Molecular variables appear to be predictive of response and outcomes among patients with acute myeloid leukemia (AML) undergoing treatment with venetoclax, according to research published in Blood.1
AML, which has a higher incidence among the elderly, has few treatments with sufficient tolerability for unfit patients. DNA methyltransferase inhibitors (DNMTis), including azacitidine and decitabine, as well as low-dose cytarabine (LDAC), were previously the most frequently used drugs in this setting, but confer only a modest survival benefit.
Venetoclax, a BCL-2 inhibitor, was approved by the US Food and Drug Administration (FDA) for elderly patients in AML, when used in conjunction with a DNMTi or LDAC. While these combinations have improved outcomes — with a median overall survival (OS) of 17.5 months with an DNMTi and a median OS of 10.1 months with LDAC — primary and secondary resistance remain a significant concern.
For this study, researchers evaluated data from 81 elderly patients with AML undergoing treatment with venetoclax to determine any molecular variables predicting primary or secondary resistance. In the overall cohort, the median age was 74 (range, 62-87), 54% of patients were male, 87.7% of patients had a performance status of 0 or 1, and 43.2% of patients had a complete response.
Genetic mutations were noted in 80 patients, and the most common were SRSF2 (43%), TET2 (24%), ASXL1 (24%), STAG2 (24%), RUNX1 (23%), and TP53 (23%). Patients with a NPM1, IDH1, IDH2, or DNMT3A mutation — which were noted in between 14% and 20% of patients — had a complete response or complete response with incomplete hematologic recovery rate of more than 80%.
Mutations in FLT3, RAS, and TP53 were, however, linked with primary or secondary resistance, and there was evidence for intratumoral mechanisms of resistance in single-cell studies.
“In summary, venetoclax in combination with conventional low-intensity approaches is a promising initial therapy for older patients with AML,” the authors wrote. “Our studies highlight clinically relevant molecular correlates of outcome that will impact future treatment strategies and combination approaches.”
DiNardo CD, Tiong IS, Quaglieri A, et al. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood. 2020;135(11):791-803.