Real‐World Analysis of Outcomes of Venetoclax+Azacitidine Versus 7+3 Induction in Acute Myeloid Leukemia

Background: Venetoclax plus azacitidine (V+A) is standard for older, intensive-ineligible patients with acute myeloid leukemia (AML). Its expanding use in younger, curative-eligible adults lacks comparative evidence against conventional 7+3 induction, raising uncertainty about potential survival compromise. Methods: We performed an age-stratified, retrospective comparative effectiveness study using de-identified TriNetX electronic health records (2018-2025). Adults receiving first-line V+A or 7+3 were propensity-matched 1:1 within prespecified age groups (18-59; ≥60) by demographics, comorbidities, socioeconomic factors, and performance status. The primary endpoint was 1-year all-cause mortality; secondary endpoints included complete remission and ICU admission. Results: After matching, 214 younger and 1724 older adults per arm were analyzed. Among younger adults, V+A was associated with significantly higher 1-year mortality versus 7+3 (20.6% vs. 8.9%; HR 2.55), with a number needed to harm of nine. Remission rates favored intensive induction (53.3% vs. 44.9%), while ICU use was similar. In older adults, mortality differences were smaller (23.1% vs. 20.5%; HR 1.34; NNH 38), though remission again favored 7+3. Conclusion: V+A appears markedly inferior to 7+3 as first-line therapy in younger, curative-eligible AML, producing a nearly fourfold greater harm signal than in older adults. These findings support restricting V+A to intensive-ineligible patients pending randomized confirmation. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.