title: Rapid mobilization of cytotoxic lymphocytes induced by dasatinib therapy.
abstract: Tyrosine kinase inhibitors (TKIs) have potent effects on malignant cells, and they also target kinases in normal cells, which may have therapeutic implications. Using a collection of 55 leukemia patients treated with TKI therapy (chronic myeloid leukemia, n=47; acute lymphoblastic leukemia, n=8), we found that dasatinib, a second-generation broad-spectrum TKI, induced a rapid, dose-dependent and substantial mobilization of non-leukemic lymphocytes and monocytes in blood peaking 1-2 h after an oral intake and the blood counts closely mirrored drug plasma concentration. A preferential mobilization was observed for natural killer (NK), NK T, B and γδ+ T cells. Mobilization was coupled with a more effective transmigration of leukocytes through an endothelial cell layer and improved cytotoxicity of NK cells. Platelet numbers decreased markedly after the drug intake in a proportion of patients. Similar effects on blood cell dynamics and function were not observed with any other TKI (imatinib, nilotinib and bosutinib). Thus, dasatinib induces a unique, rapid mobilization and activation of cytotoxic, extravasation-competent lymphocytes, which may not only enhance antileukemia immune responses but can also be causally related to the side-effect profile of the drug (pleural effusions, thrombocytopenia).
authors.affiliation: Hematology Research Unit Helsinki, Department of Medicine, Division of Hematology, University of Helsinki and Helsinki University Central Hospital (HUCH), Helsinki, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Mustjoki
authors.forename: K
authors.initials: K
authors.lastname: Auvinen
authors.forename: A
authors.initials: A
authors.lastname: Kreutzman
authors.forename: P
authors.initials: P
authors.lastname: Rousselot
authors.forename: S
authors.initials: S
authors.lastname: Hernesniemi
authors.forename: T
authors.initials: T
authors.lastname: Melo
authors.forename: A-M
authors.initials: AM
authors.lastname: Lahesmaa-Korpinen
authors.forename: S
authors.initials: S
authors.lastname: Hautaniemi
authors.forename: S
authors.initials: S
authors.lastname: Bouchet
authors.forename: M
authors.initials: M
authors.lastname: Molimard
authors.forename: R
authors.initials: R
authors.lastname: Smykla
authors.forename: F Y
authors.initials: FY
authors.lastname: Lee
authors.forename: J
authors.initials: J
authors.lastname: Vakkila
authors.forename: S
authors.initials: S
authors.lastname: Jalkanen
authors.forename: M
authors.initials: M
authors.lastname: Salmi
authors.forename: K
authors.initials: K
authors.lastname: Porkka
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics; D000069439:Dasatinib; D020869:Gene Expression Profiling; D006801:Humans; D016130:Immunophenotyping; D020014:K562 Cells; D008297:Male; D011743:Pyrimidines / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D011743:Pyrimidines; D013844:Thiazoles; D000069439:Dasatinib