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-a) 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. Am.

Modern management of myelofibrosis

“…To date, five studies, including a total of 73 IM patients treated with imatinib, have been reported Cortes et al, 2003a;De Angelo et al, 2003;Hasselbalch et al, 2003;Stagno et al, 2004). Side effects were frequent and led to treatment withdrawal in a substantial proportion of patients.…”

Assessment of fibrosis and vascularization of bone marrow stroma of chronic myeloid Leukemia patients treated with imatinib mesylate and their relationship with the cytogenetic response

“…These cells are involved in the release of various elements that compose the extracellular matrix of BM, such as reticulin. IM has an independent anti-fibrotic effect on BM of CML patients, while IFN-a proves ineffective in patients with myelofibrosis at diagnosis (Kantarjianet al, 2005;Buescheet al, 2004;;Mello, 2004;;Klion et al, 2004;Suetterlin et al, 2004;Hasselbach et al, 2003).…”

Advances in the Therapy of Chronic Idiopathic Myelofibrosis

“…Imatinib was administered at doses of 200-800 mg daily, but dropout rates were in excess of 50% across all trials. This was primarily because of a lack of tolerance secondary to edema, fatigue, and musculoskeletal pain [123][124][125][126][127][128][129]. Of note, Hasselbalch et al [128] reported proliferative effects in 9 of 11 patients who received imatinib at a dose of 400 mg daily, requiring hydroxyurea to manage leukocytosis and thrombocytosis.…”

“…This was primarily because of a lack of tolerance secondary to edema, fatigue, and musculoskeletal pain [123][124][125][126][127][128][129]. Of note, Hasselbalch et al [128] reported proliferative effects in 9 of 11 patients who received imatinib at a dose of 400 mg daily, requiring hydroxyurea to manage leukocytosis and thrombocytosis. Preliminary data on the efficacy of imatinib in CIMF reported in the European Myelofibrosis Network (EUMNET) trial documented an increase in the number of clonogenic megakaryocytic progenitors in bone marrow, suggesting that imatinib may restore megakaryocyte differentiation and thus be an effective treatment of thrombocytopenia in patients with CIMF [130].…”

“…Imatinib was tested in patients with CIMF based on its inhibition of PDGF-mediated signaling and the amelioration of bone marrow fibrosis and microvessel density in patients with CML [121,122]. In general, all phase II studies published to date [124][125][126][127][128][129] in patients with CIMF have shown modest results. Only one trial showed a significant improvement in splenomegaly, including four patients (29%) who had a normalization of spleen span [126].…”