Mechanisms of ibrutinib resistance in chronic lymphocytic leukemia and alternative treatment strategies

Introduction Development of the BTK inhibitor ibrutinib has changed the landscape of CLL treatment producing durable responses with minimal to no myelosuppression. Although remissions are durable, relapses remain a challenge. Areas covered Data from recent studies indicate that most patients relapsing on ibrutinib have mutations in BTK or PLCG2. The result of the C418S mutation in BTK is loss of covalent binding of ibrutinib to BTK resulting in reversible, transient inhibition in BTK mutant patients. There is downstream gain of function of BCR signaling with PLCG2 mutations allowing continued cell proliferation despite inhibition of BTK by ibrutinib. Agents targeting other pathways such as the BCL2 pathway, or agents binding to other BTK binding sites are promising therapies in patients with BTK-mutated resistance. Authors conducted a review of available literature on mechanism of ibrutinib resistance and management using PubMed, Medline, EMBASE, Cochrane Central, Google Scholar, and ClinicalTrials.gov. Expert opinion The current approach is to offer a clinical trial or the BCL2 inhibitor venetoclax to patients with ibrutinib-resistant CLL. We await more data from ongoing clinical trials combining different targeted therapies or using reversible BTK inhibitors will provide more options for overcoming ibrutinib resistance.