Review of Venetoclax in CLL, AML and Multiple Myeloma

Venetoclax is a highly selective and effective B-cell lymphoma-2 (BCL-2) inhibitor, which is able to reinstate the apoptotic potential of cancer cells. With its full repertoire yet to be explored, it has changed the therapeutic landscape in haematological malignancies, and most particularly chronic lymphocytic leukaemia (CLL), acute myeloid leukaemia (AML) and multiple myeloma (MM). In CLL, it has shown remarkable efficacy both as monotherapy and in combination therapy. Based on data from MURANO and CLL14 studies, fixed-duration combination therapy of venetoclax with anti-CD20 antibody is now the standard of care in numerous countries. In AML, although of limited efficacy as a single agent, venetoclax combination therapy has demonstrated encouraging outcomes including rapid, durable responses and acceptable toxicity, particularly in the older, unfit patient population. Multiple myeloma with translocation (t)(11;14) harbours high BCL-2/ myeloid cell leukaemia sequence-1 (MCL-1) and BCL-2/BCL-XL ratio and is, therefore, particularly suited for venetoclax-based therapy. Despite a wide ranging and evolving clinical role in these diseases, venetoclax treatment is not curative and, over time, clonal evolution and disease relapse appear to be the norm. While a variety of distinct resistance mechanisms have been identified, frequently emerging in a sub-clonal pattern, the full picture is yet to be characterised. Further illumination of the complex interplay of various factors is needed to pave the way for rational combination therapies aimed at circumventing resistance and improving durability of disease control. Serial molecular studies can aid in identification of new prognostically significant and/or targetable mutations.