Early bone marrow-guided venetoclax management in frontline unfit acute myeloid leukemia: a two-stage real-world study

Hypomethylating agents (HMA) plus venetoclax (VEN) is a standard frontline therapy for unfit, newly diagnosed acute myeloid leukemia (AML), but prolonged cytopenia and infections often limit treatment continuity. We performed a retrospective, two-stage cohort study (Jan 2021–Jun 2025) evaluating whether early bone marrow assessment-guided, response-adapted VEN management improves tolerability without compromising efficacy. Stage 1 compared patients undergoing early bone marrow assessment (cycle 1, days 14–21) with subsequent bone marrow-guided VEN adaptation versus a conventionally managed cohort. Stage 2 was a landmark analysis at cycle 3 day 1 (C3D1) comparing VEN shortening (≤ 14 days/cycle) versus continuation (> 14 days/cycle) in responding patients. Among 371 evaluable patients, 200 underwent early bone marrow-guided management, yielding lower day-56 infection-related hospitalization (24.0% vs. 37.4%; adjusted odds ratio [OR] 0.46, 95% confidence interval [CI] 0.28–0.79; p = 0.005), decreased cycle 1 VEN exposure, faster cycle 2 initiation, and reduced 8-week mortality. In the stage 2 landmark cohort ( n = 237), response-adapted VEN shortening ( n = 137) reduced prolonged grade 4 neutropenia (41.6% vs. 61.0%; adjusted OR 0.41, 95% CI 0.23–0.73; p = 0.003) and post-landmark infection-related hospitalization (adjusted OR 0.43, 95% CI 0.23–0.84; p = 0.014). Measurable residual disease (MRD) negativity, overall survival (OS), and relapse-free survival (RFS) did not differ significantly between schedules. Individualized VEN scheduling anchored to early bone marrow response may help optimize tolerability and treatment continuity in real-world AML care, warranting prospective validation.