Avoidance of cell death is one of the hallmarks of cancer. This is particularly true in hematological malignancies where both malignant lymphoid and myeloid cells often are able to circumvent apoptosis. Indeed, the whole field of cell death in cancer was established by the discovery of how BCL2 functioned as a novel oncogene, the first to promote cell survival rather than enhance proliferation. That pioneering research in 1988 led to a >20 year journey of discovery and development that has culminated in the entry into routine clinical practice of a drug that specifically targets and inhibits BCL2.

Venetoclax is the first of a new class of anti-cancer drugs called BH3-mimetics. These small molecules mimic the actions of BH3-only proteins which function as the physiological antagonists of BCL2 and related pro-survival proteins in cells. Venetoclax kills cells by triggering apoptosis and this is entirely dependent upon its interaction with BCL2.

Dr Roberts will outline the basis for the exquisite sensitivity of chronic lymphocytic leukemia to venetoclax and explain why BCL2 inhibition can also be effective in hematological malignancies where expression of high levels of BCL2 is less uniform. His talk will outline the principles underpinning the rational use of combination therapies in acute myeloid leukemia, acute lymphoblastic leukemia, lymphomas and myeloma, and the bone fide mechanisms of clinical resistance. After reviewing the current approved uses of venetoclax in CLL and AML, he will discuss the opportunities and challenges presented by current exploration of BCL2 inhibition in trials for patients with other hematological malignancies.