Extended Versus Standard Hypomethylating Agent Dosing in Combination With Venetoclax in Patients With Newly Diagnosed Acute Myeloid Leukemia.

The optimal duration of hypomethylating agent (HMA) therapy combined with venetoclax (Ven) in newly diagnosed acute myeloid leukemia (ND-AML) remains uncertain. Standard of care (SOC) uses 5-day decitabine (Dec-5) or 7-day azacitidine (Aza-7), while extended HMA regimens (e.g., 10-day decitabine [Dec-10] during cycle 1) have also been explored, although direct comparative data between these approaches are limited. We conducted a large retrospective analysis of 335 patients with ND-AML treated at five US centers with Dec-10/Ven (n = 102) or SOC HMA/Ven (n = 233). Baseline characteristics were largely balanced, though the Dec-10 group had more treated secondary AML, and the SOC group had more intermediate risk by ELN-2024. Dec-10/Ven exhibited significantly higher composite complete remission rates (CRc) (82% vs. 70%, p = 0.029), but similar measurable residual disease (MRD) negativity rates (27% vs. 25%, p = 0.6) at best response. Median overall survival (OS) was significantly longer for Dec-10/Ven, 22.2 versus 9.1 months for SOC (p < 0.001). Transplantation was more frequent following Dec-10/Ven (25% vs. 6%, p < 0.001). The 30-day and 60-day mortality rates were similar (7% vs. 11%, p = 0.4; 13% vs. 23%, p = 0.1). On multivariable analysis, the Dec-10 regimen, de novo AML, non-complex karyotype, and IDH2 mutation were associated with a significantly lower risk of death. Our findings suggest that Dec-10/Ven may lead to improved transplant rates and survival, providing valuable real-world support for this intensified approach in appropriate patients. Prospective randomized evaluation is warranted.