Azacitidine plus venetoclax significantly prolonged event-free survival compared with intensive induction chemotherapy in previously untreated patients with acute myeloid leukemia (AML) who were eligible for induction therapy. Results of the randomized phase II PARADIGM trial, led by Fathi et al, were published in The New England Journal of Medicine.
Intensive induction chemotherapy incorporating cytarabine and an anthracycline has been the standard up-front treatment for fit patients with AML for decades, despite substantial toxicity, prolonged hospitalization, and infectious and bleeding complications. Azacitidine plus venetoclax is an established standard for patients who are ineligible for induction chemotherapy, but prospective data comparing the approaches in induction-eligible patients have been limited.
Study Details
The investigator-initiated, open-label PARADIGM trial enrolled 172 previously untreated adults with AML at nine U.S. academic centers. All patients were considered candidates for induction chemotherapy and had an ECOG performance status of 0 to 2. The median age was 64 years, and 72% had adverse-risk disease according to the 2022 European LeukemiaNet classification.
Patients were randomly assigned 1:1 to azacitidine plus venetoclax or induction chemotherapy with either a conventional 7+3 regimen of cytarabine plus an anthracycline or CPX-351, a liposomal formulation of daunorubicin and cytarabine.
Patients with core-binding-factor fusions or FLT3 mutations were excluded, as were patients younger than 60 years with NPM1 mutations. The primary endpoint was event-free survival.
Key Findings
At a median follow-up of 21.9 months, median event-free survival was 14.5 months with azacitidine/venetoclax compared with 6.2 months with induction chemotherapy (HR = 0.57; P = .002). At 1 year, 53% of patients receiving azacitidine/venetoclax were alive without an event compared with 36% receiving induction chemotherapy.
Overall response was observed in 88% of patients receiving the investigational regimen and 62% receiving induction chemotherapy. Composite complete remission was achieved by 78% and 53%, respectively, whereas complete remission alone was achieved by 56% and 49%. Following treatment, 60% of patients in the azacitidine/venetoclax group proceeded to hematopoietic-cell transplantation compared with 40% in the induction chemotherapy group.
Median overall survival was 21.5 months with azacitidine/venetoclax and 18 months with induction chemotherapy; however, the trial was not designed to formally assess differences in overall survival.
Grade 3 or higher infections occurred in 28% of patients receiving azacitidine/venetoclax compared with 41% receiving induction chemotherapy, and grade 3 or higher hemorrhagic events occurred in 2% and 12%, respectively. No patients receiving azacitidine/venetoclax died within 30 or 60 days, whereas 30- and 60-day mortality with induction chemotherapy was 3% and 5%, respectively.
The investigational regimen was also associated with substantially less hospitalization. During the first 30 days, patients spent a mean of 12.5 days in the hospital compared with 27.3 days with induction chemotherapy. No patients receiving azacitidine/venetoclax required intensive care, compared with 10% receiving induction chemotherapy. Over the first 6 months, mean inpatient time was 39.3 vs 58.5 days.
According to the investigators, the findings should not be generalized to all patients with AML who are eligible for intensive therapy. The trial excluded patients with core-binding-factor or FLT3 alterations and younger patients with NPM1 mutations; the authors noted that induction chemotherapy remains the recommended treatment for fit patients with FLT3-mutated or favorable-risk core-binding-factor AML. Events were also assessed by treating investigators without blinded central review, and the study was conducted exclusively at academic centers.
“Our data show the superiority of [azacitidine/venetoclax] to induction chemotherapy as up-front treatment for patients who are eligible for induction chemotherapy,” the investigators wrote. They concluded that the findings support its use in fit, transplant-eligible patients with nonfavorable-risk, FLT3-nonmutated AML.
Amir T. Fathi, MD, of the Mass General Brigham Cancer Institute at Massachusetts General Hospital and Harvard Medical School, is the corresponding author of the article.
DISCLOSURE: The study was supported by AbbVie and Genentech and by a Harvard Cancer Center Support Grant. For full disclosures of the study authors, visit NEJM.org.
