Azacitidine plus venetoclax ups OS and remission rates in older patients with previously untreated AML

Azacitidine plus venetoclax improves overall survival (OS) and remission rates vs azacitidine plus placebo in older patients with previously untreated acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy, results of the phase III VIALE-A trial have shown.

The trial included 431 patients (median age, 76 years) with previously untreated AML who were ineligible for standard induction therapy due to coexisting conditions, age ≥75 years, or both. After a median follow-up of 20.5 months, the primary endpoint of OS was significantly improved in the 286 patients randomized to receive azacitidine plus venetoclax compared with the 145 patients who received azacitidine plus placebo (median, 14.7 months vs 9.6 months; hazard ratio [HR], 0.66; 95 percent confidence interval [CI], 0.52 to 0.85; p<0.001). [N Engl J Med 2020;383:617-629]

Subgroup analysis showed a significant OS benefit of azacitidine plus venetoclax vs azacitidine plus placebo in patients with secondary AML (median, 16.4 months vs 10.6 months; HR, 0.56; 95 percent CI, 0.35 to 0.91), and in those with de novo AML (median, 14.1 months vs 9.6 months; HR, 0.67; 95 percent CI, 0.51 to 0.90).

In patients with poor cytogenetic risk, median OS was 7.6 months in the azacitidine-venetoclax group vs 6 months in the azacitidine-placebo group (HR, 0.78; 95 percent CI, 0.54 to 1.1). In patients with intermediate cytogenetic risk, median OS was 20.8 months vs 12.4 months (HR, 0.57; 95 percent CI, 0.41 to 0.79).

The incidence of complete remission (CR) was also significantly higher in the azacitidine-venetoclax vs azacitidine-placebo group (36.7 percent vs 17.9 percent; p<0.001), as was composite CR (defined as CR or CR with incomplete haematologic recovery) (66.4 percent vs 28.3 percent; p<0.001). The median duration of CR and composite CR was 17.5 months vs 13.3 months and 17.5 months vs 13.6 months, respectively, while the median time to first response (either CR or CR with incomplete haematologic recovery) was 1.3 months vs 2.8 months.

“The incidence of composite CR was notably improved across all AML genomic risk groups, including patients with adverse cytogenetic risk, secondary AML, and high-risk molecular mutations,” the investigators reported.

“The higher incidence of remission with azacitidine plus venetoclax resulted in significant increases in the incidence of transfusion independence,” they noted. “Red-cell transfusion independence occurred in 59.9 percent of patients in the azacitidine-venetoclax group vs 35.2 percent of those in the control group [p<0.001], while platelet transfusion independence occurred in 68.5 percent vs 49.7 percent [p<0.001] of the patients.”

In patients who achieved composite CR, residual disease negativity was detected in 23.4 percent of patients who received azacitidine plus venetoclax vs 7.6 percent of those who received azacitidine plus placebo.

Key adverse events (AEs) in the trial included nausea of any grade (44 percent vs 35 percent in the azacitidine-venetoclax vs azacitidine-placebo group), grade ≥3 thrombocytopenia (45 percent vs 38 percent), neutropenia (42 percent vs 28 percent), and febrile neutropenia (42 percent vs 19 percent). Infections of any grade and serious AEs occurred in 85 percent vs 67 percent and 83 percent vs 73 percent of the patients, respectively.

Treatment discontinuation due to AEs occurred in 24 percent vs 20 percent of patients in the azacitidine-venetoclax vs azacitidine-placebo group, while interruptions or dose reductions due to AEs occurred in 72 percent vs 57 percent and 3 percent vs 4 percent of the patients, respectively.

“The prognosis in older patients with AML ineligible for intensive chemotherapy has been dismal. The combination of azacitidine plus venetoclax in this challenging patient population in this trial was an effective treatment regimen,” the investigators concluded. “Ongoing attentiveness to monitoring and management of myelosuppression is key for patient safety with this combination therapy.”