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654 Decitabine Versus Hydroxyurea for Advanced Proliferative CMML: Results of the Emsco Randomized Phase 3 Dacota Trial

Program: Oral and Poster Abstracts
Type: Oral
Session: 637. Myelodysplastic Syndromes—Clinical Studies: Treatment of Higher Risk Myelodysplastic syndromes
Hematology Disease Topics & Pathways:
Adult, Diseases, Non-Biological, CMML, Therapies, Elderly, chemotherapy, Myeloid Malignancies, Clinically relevant
Monday, December 7, 2020: 11:45 AM

Raphael Itzykson, MD, PhD1, Valeria Santini2*, Cendrine Chaffaut3*, Ades Lionel3*, Sylvain Thepot, MD4*, Aristoteles Giagounidis5, Margot Morabito6*, Nathalie Droin7*, Michael Luebbert8, Rosa Sapena9*, Stanislas Nimubona, MD10*, Jean E. Goasguen, MD, PhD11*, Eric Wattel, MD, PhD12*, Gina Zini, MD, PhD13*, Jose Miguel Torregrosa Diaz14*, Ulrich Germing15*, Anna Maria Pelizzari16*, Sophie Park, MD, PhD17*, Nadja Jaekel18*, Georgia Metzgeroth19*, Francesco Onida, MD20, Robert Navarro21*, Andrea Patriarca, MD22*, Aspasia Stamatoulas Bastard, MD23*, Martin Puttrich24*, Sandra Mossuto25*, Eric Solary, MD, PhD6, Silke Gloaguen, Msc26*, Sylvie Chevret, MD, PhD27*, Fatiha Chermat28*, Uwe Platzbecker, MD29 and Pierre Fenaux, MD, PhD30

1Hematology Department, Saint-Louis Hospital AP-HP Paris France, Paris, France
2MDS Unit, Azienda Ospedaliero Universitaria Careggi, University of Florence, Florence, FI, Italy
3Hopital Saint-Louis, Paris, France
4Service des Maladies du Sang, CHU Angers, Angers, France
5Marien Hospital Düsseldorf, Düsseldorf, Germany
6INSERM U1170, Université Paris-Sud, Gustave Roussy Cancer Center, Villejuif, France
7Gustave Roussy, UMR1170 - Universite Paris Sud, Villejuif, France
8Department of Hematology, Oncology and Stem Cell Transplantation, University Medical Center Freiburg, Freiburg, Germany
9Groupe Francophone des Myélodysplasies, Paris, France
10CHU rennes, Rennes, France
11Université de Rennes, Rennes, FRA
12Centre Hospitalier Lyon Sud, PIERRE BENITE, FRA
13Catholic University of the Sacred Heart Policlinico Gemelli, Rome, ITA
14Department of Hematology and Oncology, CHU de Poitiers, Poitiers, FRA
15Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Faculty of Medicine, Düsseldorf, Germany
16Department of Hematology, ASST Spedali Civili di Brescia, Brescia, Italy
17Department of Hematology, CHU Grenoble, Grenoble Cedex 9, France
18University Hospital Halle (Saale), Halle, Germany
19Department of Hematology and Oncology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
20BMT Center - Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - University of Milan, Milano, Italy
21Department of Hematology and Oncology, CHU Montpellier, Hopital Saint-Eloi, Montpellier, France
22Division of Hematology, Department of Translational Medicine,, University of Eastern Piedmont, Novara, ITA
23Henri Becquerel Center, Rouen, France
24GMIHO - innovation in hematology and medical oncology, Dresden, Germany
25FISM, Firenze, Italy
26The European Myelodysplastic Syndromes Cooperative Group (EMSCO), Leipzig, Germany
27Division of Biostatistics, Saint-Louis Hospital, GH APHP Nord Université de Paris, Paris, France
28Service d'Hématologie Séniors, Hôpital Saint-Louis, Paris, France
29Hematology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany
30Hôpital Saint-Louis, Paris, France

Context. The perhaps only CMML-specific Randomized Clinical Trial (RCT) established hydroxyurea (HY) as the main treatment (Tx) for advanced proliferative CMML (Wattel Blood 1996). In Europe, the only hypomethylating agent (HMA) approved in CMML is AZA in non proliferative CMML-2. Phase 2 trials reported the activity of decitabine (DAC) in advanced proliferative CMML (Braun Blood 2011, Santini Leukemia 2018). We performed a RCT of DAC (±HY during the first 3 cycles) vs HY alone in those pts.

Methods. The DACOTA trial (EudraCT 2014-000200-10) accrued pts with previously untreated (or < 6 weeks of HY), proliferative (WBC ≥ 13x109/L) CMML with advanced disease defined per Wattel et al as presence of extramedullary disease or ≥2 criteria among: BM blasts ≥5%, abnormal karyotype (except –Y), ANC ≥ 16x109/L, Hb < 10 g/dL, platelets < 100 x109/L or splenomegaly > 5 cm below costal margin. Pts were randomized 1:1 to DAC (20 mg/m2/d IV 5d/28d) or HY (1g/d, adjusted on WBC, 28d cycles) and treated until death, AML transformation or progression. The primary endpoint was EFS, events being death, transformation to AML, progression of myeloproliferation after 3+ cycles or progression of blasts and cytopenias after 6+ cycles. Response was assessed with IWG 2006 criteria modified to account for improvement of myeloproliferation, after central morphology review. Intent-to-treat analyses were done considering missing responses as failures.

