As reported in The New England Journal of Medicine by Andrew H. Wei, MBBS, PhD, 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. The oral formulation of azacitidine is not bioequivalent to injectable azacitidine.

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

Andrew H. Wei, MBBS, PhD

Study Details

The double-blind trial included 472 patients aged ≥ 55 years (median = 68 years) from sites in 23 countries who were in complete remission with or without complete blood count recovery and were not candidates for hematopoietic stem cell transplantation. Patients 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. Treatment was continued until > 15% blasts were present or unacceptable toxicity. The primary endpoint was overall survival.

Overall Survival

Median follow-up was 41.2 months. Median overall survival from time of random assignment 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 (P < .001). Overall survival at 1 and 2 years was 72.8% vs 55.8% and 50.6% vs 37.1%, respectively. Overall survival at 2 years favored azacitidine in most subgroups based on baseline disease characteristics, with benefit being observed regardless of receipt of any consolidation therapy, achievement of complete remission after induction chemotherapy, or presence of persistent measurable residual disease at random assignment.

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, P < .001). Rates at 6 months and 1 year were 67.4% vs 45.2% and 44.9% vs 27.4%.

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 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. For full disclosures of the study authors, visit nejm.org.