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871 Long-Term Overall Survival (OS) with Oral Azacitidine (Oral-AZA) in Patients with Acute Myeloid Leukemia (AML) in First Remission after Intensive Chemotherapy (IC): Updated Results from the Phase 3 QUAZAR AML-001 TrialClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 615. Acute Myeloid Leukemias: Commercially Available Therapies, Excluding Transplantation and Cellular Immunotherapies: Updates in treatment for high-risk AML
Hematology Disease Topics & Pathways:
Clinical Trials, AML, Workforce, Elderly, Diversity, Equity, Inclusion, and Accessibility (DEI/DEIA) , Diseases, Myeloid Malignancies, Study Population
Monday, December 13, 2021: 6:15 PM

Andrew H. Wei, MBBS, PhD1,2*, Hartmut Döhner, MD3, Hamid Sayar, MD, MSc4, Farhad Ravandi, MB Bs5, Pau Montesinos, PhD, MD6*, Hervé Dombret, MD, PhD7,8, Dominik Selleslag, MD9, Kimmo Porkka, MD, PhD10,11*, Jun Ho Jang, MD, PhD12, Barry Skikne, MD13,14*, C.L. Beach, PharmD14*, Yu (Olivia) Tian, PhD14* and Gail J. Roboz, MD15,16

1Department of Clinical Haematology, The Alfred Hospital, Melbourne, Australia
2Australian Centre for Blood Diseases, Monash University, Melbourne, Australia
3Ulm University Hospital, Ulm, Germany
4Indiana University Cancer Center, Indianapolis, IN
5Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
6Hospital Universitario y Politécnico La Fe, Valencia, Spain
7Hôpital Saint-Louis, Assistance Publique – Hôpitaux de Paris (AP-HP), Paris, France
8Institut de Recherche Saint Louis, Université de Paris, Paris, France
9AZ Sint-Jan Brugge-Oostende AV, Bruges, Belgium
10Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
11iCAN Digital Precision Cancer Center Medicine Flagship, University of Helsinki, Helsinki, Finland
12Samsung Medical Center, Seoul, Korea, Republic of (South)
13Kansas University Medical Center, Kansas City, KS
14Bristol Myers Squibb, Princeton, NJ
15Weill Cornell Medicine, New York, NY
16New York Presbyterian Hospital, New York, NY

BACKGROUND: While many older patients (pts) with AML attain complete remission (CR) after treatment (Tx) with IC, ~80% will relapse and overall survival (OS) is poor. The randomized, placebo (PBO)-controlled, phase 3 QUAZAR AML-001 trial assessed Oral-AZA (CC-486), a hypomethylating agent, in pts with AML in remission after IC who were not eligible for stem cell transplant. At the primary data cutoff in July 2019, Oral-AZA was associated with significantly prolonged OS vs. PBO: 24.7 vs. 14.8 months (mo), respectively (P < 0.001) (Wei, 2020), but the tails of the Kaplan-Meier OS curves for Oral-AZA and PBO began to converge during later time-points (after ~48 mo). More than one-quarter of all randomized pts (125/472 [26.5%]) were either still receiving Tx with Oral-AZA (n = 45) or PBO (n = 26) or remained alive in survival follow-up (n = 26 and n = 28) at the primary cutoff. Upon trial unblinding, pts continued to be followed for OS (but not relapse-free survival). We assessed longer-term OS for pts in QUAZAR AML-001 as of September 2020, after > 1 year of additional follow-up.

METHODS: Pt eligibility and study design have been reported in detail. Briefly, eligible pts were aged ≥55 years with newly diagnosed AML, intermediate- or poor-risk cytogenetics at AML diagnosis (Dx), and ECOG PS ≤3, and had achieved first CR or CRi after IC (induction ± consolidation) before screening. Within 4 mo after CR/CRi, pts were randomized 1:1 to Oral-AZA 300 mg or PBO QD for 14 days/28-day Tx cycle. After trial unblinding in July 2019, pts in the Oral-AZA arm could continue to receive Tx in an extension phase if they continued to benefit; pts in the PBO arm had Tx discontinued and were followed for OS. Kaplan-Meier estimated OS was calculated from the time of randomization until death, withdrawal of consent, or loss to follow-up, and compared between Tx arms by log-rank test. To determine whether OS was influenced by pt-related factors, we compared baseline (BL) demographic and disease characteristics of pts who were alive (on-Tx and/or in survival follow-up) for ≥ 3 years from randomization (“Long-term [LT] Survivors”) vs. those of pts who died or were censored before 3 years.

