Background
Phase 2, multicenter, open-label, randomized (1:1) trial. N=172 previously untreated adults with AML who were eligible for intensive induction chemotherapy. Core-binding-factor fusions, FLT3, and NPM1 (unless age ≥60) were excluded; 72% had ELN 2022 adverse-risk disease, median age 64. Tests whether a hypomethylating-agent + BCL2-inhibitor regimen (standard for unfit AML) can replace intensive chemotherapy in fit patients.
Results
Interventions and follow up: Arm A: Azacitidine + venetoclax
Arm B: Intensive induction chemotherapy
Primary endpoint: Event-free survival (EFS)
mFollow up: 21.9 months
Results: EFS: 14.5 vs 6.2 mo (HR 0.57, 95% CI 0.39–0.84; P=.002)
OS: NR (immature)
Arm B: Intensive induction chemotherapy
Primary endpoint: Event-free survival (EFS)
mFollow up: 21.9 months
Results: EFS: 14.5 vs 6.2 mo (HR 0.57, 95% CI 0.39–0.84; P=.002)
OS: NR (immature)
Adverse events
Infection (G≥3): 28% vs 41%
Hemorrhage (G≥3): 2% vs 12%
Hemorrhage (G≥3): 2% vs 12%
Conclusions
In induction-eligible AML, azacitidine–venetoclax significantly prolonged EFS versus intensive induction chemotherapy, with fewer grade ≥3 infections and hemorrhages. Challenges the long-held assumption that fit patients require intensive induction, though overall survival data are not yet mature.
Key Limitations
Phase 2 with modest sample size (N=172) and open-label design. EFS was the primary endpoint; OS was not reached and is required to establish a survival-neutral or survival-improving substitution. Favorable-risk subsets (CBF, FLT3, younger NPM1) were excluded, enriching for adverse-risk disease and limiting generalizability.
Clinical Context
HMA + venetoclax is the established standard for older/unfit AML; PARADIGM is the first randomized comparison against intensive induction in fit, induction-eligible patients. It is not a labeled indication for fit AML and NCCN/ELN continue to list intensive induction (7+3) as standard for fit patients—these data are practice-informing rather than practice-defining pending OS.