PI3K Inhibitors for the Treatment of Chronic Lymphocytic Leukemia: Current Status and Future Perspectives

Simple Summary The development of small agents targeting the B-cell receptor (BCR) pathway revolutionized the treatment of chronic lymphocytic leukemia (CLL). BCR-dependent leukemic cell proliferation is governed by phosphoinositide 3-kinase (PI3K) signaling. The selective PI3K delta inhibitor idelalisib and dual PI3K delta/gamma inhibitor duvelisib are currently approved by the Food and Drug Administration and European Medicine Agency (only idelalisib) for CLL treatment. Umbralisib, a selective PI3K delta and casein kinase-1 epsilon (CK1 epsilon) inhibitor, has a different chemical structure and a more favorable safety profile than other PI3K inhibitors (PiK3is); this has enabled its use in combination regimens in clinical trials in first-line and relapsed/refractory CLL. This paper summarizes the development of PI3Kis, their current role and future perspectives in the treatment of patients with CLL. Phosphoinositide 3-kinases (PI3Ks) signaling regulates key cellular processes, such as growth, survival and apoptosis. Among the three classes of PI3K, class I is the most important for the development, differentiation and activation of B and T cells. Four isoforms are distinguished within class I (PI3K alpha, PI3K beta, PI3K delta and PI3K gamma). PI3K delta expression is limited mainly to the B cells and their precursors, and blocking PI3K has been found to promote apoptosis of chronic lymphocytic leukemia (CLL) cells. Idelalisib, a selective PI3K delta inhibitor, was the first-in-class PI3Ki introduced into CLL treatment. It showed efficacy in patients with del(17p)/TP53 mutation, unmutated IGHV status and refractory/relapsed disease. However, its side effects, such as autoimmune-mediated pneumonitis and colitis, infections and skin changes, limited its widespread use. The dual PI3K delta/gamma inhibitor duvelisib is approved for use in CLL patients but with similar toxicities to idelalisib. Umbralisib, a highly selective inhibitor of PI3K delta and casein kinase-1 epsilon (CK1 epsilon), was found to be efficient and safe in monotherapy and in combination regimens in phase 3 trials in patients with CLL. Novel PI3Kis are under evaluation in early phase clinical trials. In this paper we present the mechanism of action, efficacy and toxicities of PI3Ki approved in the treatment of CLL and developed in clinical trials.

Automated summary

The development of small agents targeting the B-cell receptor (BCR) pathway has greatly improved the treatment of chronic lymphocytic leukemia (CLL). Selective inhibitors of PI3K delta, such as idelalisib and duvelisib, have been approved for CLL treatment. Umbralisib, a selective inhibitor of PI3K delta and CK1 epsilon, has shown promising results in combination regimens in clinical trials for CLL treatment.