Results: In all, 472 pts were randomized to Oral-AZA (n = 238) or PBO (n = 234). Median age was 68 years (range 55–86), 91% of pts had de novo AML, and 86% had intermediate-risk cytogenetics. Upon trial unblinding, 39 pts (16%) in the Oral-AZA arm continued into the extension phase Overall, 31.4% and 15.5% of pts received > 24 mo of Tx with Oral-AZA or PBO, respectively.

At the updated follow-up in September 2020, 54 pts (23%) in the Oral-AZA arm were alive in survival follow-up, including 31 pts (13%) still receiving Oral-AZA in the extension phase; 165 pts (69%) had died and 19 pts (8%) had withdrawn consent or were lost to follow-up. In the PBO arm, 35 pts (15%) remained alive, 176 (75%) had died, and 23 (10%) had withdrawn consent or were lost to follow-up.

At a median follow-up of 51.7 mo, median OS in each arm remained unchanged from the primary cutoff date: 24.7 vs. 14.8 mo with Oral-AZA vs. PBO, respectively (P = 0.0008); however, the KM OS curves for Oral-AZA and PBO showed greater separation with additional follow-up, and the two curves did not touch or cross at any time (Figure). KM-estimated 3-year survival rates were 37.4% vs. 27.9% in the Oral-AZA and PBO arms, respectively (∆ +9.5% [95% CI 0.9%, 18.1%]).

The LT Survivors cohort comprised 140 pts (29.7%) in the Oral-AZA (n = 83) and PBO (n = 57) arms who were known to be alive for ≥ 3 years. Compared with pts who died or were censored before 3 years, those in the LT Survivors group were more likely to have intermediate-risk cytogenetics (95% vs. 82%) and an NPM1 mutation (45% vs. 9%) at AML Dx, and less likely to be MRD+ at BL (33% vs. 52%). Among pts with post-IC MRD+ at BL, 71% (34/48) in the LT Survivors cohort achieved MRD negativity on-study, compared with 15% (26/172) in the < 3-year cohort (P < 0.0001).

Conclusions: With > 1 year of additional survival follow-up, median OS in QUAZAR AML-001 remained unchanged in both Tx arms, but the tails of the Oral-AZA and PBO OS curves showed greater separation at later time-points than in the primary analysis (which may have been confounded by extensive censoring), indicating a sustained, long-term OS benefit with Oral-AZA. Intermediate-risk cytogenetics and NPM1 mutations at AML Dx, and absence of detectable MRD post-IC, were associated with long-term survival in QUAZAR AML-001.

Disclosures: Wei: Novartis, Celgene, AbbVie, Servier, AstraZeneca, and Amgen: Research Funding; Walter and Eliza Hall Institute: Ended employment in the past 24 months; Novartis, Astellas, Pfizer, MacroGenics, AbbVie, Genentech, Servier, Celgene, Amgen, AstraZeneca, Janssen: Honoraria. Döhner: Pfizer: Research Funding; Oxford Biomedicals: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria; Jazz: Honoraria, Research Funding; Helsinn: Honoraria; GEMoaB: Honoraria; Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; AstraZeneca: Honoraria; Berlin-Chemie: Honoraria; Astex: Honoraria; Astellas: Honoraria, Research Funding; Roche: Honoraria; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Sayar: BMS: Honoraria. Ravandi: Taiho: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria; Novartis: Honoraria. Montesinos: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline/Menarini: Consultancy; Forma Therapeutics: Consultancy; Glycomimetics: Consultancy; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Tolero Pharmaceutical: Consultancy; Agios: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Selleslag: Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Teva: Consultancy, Honoraria. Skikne: Bristol Myers Squibb: Current Employment. Beach: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Tian: Bristol Myers Squibb: Current Employment. Roboz: Celgene: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Astellas: Consultancy; Jazz: Consultancy; Amgen: Consultancy; Mesoblast: Consultancy; Agios: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Janssen: Consultancy; AbbVie: Consultancy; Daiichi Sankyo: Consultancy; Helsinn: Consultancy; AstraZeneca: Consultancy; Bayer: Consultancy; Actinium: Consultancy; Astex: Consultancy; Glaxo SmithKline: Consultancy; Bristol Myers Squibb: Consultancy; Blueprint Medicines: Consultancy; Jasper Therapeutics: Consultancy; Janssen: Research Funding; Pfizer: Consultancy; Roche/Genentech: Consultancy.

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