Mechanisms of intrinsic and acquired resistance to venetoclax in B-cell lymphoproliferative disease.

Venetoclax is an oral selective BCL2 inhibitor which is highly efficacious in a variety of B-cell lymphoproliferative diseases (B-LPDs) due to their collective dependency on BCL2 over-expression as a central feature of their pathogenesis. However, despite its general efficacy across the spectrum of B-LPDs, certain subtypes are characterized by significantly higher response rates (RRs) to venetoclax (e.g. chronic lymphocytic leukemia) than others (e.g. diffuse large B-cell lymphoma). This variation in RR is the result of an underlying spectrum of primary (intrinsic) resistance to venetoclax mediated by numerous intracellular and microenvironmental mechanisms. Moreover, despite an initial response, most patients will experience disease progression on venetoclax therapy thus manifesting secondary (acquired) resistance. This review describes the molecular mechanisms in B-LPDs that drive both of these types of clinical resistance, the understanding of which is central to optimizing outcomes using this therapy.