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

Mustjoki, S.; Ekblom, Marja LU ; Arstila, T. P.; Dybedal, I.; Epling-Burnette, P. K.; Guilhot, F.; Hjorth-Hansen, H.; Hoglund, M.; Kovanen, P. and Laurinolli, T., et al. (2009) In Leukemia 23(8). p.1398-1405
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 x 10(9)/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... (More)
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 x 10(9)/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. Leukemia (2009) 23, 1398-1405; doi:10.1038/leu.2009.46; published online 19 March 2009 (Less)
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Contribution to journal
publication status
published
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keywords
Ph plus leukemia, TKI therapy, immunomodulation, dasatinib
in
Leukemia
volume
23
issue
8
pages
1398 - 1405
publisher
Nature Publishing Group
external identifiers
  • wos:000268862000005
  • scopus:68749108104
ISSN
1476-5551
DOI
10.1038/leu.2009.46
language
English
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yes
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f635f2cb-0638-4e22-adf6-fccd64151250 (old id 1478172)
date added to LUP
2009-09-23 09:12:31
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2017-12-10 04:00:41
@article{f635f2cb-0638-4e22-adf6-fccd64151250,
  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 x 10(9)/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. Leukemia (2009) 23, 1398-1405; doi:10.1038/leu.2009.46; published online 19 March 2009},
  author       = {Mustjoki, S. and Ekblom, Marja and Arstila, T. P. and Dybedal, I. and Epling-Burnette, P. K. and Guilhot, F. and Hjorth-Hansen, H. and Hoglund, M. and Kovanen, P. and Laurinolli, T. and Liesveld, J. and Paquette, R. and Pinilla-Ibarz, J. and Rauhala, A. and Shah, N. and Simonsson, B. and Sinisalo, M. and Steegmann, J. L. and Stenke, L. and Porkka, K.},
  issn         = {1476-5551},
  keyword      = {Ph plus leukemia,TKI therapy,immunomodulation,dasatinib},
  language     = {eng},
  number       = {8},
  pages        = {1398--1405},
  publisher    = {Nature Publishing Group},
  series       = {Leukemia},
  title        = {Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy},
  url          = {http://dx.doi.org/10.1038/leu.2009.46},
  volume       = {23},
  year         = {2009},
}