Long-term follow-up results from the phase 3 VIALE-A trial demonstrate sustained overall survival (OS) benefit with venetoclax in combination with azacitidine for patients with acute myeloid leukemia (AML) ineligible for intensive chemotherapy, compared to a placebo plus azacitidine, according to data presented at the 2022 American Society of Hematology (ASH) Annual Meeting & Exposition.

These findings were presented by lead author, Keith W. Pratz, MD, Division of Hematology and Oncology, Abramson Cancer Center University of Pennsylvania, Philadelphia, and include 360 survival events with an additional 2 years of follow-up, after 100% occurrence of pre-planned survival events. Previous reports from VIALE-A showed the trial met statistical significance for its primary end point of OS at the 75% OS interim analysis in March 2020, with 270 OS events.

VIALE-A included 431 patients with confirmed AML who were previously untreated and ineligible for intensive therapy. Patients were randomly assigned in a 2:1 ratio to receive azacitidine plus either venetoclax (n = 286) or placebo (n = 145). Azacitidine was administered at a standard dose of 75 mg/m² subcutaneously or intravenously on days 1 to 7 of every 28-day cycle. Venetoclax was administered at 400 mg after a 3-day ramp-up to reach the target dose in cycle 1 or a matching placebo orally, once daily, in 28-day cycles.

OS was also explored in groups of patients with molecular abnormalities of interest, which  included FLT-3, observed in 14.1% of patients receiving venetoclax-azacitidine, IDH1/2, observed in 24.9% of patients, TP53, observed in 23.3% of patients and NPM1, observed in 16.6% of patients.

With a median follow-up of 43.2 months, the median OS was 14.7 months (95% confidence interval [CI], 12.1 to 18.7) in the venetoclax-azacitidine group and 9.6 months (95% CI, 7.4 to 12.7) in the placebo-azacitidine group (hazard ratio [HR], 0.58; 95% CI, 0.47 to 0.72; nominal P <.001), maintaining the survival benefit since the interim analysis in the overall population. At data cut-off, 49 patients remained on the study (48 in the venetoclax-azacitidine group and 1 in the placebo-azacitidine group).

In patients with measurable residual disease (MRD) <10^-3 who had achieved a complete remission (CR) or CR with incomplete hematologic recovery (CRi), median OS was reached at 34.2 months (95% CI, 27.7 to 44) in the venetoclax-azacitidine group (n = 69) and 25 months (95% CI, 7 to 39.8) in the placebo-azacitidine group (n = 11). In patients with MRD >10^-3 who achieved a CR or CRi, median OS was 18.7 months (95% CI, 12.9 to 23.5) in the venetoclax-azacitidine group (n = 96) and 15.1 months (95% CI, 7.4 to 26.1) in the placebo-azacitidine group (n = 24).

In the IDH1/2 subgroup, median OS was reached at final analysis with a median OS of  19.9 months (95% CI, 12.2 to 27.7) in the venetoclax-azacitidine group and 6.2 months (95% CI, 2.3 to 12.7) in the placebo-azacitidine group (HR, 0.314; 95% CI, 0.189 to 0.522; P <.001).

Overall, safety profiles were comparable between the 2 groups. The most common treatment-emergent adverse events (AEs) of any grade, occurring in ≥20% of patients, included nausea (44.5% in the venetoclax-azacitidine group vs 36.8% in the placebo-azacitidine group), diarrhea (45.2% vs 34%), and constipation (43.8% vs 39.6%). Grade ≥3 AEs, occurring in ≥10% of patients, included thrombocytopenia (45.9% vs 39.6%), neutropenia (42.8% vs 28.5%), and febrile neutropenia (42.8% vs 18.8%). Serious AEs occurred in 85.1% of patients in the venetoclax-azacitidine group and 77.1% of those in the placebo-azacitidine group.

“The VIALE-A 2-year follow-up analysis confirms the long-term survival benefit for patients treated with [venetoclax-azacitidine], with no new safety findings,” Dr Pratz and colleagues concluded.

Source:

Pratz K, Jonas B, Pullarkat V, et al. Long-Term Follow-up of the Phase 3 Viale-a Clinical Trial of Venetoclax Plus Azacitidine for Patients with Untreated Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy. Presented at the ASH Annual Meeting & Exposition; December 10-13, 2022; New Orleans, LA, and virtual. Abstract 219.