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Older patients with acute myeloid leukemia (AML) and those with serious medical comorbidities have poor tolerance and outcomes with standard induction chemotherapy and instead may receive less-intensive therapy with azacitidine. However, azacitidine monotherapy has been associated with a remission rate ≤30% and survival of <1 year in untreated AML patients ≥65 years of age (Blood 2015; 126:291).
Now, investigators have conducted an industry-funded, multicenter phase III trial to evaluate the efficacy and safety of combining azacitidine with venetoclax in 431 previously treated AML patients (age, ≥75 years) with cardiopulmonary disease or poor performance status. Patients were randomized 2:1 to receive azacitidine with or without venetoclax.
At a median follow-up of 20.5 months, median overall survival (the primary endpoint) was improved with azacitidine plus venetoclax versus azacitidine alone (14.7 vs. 9.6 months; hazard ratio, 0.66; P<0.001). Complete remission and red-cell and platelet transfusion independence were also significantly improved with azacitidine plus venetoclax. However, high-grade neutropenia, thrombocytopenia, and febrile neutropenia occurred significantly more often with the dual therapy.
DiNardo CD et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 2020 Aug 13; 383:617. (https://doi.org/10.1056/NEJMoa2012971)
Schiffer CA.Promoting apoptosis with venetoclax — A benefit for older patients with AML. N Engl J Med 2020 Aug 13; 383:677. (https://doi.org/10.1056/NEJMe2023326)
Comment
This trial builds on previous studies demonstrating venetoclax activity in AML (e.g., Cancer Discov 2016; 6:1106) and supports the use of azacitidine plus venetoclax in older patients and those who are poor candidates for standard induction therapy. The current study also showed that AML patients with FLT3, IDH1 or IDH2 mutations had high response rates, suggesting potential approaches to tailoring therapy for individual patients and for the design of novel combinations of venetoclax with inhibitors of FLT3, IDH1, IDH2,and other molecular targets.