Venetoclax Plus Hypomethylating Agent for 7- Versus 14- Versus 21- Versus 28-Day Cycles in Newly-Diagnosed Acute Myeloid Leukemia: ELN and Mayo Genetic Risk-Stratified Analysis in 540 Patients.

Patients with newly-diagnosed acute myeloid leukemia (ND-AML) derive variable survival benefit from venetoclax (Ven) plus hypomethylating agent (HMA) therapy, and the optimal Ven duration across genetic risk groups remains undefined. Among 540 ND-AML patients receiving Ven-HMA at Mayo Clinic, outcomes were compared across Ven 7- (n = 33), 14- (n = 117), 21- (n = 96), and 28-day (n = 294) schedules during Cycle 1 and stratified by ELN 2024 and Mayo genetic risk groups. At a median follow-up of 37.7 months, allogeneic stem cell transplant (ASCT) rates were similar across Ven duration groups (15%, 18%, 18%, and 20% for 7-, 14-, 21-, and 28-day; p = 0.86). Median transplant-censored survival was comparable across Ven durations (13.3, 11.9, 16.8, and 13.2 months for 7, 14, 21, 28 days, respectively; p = 0.65), with outcomes driven by ELN risk (6.3, 11.5, 18.3 months for high, intermediate, low; p < 0.01) and Mayo genetic risk (6.9, 17.8 months, not reached; p < 0.01). Survival was comparable across Ven durations within ELN intermediate/low-risk and all Mayo risk groups. Among ELN high-risk patients, 14-day Ven was associated with inferior transplant-censored survival compared to 21- and 28-day schedules (p < 0.01). Notably, 30- and 60-day mortality were higher with shorter Ven schedules (7-day: 9%/18%; 14-day: 7%/15%) versus 28-day (2%/6%), which likely reflects treatment selection bias. In ND-AML, no significant difference in transplant-censored survival was observed across the 7-, 14-, 21-, and 28-day Ven schedules; prognosis was determined primarily by Mayo and ELN 2024 genetic risk rather than by Ven duration. Prospective trials are needed to establish risk-adapted Ven dosing strategies.