Abstract
Purpose
Tyrosine kinase inhibitors (TKIs) have well-characterized immunomodulatory effects on T and NK cells, but the effects on the humoral immunity are less well known. In this project, we studied TKI-induced changes in B cell-mediated immunity.
Methods
We collected peripheral blood (PB) and bone marrow (BM) samples from chronic myeloid leukemia (CML) patients before and during first-line imatinib (n = 20), dasatinib (n = 16), nilotinib (n = 8), and bosutinib (n = 12) treatment. Plasma immunoglobulin levels were measured, and different B cell populations in PB and BM were analyzed with flow cytometry.
Results
Imatinib treatment decreased plasma IgA and IgG levels, while dasatinib reduced IgM levels. At diagnosis, the proportion of patients with IgA, IgG, and IgM levels below the lower limit of normal (LLN) was 0, 11, and 6% of all CML patients, respectively, whereas at 12 months timepoint the proportions were 6% (p = 0.13), 31% (p = 0.042) and 28% (p = 0.0078). Lower initial Ig levels predisposed to the development of hypogammaglobulinemia during TKI therapy. Decreased Ig levels in imatinib-treated patients were associated with higher percentages of immature BM B cells. The patients, who had low Ig levels during the TKI therapy, had significantly more frequent minor infections during the follow-up compared with the patients with normal Ig values (33% vs. 3%, p = 0.0016). No severe infections were reported, except recurrent upper respiratory tract infections in one imatinib-treated patient, who developed severe hypogammaglobulinemia.
Conclusions
TKI treatment decreases plasma Ig levels, which should be measured in patients with recurrent infections.
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Acknowledgements
The authors thank the personnel at the Hematology Research Unit Helsinki, Helsinki University Hospital HUSLAB flow cytometry laboratory, and Aija Helin from HUSLAB for their expert technical assistance. This work was supported by the Academy of Finland, the Finnish Cancer Societies, the Sigrid Juselius Foundation, the Finnish Cancer Institute, the Signe and Ane Gyllenberg Foundation, the Otto A. Malm Foundation, the EUTOS project for CML 2016, and investigator initiated research grants from Pfizer, and Novartis. NordCML Study Group has received research funding from Bristol-Myers Squibb for the NordCML006 and NordCML007 clinical studies.
Funding
This work was supported by the Academy of Finland, the Finnish Cancer Societies, the Sigrid Juselius Foundation, the Finnish Cancer Institute, the Signe and Ane Gyllenberg Foundation, the Otto A. Malm Foundation, the EUTOS project for CML 2016, and investigator initiated research grants from Pfizer and Novartis. NordCML Study Group has received research funding from Bristol-Myers Squibb for the NordCML006 and NordCML007 clinical studies.
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SM, JR, and HHjH have obtained honoraria and research funding from Bristol-Myers Squibb, Novartis, Ariad, and Pfizer.
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments.
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Informed consent was obtained from all individual participants included in the study.
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Rajala, H.L.M., Missiry, M.E., Ruusila, A. et al. Tyrosine kinase inhibitor therapy-induced changes in humoral immunity in patients with chronic myeloid leukemia. J Cancer Res Clin Oncol 143, 1543–1554 (2017). https://doi.org/10.1007/s00432-017-2378-6
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DOI: https://doi.org/10.1007/s00432-017-2378-6