Abstract
The B cell receptor (BCR) signalling pathway has an integral role in the pathogenesis of many B cell malignancies, including chronic lymphocytic leukaemia, mantle cell lymphoma, diffuse large B cell lymphoma and Waldenström macroglobulinaemia. Bruton tyrosine kinase (BTK) is a key node mediating signal transduction downstream of the BCR. The advent of BTK inhibitors has revolutionized the treatment landscape of B cell malignancies, with these agents often replacing highly intensive and toxic chemoimmunotherapy regimens as the standard of care. In this Review, we discuss the pivotal trials that have led to the approval of various covalent BTK inhibitors, the current treatment indications for these agents and mechanisms of resistance. In addition, we discuss novel BTK-targeted therapies, including covalent, as well as non-covalent, BTK inhibitors, BTK degraders and combination doublet and triplet regimens, to provide insights on the best current treatment paradigms in the frontline setting and at disease relapse.
Overview
- The study focuses on the role of the B cell receptor (BCR) signalling pathway in the pathogenesis of various B cell malignancies, including chronic lymphocytic leukaemia, mantle cell lymphoma, diffuse large B cell lymphoma and Waldenström macroglobulinaemia. The study examines the key role of Bruton tyrosine kinase (BTK) as a mediator of signal transduction downstream of the BCR and the impact of BTK inhibitors on the treatment landscape of B cell malignancies. The study discusses the pivotal trials that led to the approval of various covalent BTK inhibitors, the current treatment indications for these agents, and the mechanisms of resistance. The study also explores novel BTK-targeted therapies, including covalent, as well as non-covalent, BTK inhibitors, BTK degraders, and combination doublet and triplet regimens to provide insights on the best current treatment paradigms in the frontline setting and at disease relapse.
Comparative Analysis & Findings
- The study compares the outcomes observed under different experimental conditions or interventions, specifically the impact of BTK inhibitors on the treatment landscape of B cell malignancies. The study identifies the pivotal trials that led to the approval of various covalent BTK inhibitors and discusses the current treatment indications for these agents. The study also explores the mechanisms of resistance to BTK inhibitors and discusses novel BTK-targeted therapies, including covalent, as well as non-covalent, BTK inhibitors, BTK degraders, and combination doublet and triplet regimens. The study highlights the significant impact of BTK inhibitors on the treatment landscape of B cell malignancies and the potential for novel BTK-targeted therapies to improve treatment outcomes.
Implications and Future Directions
- The study's findings have significant implications for the field of research and clinical practice. The study highlights the critical role of BTK as a mediator of signal transduction downstream of the BCR and the impact of BTK inhibitors on the treatment landscape of B cell malignancies. The study identifies the pivotal trials that led to the approval of various covalent BTK inhibitors and discusses the current treatment indications for these agents. The study also explores the mechanisms of resistance to BTK inhibitors and discusses novel BTK-targeted therapies, including covalent, as well as non-covalent, BTK inhibitors, BTK degraders, and combination doublet and triplet regimens. The study suggests that future research should focus on identifying new targets for BTK-targeted therapies and developing more effective and personalized treatment paradigms for B cell malignancies.