PI3Kdelta-selective and PI3Kalpha/delta-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma.

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Lampson BL, Brown JR

PI3Kdelta-selective and PI3Kalpha/delta-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma.

Expert Opin Investig Drugs. 2017 Nov;26(11):1267-1279. doi: 10.1080/13543784.2017.1384815. Epub 2017 Oct 6.

PubMed ID

28945111 [ View in PubMed

]

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 p110delta in regulatory T cells). We evaluate PI3K inhibitors that have entered trials for the treatment of lymphoma, focusing on agents with selectivity for PI3Kalpha and PI3Kdelta. Expert Opinion: PI3K inhibitors, particularly those that target p110delta, 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.

DrugBank Data that Cites this Article

Drugs

Duvelisib

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Duvelisib	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform	Protein	Humans	Yes	Inhibitor	Details
Duvelisib	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform	Protein	Humans	Yes	Inhibitor	Details