Prolonged Survival without Complete Remission (CR) In AML Patients (Pts) Treated with Azacitidine (AZA)

AZA has been shown to improve overall survival (OS) compared with conventional care regimens (p=0.005) in elderly pts with WHO-defined AML (20-30%) bone marrow [BM] blasts), despite a modest 18% CR rate (AZA 001 trial, JCO, 2010;10:223). AZA as frontline therapy also appears active in pts with AML with >30% blasts who are unfit for intensive chemotherapy (IC) (Thépot et al, Blood, 2009:A843). For AML pts receiving IC, CR is often considered a prerequisite to improved survival. In pts with higher-risk myelodysplastic syndromes (MDS) treated with AZA, an OS benefit has been observed in pts with a best response of partial remission (PR) or hematological improvement (HI), and most recently, stable disease (SD) (JCO, 2008;26:A7006; JCO, 2010;28:A6503). It is unknown whether OS benefits with AZA in the absence of CR will be obtained by pts with AML. We analyzed the best response to AZA obtained by pts with WHO AML (>20% blasts) from 2 independent pt cohorts who survived ≥2 years.

AZA-001 included 55 pts with WHO-defined AML (20-30% BM blasts, none of them therapy related) randomized to AZA treatment, and the French AZA compassionate program (ATU) included 148 pts with WHO-defined AML treated with AZA as frontline therapy (median 33% marrow blasts), of whom 24% had therapy-related AML and 38% had AML post-MDS. Pts received AZA at the FDA/EMEA-approved schedule (75mg/m²/d × 7d/28d) for a minimum of 6 cycles in the AZA -001 trial, as did 48% of pts in the ATU for a minimum of 4 cycles (52% of pts in the ATU received AZA in a 5-day regimen, or less often, as a flat 100mg daily dose over 7 days). Responses to AZA in the ATU cohort reflect AML response criteria (JCO 2003;21:4642), or in the case of HI, IWG 2006 criteria for MDS (Blood 2006;108:419). Responses to AZA in the AZA-001 cohort reflect IWG 2000 criteria for MDS (Blood 2000;96:3671). Best responses were evaluated in pts who survived ≥2 years in both cohorts.

The 55 pts in the AZA-001 cohort had a median age of 70 years (52-80), 23% (20-34%) median BM blast count, and 26% and 69%, had IPSS unfavorable or intermediate cytogenetics, respectively. Pts received a median of 8 (1–39) AZA treatment cycles. With a median follow-up of 20.1 months, 11/55 (20%) pts in this cohort were alive ≥2 years after beginning AZA. None of the 11 pts had achieved CR or PR with AZA. According to IWG 2000 criteria, 4 pts had achieved HI and 7 pts had SD as best responses.

In the ATU cohort, median follow-up was 15.6 months. Of 148 AML pts, 68 (46%) had entered the study ≥2 years before the reference date of analysis (Jan 2010). Of them, 29 pts had 20–30% BM blasts and 39 pts had >30% BM blasts. Of pts with 20–30% BM blasts, 7/29 (24%) were alive at 2 years. As best response to AZA, only 2 of the 7 pts (29%) had achieved CR, 2 achieved HI, and 3 had SD. Of pts with >30% BM blasts, 5/39 (13%) were alive at 2 years; best responses included CR (n=1), PR (n=1), morphologic CR with incomplete count recovery (CRi; n=2), and SD (n=1). Only 1 of the 12 AML pts who survived ′2 years had undergone allogeneic transplant (pt had AML with 20–30% BM blasts and SD as best response), after 4 cycles of AZA.

In 2 independent cohorts of pts with AML treated with AZA, most pts with 20–30% BM blasts who survived ≥2 years (16/18, 89%) did so despite a lack of CR or PR. This finding appeared less clear in patients with >30% blasts. These results warrant confirmation in larger pt numbers but suggest that, as in MDS, traditional morphological responses of CR/PR may not be required to obtain prolonged survival in pts with AML, especially pts with 20–30% BM blasts, treated with AZA.

Off Label Use: Azacitidine in Acute Myeloid Leukemia with >30% marrow blasts. Beach: Celgene: Employment. Swern: Celgene: Employment. Fenaux: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding.