This study evaluated clinical outcomes for patients with acute myeloid leukemia (AML) in the QUAZAR AML-001 trial who relapsed with 5% to 15% blasts on-study, who then received escalated 21-day dosing of the study drug. QUAZAR AML-001 was an international, randomized, double-blind phase 3 trial of the oral azacitidine formulation CC-486. Eligible patients were aged ≥55 years, 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) after induction chemotherapy ± consolidation. Patients were randomized 1:1 to receive post-CR1 maintenance therapy with CC-486 300 mg or placebo, once daily on days 1 to 14 of repeated 28-day treatment cycles within 4 months of achieving CR1/CR1i. Disease status was centrally assessed every 3 cycles. Patients who exhibited signs of relapse based on hematology parameters at routine clinic visits could have a bone marrow test to confirm AML relapse. At the investigator’s discretion, patients who developed low blast counts (5%-15%) in peripheral blood or bone marrow could receive CC-486 for 21 days/cycle. Patients could continue on treatment until follow-up blast counts exceeded 15%, unacceptable toxicity, or they received an allogeneic hematopoietic stem-cell transplant.
A total of 472 patients were randomized to CC-486 (N = 238) or placebo (N = 234) maintenance post-CR1/CR1i. Ninety-one patients (CC-486, N = 51 [21%]; placebo, N = 40 [17%]) experienced early AML relapse with 5% to 15% blasts, and were assigned to receive the study drug on a 21-day/cycle dosing schedule. The median time to dose escalation was 9.2 months (range, 1.0-52.7 months) for CC-486 and 6.0 months (range, 0.5-19.3 months) for placebo. The median number of 21-day dosing cycles was 2.0 for both arms (range: CC-486, 1-45; placebo, 1-16); however, proportionally more patients in the CC-486 (43%) arm received >3 escalated dosing cycles than in the placebo (18%) arm. Of the 78 evaluable patients with ≥5% blasts in bone marrow on or before day 1 of 21-day dosing, 23% of patients in the CC-486 arm and 11% of patients in the placebo arm regained CR1/CR1i while receiving an escalated dosing regimen. The median overall survival from the time of randomization among all patients who received escalated dosing schedules was 22.8 months in the CC-486 arm versus 14.6 months in the placebo arm (hazard ratio, 0.66; 95% confidence interval, 0.42-1.04; P = .07).
During 21-day dosing, the most common adverse events first reported were febrile neutropenia (CC-486, 24%; placebo, 3%), thrombocytopenia (22% vs 23%), anemia (22% vs 20%), and neutropenia (20% vs 10%). The proportion of patients in each arm who first experienced a grade 3/4 adverse event while receiving escalated dosing was similar (CC-486, 31%; placebo, 35%). In the CC-486 arm, 4 patients discontinued due to an adverse event during treatment, while in the placebo arm, 1 patient discontinued; no event was considered related to the study drug. As assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue and EuroQol-5 Dimension-3 Level, CC-486 dose escalation did not negatively impact patient health-related quality of life when compared with placebo.
An escalated 21-day CC-486 dosing regimen was well-tolerated and restored remission in approximately 25% of patients. Disease relapse may have contributed to the hematologic adverse events first reported during escalated dosing in both treatment arms. For patients who experience AML relapse with ≤15% blasts while receiving post-CR1/CR1i maintenance with CC-486, a 21-day dosing schedule of this agent may be a viable salvage option.
Dohner H, Wei AH, Montesinos P, et al. 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. Presented at: 62nd American Society of Hematology Annual Meeting & Exposition, December 5-8, 2020. Abstract 111.