Combining azacitidine with venetoclax significantly increased event-free survival versus intensive induction chemotherapy in patients with newly diagnosed acute myeloid leukemia, according to results from the phase 2 PARADIGM trial presented at the 2025 American Society of Hematology Annual Meeting.
In PARADIGM (NCT04801797), azacitidine plus venetoclax reduced the risk of progressive disease, persistent disease prompting therapy change, relapse, hospice, or death by 39% compared with conventional intensive induction chemotherapy (hazard ratio [HR] 0.61; P = .017). Median event-free survival (EFS) was 14.6 months with azacitidine/venetoclax versus 6.2 months with induction chemotherapy; the 1-year EFS rates were 53% and 39%, respectively. A Cox proportional hazards model showed no age effect on EFS (HR 0.61; P = .018).
Response rates favored azacitidine/venetoclax. Overall response was 88% versus 62% with induction chemotherapy (P < .001). The combined rate of complete response (CR), CR with partial hematologic recovery, and CR with incomplete hematologic recovery was 81% versus 55% (P < .001). Traditional CR rates were 59% versus 50% (P = .066). More patients proceeded to hematopoietic cell transplant (HCT) after azacitidine/venetoclax (52 patients, 61%) than after induction chemotherapy (34 patients, 40%). HCT had a protective effect for EFS, and azacitidine/venetoclax retained a protective effect after adjustment (HR 0.67; P = .0302).
Overall survival improvement did not reach statistical significance, a result investigators attributed to extensive crossover and subsequent use of both treatment approaches.
Adverse event profiles were similar between arms, with mainly hematologic grade 3–4 events. Grade 3–4 pulmonary infections occurred in 12% of the azacitidine/venetoclax arm versus 15% with induction chemotherapy; grade 3–4 sepsis occurred in 7% versus 11%. There were no 30- or 60-day deaths in the azacitidine/venetoclax arm; 30-day mortality was 3.5% and 60-day mortality was 4.7% with induction chemotherapy.
Patients receiving azacitidine/venetoclax reported significantly better quality of life in the first two weeks (P = .001), with reductions in symptom burden and depressive symptoms. Intensive care unit care during the index hospitalization was not required for any patients in the azacitidine/venetoclax arm versus 9.8% in the induction chemotherapy arm (P = .003). Index hospitalization days were fewer with azacitidine/venetoclax (median 15 vs 36 days; P < .001), as were days hospitalized in the first six months (41 vs 58 days; P < .001).
Investigators noted the trial excluded patients with favorable-risk features such as CEBPA-associated AML and patients with targetable mutations to focus on those likely to receive transplant consolidation. PARADIGM enrolled 172 previously untreated, transplant-eligible adults at nine U.S. centers and randomized them to azacitidine/venetoclax or conventional induction chemotherapy. The primary endpoint was EFS; secondary endpoints included response rates, overall survival, toxicity, measurable residual disease, hospitalization metrics, and quality of life.
Median age was 64 in the azacitidine/venetoclax arm and 65 in the induction arm; 55% and 60% were male, respectively. Risk status was 72% adverse, 15% intermediate, and 12% favorable, with arms balanced for TP53, NPM1, and IDH1/2 mutations. Patients were excluded if they were under 60 with NPM1 mutations or if they had core binding factor fusions or FLT3 mutations. Induction chemotherapy consisted of a 7+3 regimen in 54% of patients and liposomal daunorubicin plus cytarabine (CPX351) in 46%.
“Intensive induction chemotherapy comes with substantial burden and cost,” said Amir Fathi, MD. He added that the data support using azacitidine and venetoclax in functionally fit, transplant-eligible patients with intermediate- or adverse-risk, FLT3 wild-type AML.
Reference: Fathi A, Perl A, Fell G, et al. Results from PARADIGM — a phase 2 randomized multicenter study comparing azacitidine and venetoclax to conventional induction chemotherapy for newly diagnosed fit adults with acute myeloid leukemia. Presented at: American Society of Hematology Annual Meeting; December 3–7, 2025; Orlando, Florida. Abstract 6.
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