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1037 Comparative Results of Azacitidine and Decitabine from a Large Prospective Phase 3 Study in Treatment Naive Patients with Acute Myeloid Leukemia Not Eligible for Intensive Chemotherapy

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster I
Hematology Disease Topics & Pathways:
Adult, AML, Diseases, Non-Biological, Therapies, Elderly, chemotherapy, Study Population, Clinically relevant, Myeloid Malignancies
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Amer M. Zeidan, MBBS, MHS1, Pierre Fenaux, MD, PhD2, Marco Gobbi, MD3*, Jiri Mayer4*, Gail J. Roboz, MD5, Jürgen Krauter, MD6*, Tadeusz Robak, MD PhD7, Jan Philipp Bewersdorf, MD8, Hagop M. Kantarjian, MD9, Jan Novak10*, Wieslaw Wiktor Jedrzejczak, MD, PhD11*, Xavier Thomas, MD, PhD12, Mario Ojeda-Uribe13*, Yasushi Miyazaki, MD, PhD14, Yoo Hong Min, MD, PhD15, Su-Peng Yeh, MD16*, Joseph M Brandwein, MD17, Liana Gercheva, MD18*, Judit Demeter, MD19*, Elizabeth A. Griffiths, MD20, Karen W.L. Yee, MD21, Jean-Pierre Issa, MD22*, Yong Hao, MD, PhD23*, Mohammad Azab, MD, MSc, MBA24* and Hartmut Döhner25

1Yale University School of Medicine and Yale Cancer Center, New Haven, CT
2Hôpital Saint-Louis, Paris, France
3IRCCS Ospedale Policlinico San Martino, Genoa, Italy
4University Hospital Brno, Czech Republic, Brno, CZE
5Weill Medical College of Cornell University New York-Presbyterian Hospital, New York, NY
6Department of Internal Medicine III, Städtisches Klinikum Braunschweig, Braunschweig, Germany
7Department of Hematology, Medical University of Lodz, Copernicus Memorial Hospital, Lodz, Poland
8Department of Internal Medicine, Yale University, New Haven, CT
9The University of Texas M.D. Anderson Cancer Center, Houston, TX
10Department of Internal Medicine and Hematology, University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic
11Uniwersyteckie Centrum Kliniczne WUM, Warsaw, Poland
12Centre Hospitalier Universitaire de Lyon-Sud, Lyon, France
13GHR Mulhouse Sud-Alsace, Mulhouse, France
14Transfusion and Cell Therapy Unit, Nagasaki University Hospital, Nagasaki, Japan
15Severance Hospital, Yonsei University Health System, Seoul, Korea, Republic of (South)
16Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
17Division of Hematology, University of Alberta, Edmonton, AB, Canada
18Clinical Hematology Clinic, Multiprofile Hospital for Active Treatment "Sveta Marina", Varna, Bulgaria
19Semmelweis University, Budapest, HUN
20Roswell Park Comprehensive Cancer Center, Buffalo, NY
21Leukemia Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
22Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA
23Astex Pharmaceuticals, Inc., Pleasanton, CA
24Astex Pharmaceuticals, Inc., Pleasanton, NJ
25Ulm University Hospital, Ulm, Germany

Background: Prognosis of elderly (≥65 years of age) patients (pts) with acute myeloid leukemia (AML) remains dismal with a substantial proportion being deemed unfit for intensive chemotherapy. Monotherapy with the hypomethylating agents azacitidine (AZA) or decitabine (DEC) has been the de facto standard of care for the treatment of chemotherapy-ineligible AML pts although both AZA and DEC did not improve median OS compared to low-dose cytarabine (LDAC) or physician choice, respectively, in phase III trials. No clinical trials comparing AZA and DEC head-to-head in AML exist. Here, we present a subgroup analysis of pts enrolled in the phase III ASTRAL-1 trial (NCT02348489) who were randomized to the AZA or DEC control arm.

Methods: ASTRAL-1 randomized 815 treatment-naïve AML pts ineligible for intensive chemotherapy in a 1:1 ratio to either guadecitabine or treatment-choice (TC) of AZA, DEC, LDAC (NCT02348489). Study protocol and results have been presented previously (Fenaux, EHA 2019). Briefly, adult (≥18 years of age) pts with newly-diagnosed AML ineligible for intensive chemotherapy based on age of 75 years or older, major organ comorbidities, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 2-3 were eligible for enrollment. Exclusion criteria included prior treatment with AZA or DEC, extramedullary central nervous system AML, inability to tolerate treatment in the TC arm, or refractory congestive heart failure, uncontrolled active infection, or advanced pulmonary disease. Pts were pre-selected to receive either AZA, DEC, or LDAC with subsequent 1:1 randomization to either guadecitabine or TC in the respective arm. Patients treated with standard doses and schedules of AZA or DEC within the TC arm were included in the subgroup analysis presented here. Co-primary outcomes were rates of complete response (CR) and median, 1-year, and 2-year overall survival (OS) as defined by the International Working Group response criteria for AML. Composite CR (CRc) was defined as the composite of CR, CR with incomplete platelet count recovery (CRp), and CR with incomplete cell count recovery (CRi).

Rates of CR among pts treated with AZA and DEC were compared using Fisher’s exact test. Survival outcomes were compared using log-rank tests to compare the hazard ratio for death among the AZA and DEC treated pts. Subgroup analyses for OS stratified by patient and disease characteristics were performed.

