Ibrutinib Resistance in Chronic Lymphocytic Leukemia

• Published in: The New England journal of medicine Vol. 370; no. 24; pp. 2352 - 2354
• Main Authors: Furman, Richard R, Cheng, Shuhua, Lu, Pin, Setty, Menu, Perez, Alexendar R, Guo, Ailin, Racchumi, Joelle, Xu, Guozhou, Wu, Hao, Ma, Jiao, Steggerda, Susanne M, Coleman, Morton, Leslie, Christina, Wang, Y. Lynn
• Format: Journal Article
• Language: English
• Published: United States Massachusetts Medical Society 12.06.2014
• Subjects: Agammaglobulinaemia Tyrosine Kinase; Amino acids; Bruton's tyrosine kinase; Chronic lymphocytic leukemia; Drug Resistance, Neoplasm - genetics; Female; Humans; Kinases; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Lymphatic leukemia; Lymphocytes; Middle Aged; Mutation; Phosphorylation; Point Mutation; Protein-tyrosine kinase; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - chemistry; Protein-Tyrosine Kinases - metabolism; Pyrazoles - metabolism; Pyrazoles - therapeutic use; Pyrimidines - metabolism; Pyrimidines - therapeutic use; Receptors, Antigen, B-Cell - metabolism; Recurrence; Sequence Analysis, DNA; Serine
• ISSN: 0028-4793; 1533-4406
• DOI: 10.1056/NEJMc1402716

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. . . .