Ibrutinib Resistance in Chronic Lymphocytic Leukemia

Ibrutinib, a Bruton's tyrosine kinase inhibitor, is active in CLL, but resistance may emerge. The authors observed the emergence of a CLL clone with a cysteine-to-serine change in amino acid 481 of the target protein that substantially weakens drug binding and leads to resistance. To the Editor: Ibrutinib, an inhibitor that binds covalently to C481 of Bruton's tyrosine kinase (BTK), has produced remarkable responses in patients with relapsed and refractory chronic lymphocytic leukemia (CLL). 1 – 4 However, 5.3% of patients have disease progression, and the mechanism of resistance is largely unknown. Herein we describe the mechanism of resistance in such a case. A 49-year-old woman had a diagnosis of CLL established in 2000. After the failure of multiple treatments, she began receiving ibrutinib at a dose of 560 mg daily in 2010 as part of a phase 1, dose-escalation study of ibrutinib in B-cell cancers. . . .