Results: 815 patients were enrolled in the ASTRAL-1 trial across 144 sites in 24 countries with 171 and 167 pts being randomized to and treated with AZA and DEC in the TC arm of the trial, respectively. Baseline patient and disease characteristics were well-balanced between the AZA and DEC-treated pts (Table 1). The median number of treatment cycles was 6 (range [R]: 1-31) in the AZA arm and 5 (R: 1-34) in the DEC arm. There was no statistically significant difference in the co-primary endpoint of CR with 30 pts (17.5%) in the AZA and 32 pts (19.2%) in the DEC arm achieving CR (p=0.78). The rate of CRc (CR + CRp + CRi) was comparable among AZA and DEC-treated patients with 22.2% (38 out of 171 pts) and 25.1% (42 out of 167 pts), respectively (Table 2). Median OS between AZA and DEC-treated pts was similar with 8.7 months and 8.2 months in the two arms, respectively (hazard ratio [HR] for death: 0.97; 95% CI: 0.77-1.23; p=0.81). One-year and 2-year OS was comparable in both groups with 39% and 15% in the AZA arm and 32% and 14% in the DEC arm, respectively. Median OS estimates in clinically or genetically-defined patient subgroups were similar between AZA and DEC-treated pts. Serious adverse events leading to death occurred more frequently in the AZA arm compared with DEC (AZA: 38% vs 26% with DEC; p=0.02).

Conclusion: Outcomes in treatment-naïve AML pts ineligible for intensive chemotherapy treated with AZA or DEC in the randomized phase III ASTRAL-1 trial are comparable with CR rates of 17.5% and 19.2% and median OS of 8.7 months and 8.2 months, respectively. No patient, disease, or molecular characteristics predicted a higher likelihood of response to either AZA or DEC. Safety in this frail patient population was comparable to prior trails of HMAs in AML and no major safety differences between AZA and DEC were detected although fatal serious adverse events tended to be higher in the AZA-treated cohort.

Disclosures: Zeidan: Cardiff Oncology: Consultancy, Honoraria, Other; Leukemia and Lymphoma Society: Other; Epizyme: Consultancy, Honoraria; MedImmune/Astrazeneca: Research Funding; Seattle Genetics: Consultancy, Honoraria; CCITLA: Other; Taiho: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Astex: Research Funding; ADC Therapeutics: Research Funding; Astellas: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Celgene / BMS: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Aprea: Research Funding; Ionis: Consultancy, Honoraria; Trovagene: Consultancy, Honoraria, Research Funding; BeyondSpring: Consultancy, Honoraria. Fenaux: Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Roboz: Eisai: Consultancy; Celltrion: Consultancy; Bayer: Consultancy; Trovagene: Consultancy; Cellectis: Research Funding; Jasper Therapeutics: Consultancy; Epizyme: Consultancy; Helsinn: Consultancy; MEI Pharma: Consultancy; Takeda: Consultancy; Otsuka: Consultancy; Orsenix: Consultancy; AstraZeneca: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Argenx: Consultancy; Actinium: Consultancy; Sandoz: Consultancy; Jazz: Consultancy; Roche/Genentech: Consultancy; Amgen: Consultancy; GlaxoSmithKline: Consultancy; Bristol Myers Squibb: Consultancy; Mesoblast: Consultancy; Array BioPharma: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Astex: Consultancy; Amphivena: Consultancy; Agios: Consultancy. Robak: Novartis: Honoraria, Research Funding; UTX-TGR: Research Funding; Bristol Meyers Squibb: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Medical University of Lodz: Current Employment; AstraZeneca: Honoraria, Research Funding; Octapharma: Honoraria; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; BioGene: Honoraria, Research Funding; Momenta: Consultancy; Pfizer: Research Funding; GSK: Research Funding; Sandoz: Consultancy, Honoraria; Morphosys: Research Funding; Takeda: Consultancy; Acerta: Research Funding; UCB: Honoraria, Research Funding. Kantarjian: Delta Fly: Honoraria; Oxford Biomedical: Honoraria; Janssen: Honoraria; Ascentage: Research Funding; Abbvie: Honoraria, Research Funding; Aptitute Health: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; BioAscend: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Sanofi: Research Funding; Adaptive biotechnologies: Honoraria; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; BMS: Research Funding. Novak: Takeda: Consultancy; Roche: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Other: Travel expenses; Novartis: Consultancy; Janssen: Other: Travel expenses. Miyazaki: NIPPON SHINYAKU CO.,LTD.: Honoraria; Otsuka Pharmaceutical: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Novartis Pharma KK: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Celgene: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Yeh: Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Brandwein: Celgene: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Jazz Pharmaceuticals: Honoraria; Roche: Honoraria; Taiho: Honoraria; Astellas: Honoraria. Griffiths: Boston Biomedical: Honoraria; Novartis: Honoraria, Research Funding; AbbVie Inc: Honoraria; Persimmune: Research Funding; Celgene/BMS: Honoraria, Research Funding; Genentech Inc: Research Funding; Astex Pharmceuticals: Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding. Hao: Astex Pharmaceuticals, Inc.: Current Employment. Azab: Astex Pharmaceuticals: Current Employment. Döhner: Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Oxford Biomedicals: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; AROG: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Pfizer: Research Funding; Roche: Consultancy, Honoraria; Sunesis: Research Funding; GEMoaB: Consultancy, Honoraria.

*signifies non-member of ASH