Why are hypomethylating agents or low-dose cytarabine and venetoclax so effective?

Abstract

Venetoclax with backbone therapies have shown promising efficacy for newly diagnosed, previously untreated, older, unfit acute myeloid leukemia patients. This review discusses this data and potential reasons for the efficacy of these venetoclax-based combinations. Venetoclax with hypomethylators and low-dose cytarabine have resulted in high response rates, promising response durations, and significant overall survival in relatively small, uncontrolled studies. There is emerging data that these responses are due to the effective targeting of leukemia stem cells through an alteration of the metabolic environment that is poorly tolerated by this population. Venetoclax with a backbone therapy in older, untreated patients with acute myeloid leukemia has shown promising efficacy in preliminary clinical trials, and at least partially works through a novel mechanism that can target the leukemia stem cell population. Future investigations will help elucidate the mechanism and the contributions being made by each agent in the regimen.