title: Tyrosine kinase inhibitors impair B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling.
abstract: Tyrosine kinase inhibitors (TKIs) have significant off-target multikinase inhibitory effects. We aimed to study the impact of TKIs on the in vivo B-cell response to vaccination. Cellular and humoral responses to influenza and pneumococcal vaccines were evaluated in 51 chronic phase chronic myeloid leukemia (CML) patients on imatinib, or second-line dasatinib and nilotinib, and 24 controls. Following vaccination, CML patients on TKI had significant impairment of IgM humoral response to pneumococcus compared with controls (IgM titer 79.0 vs 200 U/mL, P = .0006), associated with significantly lower frequencies of peripheral blood IgM memory B cells. To elucidate whether CML itself or treatment with TKI was responsible for the impaired humoral response, we assessed memory B-cell subsets in paired samples collected before and after imatinib therapy. Treatment with imatinib was associated with significant reductions in IgM memory B cells. In vitro coincubation of B cells with plasma from CML patients on TKI or with imatinib, dasatinib, or nilotinib induced significant and dose-dependent inhibition of Bruton's tyrosine kinase and indirectly its downstream substrate, phospholipase-C-γ2, both important in B-cell signaling and survival. These data indicate that TKIs, through off-target inhibition of kinases important in B-cell signaling, reduce memory B-cell frequencies and induce significant impairment of B-cell responses in CML.
authors.affiliation: Department of Haematology, Imperial College London, Hammersmith Hospital, London, United Kingdom.
authors.forename: Hugues
authors.initials: H
authors.lastname: de Lavallade
authors.forename: Ahmad
authors.initials: A
authors.lastname: Khoder
authors.forename: Melanie
authors.initials: M
authors.lastname: Hart
authors.forename: Anushruti
authors.initials: A
authors.lastname: Sarvaria
authors.forename: Takuya
authors.initials: T
authors.lastname: Sekine
authors.forename: Abdullah
authors.initials: A
authors.lastname: Alsuliman
authors.forename: Stephan
authors.initials: S
authors.lastname: Mielke
authors.forename: Alexandra
authors.initials: A
authors.lastname: Bazeos
authors.forename: Kate
authors.initials: K
authors.lastname: Stringaris
authors.forename: Sara
authors.initials: S
authors.lastname: Ali
authors.forename: Dragana
authors.initials: D
authors.lastname: Milojkovic
authors.forename: Letizia
authors.initials: L
authors.lastname: Foroni
authors.forename: Aristeidis
authors.initials: A
authors.lastname: Chaidos
authors.forename: Nichola
authors.initials: N
authors.lastname: Cooper
authors.forename: Ian
authors.initials: I
authors.lastname: Gabriel
authors.forename: Jane
authors.initials: J
authors.lastname: Apperley
authors.forename: Sarah
authors.initials: S
authors.lastname: Belsey
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Flanagan
authors.forename: John
authors.initials: J
authors.lastname: Goldman
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Shpall
authors.forename: Peter
authors.initials: P
authors.lastname: Kelleher
authors.forename: David
authors.initials: D
authors.lastname: Marin
authors.forename: Katayoun
authors.initials: K
authors.lastname: Rezvani
mesh_terms: D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000276:immunology; D007075:Immunoglobulin M / Q000097:blood / Q000276:immunology; D007156:Immunologic Memory / Q000187:drug effects; D007252:Influenza Vaccines / Q000276:immunology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D051966:Phospholipase C gamma / Q000037:antagonists & inhibitors; D010766:Phosphorylation / Q000187:drug effects; D022242:Pneumococcal Vaccines / Q000276:immunology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D007075:Immunoglobulin M; D007252:Influenza Vaccines; D022242:Pneumococcal Vaccines; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; D051966:Phospholipase C gamma