Venetoclax-based therapy versus hypomethylating agents alone in unfit patients with newly diagnosed acute myeloid leukemia: a real-world study from the PETHEMA registry.

Real-world comparisons of venetoclax (VEN)-based versus hypomethylating agent (HMA) monotherapy in unfit, newly diagnosed AML remain limited by short follow-up, low genomic testing, and inadequate statistical power. We conducted the largest comparative analysis to date from the PETHEMA registry, including 2610 patients (929 VEN-based, 1681 HMA). Composite complete remission was higher with VEN-based therapy (64.4% vs 20.0%; P < 0.001), and both 30-day (4.8% vs 7.5%; P = 0.011) and 60-day mortality (9.7% vs 15.7%; P < 0.001) were significantly lower. Median overall survival was 11.4 versus 8.2 months (HR, 0.66; 95% CI, 0.60-0.73; P < 0.001), consistent with that of VIALE-A (HR, 0.66) despite a broader cohort (ECOG 3-4, 4.7%; secondary AML, 42.5%; adverse-risk cytogenetics, 36.5%). The benefit was confirmed by propensity score matching (HR, 0.66), era-restricted analysis (HR, 0.71), and multivariable Cox regression. A molecular gradient of benefit emerged-greatest in IDH2 (HR, 0.43), NPM1 (0.46), FLT3-ITD (0.48), IDH1 (0.55), and favorable-risk cytogenetics (0.25). In TP53-mutated AML, OS improved significantly (HR, 0.70) but remained dismal (7.0 vs 3.7 months); no benefit was observed in AML arising from antecedent MDS or MPN. These findings confirm and extend VIALE-A, refining patient selection for VEN-based therapy in routine practice.