Hanna L M Rajala1, Mohamed El Missiry1, Anniina Ruusila1, Perttu Koskenvesa1, Tim H Brümmendorf2, Bjorn T Gjertsen3, Jeroen Janssen4, Kourosh Lotfi5, Berit Markevärn3, Ulla Olsson-Strömberg6, Leif Stenke7, Jesper Stentoft8, Johan Richter9, Henrik Hjorth-Hansen10,11, Anna Kreutzman1,12, Satu Mustjoki13,14. 1. Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Haartmaninkatu 8, 00290, Helsinki, Finland. 2. Internal Medicine IV (Oncology, Hematology and Stem Cell Transplantation), University Hospital Aachen (RWTH), Aachen, Germany. 3. Institute of Medicine, Hematology Section, University of Bergen, Bergen, Norway. 4. Department of Hematology, VU University Medical Center, Amsterdam, Netherlands. 5. Department of Hematology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. 6. Department of Medical Science, Uppsala University Hospital, Uppsala, Sweden. 7. Department of Medicine, Division of Hematology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden. 8. Department of Hematology, Aarhus University Hospital, Aarhus, Denmark. 9. Department of Hematology, Oncology and Radiation Physics, Skane University Hospital, Lund, Sweden. 10. Department of Hematology, St Olavs Hospital, Trondheim, Norway. 11. Department of Cancer Research and Molecular Medicine, NTNU, Trondheim, Norway. 12. Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland. 13. Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Haartmaninkatu 8, 00290, Helsinki, Finland. satu.mustjoki@helsinki.fi. 14. Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland. satu.mustjoki@helsinki.fi.
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.
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.
Entities:
Keywords:
B cell; CML; Immunoglobulin; Tyrosine kinase inhibitor
Authors: Moshe Talpaz; Neil P Shah; Hagop Kantarjian; Nicholas Donato; John Nicoll; Ron Paquette; Jorge Cortes; Susan O'Brien; Claude Nicaise; Eric Bleickardt; M Anne Blackwood-Chirchir; Vishwanath Iyer; Tai-Tsang Chen; Fei Huang; Arthur P Decillis; Charles L Sawyers Journal: N Engl J Med Date: 2006-06-15 Impact factor: 91.245
Authors: H Jean Khoury; Jorge E Cortes; Hagop M Kantarjian; Carlo Gambacorti-Passerini; Michele Baccarani; Dong-Wook Kim; Andrey Zaritskey; Athena Countouriotis; Nadine Besson; Eric Leip; Virginia Kelly; Tim H Brümmendorf Journal: Blood Date: 2012-02-27 Impact factor: 22.113
Authors: Hagop M Kantarjian; Francis J Giles; Kapil N Bhalla; Javier Pinilla-Ibarz; Richard A Larson; Norbert Gattermann; Oliver G Ottmann; Andreas Hochhaus; Jerald P Radich; Giuseppe Saglio; Timothy P Hughes; Giovanni Martinelli; Dong-Wook Kim; Yaping Shou; Neil J Gallagher; Rick Blakesley; Michele Baccarani; Jorge Cortes; Philipp D le Coutre Journal: Blood Date: 2010-11-22 Impact factor: 22.113
Authors: Johanna M Duyvestyn; Samuel J Taylor; Samantha A Dagger; Marlene Orandle; Herbert C Morse; Christine B F Thien; Wallace Y Langdon Journal: PLoS One Date: 2014-04-09 Impact factor: 3.240
Authors: Jani Huuhtanen; Mette Ilander; Bhagwan Yadav; Olli Mj Dufva; Hanna Lähteenmäki; Tiina Kasanen; Jay Klievink; Ulla Olsson-Strömberg; Jesper Stentoft; Johan Richter; Perttu Koskenvesa; Martin Höglund; Stina Söderlund; Arta Dreimane; Kimmo Porkka; Tobias Gedde-Dahl; Björn T Gjertsen; Leif Stenke; Kristina Myhr-Eriksson; Berit Markevärn; Anna Lübking; Andreja Dimitrijevic; Lene Udby; Ole Weis Bjerrum; Henrik Hjorth-Hansen; Satu Mustjoki Journal: J Clin Invest Date: 2022-09-01 Impact factor: 19.456
Authors: Hans-Hartmut Peter; Hans D Ochs; Charlotte Cunningham-Rundles; Donald C Vinh; Peter Kiessling; Bernhard Greve; Stephen Jolles Journal: J Allergy Clin Immunol Date: 2020-09 Impact factor: 10.793