Beyond Bruton's tyrosine kinase inhibitors in mantle cell lymphoma: bispecific antibodies, antibody-drug conjugates, CAR T-cells, and novel agents.

Mantle cell lymphoma is a B cell non-Hodgkin lymphoma (NHL), representing 2-6% of all NHLs and characterized by overexpression of cyclin D1. The last decade has seen the development of many novel treatment approaches in MCL, most notably the class of Bruton's tyrosine kinase inhibitors (BTKi). BTKi has shown excellent outcomes for patients with relapsed or refractory MCL and is now being studied in the first-line setting. However, patients eventually progress on BTKi due to the development of resistance. Additionally, there is an alteration in the tumor microenvironment in these patients with varying biological and therapeutic implications. Hence, it is necessary to explore novel therapeutic strategies that can be effective in those who progressed on BTKi or potentially circumvent resistance. In this review, we provide a brief overview of BTKi, then discuss the various mechanisms of BTK resistance including the role of genetic alteration, cancer stem cells, tumor microenvironment, and adaptive reprogramming bypassing the effect of BTK inhibition, and then provide a comprehensive review of current and emerging therapeutic options beyond BTKi including novel agents, CAR T cells, bispecific antibodies, and antibody-drug conjugates.