Published September 2, 2026
N Engl J Med 2026;395:845-858
DOI: 10.1056/NEJMoa2602804
Abstract
Background
Induction chemotherapy has long been a key component of curative therapy for fit patients with acute myeloid leukemia (AML), despite its frequently severe side effects and substantial health care utilization. For patients who are ineligible for induction chemotherapy, hypomethylating therapy plus venetoclax is the standard treatment owing to its efficacy and side-effect profile.
Methods
In this multicenter, phase 2 trial, we randomly assigned, in a 1:1 ratio, previously untreated adults with AML who were eligible for induction chemotherapy to receive either azacitidine plus venetoclax or induction chemotherapy. Patients with core binding factor fusions, mutations in the gene encoding FMS-like tyrosine kinase 3 (FLT3), or mutations in the gene encoding nucleophosmin-1 (NPM1; unless the patient was ≥60 years of age) were excluded. The primary end point was event-free survival.
Results
A total of 172 patients underwent randomization, with 86 patients assigned to each group. The median age of the patients was 64 years. A total of 72% of the patients had adverse-risk disease according to the European LeukemiaNet 2022 classification. At a median follow-up of 21.9 months, the median event-free survival was 14.5 months (95% confidence interval [CI], 10.4 to 24.4) in the azacitidine–venetoclax group, as compared with 6.2 months (95% CI, 4.1 to 10.1) in the induction chemotherapy group, corresponding to a hazard ratio for event or death of 0.57 (95% CI, 0.39 to 0.84; P=0.002 by the stratified log-rank test). Infection of grade 3 or higher occurred in 28% of the patients (95% CI, 19 to 39) receiving azacitidine–venetoclax and in 41% of those (95% CI, 30 to 52) receiving induction chemotherapy; hemorrhage of grade 3 or higher occurred in 2% (95% CI, 0.3 to 8) and 12% (95% CI, 6 to 20), respectively.
Conclusions
In this phase 2, randomized trial, azacitidine–venetoclax therapy led to significantly longer event-free survival than induction chemotherapy among induction-eligible patients with AML. (Funded by AbbVie and others; PARADIGM ClinicalTrials.gov number, NCT04801797.)
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Notes
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
Supported by AbbVie and Genentech and by a Harvard Cancer Center Support Grant (5P30 CA006516).
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank the patients and their families for their participation in this trial; the staff of the Program for Coordination of Research Protocols in the Massachusetts General Hospital (MGH) Cancer Center Protocol Office for the multicenter coordination and monitoring of the trial; and Aura Ramos, Tina Som, Megan Vartanian, Sara Ruiz, Laura White, Christine Connolly, and Shannon Himber, of the MGH clinical trial research team, for their efforts during the conception and conduct of this trial.
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History
Published online: September 2, 2026
Published in issue: September 3, 2026
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- Hypomethylating Agents plus Venetoclax as Compared with Intensive Chemotherapy in Patients with AML, New England Journal of Medicine, 395, 9, (917-919), (2026)./doi/full/10.1056/NEJMe2607967
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Facts Only
* The trial involved 172 adults with AML eligible for induction chemotherapy, randomized 1:1 to receive either azacitidine plus venetoclax or induction chemotherapy.
* Patients with core binding factor fusions, FLT3 mutations, or NPM1 mutations (if under 60 years) were excluded.
* The primary endpoint was event-free survival.
* In the azacitidine–venetoclax group, median event-free survival was 14.5 months (95% CI, 10.4 to 24.4).
* In the induction chemotherapy group, median event-free survival was 6.2 months (95% CI, 4.1 to 10.1).
* The hazard ratio for event or death was 0.57 (95% CI, 0.39 to 0.84; P=0.002).
* Infection of grade 3 or higher occurred in 28% of the azacitidine–venetoclax group and 41% of the induction chemotherapy group.
* Hemorrhage of grade 3 or higher occurred in 2% (azacitidine–venetoclax) and 12% (induction chemotherapy).
Executive Summary
A randomized, multicenter phase 2 trial compared azacitidine plus venetoclax therapy against induction chemotherapy for previously untreated adults with acute myeloid leukemia (AML) eligible for induction chemotherapy. The study included 172 patients, split into two groups of 86 patients each. Patients with specific genetic markers, such as core binding factor fusions, FLT3 mutations, or NPM1 mutations (unless aged 60 or older), were excluded from the study.
The median event-free survival was longer in the azacitidine–venetoclax group, measuring 14.5 months, compared to 6.2 months in the induction chemotherapy group. This difference corresponded to a hazard ratio for event or death of 0.57. The groups also showed differing rates of severe adverse events; infection of grade 3 or higher occurred in 28% of patients in the azacitidine–venetoclax group and 41% in the induction chemotherapy group.
Full Take
The study demonstrates a significant survival advantage for the combination therapy when comparing treatment strategies for induction-eligible AML patients, suggesting that hypomethylating therapy combined with venetoclax offers a superior outcome over standard induction chemotherapy. The finding of a hazard ratio of 0.57, significantly reducing event or death risk, warrants deeper investigation into the biological mechanism driving this improved survival while carefully considering the toxicity profiles presented.
The observed differences in adverse events—specifically infection rates—require scrutiny. While the combined therapy resulted in a higher rate of Grade 3+ infection (28% vs. 41%), it concurrently yielded longer event-free survival, indicating that the benefit to overall outcome outweighs the increased risk of specific complications in this cohort. This pattern forces consideration of whether induction chemotherapy imposes an unacceptable constraint on long-term patient trajectory that is not adequately captured by short-term complication rates. Future work should focus on characterizing these side effects more granularly across different patient subgroups to establish a personalized risk-benefit framework for these treatment modalities beyond simple event-free survival measures.
What factors might explain the difference in toxicity profiles, and how do these differential risks translate into long-term quality of life versus immediate mortality benefits?
Sentinel — Human
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