Targeting the B cell receptor pathway in non-Hodgkin lymphoma

ABSTRACT

Introduction: Dysregulated B cell receptor (BCR) signaling has been identified as a potent contributor to tumor survival in B cell non-Hodgkin lymphomas (NHLs). This pathway’s emergence as a rational therapeutic target in NHL led to development of BCR-directed agents, including inhibitors of Bruton’s tyrosine kinase (BTK), spleen tyrosine kinase (SYK), and phosphatidylinositol 3 kinase (PI3K). Several drugs have become valuable assets in the anti-lymphoma armamentarium.

Areas covered: We provide an overview of the BCR pathway, its dysregulation in B cell NHL, and the drugs developed to target BCR signaling in lymphoma. Mechanisms, pharmacokinetics, pharmacodynamics, efficacy, and toxicity of currently available BTK, SYK, and PI3K inhibitors are described.

Expert opinion: While the excellent response rates and favorable toxicity profile of the BTK inhibitor ibrutinib in certain NHL subtypes have propelled it to consideration as frontline therapy in selected populations, additional data and clinical studies are needed before other agents targeting BCR signaling influence clinical practice similarly. PI3K inhibitors remain an option for some relapsed indolent lymphomas and chronic lymphocytic leukemia, but their widespread use may be limited by adverse effects. Future research should include efforts to overcome resistance to BTK inhibitors, combination therapy using BCR-targeted agents, and exploration of novel agents.

KEYWORDS:

• B cell receptor
• fostamatinib
• ibrutinib
• non-Hodgkin lymphoma

Article Highlights

• B cell NHLs frequently exploit dysregulated BCR signaling to promote tumor survival.

• Targeting the BCR pathway represents a rational treatment approach in B cell NHL, and several BCR-directed agents have emerged in recent years as valuable assets in the anti-lymphoma therapeutic arsenal.

• The BTK-inhibitor ibrutinib represents an important treatment option in CLL, MCL, and MZL.

• Lower response rates and concerning toxicity profiles have limited the role of SYK inhibitors in NHL.

• Future directions should involve efforts to understand and overcome resistance mechanisms to inhibitors of BCR signaling, studies of combination therapy incorporating BCR-targeted agents, and exploration of novel agents such as next-generation BTK inhibitors.

This box summarizes key points contained in the article.

Declaration of interest

C.R. Flowers has acted as a consultant for Abbvie, Bayer, Celgene (unpaid), Genentech/Roche (unpaid), Gilead, OptumRx, Karyopharm, Pharmacyclics/Janssen, Spectrum and previously received research funding from Abbvie, Acerta, Celgene, Gilead, Genentech/Roche, Janssen Pharmaceutical, Millennium/Takeda, Pharmacyclics, TG Therapeutics, Burroughs Wellcome Fund, Eastern Cooperative Oncology Group, National Cancer Institute, V Foundation. 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.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

C Flowers has received a grant from the NIH/National Cancer Institute (K24CA208132) for this paper.