Targeting the B cell receptor pathway in non-Hodgkin lymphoma.

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.