Patients enrolled in the RAS-AZIC study were 60 years and older with newly diagnosed acute myeloid leukemia (AML) and eligible for intensive chemotherapy (IC). In the phase 1 portion of the trial, the safety of upfront azacitidine (AZA; 75 mg/m2/day subcutaneously) for 7 days followed by IC (mitoxantrone 10 mg/m2/day on days 1 to 3 and cytarabine 1 g/m2 given twice daily on days 1, 3, 5, and 7) on day 17 was established through a 3+3 design. In the multicenter phase 2 portion, AZA was followed by either AZA or IC based on results of the day 15 bone marrow (BM) (blast count <45% vs >45%). If response at day 56 is complete remission (CR)/CR with incomplete hematologic recovery (CRi), maintenance with AZA is either continued or started. Otherwise, IC was given followed by AZA maintenance on day 90 in patients who achieve CR, CRi, or partial remission (PR). Patients in CR could be assigned to allogeneic stem-cell transplantation.1
The primary end point of this study was overall response (OR), including CR, CRi, and PR, at day 90 according to the International Working Group criteria. Safety, overall survival, and transplant-related mortality were main secondary end points. The trial was supervised by an independent Data Monitoring Committee.
The median age of the 40 patients was 70 years (55% males). De novo AML was present in 63% of patients. Cytogenetics were high risk in 29%, intermediate risk in 21%, and normal in 50% (N = 38). FLT3 and NPM1 were mutated in 11% and 17%, respectively (N = 36). All patients received upfront AZA and 93% received protocol-assigned treatment based on BM blasts on day 15: 54% continued with AZA, 46% received IC.
In the 83% of patients who continued therapy per protocol until day 90, OR was achieved in 83% (CR/CRi, 17/7; PR, 3). In the intention-to-treat cohort of 40 patients, this represents an OR of 68% (CR/CRi, 60%; PR, 7.5%) with AZA plus 1 IC cycle (n = 28) or 2 IC cycles (n = 3). Transplant-related mortality on day 30 and day 90 was 0% and 5%, respectively.
After a median follow-up of 202 days, OS was 85% for the entire cohort and 96% for responding patients. Grade 1/2 constipation was the most frequently reported adverse event (AE) with AZA (45%). Overall, the most frequent grade 3/4 nonhematologic AE was infection (11 times in 31 IC cycles, 35%; 7 times in 60 AZA cycles, 12%).
These data imply that sequential AZA and IC in elderly patients with AML in an individualized response-based approach is feasible with low treatment-related mortality. This approach results in response rates that are at least comparable to those achieved after repeated cycles of standard chemotherapy. The final results of RAS-AZIC will validate these data and evaluate the impact of response-based treatment on long-term survival in AML.