Beyond chronic myelogenous leukemia

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), ag- 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.

Successful Treatment of Chronic Myeloproliferative Disease-unclassifiable (CMPD-U) with No Chromosomal Abnormalities by Imatinib Mesylate

“…This selective activity has translated into remarkable response efficacy in patients with Ph chromosome positive CML (2,3). In addition to its inhibitory activity against cabl and bcr-abl, imatinib also inhibits two other tyrosine kinases, c-kit and platelet-derived growth factor receptor (PDGFR) (4,5,(15)(16)(17). In vitro inhibition of these kinases was achieved at concentrations similar to those required to inhibit bcr-abl, whereas minimal if any inhibition of other tyrosine kinases (e.g., epidermal growth factor receptor, JAK2, c-erbB2) was obtained at these concentrations (15).…”

Developing Target Therapy Against Oncogenic Tyrosine Kinase in Myeloid Maliganacies

“…The clinical efficacy of an ABL kinase inhibitor, imatinib, has been established [21][22][23], and one contemporary issue is against which malignancies other than Ph+ leukemia imatinib is indicated [7,[24][25][26]. The TEL(ETV6) gene is fused with the ABL gene in atypical CML [27].…”

Preclinical and clinical experience with dasatinib in philadelphia chromosome-negative leukemias and myeloid disorders

“…Elevated plasma levels of PDGF found in patients with ET, PV, and PMF is thought to stimulate, along with several other cytokines, bone marrow fibrosis, a process that should be reversible with appropriate treatment (e.g., PDGFR inhibition) [3,36]. The clinical benefits of imatinib in PV have been reported in two studies where treatment with imatinib resulted in the reduction of phlebotomy requirements in some patients [37,38], thought to be the result of its non specific myelosuppressive effect.…”

“…In vitro studies have shown that in addition to Abl, imatinib potently inhibits platelet-derived growth factor receptor (PDGFR) and the class III tyrosine kinase KIT [2], leading to clinical studies of imatinib in other hematologic diseases where these molecular targets may be important [3]. …”