PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma

ABSTRACT

Introduction: The efficacy of the prototypical phosphatidylinositol-3-kinase (PI3K) inhibitor idelalisib for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL) has led to development of multiple compounds targeting this pathway.

Areas Covered: We review the hypothesized therapeutic mechanisms of PI3K inhibitors, including abrogation of B cell receptor signaling, blockade of microenvironmental pro-survival signals, and enhancement of anti-tumor immunity. We examine toxicities of idelalisib, including bacterial infections (possibly secondary to drug-induced neutropenia), opportunistic infections (possibly attributable to on-target inhibition of T cell function), and organ toxicities such as transaminitis and enterocolitis (possibly autoimmune, secondary to on-target inhibition of p110δ in regulatory T cells). We evaluate PI3K inhibitors that have entered trials for the treatment of lymphoma, focusing on agents with selectivity for PI3Kα and PI3Kδ.

Expert Opinion: PI3K inhibitors, particularly those that target p110δ, have robust efficacy in the treatment of CLL and iNHL. However, idelalisib has infectious and autoimmune toxicities that limit its use. Outside of trials, idelalisib should be restricted to CLL patients with progression on ibrutinib or iNHL patients with progression on two prior therapies. Whether newer PI3K inhibitors will demonstrate differentiated toxicity profiles in comparable patient populations while retaining efficacy remains to be seen.

KEYWORDS:

• PI3-kinase inhibitors
• chronic lymphocytic leukemia
• indolent non-Hodgkin lymphoma
• idelalisib
• duvelisib
• umbralisib
• copanlisib

Article highlights

• PI3K inhibitors represent a novel class of targeted therapies with demonstrated efficacy in the treatment of indolent non-Hodgkin lymphoma.

• PI3K inhibitors likely exert their anti-neoplastic effects through a variety of mechanisms including abrogation of B cell receptor signaling, blockade of microenviromental signals, and enhancement of anti-tumor immunity.

• Idelalisib is the prototypical p110δ-selective PI3K inhibitor, and multiple other agents with varying selectivity among the PI3K isoforms are currently in clinical development for the treatment of both aggressive and indolent non-Hodgkin lymphoma.

• Toxicities seen with idelalisib include transaminitis, colitis, and pneumonitis – all of which may be autoimmune in origin and are responsive to steroids – as well as bacterial and opportunistic infections.

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Declaration of interest

J. R. Brown has served as a consultant for Astra-Zeneca, Acerta, Gilead, Infinity, Janssen, Pharmacyclics, Roche/Genentech, and TG Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.