Azacitidine Plus Venetoclax Improves EFS in Acute Myeloid Leukemia

Results from the phase 2 PARADIGM trial (NCT04801797) that were shared at the 2025 American Society of Hematology Annual Meeting and Exposition demonstrated that treatment with azacitidine plus venetoclax (Venclexta) improved event-free survival (EFS) compared with intensive induction chemotherapy for patients with acute myeloid leukemia (AML).

In the trial, patients receiving azacitidine/venetoclax had a 39% reduction in risk of progressive disease, persistent disease prompting therapy change, relapse, hospice, or death compared with those receiving conventional intensive induction chemotherapy (HR, 0.61; P =.017). Patients also had improved quality of life (QOL) with azacitidine/venetoclax.

Induction chemotherapy with cytarabine plus anthracycline has been the standard of care for decades, but is not tolerable in older or less fit patients and can still yield suboptimal long-term outcomes in fitter patients. The hypomethylating agent (HMA) azacitidine plus the BCL2 inhibitor venetoclax was established as the regimen of choice for patients who were not eligible for induction chemotherapy based on the phase 3 VIALE-A trial (NCT02993523), but no prospective randomized trials have shown an advantage with direct comparison.

“Intensive induction chemotherapy comes with substantial burden and cost,” said Amir Fathi, MD, program director of the Center for Leukemia at the Massachusetts General Hospital Cancer Center, in a press briefing. “It’s associated with significant morbidity, including deep and prolonged marrow suppression, weeks’ long hospitalizations, frequent infections and bleeding complications, mucositis, malnutrition, deleterious psychosocial effects, and an increased risk of cardiac injury and secondary malignancies.”

PARADIGM Trial Design

The open-label, multicenter, investigator-initiated PARADIGM clinical trial randomly assigned 172 patients with previously untreated AML at 9 centers in the United States to receive induction chemotherapy or azacitidine/venetoclax. The primary end point was EFS with secondary end points including response rates, overall survival, toxicity, measurable residual disease, hospitalization metrics, and QOL. Patients were excluded if they were below 60 years old and had NPM1 mutations, or if they had core binding factor fusions or FLT3 mutations.

The median age was 64 years in the experimental arm and 65 years in the comparator arm, and 55% vs 60% were male in these respective arms. Seventy-two percent had adverse risk with 15% having intermediate and 12% having favorable risk status. The arms were balanced for risk status as well as TP53, NPM1, and IDH1/IDH2 mutations.

The induction chemotherapy used was a 7+3 regimen (cytarabine plus an anthracycline) in 54% with the remaining 46% receiving liposomal daunorubicin plus cytarabine (CPX351).

Efficacy Outcomes in PARADIGM

Results were reported as of July 25, 2025. The median number of treatment cycles was 4 with azacitidine/venetoclax vs 2 with induction chemotherapy.

The overall response rate was 88% with azacitidine/venetoclax vs 62% with the comparator (P <.001). The rate of complete response (CR), CR with partial hematologic recovery, and CR with incomplete hematologic recovery was 81% vs 55%, respectively (P <.001). Although these were statistically significant, the CR rates were not significantly different (59% vs 50%; P =.066). Both arms were allowed to proceed to hematopoietic cell transplant (HCT); 52 patients (61%) received HCT after azacitidine/venetoclax vs 34 patients (40%) after induction chemotherapy. HCT had a significant protective effect for EFS, but after adjustment in univariate and multivariate models, azacitidine/venetoclax still showed protective effect on EFS (HR, 0.67; P =.0302).

The median EFS was 14.6 months for azacitidine/venetoclax vs 6.2 months for induction chemotherapy, and the 1-year rate of EFS was 53% vs 39%, respectively, with the Cox proportional hazard model showing no age effect on EFS with the HR remaining at 0.61 (P =.018).

Fathi stated that overall survival improvement was not statistically significant, but this was a difficult end point to interpret compared with EFS because patients could benefit from receiving the trial regimens as subsequent therapy. “Even if we were to do a larger phase 3 study, overall survival, in my opinion is going to be fraught with challenge because of this extensive crossover in both directions, but mainly from intensive therapy to azacitidine/venetoclax,” he said.

Tolerability, QOL, and Hospitalization

In terms of adverse events (AEs), there were similar rates of grade 3 or 4 treatment-related AEs, which were mainly hematologic. Grade 3 or 4 lung infections were reported in 12% in the experimental arm vs 15% in the comparator arm, and grade 3/4 sepsis occurred in 7% vs 11%, respectively. There was no 30- and 60-day mortality with azacitidine/venetoclax, whereas 30-day mortality was 3.5% and 60-day mortality was 4.7% with induction chemotherapy.

Quality of life was also assessed, with patients in the experimental arm reporting significantly better QOL (P =.001) in the first 2 weeks. Symptom burden and depression symptoms were also significantly improved.

Intensive care unit care during index hospitalization was not needed in any patients receiving azacitidine/venetoclax compared with 9.8% with induction chemotherapy (P =.003). They also had fewer days of inpatient index hospitalization vs those receiving induction chemotherapy (15 vs 36; P <.001) and fewer days hospitalized in the first 6 months (41 vs 58; P <.001).

Fathi noted that those with favorable risk, such as CEBPA-associated AML and those with targetable mutations, were excluded to maintain equipoise and characterize the patient population who would likely receive HCT as consolidation. “This was really a study aimed at patients who were transplant eligible for consolidation, and in that patient population, it met its primary end point,” he said.

“We therefore believe these data support the use of azacitidine and venetoclax in functionally fit patients eligible for transplant with intermediate or adverse risk, FLT3 wild-type AML,” Fathi concluded.

Reference

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: American Society of Hematology Annual Meeting; December 3-7, 2025; Orlando, Florida. Abstract 6.