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

Research output: Contribution to journalArticle

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

Details

Authors
  • S. Mustjoki
  • Marja Ekblom
  • T. P. Arstila
  • I. Dybedal
  • P. K. Epling-Burnette
  • F. Guilhot
  • H. Hjorth-Hansen
  • M. Hoglund
  • P. Kovanen
  • T. Laurinolli
  • J. Liesveld
  • R. Paquette
  • J. Pinilla-Ibarz
  • A. Rauhala
  • N. Shah
  • B. Simonsson
  • M. Sinisalo
  • J. L. Steegmann
  • L. Stenke
  • K. Porkka
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology

Keywords

  • Ph plus leukemia, TKI therapy, immunomodulation, dasatinib
Original languageEnglish
Pages (from-to)1398-1405
JournalLeukemia
Volume23
Issue number8
Publication statusPublished - 2009
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Hematopoietic Stem Cell Laboratory (013022012)