Duvelisib: a phosphoinositide-3 kinase δ/γ inhibitor for chronic lymphocytic leukemia

ABSTRACT

Introduction: Frontline chemotherapy is successful against chronic lymphocytic leukemia (CLL), but results in untoward toxicity. Further, prognostic factors, cytogenetic anomalies, and compensatory cellular signaling lead to therapy resistance or disease relapse. Therefore, for the past few years, development of targeted therapies is on the rise. PI3K is a major player in the B-cell receptor (BCR) signaling axis, which is critical for the survival and maintenance of B cells. Duvelisib, a PI3K δ/γ dual isoform specific inhibitor that induces apoptosis and reduces cytokine and chemokine levels in vitro, holds promise for CLL.

Areas covered: Herein, we review PI3K isoforms and their inhibitors in general, and duvelisib in particular; examine literature on preclinical investigations, pharmacokinetics and clinical studies of duvelisib either as single agent or in combination, for patients with CLL and other lymphoid malignancies.

Expert opinion: Duvelisib targets the PI3K δ isoform, which is necessary for cell proliferation and survival, and γ isoform, which is critical for cytokine signaling and pro-inflammatory responses from the microenvironment. In phase I clinical trials, duvelisib as a single agent showed promise for CLL and other lymphoid malignancies. Phase II and III trials of duvelisib alone or in combination with other agents are ongoing.

KEYWORDS:

• CLL
• duvelisib
• leukemia
• PI3K
• therapy

Acknowledgments

The authors would like to acknowledge manuscript editing assistance from Joe Munch, Department of Scientific Publications, UT MD Anderson Cancer Center and Sue Davis, Director, Research Planning and Development, UT MD Anderson Cancer Center.

Declaration of interest

V. Gandhi has received a sponsored research grant from Infinity. 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.

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Funding

This work was supported in part by grant CLL PO1 CA81534 from the National Cancer Institute, Department of Health and Human Services; Alliance grant from the CLL Global Research Foundation; and Sponsored Research Agreement from Infinity Pharmaceuticals.