Beyond Chronic Myelogenous Leukemia: Potential Role for Imatinib in Philadelphia-Negative Myeloproliferative Disorders

Jorge Cortes, Hagop Kantarjian

Research output: Contribution to journalReview article

Abstract

The myeloproliferative disorders (MPDs) are chronic malignant conditions originating from the clonal expansion of a multipotential hematopoietic stem cell. These diseases include polycythemia vera (PV), essential thrombocythenia, atypical chronic myeloid leukemia, idiopathic hypereosinophilic syndrome (HES), agnogenic myeloid metaplasia with myelofibrosis, and others. Receptor tyrosine kinases-the platelet-derived growth factor receptors (PDGFRs) and c-Kit-and their respective ligands have been implicated in the pathogenesis of MPDs. For example, a constitutively activated PDGFR fusion tyrosine kinase (FIP1L1-PDG-FRA) was identified in some patients with HES, a disease characterized by sustained overproduction of eosinophils that has been classified by the World Health Organization as a chronic subtype of the MPDs. Imatinib is a selective inhibitor of PDGFRs, c-Kit, Abl and Arg protein-tyrosine kinases, as well as Bcr-Abl, the oncogenic tyrosine kinase that causes chronic myeloid leukemia. The efficacy of imatinib in treating HES, systemic mast cell disease, chronic myelomonocytic leukemia associated with PDGFRβ fusion genes, and (to a lesser extent) PV and idiopathic myelofibrosis was reviewed from institutional experience and a review of the literature. In 3 studies that involved 11 patients with PV, 10 patients had reductions in phlebotomy with imatinib. Eight studies of 42 patients with HES indicated that 70% achieved complete hematologic remissions with imatinib. Four studies of 6 patients with MPD indicated responses with imatinib in 5 patients. Insight into the molecular pathogenesis of MPDs will improve the definitions of different disease categories and suggests that signal transduction inhibition is likely to be an increasingly important treatment option in the future.

Original languageEnglish (US)
Pages (from-to)2064-2078
Number of pages15
JournalCancer
Volume100
Issue number10
DOIs
StatePublished - May 15 2004
Externally publishedYes

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Myeloproliferative Disorders
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Hypereosinophilic Syndrome
Polycythemia Vera
Primary Myelofibrosis
Platelet-Derived Growth Factor Receptors
Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative
bcr-abl Fusion Proteins
Leukemia, Myelomonocytic, Chronic
Systemic Mastocytosis
Proto-Oncogene Proteins c-fos
Phlebotomy
Gene Fusion
Hematopoietic Stem Cells
Eosinophils
Protein-Tyrosine Kinases
Imatinib Mesylate
Signal Transduction
Ligands

Keywords

  • Drug therapy
  • Hypereosinophilic syndrome
  • Idiopathic myelofibrosis
  • Imatinib
  • Myeloproliferative disorders
  • Polycythemia vera

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Beyond Chronic Myelogenous Leukemia : Potential Role for Imatinib in Philadelphia-Negative Myeloproliferative Disorders. / Cortes, Jorge; Kantarjian, Hagop.

In: Cancer, Vol. 100, No. 10, 15.05.2004, p. 2064-2078.

Research output: Contribution to journalReview article

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abstract = "The myeloproliferative disorders (MPDs) are chronic malignant conditions originating from the clonal expansion of a multipotential hematopoietic stem cell. These diseases include polycythemia vera (PV), essential thrombocythenia, atypical chronic myeloid leukemia, idiopathic hypereosinophilic syndrome (HES), agnogenic myeloid metaplasia with myelofibrosis, and others. Receptor tyrosine kinases-the platelet-derived growth factor receptors (PDGFRs) and c-Kit-and their respective ligands have been implicated in the pathogenesis of MPDs. For example, a constitutively activated PDGFR fusion tyrosine kinase (FIP1L1-PDG-FRA) was identified in some patients with HES, a disease characterized by sustained overproduction of eosinophils that has been classified by the World Health Organization as a chronic subtype of the MPDs. Imatinib is a selective inhibitor of PDGFRs, c-Kit, Abl and Arg protein-tyrosine kinases, as well as Bcr-Abl, the oncogenic tyrosine kinase that causes chronic myeloid leukemia. The efficacy of imatinib in treating HES, systemic mast cell disease, chronic myelomonocytic leukemia associated with PDGFRβ fusion genes, and (to a lesser extent) PV and idiopathic myelofibrosis was reviewed from institutional experience and a review of the literature. In 3 studies that involved 11 patients with PV, 10 patients had reductions in phlebotomy with imatinib. Eight studies of 42 patients with HES indicated that 70{\%} achieved complete hematologic remissions with imatinib. Four studies of 6 patients with MPD indicated responses with imatinib in 5 patients. Insight into the molecular pathogenesis of MPDs will improve the definitions of different disease categories and suggests that signal transduction inhibition is likely to be an increasingly important treatment option in the future.",
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