Hematologic and Cytogenetic Responses to Imatinib Mesylate in Chronic Myelogenous Leukemia

Kantarjian, Hagop M.; Sawyers, Charles L.; Hochhaus, Andreas; Guilhot, Joëlle; Schiffer, Charles A.; Gambacorti‐Passerini, Carlo; Niederwieser, Dietger; Resta, Debra; Capdeville, Renaud; Zoellner, Ulrike; Talpaz, Moshe; Druker, Brian J.

doi:10.1056/nejmoa011573

Cited by 1,821 publications

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“…Findings in the current study suggest that imatinib mesylate is a strong antifibrotic agent that is generally well tolerated, as has been confirmed in the treatment of other diseases such as chronic myeloid leukemia (17). Only ϳ1% of patients with chronic myeloid leukemia have had to discontinue the therapy because of side effects (16)(17)(18)(19). Furthermore, imatinib mesylate has favorable pharmacokinetic properties.…”

Section: Discussionsupporting

confidence: 63%

“…Orally administered imatinib mesylate is currently widely used in the treatment of Bcr-Abl-positive chronic myelogenous leukemia and gastrointestinal stromal tumors. Previous clinical trials in patients with chronic myelogenous leukemia demonstrated that it is well tolerated, with adverse side effects leading to discontinuation of the drug in Ͻ1% of patients (16)(17)(18)(19).…”

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confidence: 99%

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Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

Distler¹,

Jüngel²,

Huber³

et al. 2007

Arthritis & Rheumatism

361

273

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Objective. Imatinib mesylate is a clinically welltolerated small molecule inhibitor that exerts selective, dual inhibition of the transforming growth factor ␤ (TGF␤) and platelet-derived growth factor (PDGF) pathways. This study was undertaken to test the potential use of imatinib mesylate as an antifibrotic drug for the treatment of dermal fibrosis in systemic sclerosis (SSc).Methods. The expression of extracellular matrix (ECM) proteins in SSc and normal dermal fibroblasts was analyzed by real-time polymerase chain reaction, Western blot, and Sircol collagen assay. Proliferation capacity was assessed with the MTT assay. Cell viability was analyzed by mitochondrial membrane potential and by annexin V/propidium iodide staining. Bleomycininduced experimental dermal fibrosis was used to assess the antifibrotic effects of imatinib mesylate in vivo.Results. Imatinib mesylate efficiently reduced basal synthesis of COL1A1, COL1A2, and fibronectin 1 messenger RNA in SSc and normal dermal fibroblasts, in a dose-dependent manner. The induction of ECM proteins after stimulation with TGF␤ and PDGF was also strongly and dose-dependently inhibited by imatinib mesylate. These results were confirmed at the protein level. Imatinib mesylate did not alter proliferation or induce apoptosis and necrosis in dermal fibroblasts. Consistent with the in vitro findings, imatinib mesylate reduced dermal thickness, the number of myofibroblasts, and synthesis of ECM proteins in experimental dermal fibrosis, without evidence of toxic side effects. Conclusion. These data show that imatinib mesylate at biologically relevant concentrations has potent antifibrotic effects in vitro and in vivo, without toxic side effects. Considering its favorable pharmacokinetics and clinical experience with its use in other diseases, imatinib mesylate is a promising candidate for the treatment of fibrotic diseases such as SSc.

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Section: Discussionsupporting

confidence: 63%

mentioning

confidence: 99%

Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

Distler¹,

Jüngel²,

Huber³

et al. 2007

Arthritis & Rheumatism

361

273

View full text Add to dashboard Cite

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“…10 Cytogenetic response was recorded by routine conventional cytogenetic studies performed on at least 20 metaphases as follows: complete response: Ph-positivity of 0%; partial response: Ph-positivity of 1-34%; minor response: Ph-positivity of 35% to Ͻ 90%; and none: Ph-positivity of Ն 90%.…”

Section: Methodsmentioning

confidence: 99%

Imatinib mesylate therapy reduces bone marrow fibrosis in patients with chronic myelogenous leukemia

Bueso‐Ramos

Cortes

Talpaz

et al. 2004

Cancer

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BACKGROUNDReticulin‐stained bone marrow fibrosis is associated with a poor prognosis in patients with chronic myelogenous leukemia (CML). Resolution of fibrosis with therapy may improve patient outcome.METHODSThe effect of imatinib therapy on bone marrow fibrosis was evaluated in 40 patients with chronic‐phase CML who were treated after interferon‐α failure.RESULTSThirty‐one patients (78%) had severe (Grade 3 or 4) reticulin fibrosis prior to therapy. After imatinib therapy was administered for 3 to > 24 months, fibrosis was reduced by at least 2 grades in 19 of the 31 patients (61%) and by at least 1 grade in 34 patients (85%). There was no correlation noted between reduction of fibrosis and cytogenetic response. However, a reduction in fibrosis was found to correlate with a reduction in bone marrow megakaryocytosis (P = 0.002).CONCLUSIONSTreatment with imatinib mesylate appears to reduce CML‐associated bone marrow fibrosis in most patients who are treated during the chronic phase of disease. This effect may be independent of the degree of suppression of Philadelphia chromosome‐positive cells, and may improve prognosis in patients with CML. Cancer 2004. © 2004 American Cancer Society.

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“…This compound was demonstrated to be effective in all stages of the disease (Kantarjian et al, 2002;Sawyers et al, 2002). Imatinib binds competitively with ATP to BCR-ABL and blocks its abnormal signalling.…”

Section: Dynamics Of CMLmentioning

confidence: 99%

Mathematical models of targeted cancer therapy

Abbott

Michor

2006

Br J Cancer

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Improved understanding of the molecular underpinnings of cancer initiation and progression has led to the development of targeted cancer therapies. The importance of these new methods of cancer treatment necessitates further research into the dynamic interactions between cancer cells and therapeutic agents, as well as a means of analysing their relationship quantitatively. The present review outlines the application of mathematical modelling to the dynamics of targeted cancer therapy, focusing particular attention on chronic myeloid leukaemia and its treatment with imatinib (Glivec).

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Hematologic and Cytogenetic Responses to Imatinib Mesylate in Chronic Myelogenous Leukemia

Abstract: Imatinib induced high rates of cytogenetic and hematologic responses in patients with chronic-phase CML in whom previous interferon therapy had failed.

Cited by 1,821 publications

References 23 publications

Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

Imatinib mesylate therapy reduces bone marrow fibrosis in patients with chronic myelogenous leukemia

Mathematical models of targeted cancer therapy

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