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Oral Azacitidine Prolongs Survival in Patients with Acute Myeloid Leukemia

JHOP - April 2021 Vol 11, No 2 - From the Literature, Leukemia
With Commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP, FHOPA
Robert J. Ignoffo, PharmD, FASHP, FCSHP, FHOPA
Clinical Professor Emeritus
University of California, San Francisco
Professor of Pharmacy
College of Pharmacy, Touro University–California
Mare Island, Vallejo, CA
Clinical Professor Emeritus, University of California, San Francisco; Professor Emeritus, Touro University–California, Mare Island, Vallejo, CA
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BACKGROUND: Induction chemotherapy leads to remission in many patients with acute myeloid leukemia (AML) aged ≥60 years; however, the disease relapses in the majority of patients, and the overall survival (OS) is poor. For patients who are not candidates for hematopoietic stem-cell transplant, effective maintenance treatments for AML are needed that can reduce the risk for relapse and improve OS, without causing unacceptable adverse events or compromising quality of life. Based on data from a recent study, in September 2020, the FDA approved azacitidine tablets for adults with AML who are not candidates for transplant.

METHODS: This international, randomized, double-blind, placebo-controlled, phase 3 QUAZAR AML-001 study evaluated the efficacy and safety of oral azacitidine as maintenance therapy in patients with AML who were in first remission after intensive chemotherapy. Eligibility criteria included age ≥55 years, being in complete remission (regardless of complete blood count recovery), and being ineligible for transplant. A total of 472 adults were randomized in a 1:1 ratio to azacitidine 300 mg (N = 238) or to placebo (N = 234) once daily, on days 1 to 14 of each 28-day treatment cycle. Patients had intermediate-risk (86%) or poor-risk (14%) cytogenetics and an Eastern Cooperative Oncology Group performance status score of ≤3. The primary end point was OS. The secondary end points included relapse-free survival and health-related quality of life.

RESULTS: With a median follow-up of 42.1 months, azacitidine led to a significant improvement in OS compared with placebo (24.7 months vs 14.8 months, respectively; P <.001). In a subgroup analysis, OS benefit was seen in the azacitidine group regardless of baseline cytogenetic risk, initial response to induction chemotherapy, receipt of consolidation therapy, or measurable residual disease status. The median relapse-free survival was also significantly longer in the azacitidine arm than in the placebo arm (10.2 months vs 4.8 months, respectively; P <.001). Oral azacitidine had a safety profile consistent with that of injectable azacitidine. Grade 1 or 2 gastrointestinal adverse events that were common in both groups included nausea, vomiting, and diarrhea, which were controlled with antiemetic and antidiarrheal agents. The most common grade 3 or 4 hematologic adverse events with azacitidine versus placebo were neutropenia (41% vs 24%), thrombocytopenia (22% vs 21%), and anemia (14% vs 13%). Quality of life was maintained throughout the treatment with azacitidine.

Source: Wei AH, Döhner H, Pocock C, et al; for the QUAZAR AML-001 trial investigators. Oral azacitidine maintenance therapy for acute myeloid leukemia in first remission. N Engl J Med. 2020;383:2526-2537.

Commentary by Robert J. Ignoffo

The QUAZAR study was a randomized, placebo-controlled, international, multi-institutional study that showed that oral azacitidine prolongs overall as well as relapse-free survival among older patients who attained complete remission after intensive chemotherapy. To date, no other study of its kind has been reported in the literature. Some of the benefits of injectable azacitidine are believed to come from its hypomethylation effect on malignant myeloid cells. Prolonging hypomethylation may even have a more pronounced effect. Thus, an oral formulation has the advantage of being administered over a prolonged period.

Other studies have shown that the dosing of azacitidine over a 14-day period in a 28-day cycle can significantly reduce methylation of gene loci over a sustained treatment cycle.1,2 Furthermore, the results of a pharmacokinetic study showed that food or concomitant use of a proton-pump inhibitor did not affect the plasma levels of azacitidine.3 In summary, oral azacitidine is a major advance for the maintenance therapy of elderly patients with AML who have attained remission after induction chemotherapy.

  1. Laille E, Shi T, Garcia-Manero G, et al. Pharmacokinetics and pharmacodynamics with extended dosing of CC-486 in patients with hematologic malignancies. PLoS One. 2015(8):e0135520. doi:10.1371/jour nal.pone.0135520.
  2. Garcia-Manero G, Gore SD, Kambhampati S, et al. Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. Leukemia. 2016;30:889-896.
  3. Laille E, Savona MR, Scott BL, et al. Pharmacokinetics of different formulations of oral azacitidine (CC‐486) and the effect of food and modified gastric pH on pharmacokinetics in subjects with hematologic malignancies. J Clin Pharmacol. 2014;54:630-639.
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