Chronic lymphocytic leukemia following venetoclax treatment failure

Abstract

Venetoclax (ABT-199) is a highly selective and potent inhibitor of BCL-2, capable of inducing deep remission in chronic lymphocytic leukemia (CLL). The introduction of this compound to the treatment armamentarium of CLL represented a real breakthrough, as the drug is effective in high-risk CLL patients and in the setting of Bruton’s tyrosine kinase inhibitors (BTKi) failure. Nevertheless, treatment failure or progression following venetoclax treatment occurs over time. Potential mechanisms of refractoriness, including BCL-2 mutations or activation of alternative anti-apoptotic pathways, have been identified. So far, questions regarding patient management after venetoclax and venetoclax-based regimen failure have yet to be answered, and only a few studies have addressed this problem. With increasing use of venetoclax-based treatment, the optimal sequencing and the most suitable next line treatment should be addressed in upcoming guidelines. In this review, we summarize the possible mechanism of resistance to venetoclax, and explore possible therapeutic options in cases of venetoclax failure.