelomonocytic leukemia Meldi J Clin Invest 2015

CMML: DACOTA Trial A Randomized Phase III study of Decitabine with or without Hydroxyurea versus Hydroxyurea in patients with advanced proliferative Chronic Myelomonocytic Leukemia CMML Decitabine 20mg/m 2 /d x5d q.28d N=84 WBC > 13 G/L � HY during the first 3 cycles ≥ 2 criteria: HY N=84 Marrow blasts ≥5 % Abnormal K (except –Y) ANC > 16 G/l Primary Endpoint: Event-free Survival Hb < 10 g/dL - Disease Progression Platelets < 100 G/L - Transformation to AML Splenomegaly > 5 cm - Death Or Extramedullary localization V. Santini, U. Platzbecker, R. Itzykson

CMML: EHA/ELN guidelines Hemasphere 2018, in press

Ac Acknowledgements Saint-Louis MDS group Saint-Louis Data Center U Florence, FISM Ramy Rahmé Jérôme Lambert Alessandro Sanna Marie Sébert Sylvie Chevret Valeria Santini Emmanuel Raffoux Marie Passet Gustave Roussy Institute U Dresden, German MDS group Anna Raimbault Dorothée Selimoglu-Buet Silke Gloaguen Emmanuelle Clappier Nathalie Droin Uwe Platzbecker Jean Soulier Margot Morabito Lionel Adès Françoise Porteu Lowy Cancer Center Sidney Pierre Fenaux Eric Solary Ashwin Unnikrishnan John Pimanda GFM Biology Group GFM Staff Matthieu Duchmann Mayo Clinic Rosa Sapena Olivier Kosmider Fayez Yalniz Raphael Petit Orianne Wagner-Ballon Mrinal Patnaik Karine Lemarie Jean Goasguen Fatiha Chermat Valérie Bardet Moffitt Cancer Center Michaela Fontenay Eric Padron David Sallman All GFM and EMSCO investigators MSKCC Callie Coombs Rajiit Rampal