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Therapy

Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy

Leukemia volume 23, pages 1398–1405 (2009)Cite this article

Abstract

Dasatinib, a broad-spectrum tyrosine kinase inhibitor (TKI), predominantly targets BCR-ABL and SRC oncoproteins and also inhibits off-target kinases, which may result in unexpected drug responses. We identified 22 patients with marked lymphoproliferation in blood while on dasatinib therapy. Clonality and immunophenotype were analyzed and related clinical information was collected. An abrupt lymphocytosis (peak count range 4–20 × 109/l) with large granular lymphocyte (LGL) morphology was observed after a median of 3 months from the start of therapy and it persisted throughout the therapy. Fifteen patients had a cytotoxic T-cell and seven patients had an NK-cell phenotype. All T-cell expansions were clonal. Adverse effects, such as colitis and pleuritis, were common (18 of 22 patients) and were preceded by LGL lymphocytosis. Accumulation of identical cytotoxic T cells was also detected in pleural effusion and colon biopsy samples. Responses to dasatinib were good and included complete, unexpectedly long-lasting remissions in patients with advanced leukemia. In a phase II clinical study on 46 Philadelphia chromosome-positive acute lymphoblastic leukemia, patients with lymphocytosis had superior survival compared with patients without lymphocytosis. By inhibiting immunoregulatory kinases, dasatinib may induce a reversible state of aberrant immune reactivity associated with good clinical responses and a distinct adverse effect profile.

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Acknowledgements

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, Blood Disease Foundation and KA Johansson Foundation. We would like to thank Professors P Ljungman and J Viikari and Drs J Vakkila and F Lee for valuable comments on the paper and Drs A Almqvist, F Ebeling, F Garzon, T Gedde-Dahl, E Koivunen, P Koskenvesa, J Laine and T Lundan for help with the patient data collection and Dr T Olofsson for providing patient sample material. Personnel at the Hematology Research Unit Helsinki and flow cytometry laboratory, HUSLAB are acknowledged for their expert technical assistance. This study is an European Leukemia Networking party 4 deliverable.

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Authors and Affiliations

  1. Hematology Research Unit, Biomedicum Helsinki, Helsinki University Central Hospital, Helsinki, Finland

    S Mustjoki & K Porkka

  2. Division of Hematology, Department of Medicine and Department of Clinical Chemistry, HUCH, Helsinki, Finland

    S Mustjoki & K Porkka

  3. Lund University Central Hospital, Lund, Sweden

    M Ekblom

  4. Department of Immunology and Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland

    T P Arstila, P Kovanen & T Laurinolli

  5. Rikshospitalet University Hospital, Oslo, Norway

    I Dybedal

  6. Immunology Program and Malignant Hematology Division, H Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL, USA

    P K Epling-Burnette & J Pinilla-Ibarz

  7. Clinical Investigation Centre INSERM, Poitiers, France

    F Guilhot

  8. Department of Hematology, St Olavs Hospital and Department of Molecular Medicine and Cancer Research, Norwegian University of Science and Technology (NTNU), Trondheim, Norway

    H Hjorth-Hansen

  9. Uppsala University Hospital, Uppsala, Sweden

    M Höglund & B Simonsson

  10. Department of Medicine, University of Rochester, Rochester, NY, USA

    J Liesveld

  11. University of California at Los Angeles, Los Angeles, CA, USA

    R Paquette

  12. Vaasa Central Hospital, Vaasa, Finland

    A Rauhala

  13. University of California at San Francisco, San Francisco, CA, USA

    N Shah

  14. Tampere University Hospital, Tampere, Finland

    M Sinisalo

  15. La Princesa University Hospital, Madrid, Spain

    J L Steegmann

  16. Karolinska University Hospital, Stockholm, Sweden

    L Stenke

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  1. S Mustjoki
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Correspondence to K Porkka.

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The authors declare that there is no conflict of interest.

Supplementary information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Mustjoki, S., Ekblom, M., Arstila, T. et al. Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy. Leukemia 23, 1398–1405 (2009). https://doi.org/10.1038/leu.2009.46

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