Resistance to Bruton tyrosine kinase inhibitors: the Achilles heel of their success story in lymphoid malignancies

Author:

Stephens Deborah M.1ORCID,Byrd John C.2

Affiliation:

1. Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; and

2. Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH

Abstract

Abstract Bruton tyrosine kinase inhibitors (BTKi) have significantly changed the treatment landscape for patients with B-cell malignancies, including chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, mantle cell lymphoma, and marginal zone lymphoma. Unfortunately, patients with BTKi-resistant disease have shortened survival. Clinical and molecular risk factors, such as number of prior therapies and presence of TP53 mutations, can be used to predict patients at the highest risk of developing BTKi resistance. Many mechanisms of BTKi resistance have been reported with mutations in BTK and phospholipase C γ2 supported with the most data. The introduction of venetoclax has lengthened the survival of patients with BTKi-resistant disease. Ongoing clinical trials with promising treatment modalities, such as next-generation BTKi and chimeric antigen receptor T-cell therapy, have reported promising efficacy in patients with BTKi-resistant disease. Continued research focusing on resistance mechanisms and methods of how to circumvent resistance is needed to further prolong the survival of patients with BTKi-resistant B-cell malignancies.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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