Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin lymphoma in which immunochemotherapy +/- high dose therapy and autologous stem cell transplantation remains standard front-line therapy. Despite clear efficacy, patients envitably relapse requiring subsequent therapy. Within this review, we discuss the key therapeutic approaches in the management of patients with relapsed MCL, covering in depth the data supporting the use of covalent Bruton tyrosine kinase (BTK) inhibitors at first or subsequent relapse. We describe the outcomes of patients progressing through BTK inhibitors, discuss mechanisms of covalent BTKi-resistance and treatment options post-covalent BTKi treatment. Options in this setting may depend of treatment availability, patient and physician preference, and patient age and comorbidity status. We discuss the rapid recent development of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in this space as well as the utility of allogenic stem cell transplantation and novel therapies such as non-covalent, reversible BTK inhibitors, ROR1 antibody drug conjugates and bispecific antibodies.

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