In the 30 years since the initial discovery of BCL2 as a characteristic feature of malignancies such as follicular lymphoma, its established role in driving carcinogenesis and chemotherapeutic resistance have made it an obvious target for drug development. Early attempts at therapeutic targeting of BCL2 were plagued by off target effects and poor clinical efficacy. However, the description of the first specific BCL2 inhibitor, venetoclax, in 2013 has opened the way to clinical trials of BCL2 inhibition in multiple human malignancies.
The role of venetoclax is most established in chronic lymphocytic leukemia (CLL) where it is associated with an overall response rate of 80% and a 20% complete response rate even amongst the highest risk genetic subtypes. Disappointingly however responses are often not durable with a progression free survival of approximately 2 years. Factors associated with shorter duration of disease response include deletion 17p, fludarabine refractory disease, complex karyotype and failure to achieve a deep response to drug.
Understanding biomarkers for disease response will facilitate targeting therapy to patients most likely to benefit. Understanding the mechanisms by which drug resistance emerges during treatment is another crucial element to optimizing patient outcome in response to these drugs. Clinical trials are currently exploring the use of venetoclax in combination with immunotherapy, chemotherapy and other novel agents to establish which combinations and sequences of therapies are associated with optimal patient outcomes.