title: Expansion of highly differentiated CD8+ T-cells or NK-cells in patients treated with dasatinib is associated with cytomegalovirus reactivation.
abstract: The tyrosine kinase inhibitor dasatinib exerts immunosuppressive effects on T-cells and NK-cells in vitro. However, in some dasatinib-treated leukemia patients, clonal lymphocytosis with large granular lymphocyte (LGL) morphology develops, and this is associated with enhanced therapeutic responses. To elucidate the mechanistic basis for this paradoxical observation, we conducted detailed phenotypic and functional analyses of T-cell and NK-cell populations from 25 dasatinib-treated leukemia patients. All tested patients with LGL expansions (15/16) were cytomegalovirus (CMV) immunoglobulin (IgG) seropositive with high frequencies of CMV-specific CD8(+) T-cells; 5/16 LGL patients also experienced symptomatic CMV reactivation during dasatinib therapy. Expanded T-cell and NK-cell populations exhibited late differentiated (CD27(-)CD57(+)) phenotypes; this was associated with a predisposition to apoptosis within the T-cell compartment and impaired NK-cell cytotoxicity. Only 3/9 non-LGL patients were CMV IgG seropositive. Dasatinib inhibited in vitro lymphocyte functions, similarly in LGL patients and controls. Notably, distinct CD8(high) and CD8(low) T-cell subsets were observed in LGL patients; this phenotypic dichotomy was also apparent in CMV-specific CD8(+) T-cell populations, and exhibited features consistent with antigen-driven activation. In addition, plasma levels of IP-10, IL-6, monokine induced by interferon-γ and interleukin-2R were significantly increased in LGL patients. These data provide evidence that dasatinib-associated LGL expansion is linked to CMV reactivation and suggest a potential mechanism for this phenomenon.
authors.affiliation: Hematology Research Unit, Biomedicum Helsinki, Department of Medicine, Division of Hematology, Helsinki University Central Hospital (HUCH) and University of Helsinki, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Kreutzman
authors.forename: K
authors.initials: K
authors.lastname: Ladell
authors.forename: C
authors.initials: C
authors.lastname: Koechel
authors.forename: E
authors.initials: E
authors.lastname: Gostick
authors.forename: M
authors.initials: M
authors.lastname: Ekblom
authors.forename: L
authors.initials: L
authors.lastname: Stenke
authors.forename: T
authors.initials: T
authors.lastname: Melo
authors.forename: H
authors.initials: H
authors.lastname: Einsele
authors.forename: K
authors.initials: K
authors.lastname: Porkka
authors.forename: D A
authors.initials: DA
authors.lastname: Price
authors.forename: S
authors.initials: S
authors.lastname: Mustjoki
authors.forename: R
authors.initials: R
authors.lastname: Seggewiss
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D002455:Cell Division; D003587:Cytomegalovirus / Q000502:physiology*; D017931:DNA Primers; D000069439:Dasatinib; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology*; D007938:Leukemia / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011743:Pyrimidines / Q000009:adverse effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013844:Thiazoles / Q000009:adverse effects*; D014775:Virus Activation
chemical_list: D017931:DNA Primers; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000069439:Dasatinib