Impact of Azacitidine Maintenance Therapy on Survival of Patients with AML in Remission Depending on Initial Chemotherapy

Study Design

Oral azacitidine (oral AZA) is a hypomethylating agent approved for the treatment of adults with AML in first remission after intensive chemotherapy. The randomized, placebo-controlled, double-blind QUAZAR AML-001 study included 472 patients older than 55 years with this diagnosis, who achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi) after induction ± consolidation therapy, had intermediate or unfavorable cytogenetic risk according to NCCN 2011 criteria, an ECOG performance status of ≤ 3, and were not candidates for HSCT. They were randomized in a 1:1 ratio to receive oral AZA 300 mg or placebo once daily for 14 days of each 28-day cycle.

Patient Subgroups by Consolidation Therapy

Before study enrollment, most patients used cytarabine (99% in induction and 80% in consolidation), idarubicin (55% induction, 20% consolidation), and daunorubicin (33% induction, 8% consolidation) with similar distribution between the oral AZA and placebo arms. Eighty percent of patients (78% in the oral AZA arm and 82% in the placebo arm) received consolidation therapy following induction. One cycle of consolidation therapy was used by 46% in the oral AZA arm and 44% in the placebo arm, while 32% and 38%, respectively, received at least two cycles. Baseline characteristics were similar across treatment arms within subgroups divided by consolidation therapy. Patients without consolidation therapy were older and less likely to achieve MRD negativity in both treatment arms.

Survival Outcomes by Prior Consolidation Therapy

Oral azacitidine significantly prolonged both the time to disease relapse (RFS) and overall survival (OS) compared to placebo regardless of whether patients received consolidation therapy before study entry. In patients without consolidation therapy, oral AZA extended the median RFS by 4.5 months compared to placebo (8.4 vs. 3.9 months; hazard ratio [HR] 0.58; 95% confidence interval [CI] 0.36-0.94; p = 0.0258), with one-year RFS rates of 40.8% vs. 22.0%. Similarly, median OS was significantly longer with oral azacitidine than with placebo in patients without consolidation therapy (23.3 vs. 10.9 months; HR 0.54; 95% CI 0.33-0.87; p = 0.0103), with one-year survival rates of 71.2% with oral azacitidine vs. 40.5% with placebo.

In patients who did not use consolidation therapy post-induction, oral AZA more than doubled the RFS compared to placebo (10.2 vs. 5.0 months; HR 0.67; 95% CI 0.53-0.85; p = 0.001), with one-year RFS rates of 45.9% vs. 28.6%. Median OS was 24.7 months with oral AZA and 15.4 months with placebo (HR 0.74; 95% CI 0.58-0.94; p = 0.0147), with one-year survival rates of 73.2% vs. 59.2%, respectively.

Analysis of RFS by the number of consolidation therapy cycles showed approximately double the RFS with oral AZA compared to placebo for both one-cycle and ≥ two-cycle subgroups, with oral AZA increasing one-year RFS rates by 17.3% and 19.6%, respectively. Additionally, median OS was longer with oral AZA than with placebo in both the one-cycle subgroup (21.0 vs. 10.9 months) and the ≥ two-cycle subgroup (28.6 vs. 17.6 months).

The safety profile of oral AZA was similar across all consolidation therapy subgroups and consistent with the safety profile observed in the overall treatment arm. There was no correlation between the number of consolidation therapy cycles and dose adjustments of oral AZA.

Conclusion

These results indicate that subsequent maintenance therapy with oral AZA is an important part of the therapeutic strategy for patients with AML of intermediate or unfavorable risk who achieve remission after intensive chemotherapy and are not suitable candidates for HSCT, irrespective of consolidation therapy administration and the number of consolidation therapy cycles received.

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Source: Wei A. H., Roboz G. J., Dombret H. et al. Survival outcomes with oral azacitidine maintenance in patients with acute myeloid leukemia in remission by receipt of initial chemotherapy: subgroup analyses from the phase III QUAZAR AML-001 trial. Haematologica 2023 Oct 1; 108 (10): 2820-2825, doi: 10.3324/haematol.2022.282296.

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2011-CZ-2400002