Combination regimens involving hypomethylating agents are well tolerated and demonstrate promising activity in older patients with previously untreated acute myeloid leukemia (AML), according to research published in The Lancet Oncology (January 12, 2018; doi:10.1016/S1470-2045(18)30010-X).
Patients aged at least 65 years with AML have poor outcomes because no effective standard of care has been documented. Treatment with hypomethylating agents such as azacitidine and decitabine is common, but responses to these therapies are limited and short-lived. Venetoclax, an oral anti-apoptotic B-cell lymphoma 2 protein inhibitor, has demonstrated promising activity as a single agent in relapsed or refractory disease and preclinical data has suggested synergy between its use and the use of hypomethylating agents.
Daniel A Pollyea, MD, University of Colorado School of Medicine, and colleagues conducted an open-label, phase Ib study to assess the effectiveness of venetoclax plus azacitidine or decitabine in older patients with previously untreated AML. A total of 57 patients were enrolled with ECOG performance status of 0-2 and either intermediate-risk or poor-risk cytogenetics. Patients were categorized into one of three groups for the dose-escalation phase of the study: group A (n = 23; venetoclax and intravenous decitabine), group B (n = 22; venetoclax and subcutaneous or intravenous azacitidine), and group C (n = 12; a venetoclax and decitabine sub-study with the oral CYP3A inhibitor posaconazole).
The primary endpoints of the study were safety and pharmacokinetics of venetoclax plus azacitidine or decitabine, and to determine the maximum tolerated dose and recommended phase II dose.
Researchers reported the most common grade 3/4 treatment-related adverse events were thrombocytopenia, febrile neutropenia, neutropenia, nausea, decreased neutrophil count, leucopenia, vomiting, decreased platelet count, and lung infection. Tumor lysis syndrome was not observed.
Overall, 61% of patients (n = 35) achieved complete remission after therapy. The maximum tolerates dose was not reached, and the recommended phase II dose is listed as 400 mg once daily or 800 mg with an interrupted dosing schedule.
Dr Pollyea concluded that venetoclax plus hypomethylating agent therapy is a novel, well-tolerated regimen with promising activity in older patients with previously untreated AML. Evaluation of expansion cohorts at 400 mg and 800 mg dosing using both hypomethylating agent combinations is ongoing, they noted.