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Bruton's tyrosine kinase inhibitors: lessons learned from bench-to-bedside (first) studies

Ysebaert, Loica; Michallet, Anne-Sophieb

doi: 10.1097/CCO.0000000000000114
LYMPHOMA: Edited by Bertrand Coiffier and Anne-Sophie Michallet

Purpose of review: Targeted inhibitors of B-cell receptor signaling have emerged as the most promising therapeutic options against non-Hodgkin's lymphoma. The inhibitor agents that target Bruton's tyrosine kinase (BTK) have elicited particularly high enthusiasm given the unprecedented positive responses observed in Phase I trials. The sheer amount of clinical data published since last year now requires reinterpretation in light of recently published findings on BTK.

Recent findings: Clinical trial data pertaining to various B-cell dyscrasia forms must be interpreted with great caution. The differing response rates reported with various BTK inhibitors for a range of lymphoma subtypes most likely mirror BTK's disease-specific pivotal role in the regulation of cell survival, migration, and proliferation pathways. It must also be stressed that activating or inhibitory somatic mutations affecting other critical components of targeted signaling cascades dramatically impact BTK inhibitor efficacy, and scientific evidence is mounting that warrants patient screening to identify those who, based on B-cell receptor activation modes, most likely benefit from BTK inhibitors.

Summary: Recent developments in BTK-based therapeutic strategies have undoubtedly changed the way we approach lymphoma therapy. As of yet, there is no cure for indolent lymphoma, and the future of BTK inhibitor therapy will undoubtedly include rational combinations to exploit synthetic lethality in distinct lymphoma subsets.

aDepartment of Hematology, IUC Toulouse-Oncopole, and Cancer Research Center of Toulouse (CRCT), INSERM UMR1037-CNRS ERL5294, Toulouse

bService d’Hématologie, Centre Hospitalier Lyon Sud, Pierre Bénite, France

Correspondence to Anne-Sophie Michallet, Centre Hospitalier Lyon Sud, 165 chemin du Grand Revoyet, 69495 Pierre Bénite, France. Tel: +33 478864379; fax: +33 478864326; e-mail: anne-sophie.michallet@chu-lyon.fr

© 2014 Lippincott Williams & Wilkins, Inc.