The Bruton’s tyrosine kinase inhibitor ibrutinib is a highly effective, new targeted therapy for chronic lymphocytic leukemia (CLL) that thwarts leukemia cell survival, growth, and tissue homing. The effects of ibrutinib treatment on the T cell compartment, which is clonally expanded and thought to support the growth of malignant B cells in CLL, are not fully characterized. Using next-generation sequencing technology, we characterized the diversity of TCRβ-chains in peripheral blood T cells from 15 CLL patients before and after 1 y of ibrutinib therapy. We noted elevated CD4+ and CD8+ T cell numbers and a restricted TCRβ repertoire in all pretreatment samples. After 1 y of ibrutinib therapy, elevated peripheral blood T cell numbers and T cell–related cytokine levels had normalized, and T cell repertoire diversity increased significantly. Dominant TCRβ clones in pretreatment samples declined or became undetectable, and the number of productive unique clones increased significantly during ibrutinib therapy, with the emergence of large numbers of low-frequency TCRβ clones. Importantly, broader TCR repertoire diversity was associated with clinical efficacy and lower rates of infections during ibrutinib therapy. These data demonstrate that ibrutinib therapy increases diversification of the T cell compartment in CLL patients, which contributes to cellular immune reconstitution.
This work was supported by a Leukemia and Lymphoma Society Scholar Award in Clinical Research (to J.A.B.), a Cancer Center Support Grant (National Cancer Institute Grant P30 CA016672), The University of Texas MD Anderson Cancer Center Moon Shots Program in Chronic Lymphocytic Leukemia, and the National Natural Science Foundation of China (Grant 81000921).
The online version of this article contains supplemental material.
- Received July 8, 2016.
- Accepted December 13, 2016.
- Copyright © 2017 by The American Association of Immunologists, Inc.