Oral Azacitidine Improves Overall Survival vs Placebo as Maintenance Therapy for AML in First Remission

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Andrew H. Wei, MB, BS, PhD

Andrew H. Wei, MB, BS, PhD

As reported in The New England Journal of Medicine by Andrew H. Wei, MB, BS, PhD, of the Australian Centre for Blood Diseases, Monash University, Melbourne, and colleagues, the phase III QUAZAR AML-001 trial has shown prolonged overall survival with oral azacitidine maintenance therapy vs placebo in patients with acute myeloid leukemia (AML) in first remission who were not candidates for hematopoietic stem cell transplantation (HSCT).1 The oral formulation of azacitidine is not bioequivalent to injectable azacitidine.

The trial supported the September 2020 approval of oral azacitidine for continued treatment of patients with AML who achieved first complete remission or complete remission with incomplete blood cell count recovery following intensive induction chemotherapy and who are not able to complete intensive curative therapy.

Study Details

In the double-blind trial, 472 patients aged ≥ 55 years from sites in 23 countries who were in complete remission with or without complete blood cell count recovery and were not candidates for HSCT were randomly assigned between May 2013 and October 2017 to receive oral azacitidine at 300 mg once daily (n = 238) or placebo (n = 234) for 14 days in 28-day cycles. Patients had to have newly diagnosed de novo AML or secondary AML and intermediate- or poor-risk cytogenetic characteristics. All patients were permitted to receive supportive care according to local practice. Treatment was continued until at least 15% blasts were present or unacceptable toxicity. The primary endpoint was overall survival.

For the azacitidine vs placebo groups, median patient age was 68 years (range = 55–86 years) vs 68 years (range = 55–82 years), 50% vs 54% were male, and the AML type was de novo in 89% vs 92% and secondary in 11% vs 8%. Response after induction therapy was complete remission in 79% vs 84% and complete remission with incomplete blood cell count recovery in 21% vs 16%; 78% vs 82% received consolidation therapy. Median bone marrow blasts were 2.0% (range = 0.0%–5.0%) vs 2.0% (range = 0.0%–6.5%); and 43% vs 50% were positive for measurable residual disease (MRD).

Overall Survival

Median follow-up was 41.2 months. Median overall survival from the time of randomization was 24.7 months (95% confidence interval [CI] = 18.7–30.5 months) in the azacitidine group vs 14.8 months (95% CI = 11.7–17.6 months) in the placebo group (difference = 9.9 months, P < .001). Overall survival at 1 and 2 years was 72.8% vs 55.8% and 50.6% vs 37.1% (difference = 13.5%, 95% CI = 4.5%–22.5%).

Overall survival at 2 years favored azacitidine in most subgroups based on baseline disease characteristics. Rates were 50.8% vs 39.2% among those receiving consolidation therapy and 50.0% vs 27.4% in those not receiving consolidation; 49.7% vs 36.7% in those with complete remission and 55.1% vs 38.6% among those with complete remission with incomplete blood cell count recovery after induction chemotherapy; 39.5% vs 22.0% among those with persistent MRD and 58.6% vs 51.7% among those without MRD at randomization; and 54.1% vs 40.4% among those with intermediate-risk cytogenetics and 30.3% vs 15.5% among those with poor-risk cytogenetics.


  • Oral azacitidine significantly improved overall and relapse-free survival vs placebo.
  • Median overall survival was 24.7 months vs 14.8 months.

Median relapse-free survival was 10.2 months (95% CI = 7.9–12.9 months) vs 4.8 months (95% CI = 4.6–6.4 months; difference = 5.3 months, P < .001). Rates at 6 months and 1 year were 67.4% vs 45.2% and 44.9% vs 27.4%.

Escalated 21-day dosing schedules were administered upon AML relapse, with 5% to 15% blasts in 51 patients (21%) in the azacitidine group and 40 patients (17%) in the placebo group. The median time to escalated dosing was 9.2 months vs 6.0 months. Median overall survival from the time of randomization among these patients was 22.8 months vs 14.6 months.

Overall, 58% of the azacitidine group vs 73% of the placebo group received subsequent therapy after discontinuation of study treatment, including 96% vs 94% of those experiencing relapse during the trial. Overall, 15 patients (6%) in the azacitidine group proceeded to HSCT; 6 remained in first remission at the time of HSCT and 9 had experienced relapse. In the placebo group, 32 patients (14%) underwent HSCT, all of whom had experienced relapse.

Adverse Events

The median durations of treatment were 12 cycles in the azacitidine group and 6 cycles in the placebo group. The most common adverse events in both groups were grade 1 or 2 gastrointestinal events. Grade 3 or 4 adverse events occurred in 72% vs 63% of patients, with the most common in the azacitidine group being neutropenia (41% vs 24% in placebo group), thrombocytopenia (22% vs 21%), and anemia (14% vs 13%). The most common serious adverse events were infections (17% vs 8%). Adverse events led to treatment discontinuation in 13% vs 4% of patients, with the most common cause being gastrointestinal adverse events (5% vs < 1%). Fatal adverse events occurred in nine patients (4%) in the azacitidine group (sepsis in two, cerebral hemorrhage in two, sepsis and multiorgan failure in one, and intracranial hemorrhage, cardiogenic shock, aspiration pneumonia, and suicide in one each) and in four patients (2%) in the placebo group (multiorgan failure in two, cerebral hemorrhage in one, and general health deterioration in one).

Analysis of health-related quality of life using the Functional Assessment of Chronic Illness Therapy–Fatigue Scale and three-level version of the European Quality of Life–5 Dimensions instruments showed no clinically meaningful differences in least-squares mean changes from baseline between the treatment groups at any study visit.

The investigators concluded: “[Oral azacitidine] maintenance therapy was associated with significantly longer overall and relapse-free survival than placebo among older patients with AML who were in remission after chemotherapy. Side effects were mainly gastrointestinal symptoms and neutropenia. Quality-of-life measures were maintained throughout treatment.” 

DISCLOSURE: The study was supported by Celgene. Dr. Wei has received honoraria from AbbVie/Genentech, Amgen, Celgene, Janssen Oncology, Novartis, Pfizer, Roche, and Servier; has served as a consultant or advisor to AbbVie/Genentech, Amgen, Celgene, MacroGenics, Novartis, Pfizer, and Servier; has participated in a speakers bureau for AbbVie/Genentech, Amgen, Celgene, and Novartis; has received institutional research funding from AbbVie, AstraZeneca, Celgene, Novartis, and Servier; “receives milestone and royalty payments related to venetoclax”; and has been reimbursed for travel, accommodations, or other expenses by AbbVie, Amgen, Celgene, Janssen Oncology, Novartis, Pfizer, and Servier.


1. Wei AH, Döhner H, Pocock C, et al: Oral azacitidine maintenance therapy for acute myeloid leukemia in first remission. N Engl J Med 383:2526-2537, 2020.