Long‐term survival with oral azacitidine for patients with acute myeloid leukemia in first remission after chemotherapy: Updated results from the randomized, placebo‐controlled, phase 3 QUAZAR AML‐001 trial

TL;DR: Wei et al. as discussed by the authors showed that oral azacitidine (Oral-AZA) significantly prolonged the 5-year overall survival for patients with acute myeloid leukemia (AML).

Abstract: To the Editor: Despite recent therapeutic advances, outcomes remain poor for older patients with acute myeloid leukemia (AML). For patients in the USA diagnosed with AML between 2010–2017, the 5-year overall survival (OS) rate was 22% for patients aged 60–69 years, and only 5% for those aged ≥70 years. Survival outcomes are influenced by patientand disease-related factors, including age, comorbidities, cytogenetic abnormalities, gene mutations, and persistence of leukemic cells after intensive chemotherapy (IC) (i.e., measurable residual disease [MRD]). For patients with AML in remission, hematopoietic stem cell transplantation (HSCT) is often the only potentially curative option, but many patients are not candidates for HSCT due to advanced age, poor performance status, comorbidities, patient preference, or favorable AML European Leukemia Net risk, particularly in younger patients. Thus, there is a need for effective maintenance therapies to prolong survival among HSCT-ineligible patients in complete remission. In the randomized, double-blind, phase 3 QUAZAR AML-001 trial, oral azacitidine (Oral-AZA) significantly prolonged OS and relapse-free survival (RFS) versus placebo in patients ≥55 years with AML in first remission after IC who were not HSCT candidates. At the July 2019 primary data cutoff, with a median follow-up time of 41.2 months, approximately one-quarter of all patients were alive and in survival follow-up. Here, we present updated OS outcomes (data cutoff March 2022) with the median follow-up time now 55.5 months and investigate clinical and biological variables predictive of long-term survival, defined here as survival ≥3 years from randomization, in patients treated with Oral-AZA or placebo. The study design was described in detail in Wei et al. Briefly, patients aged ≥55 years with intermediate-or poor-risk cytogenetics at diagnosis who achieved first complete remission (CR) or CR with incomplete blood count recovery (CRi) with IC, were randomized 1:1 to receive Oral-AZA 300-mg or placebo once-daily for 14 days in repeated 28-day cycles. Patients in the Oral-AZA arm could continue treatment in an optional open-label extension phase after trial unblinding (Figure S1). The primary endpoint was OS, defined as the time from randomization until death. Patients who withdrew consent or were lost to follow-up were then censored for OS. OS was estimated by Kaplan–Meier methods and compared between treatment groups by stratified log-rank test. NPM1 and FLT3 gene mutations were assessed locally at diagnosis for most patients; post-IC MRD status was assessed centrally at study screening by multiparameter flow cytometry. During study therapy, surveillance bone marrow monitoring for hematologic remission and MRD status was performed every 3 cycles from cycles 3–24, then every 6 cycles or as clinically indicated. For patients MRD+ at baseline (≥0.1%), MRD response was defined as achieving MRD negativity (<0.1%) at ≥2 consecutive assessments during study. In all, 472 patients were randomized to Oral-AZA (n = 238) or placebo (n = 234). At diagnosis, 86% of patients had intermediate-risk cytogenetics, 29% had NPM1, and 14% had FLT3 (Table S1). Median age was 68 (range 55–86) years and 47% of patients were MRD+ at screening. Median OS at the primary data cutoff (median follow-up 41.2 months) was 24.7 versus 14.8 months with Oral-AZA versus placebo, respectively (p < .001); estimated 2-year survival rates were 50.6% versus 37.1% (difference [Δ] +13.5%; 95% confidence interval [CI], +4.5% to +22.5%). Over one-fourth of randomized patients (26.5%) were being followed for survival and censored for OS, including 71 patients still receiving Oral-AZA (n = 45) or placebo (n = 26) (Figure S2). After unblinding, 39 (16%) patients continued receiving Oral-AZA in an optional extension phase and 6 patients discontinued (3 withdrew consent, 2 relapsed, and 1 died). Patients still receiving placebo at unblinding had treatment discontinued and were followed for OS. After the primary data cutoff, patients not receiving active therapy (including patients who discontinued Oral-AZA during the extension phase) were followed for OS for up to 12 months. At the updated March 2022 cutoff, median study follow-up was 55.5 months and 25 (11%) patients were receiving Oral-AZA maintenance in the extension phase (Figure S2). Overall, 54 (23%) patients in Received: 31 October 2022 Revised: 10 January 2023 Accepted: 12 January 2023