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Chronic Myeloproliferative Neoplasias

Rapid mobilization of cytotoxic lymphocytes induced by dasatinib therapy

Leukemia volume 27, pages 914–924 (2013)Cite this article

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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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Acknowledgements

We thank Kirsi Latvala, Minna Pajuportti, Saara Vaalas, Riikka Sjöroos and Etta Väänänen for expert technical help. This work was supported by the Finnish special governmental subsidy for health sciences, research and training, by the Finnish Cancer Societies, Emil Aaltonen Foundation, Academy of Finland, Finnish Medical Foundation, Sigrid Juselius Foundation, Biocentrum Helsinki, Gyllenberg Foundation, Blood Disease Foundation and KA Johansson Foundation.

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  1. K Auvinen and A Kreutzman: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Division of Hematology, Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Central Hospital (HUCH), Helsinki, Finland

    S Mustjoki, A Kreutzman, S Hernesniemi, J Vakkila & K Porkka

  2. MediCity Research Laboratory, University of Turku, National Institute of Health and Welfare, Turku, Finland

    K Auvinen, S Jalkanen & M Salmi

  3. Service d’Hématologie et d’Oncologie, Hôpital André Mignot Université Versailles Saint Quentin en Yvelines, Le Chesnay, France

    P Rousselot

  4. Hospital de S Joao, Porto, Portugal

    T Melo

  5. Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland

    A-M Lahesmaa-Korpinen & S Hautaniemi

  6. Département de Pharmacologie, Université de Bordeaux, Bordeaux, France

    S Bouchet & M Molimard

  7. Bristol-Myers Squibb Company, Princeton, NJ, USA

    R Smykla & F Y Lee

  8. Department of Medical Microbiology and Immunology, University of Turku, Turku, Finland

    S Jalkanen

  9. Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland

    M Salmi

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  1. S Mustjoki
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Correspondence to K Porkka.

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Competing interests

FL and RS are employed by Bristol-Myers Squibb. SM and KP have received honoraria and research grants from Novartis and Bristol-Myers Squibb.

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Mustjoki, S., Auvinen, K., Kreutzman, A. et al. Rapid mobilization of cytotoxic lymphocytes induced by dasatinib therapy. Leukemia 27, 914–924 (2013). https://doi.org/10.1038/leu.2012.348

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