Rapid mobilization of cytotoxic lymphocytes induced by dasatinib therapy

S Mustjoki, K Auvinen, A Kreutzman, P Rousselot… - Leukemia, 2013 - nature.com
S Mustjoki, K Auvinen, A Kreutzman, P Rousselot, S Hernesniemi, T Melo…
Leukemia, 2013nature.com
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 …
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).
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