Professor Andrew Roberts, Royal Melbourne Hospital, Walter & Eliza Hall Institute of Medical Research & University of Melbourne. Parkville, VIC
Dysregulated overexpression of the anti-apoptotic proteins BCL2 is a hallmark of pathogenesis of many B-cell malignancies underpinning inappropriate survival and contributing to chemotherapy resistance. While the preclinical development of effective inhibitors has proved challenging, clinically active BCL2 antagonists are now in clinical trials. Venetoclax (ABT-199) is a potent, orally bioavailable selective BCL2 inhibitor, now in Phase 1, 2 and 3 clinical trials in blood cancers. To date, clinical data demonstrate that venetoclax is highly active in patients with relapsed, refractory chronic lymphocytic leukemia (CLL), including those with del(17p) or fludarabine-refractory disease (NEJM 374:311-22, 2016); as well as in patients with relapsed mantle cell lymphoma and in some patients with follicular lymphoma and diffuse-large B cell lymphoma. Activity in acute myeloid leukaemia has also been observed. Venetoclax’s effect on cell survival is clearly observed in patients with CLL where apoptosis of CLL cells in vivo is observed within 8 hours after first exposure. The major toxicity to date has been tumour lysis, and this risk has now been mitigated through careful dose escalation. The potential potency of targeting cell survival pathways is highlighted by the observation of complete remissions in approximately 20% of patients with refractory CLL in the Phase I study. Preclinical and now clinical data demonstrate that venetoclax can synergise with other anti-cancer agents, and that targeting BCL2 is effective even in blood cancers lacking a functional TP53 pathway. Collectively, these data suggest that BCL2 inhibition could represent a major advance in targeted therapy for BCL2 overexpressing lymphoid cancers, either alone or in combination. Milestones in the development of BCL2 inhibitors will be reviewed, and the current questions requiring further clinical and translational investigation will be explored.
Andrew Roberts is the inaugural Metcalf Chair of Leukaemia Research at the University of Melbourne, a clinical haematologist at the Royal Melbourne Hospital and Head of Clinical Translation at the Walter & Eliza Hall Institute where he also leads an experimental haematology laboratory. His major research interests are the development of new treatments for leukaemia, lymphoma and myeloma through translational and clinical research. He led the academic clinical development of the novel targeted BCL2 inhibitor, venetoclax, from the research laboratory through clinical trials to FDA approval. He was President of the Haematology Society of Australia and New Zealand 2005 – 07, and now serves on the boards of Cancer Council Victoria (Chair) and the Australasian Leukaemia and Lymphoma Group. He also advises the Australian government on the cost-effectiveness of new drug therapies as a member of Pharmaceutical Benefits Advisory Committee. In 2015, he was the first non-North American to serve as Scientific Co-Chair of the American Society of Hematology Annual Meeting.