Targeted therapies in CLL: mechanisms of resistance and strategies for management

The therapy of relapsed chronic lymphocytic leukemia (CLL) has changed dramatically in the past year with the regulatory approval of idelalisib and ibrutinib, with other therapeutic small molecules likely to become widely available in the next few years. Although durable remissions are being seen in many patients with these agents, it is becoming apparent that some patients with high genomic risk disease will relapse. Next-generation sequencing in patients as well as in vitro models is affording us the opportunity to understand the biology behind these relapses, which is the first step to designing rational therapies to prevent and treat targeted therapy-resistant CLL. These strategies are critical, as these relapses can be very difficult to manage, and a coordinated effort to put these patients on clinical trials will be required to efficiently determine the optimal therapies for these patients. In this review, we will describe-mechanisms of resistance, both proven and hypothesized, for idelalisib, ibrutinib, and venetoclax, describe patterns of resistance that have been described with ibrutinib, and discuss potential strategies for management of disease resistant to these drugs as well as potential strategies to prevent resistance.