Tyrosine kinase inhibitor therapy-induced changes in humoral immunity in patients with chronic myeloid leukemia.
OBJECTIVE
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.
Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Haartmaninkatu 8, 00290, Helsinki, Finland.
Hanna L M
HLM
Rajala
Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Haartmaninkatu 8, 00290, Helsinki, Finland.
Mohamed El
ME
Missiry
Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Haartmaninkatu 8, 00290, Helsinki, Finland.
Anniina
A
Ruusila
Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Haartmaninkatu 8, 00290, Helsinki, Finland.
Perttu
P
Koskenvesa
Internal Medicine IV (Oncology, Hematology and Stem Cell Transplantation), University Hospital Aachen (RWTH), Aachen, Germany.
Tim H
TH
Brümmendorf
Institute of Medicine, Hematology Section, University of Bergen, Bergen, Norway.
Bjorn T
BT
Gjertsen
Department of Hematology, VU University Medical Center, Amsterdam, Netherlands.
Jeroen
J
Janssen
Department of Hematology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Kourosh
K
Lotfi
Institute of Medicine, Hematology Section, University of Bergen, Bergen, Norway.
Berit
B
Markevärn
Department of Medical Science, Uppsala University Hospital, Uppsala, Sweden.
Ulla
U
Olsson-Strömberg
Department of Medicine, Division of Hematology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
Leif
L
Stenke
Department of Hematology, Aarhus University Hospital, Aarhus, Denmark.
Jesper
J
Stentoft
Department of Hematology, Oncology and Radiation Physics, Skane University Hospital, Lund, Sweden.
Johan
J
Richter
Department of Hematology, St Olavs Hospital, Trondheim, Norway.|Department of Cancer Research and Molecular Medicine, NTNU, Trondheim, Norway.
Henrik
H
Hjorth-Hansen
Hematology Research Unit Helsinki, Department of Hematology, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Haartmaninkatu 8, 00290, Helsinki, Finland.|Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland.
Anna
A
Kreutzman
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.|Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland. satu.mustjoki@helsinki.fi.
Satu
S
Mustjoki
D000328:Adult; D000814:Aniline Compounds / Q000008:administration & dosage; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D000069439:Dasatinib / Q000008:administration & dosage; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage; D056724:Immunity, Humoral / Q000187:drug effects*; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood* / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000008:administration & dosage; D011804:Quinolines / Q000008:administration & dosage; D016896:Treatment Outcome
D000814:Aniline Compounds; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011804:Quinolines; C471992:bosutinib; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; C498826:nilotinib; D000069439:Dasatinib
B cell; CML; Immunoglobulin; Tyrosine kinase inhibitor