Azacitidine-Venetoclax Beats Induction Chemo as Upfront AML Therapy

A less-intensive combination of azacitidine and venetoclax (Venclexta) more than doubled event-free survival (EFS) compared with intensive induction chemotherapy in adults with newly diagnosed acute myeloid leukemia (AML) who were eligible for induction chemotherapy, according to results published in The New England Journal of Medicine (NEJM).¹

Findings from the phase 2 PARADIGM trial (NCT04801797) showed that at a median follow-up of 21.9 months, median EFS was 14.5 months (95% CI, 10.4-24.4) with azacitidine-venetoclax vs 6.2 months (95% CI, 4.1-10.1) with induction chemotherapy (HR, 0.57; 95% CI, 0.39-0.84; stratified log-rank P = .002).

“Less intensive treatment does not necessarily mean less effective treatment,” lead author Amir T. Fathi, MD, director of the Leukemia Program at the Mass General Brigham Cancer Institute, stated in a news release from the institution.² “Our goal is to optimally treat acute myeloid leukemia while reducing serious complications and the amount of time patients spend in the hospital.”

Trial Design

The azacitidine-venetoclax combination is already standard treatment for older patients with AML or those unable to tolerate intensive chemotherapy; PARADIGM tested whether it could perform as well or better in patients, including younger patients, who could tolerate intensive chemotherapy.

The trial randomly assigned 172 previously untreated adults with AML who were eligible for induction chemotherapy to azacitidine plus venetoclax or induction chemotherapy at 9 US centers in a 1:1 ratio. Induction chemotherapy included cytarabine and idarubicin or daunorubicin per standard of care. Patients with core binding factor fusions, mutations in FLT3, or mutations in NPM1 (unless the patient was 60 years of age or older) were excluded. The primary end point was EFS.¹

Median patient age was 64 years, and 72% of patients had adverse-risk disease by European LeukemiaNet 2022 classification. The trial was investigator-initiated, with funding for its conduct and provision of venetoclax provided by AbbVie and Genentech, according to the news release.²

Additional Efficacy and Safety Findings

Results were previously presented at the 2025 American Society of Hematology Annual Congress, demonstrating the EFS benefit as of July 25, 2025.³

According to the published results, treatment brought leukemia into a remission state in 78% of patients receiving azacitidine-venetoclax vs 53% of those receiving induction chemotherapy, and more patients receiving the combination proceeded to stem cell transplantation (60% vs 40%).¹

Infection of grade 3 or higher occurred in 28% of patients (95% CI, 19-39) receiving azacitidine-venetoclax vs 41% (95% CI, 30-52) receiving induction chemotherapy. Hemorrhage of grade 3 or higher occurred in 2% of patients (95% CI, 0.3%-8%) receiving azacitidine-venetoclax vs 12% (95% CI, 6%-20%) receiving induction chemotherapy. Patients receiving the combination spent 12.5 days in the hospital during the first 30 days, compared with 27.3 days for those receiving induction chemotherapy.

Clinical Implications

“For decades, intensive chemotherapy has been the standard upfront treatment for patients considered able to tolerate it,” Fathi said in the news release.² “Our findings suggest that some of these patients may do better with a less intensive approach.”

The study authors noted that PARADIGM was not designed to show whether either treatment helped patients live longer, and that future studies should evaluate less-intensive treatment in the groups excluded from this trial, including patients younger than 60 years with NPM1-mutated AML and those with FLT3-mutated AML.

REFERENCES

1. Fathi AT, Perl AE, Fell GG, et al. Azacitidine–venetoclax or induction chemotherapy for acute myeloid leukemia. N Engl J Med. 2026;395(9):845-858. doi:10.1056/NEJMoa2602804

2. Mass General Brigham-led trial shows a less-intensive drug combination is more effective in treating AML. News release. Mass General Brigham. September 2, 2026. Accessed September 4, 2026. https://tinyurl.com/yckbndkn

3. Fathi A, Perl A, Fell G, et al. Results from paradigm - a phase 2 randomized multi-center study comparing azacitidine and venetoclax to conventional induction chemotherapy for newly diagnosed fit adults with acute myeloid leukemia. Presented at: ASH 2025; December 3-7, 2025; Orlando, FL. Abstract 6.