Idelalisib for relapsed/refractory indolent B-cell non-Hodgkin’s lymphoma: an overview of pharmacokinetics and clinical trial outcomes

Abstract

Indolent non-Hodgkin’s lymphoma (iNHL) describes a group of B-cell lymphomas with a long median survival and a relapsing–remitting clinical course. Although existing treatments are initially effective, patients often relapse, demonstrating decreasing efficacy with successive treatment courses. Alternative treatments are needed. PI3Kδ plays an essential, non-redundant role in B-cell receptor signaling critical to the pathogenesis of iNHL. It is expressed predominantly in hematopoietic cells, making PI3Kδ an attractive therapeutic target. Idelalisib is an oral PI3Kδ inhibitor approved in 2014 in the USA and the EU as monotherapy in relapsed follicular lymphoma or relapsed small lymphocytic lymphoma previously treated with two or more prior systemic therapies, or as part of combination therapy with rituximab in patients with chronic lymphocytic leukemia, for whom rituximab monotherapy would be considered appropriate due to the presence of comorbidities. Herein, we review the available data for idelalisib, with an emphasis on relapsed/refractory B-cell iNHL.

Keywords:

• CAL-101
• clinical
• GS-1101
• idelalisib
• non-Hodgkin’s lymphoma
• pharmacokinetics
• PI3K
• refractory
• relapsed
• rituximab

Financial & competing interests disclosure

A Davies has received research funding and speaking honoraria from and has participated in advisory boards for Gilead Sciences. He has also received research funding from Hoffman-La Roche, Celgene, GlaxoSmithKline, Bayer, Pfizer, Takeda, Janssen and has attended advisory boards for Hoffman-La Roche, Mundipharma, Celgene, CTI and Karyopharm. He has also received honoraria for unrestricted speaking engagements from Hoffman-La Roche, Mundipharma, CTI and Janssen. Third-party writing assistance was supported and paid for by Gilead Sciences. Writing assistance was provided by Ashfield Healthcare Communications, part of UDG Healthcare plc. The author has 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.

Key issues

• Idelalisib is an oral, PI3Kδ inhibitor that has been approved in the USA and the EU for use as monotherapy in patients with relapsed follicular lymphoma or relapsed small lymphocytic lymphoma previously treated with ≥2 prior systemic therapies, or as part of combination therapy with rituximab in patients with chronic lymphocytic leukemia, for whom rituximab monotherapy would be considered appropriate due to the presence of comorbidities.

• Idelalisib is administered twice daily at 150 mg. No dose adjustments are necessary for patients with hepatic or renal impairment; however, patients with hepatic impairment should be monitored for hepatotoxicity prior to treatment initiation.

• Idelalisib should not be coadministered with cytochrome P450 3A inducers or substrates.

• Current data indicate that idelalisib does not have pro-arrhythmic potential.

• In patients with previously treated indolent non-Hodgkin’s lymphoma (NHL), idelalisib monotherapy showed good antitumor activity and favorable tolerability. Treatment responses to idelalisib monotherapy were rapid and durable.

• In a Phase I study of patients with relapsed/refractory indolent B-cell NHL, combination treatment with idelalisib plus rituximab and/or bendamustine elicited high overall response rates and had a favorable safety profile.

• Common grade ≥3 adverse events associated with idelalisib include diarrhea/colitis and hepatotoxicity.

• Two Phase III clinical trials have been initiated to evaluate the use of idelalisib in combination with rituximab ± bendamustine in patients with previously treated indolent B-cell NHL.

Notes