PI3K inhibitors in chronic lymphocytic leukemia: where do we go from here?

Abstract

Phosphatidylinositol 3-kinase (PI3K) inhibitors are effective in chronic lymphocytic leukemia (CLL). However, the severe toxicity profile associated with the first-generation inhibitors idelalisib and duvelisib, combined with the availability of other more tolerable agents, have limited their use. CLL is still considered incurable, and relapse after treatment, development of resistance, and treatment intolerance are common. It is therefore of interest to optimize the administration of currently approved PI3K inhibitors and to develop next-generation agents to improve tolerability, so that this class of agents will be considered an effective and safe treatment option when needed. These efforts are reflected in the large number of emerging clinical trials with PI3K inhibitors in CLL. Current strategies to overcome treatment limitations include intermittent dosing, which is established for copanlisib and zandelisib and under investigation for duvelisib and parsaclisib. A second strategy is to combine the PI3K inhibitor with another novel agent, either as a continuous regimen or a fixedduration regimen, to deepen responses. In addition to these approaches, it is of interest to identify higher-resolution actionable biomarkers that can predict treatment responses and toxicity, and inform personalized treatment decisions. Here, we discuss the current status of PI3K inhibitors in CLL, factors limiting the use of currently approved PI3K inhibitors in CLL, current strategies to overcome these limitations, and where to go next.

Figure 1.

PI3K inhibitors in clinical trials in chronic lymphocytic leukemia. Overview of the number of phase I, II, and III clinical trials with the indicated PI3K inhibitors in chronic lymphocytic leukemia (CLL) registered at ClinicalTrials.gov. Agents that have not been studied in clinical trials in CLL since the approval of idelalisib in 2014 were excluded from the analysis. PI3K inhibitors with European Medicines Agency/Food and Drug Administration approval in CLL are indicated with a star. *Excluding terminated or withdrawn trials.

Figure 2.

Current strategies to overcome the limitations of PI3K inhibitors. The figure shows current strategies to overcome PI3K inhibitor limitations discussed in the main text, and indicates which strategies are employed for the different inhibitors. The color key indicates the p110 specificity of the inhibitors. CAR-T: chimeric antigen receptor T-cell; Bcl-2i: B-cell lymphoma-2 inhibitor; BTKi: Bruton tyrosine kinase inhibitor; PD-L1: programmed death ligand 1; Treg: regulatory T cell.