Treating First AML Low Blast Count Relapse with Escalated Dosing Schedules of CC-486 Is Effective and Well-Tolerated

QUAZAR AML-001 was an international, randomized, double-blind phase 3 trial of the oral azacitidine formulation CC-486 in patients with acute myeloid leukemia (AML). This study evaluated clinical outcomes among patients in the QUAZAR AML-001 trial who relapsed with 5% to 15% blasts on-study and subsequently received escalated 21-day dosing of CC-486. Patients eligible for this study were aged ≥55, with intermediate- or poor-risk cytogenetics and Eastern Cooperative Oncology Group performance status scores ≤3, and had achieved their first complete remission (CR1) or CR1 with incomplete blood count recovery (CR1i) following induction chemotherapy ± consolidation. Patients were randomized (1:1) within 4 months of achieving CR1/CR1i to receive maintenance therapy with CC-486 300 mg or placebo, once daily on days 1 to 14 of repeated 28-day treatment cycles. Disease status was assessed centrally every 3 cycles. Patients could have a bone marrow test to confirm AML relapse if they exhibited signs of relapse based on hematology parameters at routine clinic visits. Patients who developed low blast counts (5%-15%) in peripheral blood or bone marrow could receive CC-486 for 21 days/cycle, at the discretion of the investigator. Patients could continue treatment until blast counts exceeded 15%, they experienced unacceptable toxicity, or they had an allogeneic hematopoietic stem-cell transplant.

In the QUAZAR AML-001 trial, 91 patients (CC-486, n = 51 [21%]; placebo, n = 40 [17%]) experienced post CR/CRi AML relapse with 5% to 15% blasts and were randomized (CC-486, n = 51; placebo, n = 40). In the CC-486 arm, the median time to dose escalation was 9.2 months (range, 1.0-52.7 months) compared with 6.0 months (range, 0.5-19.3 months) in the placebo arm. While the median number of 21-day dosing cycles was the same for both arms (2.0; range: CC-486, 1-45; placebo, 1-16), proportionally more patients in the CC-486 arm received >3 escalated dosing cycles than in the placebo arm (43% vs 18%, respectively). Of the 78 evaluable patients, 23% of patients in the CC-486 arm and 11% of patients in the placebo arm attained CR/CRi. From the time of randomization, the median overall survival was 22.8 months in the CC-486 arm compared with 14.6 months in the placebo arm (hazard ratio, 0.66; 95% confidence interval, 0.42-1.04; P = .07).

The most common adverse events (AEs) first reported were febrile neutropenia (24% vs 3%), thrombocytopenia (22% vs 23%), anemia (22% vs 20%), and neutropenia (20% vs 10%) in the CC-486 arm and the placebo arm, respectively. The percentage of patients who first experienced a grade 3/4 AE while receiving escalated dosing was similar in each arm (CC-486, 31%; placebo, 35%). Four patients in the CC-486 arm discontinued due to an AE during treatment compared with 1 patient in the placebo arm. None of the AEs leading to discontinuation were determined to be related to the study drug. When compared with placebo, CC-486 dose escalation did not adversely impact health-related quality of life as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue and EuroQol-5 Dimension-3 Level.

An escalated 21-day dosing schedule of CC-486 was well-tolerated and restored remission in approximately 25% of patients. The hematologic AEs observed during escalated dosing in both treatment arms may have been partially attributed to disease relapse. For AML patients receiving post-CR1/CR1i maintenance with CC-486 who relapse with ≤15% blasts, an escalated 21-day dosing regimen of CC-486 may be a viable salvage option.

Reference

Abstract 111. ASH 2020. December 5, 2020. Escalated Dosing Schedules of CC-486 Are Effective and Well Tolerated for Patients Experiencing First Acute Myeloid Leukemia (AML) Relapse: Results from the Phase III QUAZAR AML-001 Maintenance Trial.

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