Results. From Oct 2014 to Sep 2019, 217 pts from 47 centers were screened and 170 randomized (84 DAC and 86 HY), including 12 pts (6 DAC and 6 HY) who never started Tx. Median age was 73 years (IQR 68-78). WHO was CMML-NA/1/2 in 2, 114 and 54 pts, respectively (resp). Median WBC 34.9 x109/L (IQR 22.9-55.7). Cytogenetic risk (Such Haematologica 2011) was fav 69%, int 12%, adv 18% NA 1%. Mutations in TET2, SRSF2, ASXL1 and signaling genes (CBL, JAK2, FLT3, KIT, NRAS, KRAS and CSF3R) were present in 64%, 51%, 62% and 57% resp. 72 pts had received HY for a median 27 days prior to randomization.

Aside from older age in the HY arm (median 74 vs 71.5y in the DAC arm), there was no imbalance between Tx arms. DAC and HY pts received a median of 5 (IQR 3-12) and 6 (IQR 3-14) cycles, resp. As of 15th June 2020, 5 and 10 DAC and HY pts were still on Tx. Reasons for Tx cessation in the DAC arm were death (n=19), AML transformation (n=16), progression (n=9) , hematological toxicity (n=13) or other (n=21). Reasons for Tx cessation in the HY arm were death (n=14), AML transformation (n=13), progression (n=18), hematological toxicity (n=6) or other (n=20). 126 and 85 pts received 3 and 6 cycles, resp. In the ITT population, ORR at 3 cycles was 56% (7CR, 25 mCR±HI, 15 SD+HI) and 30% (0 CR, 8 mCR±HI, 18 SD+HI) in the DAC and HY arms, resp (p=0.0011) and ORR at 6 cycles was 32% (6 CR, 9 mCR±HI, 12 SD+HI) and 17% (2 CR, 4 mCR±HI, 9 SD+HI) in the DAC and HY arms, resp (p=0.033). Median response duration was 15.9 vs 18.2 months (mos) in the DAC and HY arm, resp (p=0.81). Infection and hemorrhage occurred at least once in 49% and 31% of pts, resp. 55% of DAC pts and 38% of HY pts required hospitalization at least once (p=0.05). Non-heme ≥ grade 2 AEs occurred in 79% and 63% of DAC and HY arms, resp (p=0.03). Grade ≥3 cardiac AEs occurred in 13 DAC and 4 HY pts, resp.

With a median follow-up of 13.9 mos, median EFS was 12.6 vs 10.3 mos in the DAC and HY arms, resp (reference DAC arm, HR= 1.14 CI95 0.8-1.64, p= 0.46). Median AML-free survival (AMLFS) was 13.6 and 15.8 mos in the DAC and HY arms resp (p=0.86). Median OS was 18.4 and 23.1 mos in the DAC and HY arms, resp (p=0.72). Considering death and AML transformation as competing risks there was no significant difference in cumulative incidence of AML (p=0.1) or death without transformation (p=0.06) between arms. 30 pts from the HY arm received an HMA (DAC n= 13, AZA n= 16, both=1) after study exit. Censoring at HMA onset in the HY arm, median OS was 18.4 vs 30.4 in the DAC and HY arm, resp (p=0.15). 13 pts were transplanted (DAC n= 10, HY n= 3). There was no interaction between Tx arm and CMML-0/1 vs -2, platelets ≥ vs <100 x109/L and anemia (Hb < 8 g/dL or RBC-TD vs Hb ≥8) on both EFS and OS (all p>0.05).

Conclusion. RCTs are feasible in advanced proliferative CMML, which remains an unmet medical need. In these pts, DAC did not provide an overall or event-free survival advantage over HY. HY remains a valid option in advanced proliferative CMML. However, one third of HY pts subsequently received an HMA and more DAC pts achieved a response and were bridged to HSCT.

Disclosures: Itzykson: Abbvie: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharma: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Sanofi: Honoraria; BMS (Celgene): Honoraria; Janssen: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Stemline: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncoethix (now Merck): Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Santini: BMS, J&J, Novartis: Honoraria; Acceleron, BMS, Menarini, Novartis: Consultancy; Takeda, Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding. Lionel: Abbvie: Consultancy; Takeda: Consultancy; Celgene/BMS: Consultancy, Research Funding; Novartis: Consultancy; Jazz: Consultancy, Research Funding. Thepot: astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Giagounidis: AMGEN: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Luebbert: Janssen: Research Funding. Park: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Other: Travel expenses. Stamatoulas Bastard: Pfizer: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria; Takeda: Consultancy. Solary: Janssen: Research Funding. Platzbecker: Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Bergenbio: Research Funding; JAZZ: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Fenaux: Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding.

OffLabel Disclosure: Decitabine for CMML with WBC > 13 x109/L.

*signifies non-member of ASH