Ibrutinib resistance in mantle cell lymphoma: clinical, molecular and treatment aspects

Mantle cell lymphoma (MCL) is a lymphoproliferative disorder comprising about 6-10% of all B cell lymphoma cases. Ibrutinib is an inhibitor of Bruton tyrosine kinase (BTK), a key component of early B-cell receptor (BCR) signalling pathways. Although treatment with ibrutinib has significantly improved the outcome of MCL patients, approximately one-third of the patients have primary drug resistance while others appear to develop acquired resistance. Understanding the molecular events leading to the primary and acquired resistance to ibrutinib is essential for achieving better outcomes in patients with MCL. In this review, we describe the biology of the BCR signalling pathway and summarize the landmark clinical trials that have led to the approval of ibrutinib. We review the molecular mechanisms underlying primary and acquired ibrutinib resistance as well as recent studies dealing with overcoming ibrutinib resistance.