In VIALE-A clinical trial, previously untreated patients with acute myeloid leukaemia (AML) who were ineligible for intensive chemotherapy due to advanced age (at least 75 years), or if they had at least one of the coexisting conditions precluding intensive chemotherapy, or both, the overall survival (OS) was longer and the incidence of remission was higher among those patients who received azacitidine and venetoclax than among patients who received azacitidine and placebo. However, the incidence of febrile neutropenia was higher in the combination of azacytidine and venetoclax group. The findings are published by Dr. Courtney D. DiNardo of the University of Texas M.D. Anderson Cancer Center in Houston, TX, USA and colleagues on 13 August 2020 in The New England Journal of Medicine.
The authors wrote in the study background that AML is primarily a disease of older adults, with a median age of 68 years at diagnosis. Standard curative treatment for AML consists of intensive induction chemotherapy followed by consolidation chemotherapy, allogeneic stem-cell transplantation, or both. However, because of incidence of unfavourable genomic features, older patients are frequently ineligible for or have disease that is refractory to standard chemotherapy. Instead, such patients often receive less intensive regimens, including hypomethylating agents, azacitidine or decitabine, and low-dose cytarabine.
Increased expression of Bcl-2 family proteins in AML blasts has been reported, and a majority of AML stem cells express aberrantly high levels of Bcl-2 and are dependent on Bcl-2 for survival. Venetoclax is a selective small-molecule Bcl-2 inhibitor that showed in preclinical studies to induce apoptosis in malignant cells dependent on Bcl-2 for survival. However, as a single-agent venetoclax has had modest activity in AML. Azacitidine and venetoclax induced cell death in AML-derived cell lines in preclinical studies. The findings from a previous phase Ib study of the combination of azacitidine and venetoclax showed promising efficacy.
Confirmatory trial, VIALE-A was designed to evaluate the efficacy and safety of the azacytidine and venetoclax combination regimen as compared with a control regimen of azacytidine and placebo in previously untreated patients with AML who were ineligible for intensive induction therapy. In this phase III, multicentre, randomised, double-blind, placebo-controlled trial, the study investigators randomly assigned previously untreated patients with confirmed AML who were ineligible for standard induction therapy because of coexisting conditions, because they were 75 years of age or older, or both to azacitidine and either venetoclax or placebo. The study primary endpoint was OS.
The intention-to-treat population included 431 patients, 286 in the azacytidine and venetoclax combination group and 145 in the azacytidine and placebo group. The median age was 76 years in both groups. At a median follow-up of 20.5 months, the median OS was 14.7 months in the azacytidine and venetoclax combination group and 9.6 months in the azacytidine and placebo group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; p < 0.001).
The incidence of complete remission was higher with azacytidine and venetoclax combination than with azacitidine and placebo regimen (36.7% vs. 17.9%; p < 0.001), as was the composite complete remission defined as complete remission or complete remission with incomplete haematologic recovery (66.4% vs. 28.3%; p < 0.001).
Key adverse events included nausea of any grade in 44% of the patients in the azacytidine and venetoclax group and 35% of those in the azacytidine and placebo group and grade 3 or higher thrombocytopenia in 45% and 38%, respectively, neutropenia in 42% and 28%, and febrile neutropenia in 42% and 19%. Infections of any grade occurred in 85% of the patients in the azacytidine and venetoclax group and 67% of those in the azacytidine and placebo group, and serious adverse events occurred in 83% and 73%, respectively.
The authors concluded that the combination of azacitidine and venetoclax in this challenging patient population was an effective treatment regimen in this trial that led to significant improvements in the incidence of composite complete remission and OS. Unlike monitoring of patients who receive azacitidine alone, special attention in the monitoring and management of myelosuppression is key for patient safety with this combination therapy.
The study was funded by AbbVie and Genentech.
DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med 2020;383:617-29.