CC-486 Improves Overall Survival (OS) and Relapse-Free Survival (RFS) for Patients with Acute Myeloid Leukemia (AML) in First Remission after Intensive Chemotherapy (IC), Regardless of Amount of Consolidation Received: Results from the Phase III QUAZAR AML-001 Maintenance Trial
Authors: Wei Andrew , Roboz Gail J. , Dombret Hervé , Döhner Hartmut , Schuh Andre C. , Montesinos Pau , Pocock Christopher , Selleslag Dominik , Bondarenko Sergey N. , La Torre Ignazia , Skikne Barry , Kumar Keshava , Dong Qian , Beach C.L. , Ravandi Farhad 
Published: November 2020

Background: Approximately 40-60% of older patients (pts) with AML achieve complete remission (CR) with IC. Factors influencing the use of consolidation after induction include disease-related considerations, extent of hematopoietic recovery, pt fitness, and physician and pt preference. Most older pts who achieve AML remission will experience disease relapse despite consolidation therapy (Schlenk, Haematologica, 2018). In the phase III, randomized, double-blind QUAZAR AML-001 Maintenance Trial, CC-486, an oral hypomethylating agent, was shown to significantly prolong OS and RFS vs. placebo (PBO) in pts with AML in first remission following induction ± consolidation. Prior to study entry, the use of consolidation chemotherapy and number of consolidation cycles was at the discretion of the treating physician, with study eligibility not contingent on the use of consolidation.
Objective: Assess survival outcomes in the QUAZAR AML-001 trial in pt subgroups defined by number of consolidation courses received before study entry.
Methods: Eligible pts were aged ≥55 years with newly diagnosed AML, intermediate- or poor-risk cytogenetics, and ECOG PS ≤3. Within 4 months (mo) of attaining first CR or CR with incomplete blood count recovery (CRi), pts were randomized 1:1 to CC-486 300 mg or PBO QD for 14 days per 28-day treatment (Tx) cycle.
OS and RFS were compared among pts who received no consolidation ("No Consolidation"), 1 cycle of consolidation ("1 Consolidation"), or ≥2 cycles of consolidation ("≥2 Consolidations"). For these analyses, "induction" and "consolidation" defined regimens received before and after, respectively, the reported date of first CR/CRi. OS was defined as the time from randomization to death, and RFS as time from randomization to relapse or death. Kaplan-Meier OS/RFS estimates were compared for CC-486 vs. PBO using log-rank test. Hazard ratios (HRs) and 95% CIs were generated using a stratified Cox proportional hazards model. These analyses were not powered sufficiently to determine statistical significance.
Results: 472 pts were randomized to CC-486 (N=238) or PBO (N=234). Most pts (80%) received consolidation before study entry. The No Consolidation cohort comprised 94 pts (20%; CC-486 52, PBO 42), the 1 Consolidation cohort comprised 212 pts (45%; CC-486 110, PBO 102), and the ≥2 Consolidations cohort comprised 166 pts (35%; CC-486 76, PBO 90), including 19 pts (CC-486 6, PBO 13) who received 3 consolidation cycles. Common agents used for consolidation were cytarabine (377/378 pts), idarubicin (95/378), and daunorubicin (37/378). While most pts received 1 induction, 97 pts received ≥2 induction courses; of them, 21 (CC-486 14, PBO 7) did not receive consolidation and 76 (CC-486 43, PBO 33) received ≥1 consolidation cycle.
Baseline characteristics (eg, CR / CRi after IC, ECOG PS, cytogenetic risk at diagnosis) were generally similar among Tx arms and cohorts. Median (range) ages of pts in the 0 / 1 / ≥2 Consolidation cohorts were 71 (58-84), 68 (55-86), and 67 (55-82) years, respectively. In the No Consolidation cohort, median OS from the time of randomization with CC-486 vs. PBO was 23.3 vs. 10.9 mo, respectively (HR 0.55 [95%CI 0.34, 0.89]), and median RFS was 8.4 vs. 3.9 mo (0.55 [0.34, 0.88]) (Figure A). In the 1 Consolidation cohort, median OS was 21.0 vs. 14.3 mo with CC-486 vs. PBO, respectively (HR 0.75 [95%CI 0.55, 1.02]), and median RFS was 10.0 vs. 4.7 mo (0.72 [0.53, 0.99]) (Figure B). In the ≥2 Consolidations cohort, median OS was 28.6 mo with CC-486 vs. 17.6 mo with PBO (HR 0.75 [95%CI 0.50, 1.11]), and median RFS was 13.0 vs. 6.1 mo (0.59 [0.41, 0.87]) (Figure C).
Conclusions: CC-486 was associated with consistent survival benefits vs. PBO regardless of number of prior consolidation cycles. Use of consolidation was generally associated with nominal improvements in OS and RFS within each Tx arm; however, in the CC-486 arm, median OS for pts who did not receive consolidation was similar to those who received 1 consolidation cycle (23.3 and 21.0 mo, respectively). Results should be interpreted with caution, as these cohorts were not prospectively defined and the study was not powered to detect significant differences between subgroups. Nevertheless, these data clearly suggest that older pts with AML in first remission after induction can benefit from CC-486, regardless of their fitness to receive consolidation or the number of consolidation cycles received before starting CC-486.

Disclosures
Wei: AMGEN: Honoraria, Other: Advisory committee, Research Funding; Walter and Eliza Hall Institute: Patents & Royalties; Novartis: Honoraria, Research Funding, Speakers Bureau; Abbvie: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau; Genentech: Honoraria, Other: Advisory committee; Servier: Consultancy, Honoraria, Other: Advisory committee; Astellas: Honoraria, Other: Advisory committee; Pfizer: Honoraria, Other: Advisory committee; Macrogenics: Honoraria, Other: Advisory committee; Celgene: Honoraria, Other: Advisory committee, Speakers Bureau; Astra-Zeneca: Honoraria, Other: Advisory committee, Research Funding; Janssen: Honoraria, Other. Roboz:Orsenix: Consultancy; Actinium: Consultancy; Argenx: Consultancy; Jazz: Consultancy; Astex: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Array BioPharma: Consultancy; Abbvie: Consultancy; Agios: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; AstraZeneca: Consultancy; Jasper Therapeutics: Consultancy; Cellectis: Research Funding; Otsuka: Consultancy; Takeda: Consultancy; Trovagene: Consultancy; Eisai: Consultancy; Celltrion: Consultancy; Epizyme: Consultancy; Helsinn: Consultancy; MEI Pharma: Consultancy; Sandoz: Consultancy; Roche/Genentech: Consultancy; Amphivena: Consultancy. Dombret:Sunesis: Consultancy; Abbvie: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy; Otsuka: Consultancy; Janssen: Consultancy; Menarini: Consultancy; Pfizer: Consultancy, Research Funding; Jazz Pharma: Consultancy, Research Funding; Celgene: Consultancy; Nova: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Astellas: Consultancy; Servier: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Cellectis: Consultancy. Döhner:Janssen: Consultancy, Honoraria; Celgene: 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; Sunesis: Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Pfizer: Research Funding; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; GEMoaB: Consultancy, Honoraria. Selleslag:Amgen: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Belgian College: Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. La Torre:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Skikne:Bristol Myers Squibb: Current Employment. Kumar:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dong:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Beach:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ravandi:Macrogenics: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria.