BCL-2 inhibition in acute myeloid leukemia: resistance and combinations

INTRODUCTION: The introduction of venetoclax has revolutionized the treatment landscape of acute myeloid leukemia, offering new therapeutic opportunities. However, the clinical response to venetoclax varies significantly between patients, with many experiencing limited duration of response. AREAS COVERED: Identified resistance mechanisms include both intrinsic and acquired resistance to VEN. The former is associated with cell lineage and differentiation state. The latter includes dependency on alternative BCL-2 family anti-apoptotic protein(s) mediated by genetic, epigenetic, or post-translational mechanisms, mitochondrial and metabolic involvement, as well as microenvironment. Understanding these mechanisms is crucial for optimizing venetoclax-based therapies and enhancing treatment outcomes for patients with acute myeloid leukemia. This review aims to elucidate the primary mechanisms underlying resistance to venetoclax and explore current therapeutic strategies to overcome this challenge. EXPERT OPINION: In patients with venetoclax resistance, alternative options include targeted combination therapies tailored to individual cases based on cytogenetics and prior treatments. Many of these therapies require further clinical investigation to validate their safety and efficacy.