Among fit patients with acute myeloid leukemia, the combination of azacitidine plus Venclexta (venetoclax) was associated with a significantly improved event-free survival (EFS) compared with intensive induction chemotherapy, study results have shown.
Results from the phase 2 PARADIGM trial were presented at the 2025 ASH Annual Meeting. In the trial, patients receiving azacitidine/Venclexta 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. Patients also had improved quality of life (QOL) with azacitidine/Venclexta.
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 Venclexta was established as the regimen of choice for patients who were not eligible for induction chemotherapy based on the phase 3 VIALE-A trial, but no prospective randomized trials have shown an advantage with direct comparison.
Glossary
Event-Free Survival (EFS): The length of time after treatment during which a patient has no major problems related to the cancer—such as the disease coming back, getting worse, or needing new treatment.
Mucositis: Soreness and inflammation of the lining of the mouth or digestive tract. It can cause mouth sores, pain, and difficulty eating, and is a common side effect of some cancer treatments.
Complete Response (CR): When all signs of cancer disappear on tests after treatment. It does not always mean the cancer is cured, but it means doctors cannot detect it.
CR with Partial Hematologic Recovery (CRh): A type of complete response where the cancer is gone, but blood counts—especially platelets and certain infection-fighting cells—have only partially recovered.
CR with Incomplete Hematologic Recovery (CRi): A type of complete response where the cancer is gone, but some blood counts are still below normal. Patients may still need monitoring and support while blood levels improve.
Hematopoietic Cell Transplant: A procedure that replaces damaged or diseased blood-forming cells with healthy ones. The cells may come from the patient (autologous transplant) or from a donor (allogeneic transplant). This helps rebuild the blood and immune system after intensive treatment.
“Intensive induction chemotherapy comes with substantial burden and cost,” said Dr. Amir Fathi, 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 nine centers in the United States to receive induction chemotherapy or azacitidine/Venclexta. 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% versus 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 four with azacitidine/Venclexta versus two with induction chemotherapy.
The overall response rate was 88% with azacitidine/Venclexta versus 62% with the comparator. The rate of complete response (CR), CR with partial hematologic recovery and CR with incomplete hematologic recovery was 81% versus 55%, respectively. Although these were statistically significant, the CR rates were not significantly different (59% versus 50%). Both arms were allowed to proceed to hematopoietic cell transplant (HCT); 52 patients (61%) received HCT after azacitidine/Venclexta versus 34 patients (40%) after induction chemotherapy. HCT had a significant protective effect for EFS, but after adjustment in univariate and multivariate models, azacitidine/Venclexta still showed protective effect on EFS.
The median EFS was 14.6 months for azacitidine/Venclexta versus 6.2 months for induction chemotherapy, and the one-year rate of EFS was 53% versus 39%, respectively.
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/[Venclexta],” he said.
Tolerability, QOL and Hospitalization
In terms of side effects, there were similar rates of grade 3 (severe) or 4 (life-threatening) treatment-related side effects, which were mainly hematologic. Grade 3 or 4 lung infections were reported in 12% in the experimental arm versus 15% in the comparator arm, and grade 3/4 sepsis occurred in 7% versus 11%, respectively. There was no 30- and 60-day mortality with azacitidine/Venclexta, 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 in the first two 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/Venclexta compared with 9.8% with induction chemotherapy. They also had fewer days of inpatient index hospitalization versus those receiving induction chemotherapy (15 versus 36) and fewer days hospitalized in the first six months (41 versus 58).
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 [Venclexta] in functionally fit patients eligible for transplant with intermediate or adverse risk, FLT3 wild-type AML,” Fathi concluded.
Reference
1. “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,” by Dr. Amir Fathi et al., Blood.
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