Rapid mobilization of cytotoxic lymphocytes induced by dasatinib therapy

Tyrosine kinase inhibitors (TKIs) have potent effects on malignant cells, and they also target kinases in normal cells, which mayhave therapeutic implications. Using a collection of 55 leukemia patients treated with TKI therapy (chronic myeloid leukemia,n¼47; acute lymphoblastic leukemia, n¼8), we found that dasatinib, a second-generation broad-spectrum TKI, induced arapid, dose-dependent and substantial mobilization of non-leukemic lymphocytes and monocytes in blood peaking 1–2h after anoral intake and the blood counts closely mirrored drug plasma concentration. A preferential mobilization was observed for naturalkiller (NK), NK T, B and gdþ T cells. Mobilization was coupled with a more effective transmigration of leukocytes through anendothelial cell layer and improved cytotoxicity of NK cells. Platelet numbers decreased markedly after the drug intake in aproportion 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-competentlymphocytes, which may not only enhance antileukemia immune responses but can also be causally related to the side-effectprofile of the drug (pleural effusions, thrombocytopenia).Leukemia advance online publication, 8 January 2013; doi:10.1038/leu.2012.348Keywords: lymphocyte; mobilization; immune activation; CML; dasatinibINTRODUCTIONTyrosine kinase inhibitors (TKIs) are the first molecularly targeteddrugs that have entered into a widespread clinical use in treatingselected malignancies, such as kidney, lung and blood cancers. Inparticular, TKIs have significantly improved the outcome ofchronic myeloid leukemia (CML) and Philadelphia-chromosome-positive (Phþ) acute lymphoblastic leukemia (ALL) and currentlyare the standard first-line therapy for these disorders.