Azacitidine (Vidaza) plus venetoclax (Venclexta) led to significantly longer event-free survival (EFS) than induction chemotherapy among patients with newly diagnosed acute myeloid leukemia (AML) who were eligible for induction chemotherapy, according to results from the phase 2 PARADIGM trial (NCT04801797) published in The New England Journal of Medicine.
What were the efficacy findings from the PARADIGM trial?
At a median follow-up of 21.9 months (95% CI, 16.6-25.7), the median EFS—the primary end point—was 14.5 months (95% CI, 10.4-24.4) in the azacitidine/venetoclax group vs 6.2 months (95% CI, 4.1-10.1) in the induction chemotherapy group, (HR, 0.57; 95% CI, 0.39-0.84; P = .002 by stratified log-rank test). The 1-year EFS rate was 53% with azacitidine/venetoclax vs 36% with induction chemotherapy, and the benefit persisted in a multivariable analysis (HR, 0.59; 95% CI, 0.40-0.87).
The median overall survival (OS) was 21.5 months (95% CI, 17.2-not reached) with azacitidine/venetoclax vs 18.0 months (95% CI, 12.5-not reached) with induction chemotherapy. More patients in the azacitidine/venetoclax group proceeded to hematopoietic-cell transplantation (60%; 95% CI, 53%-68%) than in the induction chemotherapy group (40%; 95% CI, 32%-47%).
What were the safety data from PARADIGM?
Grade 3 or higher infection occurred in 28% of patients (95% CI, 19%-39%) receiving azacitidine/venetoclax and in 41% (95% CI, 30%-52%) receiving induction chemotherapy. Grade 3 or higher hemorrhage occurred in 2% (95% CI, 0.3%-8%) and 12% (95% CI, 6%-20%), respectively.
In the first 30 days following randomization, the mean number of inpatient days was 12.5 (95% CI, 11.0-13.9) in the azacitidine/venetoclax arm compared with 27.3 (95% CI, 25.8-28.7) in the chemotherapy arm. No patients in the experimental arm were admitted to the intensive care unit compared with 10% of those who received chemotherapy. In the induction chemotherapy group, the 30-day mortality rate was 3%, and the 60-day mortality rate was 5%; no patients in the azacitidine/venetoclax arm died in this period.
“I hope that over time people will increasingly use less toxic, more gentle therapies in [patients with] AML, and, specifically in relation to our study and the subsets of patients that we studied, that they realize that azacitidine/venetoclax or hypomethylating agents [HMA] plus venetoclax therapies can be used as finite treatments to try and get patients into a remission and bridge them to transplant, as opposed to indefinite treatments,” corresponding author Amir T. Fathi, MD, director of the Leukemia Program at the Massachusetts General Brigham Cancer Institute in Boston and a professor of medicine at Harvard Medical School, stated in an interview with CancerNetwork® regarding these findings. “Over time, [I hope] this lays the groundwork for larger trials or even similarly designed trials that look at subsets or populations we did not look at. I think that would be a welcome development.”
How was the PARADIGM trial designed?
PARADIGM is a multicenter, phase 2 trial that randomly assigned 172 previously untreated adults with AML who were eligible for induction chemotherapy in a 1:1 ratio to receive either azacitidine plus venetoclax (n = 86) or induction chemotherapy (n = 86). Patients with core binding factor fusions, FLT3 mutations, or NPM1 mutations (unless the patient was 65 years or older) were excluded. The median age was 64 years (range, 28-79), and 72% of patients had adverse-risk disease according to the 2022 European LeukemiaNet classification. In the induction chemotherapy group, 54% of patients received the 7+3 regimen, and 46% received CPX-351 (Vyxeos).
The primary end point of the study was EFS. Secondary end points included complete remission, composite complete remission, OS, measurable residual disease, and safety.
The authors noted that the trial excluded patients with core binding factor, FLT3, and NPM1 alterations, for whom induction chemotherapy or FLT3 inhibitor–based approaches remain standard, and that dedicated studies are needed to determine whether a hypomethylating agent plus venetoclax holds promise in those mutational subgroups.
“We did not study every single [patient with] AML. Important key subsets of patients were excluded from study; for example, [patients with] FLT3 mutations were excluded,” Fathi said. “Over time, clinical trials [can] maybe look at targeted therapies, incorporate them into HMAs, and do randomized studies specifically into those subsets. Hopefully, over time, more gentle approaches can also become relevant for them as well.”
Reference
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
