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The Intriguing Clinical Success of BCL-2 Inhibition in Acute Myeloid Leukemia

Over the past several decades numerous preclinical and clinical studies have pursued new approaches for the treatment of acute myeloid leukemia (AML). While some degree of clinical response has been demonstrated for many therapies, for the most part, fundamental changes in the treatment landscape have been lacking. Recently, the use of the BCL-2 inhibitor venetoclax has emerged as a potent therapy for a majority of newly diagnosed AML patients. Venetoclax regimens have shown broad response rates with deep and durable remissions, with a superior toxicity profile compared with traditional intensive chemotherapy agents. Numerous ongoing studies are now using venetoclax in combination with a wide range of other agents as investigators seek even more effective and well-tolerated regimens. Notably, however, while the empirical results of BCL-2 inhibition are encouraging, the mechanisms that have led to these successful clinical outcomes remain unclear. Intriguingly, the activity of venetoclax in AML patients appears to go beyond simply modulating canonical antiapoptosis mechanisms; in addition, the efficacy of venetoclax is linked to its combined use with conventional low-intensity backbone therapies. This article will evaluate the state of the field, provide a summary of key considerations, and propose directions for future studies.