title: Ibrutinib Therapy Increases T Cell Repertoire Diversity in Patients with Chronic Lymphocytic Leukemia.
abstract: 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.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77230.|Department of Leukemia, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Henan Institute of Hematology, Zhengzhou, Henan 450009, China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Yin
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77230.
authors.forename: Mariela
authors.initials: M
authors.lastname: Sivina
authors.affiliation: Adaptive Biotechnologies, Seattle, WA 98102; and.|Fred Hutchinson Cancer Research Center, Seattle, WA 98109.
authors.forename: Harlan
authors.initials: H
authors.lastname: Robins
authors.affiliation: Adaptive Biotechnologies, Seattle, WA 98102; and.
authors.forename: Erik
authors.initials: E
authors.lastname: Yusko
authors.affiliation: Adaptive Biotechnologies, Seattle, WA 98102; and.
authors.forename: Marissa
authors.initials: M
authors.lastname: Vignali
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77230.
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77230.
authors.forename: Michael J
authors.identifier: 0000-0002-9121-6450
authors.initials: MJ
authors.lastname: Keating
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77230.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ferrajoli
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77230.
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77230.
authors.forename: Nitin
authors.initials: N
authors.lastname: Jain
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77230.
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77230; jaburger@mdanderson.org.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000368:Aged; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D010880:Piperidines; D011505:Protein-Tyrosine Kinases; D011720:Pyrazoles / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*
chemical_list: D016207:Cytokines; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000225:Adenine