Mechanisms of ibrutinib resistance in chronic lymphocytic leukaemia and non-Hodgkin lymphoma

Bruton tyrosine kinase (BTK), a mediator of B-cell receptor (BCR) signalling, has been implicated in the pathogenesis of chronic lymphocytic leukaemia (CLL) and other B-cell malignancies. Ibrutinib is an orally bioavailable and highly specific BTK inhibitor that was recently approved for treatment of patients with recurrent CLL and mantle cell lymphoma (MCL). In addition, ibrutinib has shown efficacy in subsets of patients with diffuse large B cell lymphoma (DLBCL) and Waldenstrom macroglobulinaemia (WM). However, despite ibrutinib's activity in multiple B-cell malignancies, cases of primary and secondary resistance have emerged. The overall reported frequency of resistance is low, but follow-up in many trials was short, and we predict that the incidence of observed resistance will increase as clinical use outside clinical trials expands over time. Mutations within BTK have been described and clearly interfere with drug binding; however, there are also emerging alternative mechanisms that bypass BTK entirely and offer new opportunities for other targeted agents. Improved understanding of mechanisms of primary and secondary resistance is essential to developing appropriate therapeutic strategies to both prevent and address resistance. This review provides a comprehensive analysis of ibrutinib resistance in CLL, MCL, DLBCL and WM and considers potential strategies for further study.