title: Imatinib mesylate in idiopathic and postpolycythemic myelofibrosis.
abstract: Imatinib mesylate targets the adenosine triphosphate (ATP)-binding sites of the protein tyrosine kinase domains associated with Bcr-abl, the platelet-derived growth factor (PDGF) and c-kit. In idiopathic myelofibrosis (IMF) PDGF is considered to be one of the growth factors responsible for the development of bone marrow fibrosis. Recently, it has been shown that imatinib has antifibrogenic effect on bone marrow fibrosis in chronic myelogenous leukemia. Treatment with imatinib alone in IMF has been associated with significant side effects. In this study, the safety and efficacy of imatinib therapy in IMF, either administered as a single agent or in combination with hydroxyurea (HU) and/or alpha-interferon (IFN-alpha) are evaluated. Eleven patients (median age, 63 years; range, 33-82 years) with IMF (n = 8) or postpolycythemic myelofibrosis (PPMF) (n = 3) were studied All patients had been treated with HU (n = 9) and/or IFN (n = 7) before study entry. In all but one patient, treatment with these agents was discontinued when imatinib therapy was instituted. One patient continued IFN when treatment with imatinib was started. Imatinib was given at a dose of 400 mg/day. Nine patients were in an advanced disease phase. The patients have been followed for a median period of 2 months (range, 0.5-12 months). Treatment with imatinib has been stopped in six patients (55%), because of overt side effects (n = 4), recurrence of transitory dizziness and visual defects owing to a rising platelet count (n = 1), or the occurrence of an acute subdural hemorrhage that was evacuated without neurological deficits (n = 1). In nine patients imatinib treatment was followed by a rise in leukocyte and platelet counts that required combination with HU or IFN. The combined treatment modalities were followed by a rapid decrease in cell counts and were well tolerated apart from IFN side effects. A beneficial effect of imatinib was documented in three patients. It is concluded that leukocytosis and thrombocytosis are seen in most patients with myelofibrosis during treatment with imatinib. Combination therapy with HU or IFN seems safe and well tolerated and followed by a decrease in disease activity. A subgroup of patients in an early disease phase might benefit from imatinib therapy alone.
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, Roskilde Hospital, Denmark.
authors.forename: Hans Carl
authors.initials: HC
authors.lastname: Hasselbalch
authors.forename: Ole Weiss
authors.initials: OW
authors.lastname: Bjerrum
authors.forename: Bjarne Anker
authors.initials: BA
authors.lastname: Jensen
authors.forename: Nielsaage Tøffner
authors.initials: NT
authors.lastname: Clausen
authors.forename: Per Boye
authors.initials: PB
authors.lastname: Hansen
authors.forename: Henrik
authors.initials: H
authors.lastname: Birgens
authors.forename: Marianne Hamilton
authors.initials: MH
authors.lastname: Therkildsen
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ralfkiaer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000633:toxicity; D001549:Benzamides; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use; D000068877:Imatinib Mesylate; D016898:Interferon-alpha / Q000627:therapeutic use; D007964:Leukocytosis / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage* / Q000633:toxicity*; D011086:Polycythemia / Q000150:complications; D055728:Primary Myelofibrosis / Q000188:drug therapy* / Q000209:etiology; D011743:Pyrimidines / Q000008:administration & dosage* / Q000633:toxicity*; D013922:Thrombocytosis / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D001549:Benzamides; D016898:Interferon-alpha; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D006918:Hydroxyurea