A Randomized Phase 2 Trial of 28-Day (Arm A) Versus 14-Day (Arm B) Schedule of Venetoclax + Azacitidine in Newly Diagnosed Acute Myeloid Leukemia Patients ≥ 60 Years

Background: Treatment options for older, less fit acute myeloid leukemia (AML) patients continue to be challenging, with toxicities and limited efficacy. The combination therapy of azacitidine (Aza) and the bcl-2 inhibitor venetoclax (Ven) showed superior benefit in response rates and overall survival compared to Aza alone, leading to the combination's FDA approval in newly diagnosed AML patients ≥ 75 years and younger patients ineligible for intensive chemotherapy. While Ven-Aza is a very effective and potent therapy, the 28-day continuous dosing of Ven combined with 7 days of Aza resulted in interrupted dosing or shortened dosing schedules due to persistent cytopenias in more than 50% of treated patients in the VIALE-A trial and subsequent real-world data. Furthermore, investigation of novel agents in combination with Ven-Aza has been challenging due to prolonged cytopenias even when monotherapy with the new agent shows no myelosuppression. Given that Ven-Aza is not curative, successful integration of other agents with this standard of care remains important in AML. The growing knowledge of Ven-Aza toxicities prompted attention to developing a safer dosing regimen while maintaining similar efficacy. Our study will examine the FDA label of 28 days of Ven, versus 14 days, in combination with Aza for newly diagnosed AML patients ≥ 60 years who are not candidates for intensive chemotherapy. The primary objective of this study is to compare complete remission (CR) rates with an abbreviated schedule of Ven (14 days) versus the current package insert approved schedule (28 days). We hypothesize that reducing the dosing duration of Ven would reduce the associated toxicities while maintaining a comparable response rate.