Journal
LEUKEMIA
Volume 27, Issue 4, Pages 914-924Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2012.348
Keywords
lymphocyte; mobilization; immune activation; CML; dasatinib
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Funding
- Novartis
- Bristol-Myers Squibb
- Finnish special governmental subsidy for health sciences, research and training
- Finnish Cancer Societies
- Emil Aaltonen Foundation
- Academy of Finland
- Finnish Medical Foundation
- Sigrid Juselius Foundation
- Biocentrum Helsinki
- Gyllenberg Foundation
- Blood Disease Foundation
- KA Johansson Foundation
- Cancer Foundation Finland sr [110101, 100118] Funding Source: researchfish
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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 gamma delta+ 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). Leukemia (2013) 27, 914-924; doi:10.1038/leu.2012.348
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