The challenge of targeting key drivers of CLL and sequencing therapy in an era of experimental therapeutics

Treatment of chronic lymphocytic leukemia (CLL) has been revolutionized with the introduction of small molecule inhibitors targeting both the B-cell receptor (BCR) signaling pathway and B-cell lymphoma-2 (BCL-2) family of proteins. Inhibitors of Bruton's tyrosine kinase (BTK) and the BH3 mimetic venetoclax are bothcurrently used as the standard of care for patients in the frontline and relapsed/refractory setting of CLL. With the clinical success of both these classes of therapies, sequencing of these agents has become a major challenge in treatment of CLL. In this review we will discuss the current data available for both classes of agents in the front-line and relapsed/refractor setting, considerations when giving these agents, and how we can continue to improve the treatment landscape for CLL.