Venetoclax and azacitidine for younger acute myeloid leukemia patients independent of fitness for intensive chemotherapy

Venetoclax (ven) + azacitidine (aza) is the standard of care for newly-diagnosed acute myeloid leukemia (AML) patients who are not candidates for intensive chemotherapy (IC). Because prognostic factors for ven/aza and IC differ, an AML patient fit for IC may derive more benefit from ven/aza. We therefore designed a trial for younger, newly-diagnosed AML patients with non-favorable-risk disease to receive ven/aza regardless of "fitness" for IC (clinicaltrials gov. Identifier: NCT03573024). We aimed to understand toxicity and efficacy in this population, and retrospectively compared outcomes to matched IC patients. Newly-diagnosed non-favorable-risk patients ≤60 years old were enrolled and received ven, dose escalated to 600 mg/daily x28 days, with aza 75 mg/m2 x7 days on a 28-day cycle. Subjects were encouraged to move expeditiously to allogeneic stem cell transplant (ASCT) in first remission. Thirty-six subjects enrolled. Median age was 49 years (range, 22-59). Grade ≥3 neutropenia (42%), anemia (33%), thrombocytopenia (53%) and febrile neutropenia (36%) were common. The overall response rate (ORR) was 25 of 36 (69%) with 19 (53%) complete remissions; 68% of responders achieved MRD-negativity. Most subjects (53%) bridged to ASCT, and the majority of non-responders were successfully salvaged with IC. The median progression-free-survival and overall survival have not been reached (median follow-up 2.9 years). Compared to IC-matched controls, the ORR, ASCT rate and progression-free survival were significantly improved (69% vs. 44%; P=0.0495; 53% vs. 28%; P=0.0290; and not reached vs. 60.8 months; P=0.007). Hospital days, transfusions and infectious complications were significantly reduced for ven/aza subjects. Ven/aza is feasible for newly-diagnosed, younger, non-favorable-risk AML patients, and appears at least as effective as IC.