A multicenter, randomized, open-label, phase III trial among the difficult-to-treat population of patients aged aged 65 and older with acute myeloid leukemia (AML) with > 30% bone marrow blasts “showed that azacitidine was associated with a clinically meaningful improvement” in median overall survival and 1-year survival, researchers reported in Blood. Among 488 patients with newly diagnosed AML, median overall survival was 10.4 months for those receiving azacitidine (Vidaza) vs 6.5 months for those treated with commonly used current AML treatments (P = .1009), and the respective 1-year survival rates were 46.5% vs 34.2%.
The trial was conducted by an international team of researchers from 18 countries in Asia, Australia, Europe, and the United States, including Richard M. Stone, MD, of Dana-Farber Cancer Institute, Boston.
Before randomization, a conventional care regimen was preselected by a physician for each patient. Patients then were assigned 1:1 to receive azacitidine (n = 241) or conventional care (n = 247). Those assigned to conventional care received their preselected treatment, with 158 receiving low-dose cytarabine, 45 receiving best supportive care, and 44 receiving standard induction chemotherapy. Those assigned to azacitidine received 75 mg/m2/d for 7 consecutive days per 28-day treatment cycle, completing at least six cycles.
“Adverse events were consistent with the well-established safety profile of azacitidine,” the researchers reported. Treatment-emergent adverse events occurred in 99.2% of patients receiving azacitidine and 100% of those receiving conventional care. Grade 3-4 treatment-emergent adverse events occurring in ≥ 10% of patients receiving azacitidine were febrile neutropenia, neutropenia, and thrombocytopenia. Treatment-emergent adverse events leading to study discontinuation occurred in 9.3% of patients in the azacitidine group, 13.1% in the low-dose cytarabine group, and 11.9% in the induction chemotherapy group.
Overall, adverse events were the most common reason for early discontinuation in the trial, leading to 89 patients (37%) in the azacitidine group and 66 patients (28%) in the conventional care group discontinuing. The second most common reasons for discontinuation was the death of 53 patients (22%) receiving azacitidine and 58 patients (24%) receiving conventional care. By the end of the study, 394 patients (80.7%) had died, 193 patients (80.1%) in the azacitidine group and 201 patients (81.4%) in the conventional care group.
In a prespecified analysis censoring patients who received AML treatment after discontinuing the study drug, 1-year survival rates were 50.7% for azacitidine and 37.7% for conventional care. Median overall survival in these patients was 12.1 months for azacitidine vs 6.9 months for conventional care (P = .0190).
“Univariate analysis showed favorable trends for azacitidine compared with conventional care across all subgroups defined by baseline demographic and disease features,” the authors stated. They also acknowledged, “the primary endpoint was not met (stratified hazard ratio = 0.85 [95% confidence interval: 0.60–1.03], P = .1009) influenced by the convergence of the Kaplan-Meier curves at around 22 months. Such convergence is not unexpected in a disease with no cure and a patient population with poor overall survival,” the researchers wrote.
“Combination treatment regimens may further improve outcomes for older patients with AML,” the investigators noted, citing promising response rates of 30% to 40% in early trails of azacitidine in combination with lenalidomide (Revlimid), panobinostat (Farydak), and sorafenib (Nexavar). “Larger studies are need to confirm these findings,” the authors stated.
The study is registered at ClinicalTrials.gov as NCT01074047. ■
Dombret H, et al: Blood 126:291-299, 2015.