Faculty Collaboration Database

BTK^C481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia. J Clin Oncol 2017 May 01;35(13):1437-1443

Date

04/19/2017

Pubmed ID

28418267

Pubmed Central ID

PMC5455463

DOI

10.1200/JCO.2016.70.2282

Scopus ID

2-s2.0-85018308247 (requires institutional sign-in at Scopus site)   349 Citations

Abstract

Purpose Therapeutic targeting of Bruton tyrosine kinase (BTK) with ibrutinib in chronic lymphocytic leukemia has led to a paradigm shift in therapy, and relapse has been uncommon with current follow-up. Acquired mutations in BTK and PLCG2 can cause relapse, but data regarding the prevalence and natural history of these mutations are limited. Patients and Methods Patients accrued to four sequential studies of ibrutinib were included in these analyses. Deep sequencing for BTK and PLCG2 was performed retrospectively on patients who experienced relapse and prospectively on a screening population. Results With a median follow-up time of 3.4 years, the estimated cumulative incidence of progression at 4 years is 19% (95% CI, 14% to 24%). Baseline karyotypic complexity, presence of del(17)(p13.1), and age less than 65 years were risk factors for progression. Among patients who experienced relapse, acquired mutations of BTK or PLCG2 were found in 85% (95% CI, 71% to 94%), and these mutations were detected an estimated median of 9.3 months (95% CI, 7.6 to 11.7 months) before relapse. Of a group of 112 patients examined prospectively, eight patients have experienced relapse, and all of these patients had acquired resistance mutations before relapse. A resistance mutation was detected in an additional eight patients who have not yet met criteria for clinical relapse. Conclusion Relapse of chronic lymphocytic leukemia after ibrutinib is an issue of increasing clinical significance. We show that mutations in BTK and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.

Author List

Woyach JA, Ruppert AS, Guinn D, Lehman A, Blachly JS, Lozanski A, Heerema NA, Zhao W, Coleman J, Jones D, Abruzzo L, Gordon A, Mantel R, Smith LL, McWhorter S, Davis M, Doong TJ, Ny F, Lucas M, Chase W, Jones JA, Flynn JM, Maddocks K, Rogers K, Jaglowski S, Andritsos LA, Awan FT, Blum KA, Grever MR, Lozanski G, Johnson AJ, Byrd JC

Author

Samantha M. Jaglowski MD, MPH Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenine
Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal
Antibodies, Monoclonal, Humanized
Antineoplastic Combined Chemotherapy Protocols
Drug Resistance, Neoplasm
Humans
Leukemia, Lymphocytic, Chronic, B-Cell
Male
Middle Aged
Phospholipase C gamma
Piperidines
Protein-Tyrosine Kinases
Pyrazoles
Pyrimidines