Idelalisib for the treatment of B-cell malignancies

Abstract

Introduction: The standard of care for B-cell malignancies is chemotherapy or chemo-immunotherapy, which can manage, but not cure, these diseases. However, myelotoxicity and secondary malignancies limit their use. The B-cell receptor (BCR) plays a critical role in malignant B-cell proliferation and survival; inhibition of pivotal signaling nodes in the BCR pathway provides novel mechanisms for targeted therapy. Among these nodes, the phosphoinositide 3-kinase p110δ catalytic subunit (PI3Kδ) is particularly attractive. P110δ expression is restricted to hematopoietic cells and is highly expressed in B lymphocytes. Idelalisib (Zydelig) is an orally bioavailable ATP-competitive kinase inhibitor that targets PI3Kδ with high potency and selectivity. Idelalisib was approved in 2014 both in the US and EU in combination with rituximab for relapsed chronic lymphocytic leukemia (CLL) and as monotherapy for patients with relapsed follicular lymphoma and small lymphocytic lymphoma. Additionally approval was granted in the EU for first line use in poor prognosis CLL with 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy.

Areas covered: We describe idelalisib’s discovery and selectivity in biochemical and cellular assays and the outcomes of clinical trials in CLL, indolent NHL, and mantle cell lymphoma.

Expert opinion: Idelalisib will shape the future clinical landscape of B-cell malignancies.

Keywords:

• CAL-101
• chronic lymphocytic leukemia
• follicular lymphoma
• GS-1101
• idelalisib
• phosphoinositide 3-kinase p110δ catalytic subunit

Acknowledgements

The authors are grateful to Lauren Cutler, Patrick Kilgannon, Terry Newcomb, Elizabeth Hess, and Tim DiChiara for their critical review of the manuscript. Q Yang and P Modi contributed equally to this work.

Declaration of interest

V Gandhi has received financial support from Gilead as a sponsored research agreement. S Ramanathan and C Quéva are employees and shareholders of Gilead Sciences. The remaining two authors do not have any conflict of interest. This work was supported in part by grant P01 CA81534 from the National Cancer Institute, a CLL Global Research Foundation Alliance grant award, and a sponsored research agreement from Gilead Sciences. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Notes