Management of adverse events in patients with acute myeloid leukemia in remission receiving oral azacitidine: experience from the phase 3 randomized QUAZAR AML-001 trial

Abstract

Background 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. 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. Methods QUAZAR 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. Results A 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. Conclusion Oral 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.

Acute myeloid leukemia

“…These regimens are administered every 4 weeks until the disease progresses or the patient can no longer tolerate therapy. 16 Oral formulations of azacitidine and decitabine/cedazuridine are not FDA-approved for this type of AML treatment and should not be interchanged for their parenteral counterparts. Maintenance therapy for AML with oral azacitidine is discussed later.…”

“…6 Cytogenetic abnormalities and gene mutations frequently are identified in AML cells and are an important component in stratifying disease risk. 1,7 Cytogenetic abnormalities t(8;21) and inv (16) constitute core-binding factor AML (CBF-AML), a subset of AML thought to be considered favorable risk. 8 These abnormalities can be detected by conventional cytogenetics or fluorescence in situ hybridization (FISH) from cells obtained from the bone marrow aspirate or peripheral blood.…”

Exploiting RIG-I-like receptor pathway for cancer immunotherapy

“…With regard to viral mimicry, randomized phase III trial in patients with acute myeloid leukemia demonstrates that oral azacitidine maintenance has a generally favorable safety profile [ 306 ]. The combination of viral mimicry with immune checkpoint blockade has been extensively evaluated in clinical trials.…”

Targeting and Monitoring Acute Myeloid Leukaemia with Nucleophosmin-1 (NPM1) Mutation

“…It can be easily transported due to its similarities to nucleotide cytidine and can be easily incorporated into DNA both RNA. Classified as an antimetabolite and a demethylating agent, trials developed till phase 3, QUAZAR AML-001 trial (NCT01757535), show good tolerability and outcome in AML, therefore suggesting a good alternative for elderly patients who are unfit for intensive chemotherapy [ 135 ]. HMA’s have also been used in relapsed/refractory patients due to their ability to sensitise leukemic cells for further chemotherapy and its utility in maintenance therapy.…”