Abstract
BackgroundMost older patients with acute myeloid leukemia (AML) who attain morphologic remission with intensive chemotherapy (IC) will eventually relapse and post-relapse prognosis is dismal. In the pivotal QUAZAR AML-001 trial, oral azacitidine maintenance therapy significantly prolonged overall survival by 9.9 months (P < 0.001) and relapse-free survival by 5.3 months (P < 0.001) compared with placebo in patients with AML in first remission after IC who were not candidates for transplant. Currently, the QUAZAR AML-001 trial provides the most comprehensive safety information associated with oral azacitidine maintenance therapy. Reviewed here are common adverse events (AEs) during oral azacitidine treatment in QUAZAR AML-001, and practical recommendations for AE management based on guidance from international cancer consortiums, regulatory authorities, and the authors’ clinical experience treating patients in the trial.MethodsQUAZAR AML-001 is an international, placebo-controlled randomized phase 3 study. Patients aged ≥ 55 years with AML and intermediate- or poor-risk cytogenetics at diagnosis, who had attained first complete remission (CR) or CR with incomplete blood count recovery (CRi) within 4 months before study entry, were randomized 1:1 to receive oral azacitidine 300 mg or placebo once-daily for 14 days in repeated 28-day cycles. Safety was assessed in all patients who received ≥ 1 dose of study drug.ResultsA total of 469 patients received oral azacitidine (n = 236) or placebo (n = 233). Median age was 68 years. Patients received a median of 12 (range 1–80) oral azacitidine treatment cycles or 6 (1–73) placebo cycles. Gastrointestinal AEs were common and typically low-grade. The most frequent grade 3–4 AEs during oral azacitidine therapy were hematologic events. AEs infrequently required permanent discontinuation of oral azacitidine (13%), suggesting they were effectively managed with use of concomitant medications and oral azacitidine dosing modifications.ConclusionOral azacitidine maintenance had a generally favorable safety profile. Prophylaxis with antiemetic agents, and blood count monitoring every other week, are recommended for at least the first 2 oral azacitidine treatment cycles, and as needed thereafter. Awareness of the type, onset, and duration of common AEs, and implementation of effective AE management, may maximize treatment adherence and optimize the survival benefits of oral azacitidine AML remission maintenance therapy.Trial registration This trial is registered on clinicaltrials.gov: NCT01757535 as of December 2012.
Highlights
Most older patients with acute myeloid leukemia (AML) who attain morphologic remission with intensive chemotherapy (IC) will eventually relapse and post-relapse prognosis is dismal
Adverse event (AE) infrequently required permanent discontinuation of oral azacitidine (13%), suggesting they were effectively managed with use of concomitant medications and oral azacitidine dosing modifications
Patients and overall safety in QUAZAR AML‐001 In all, 472 patients were randomized to treatment; the safety-evaluable population comprised 469 patients (99%) who received ≥ 1 dose of oral azacitidine (n = 236) or placebo (n = 233)
Summary
Most older patients with acute myeloid leukemia (AML) who attain morphologic remission with intensive chemotherapy (IC) will eventually relapse and post-relapse prognosis is dismal. Well-tolerated maintenance therapies are needed to prolong remission, reduce risk of relapse, and improve survival for older patients with AML. Azacitidine is a DNA methyltransferase inhibitor and hypomethylating agent (HMA) that, when administered parenterally for 5–7 days per 28-day treatment cycle, induces clinical responses and prolongs overall survival (OS) as front-line treatment in older patients with AML or higher-risk myelodysplastic syndromes (MDS) [10, 11]. Injectable azacitidine has been shown to prolong disease-free survival (DFS)—but not OS—as maintenance therapy in patients ≥ 60 years of age with AML in remission after IC [12]. The oral and parenteral formulations of azacitidine are not bioequivalent and not interchangeable [20]
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