Imatinib Mesylate for Cerebral Langerhans'-Cell Histiocytosis
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《新英格兰医药杂志》
To the Editor: Langerhans'-cell histiocytosis (LCH) is a rare disorder characterized by tissue infiltrates of CD1a+ Langerhans' cells, eosinophils, neutrophils, macrophages, and lymphocytes. Systemic treatments for refractory LCH are unsatisfactory and usually toxic. We report the use of imatinib mesylate to control parenchymal brain involvement in a patient with multisystem LCH.
A 37-year-old woman was hospitalized because of severe headache and visual impairment after fainting. She had a 14-year-history of LCH, with involvement of bone and lungs, and diabetes insipidus and had previously been treated with thymic peptides, chemotherapy, and radiotherapy of the occipital bone. Neurologic examination revealed mydriasis, slow pupillary reflexes, and hypokinesia and hyperreflexia of both her arms and legs. Magnetic resonance imaging showed a lytic lesion that involved the occipital and parietal bones and multiple lesions in the brain. Localization of LCH to the brain was confirmed on pathological examination. Whole-brain radiotherapy plus treatment with dexamethasone, mannitol, and phenobarbital did not improve the neurologic picture. We studied KIT and platelet-derived growth factor (PDGF) receptor beta expression in a paraffin-fixed, formalin-embedded tissue specimen with LCH involvement. The Langerhans' cells were strongly positive for PDGF receptor beta and were negative for KIT (Figure 1). After obtaining written informed consent, we started treatment with 100 mg of imatinib mesylate daily.
Figure 1. Skin-Biopsy Specimen from a Woman with Langerhans'-Cell Histiocytosis.
Panel A shows numerous Langerhans' cells mixed with inflammatory cells (hematoxylin and eosin). Panel B shows Langerhans' cells strongly reacting to PDGF receptor beta antibody (immunohistochemical stain).
Within one month, the patient's headache disappeared, and drainage from the intrathecal catheter stopped. The dose of imatinib was then increased to 400 mg daily. Mannitol was stopped, and dexamethasone and phenobarbital were gradually reduced. After 18 months of therapy, MRI showed considerable reduction of the lesions in the occipital lobe. The patient recovered all neurologic function apart from vision.
This case indicates that treatment with imatinib mesylate can improve LCH. The drug selectively inhibits the ABL, KIT, and PDGF kinases.1 The increased production of PDGF by alveolar macrophages has been demonstrated in pulmonary LCH.2 Moreover, stimulated monocytes express the c-sis proto-oncogene, which encodes one of the PDGF chains.3 Recently, imatinib mesylate was found to inhibit the differentiation of CD34+ progenitors into dendritic cells as well as the ability of dendritic cells to activate lymphocyte responses.4 We suggest that direct activity against dendritic Langerhans' cells, modulation of the cytokine storm within LCH tissue infiltrates, or both, probably through the inhibition of the PDGF or PDGF-receptor system, account for the activity of imatinib in LCH.
Liliana Montella, M.D.
S. Giovanni di Dio Hospital
80027 Naples, Italy
Giovannella Palmieri, M.D.
University Federico II
80131 Naples, Italy
References
Buchdunger E, Cioffi CL, Law N, et al. ABL protein-tyrosine kinase inhibitor STI 571 inhibits in vitro signal transduction mediated by c-kit and platelet-driven growth factor receptors. J Pharmacol Exp Ther 2000;295:139-145.
Uebelhoer M, Bewig B, Kreipe H, Nowak D, Magnussen H, Barth J. Modulation of fibroblast activity in histiocytosis X by platelet-derived growth factor. Chest 1995;107:701-705.
Martinet Y, Bitterman PB, Mornex JF, Grotendorst GR, Martin GR, Crystal RG. Activated human monocytes express the c-sis proto-oncogene and release a mediator showing PDGF-like activity. Nature 1986;319:158-160.
Appel S, Boehmler AM, Grunebach F, et al. Imatinib mesylate affects the development and function of dendritic cells generated from CD34+ peripheral blood progenitor cells. Blood 2004;103:538-544.
A 37-year-old woman was hospitalized because of severe headache and visual impairment after fainting. She had a 14-year-history of LCH, with involvement of bone and lungs, and diabetes insipidus and had previously been treated with thymic peptides, chemotherapy, and radiotherapy of the occipital bone. Neurologic examination revealed mydriasis, slow pupillary reflexes, and hypokinesia and hyperreflexia of both her arms and legs. Magnetic resonance imaging showed a lytic lesion that involved the occipital and parietal bones and multiple lesions in the brain. Localization of LCH to the brain was confirmed on pathological examination. Whole-brain radiotherapy plus treatment with dexamethasone, mannitol, and phenobarbital did not improve the neurologic picture. We studied KIT and platelet-derived growth factor (PDGF) receptor beta expression in a paraffin-fixed, formalin-embedded tissue specimen with LCH involvement. The Langerhans' cells were strongly positive for PDGF receptor beta and were negative for KIT (Figure 1). After obtaining written informed consent, we started treatment with 100 mg of imatinib mesylate daily.
Figure 1. Skin-Biopsy Specimen from a Woman with Langerhans'-Cell Histiocytosis.
Panel A shows numerous Langerhans' cells mixed with inflammatory cells (hematoxylin and eosin). Panel B shows Langerhans' cells strongly reacting to PDGF receptor beta antibody (immunohistochemical stain).
Within one month, the patient's headache disappeared, and drainage from the intrathecal catheter stopped. The dose of imatinib was then increased to 400 mg daily. Mannitol was stopped, and dexamethasone and phenobarbital were gradually reduced. After 18 months of therapy, MRI showed considerable reduction of the lesions in the occipital lobe. The patient recovered all neurologic function apart from vision.
This case indicates that treatment with imatinib mesylate can improve LCH. The drug selectively inhibits the ABL, KIT, and PDGF kinases.1 The increased production of PDGF by alveolar macrophages has been demonstrated in pulmonary LCH.2 Moreover, stimulated monocytes express the c-sis proto-oncogene, which encodes one of the PDGF chains.3 Recently, imatinib mesylate was found to inhibit the differentiation of CD34+ progenitors into dendritic cells as well as the ability of dendritic cells to activate lymphocyte responses.4 We suggest that direct activity against dendritic Langerhans' cells, modulation of the cytokine storm within LCH tissue infiltrates, or both, probably through the inhibition of the PDGF or PDGF-receptor system, account for the activity of imatinib in LCH.
Liliana Montella, M.D.
S. Giovanni di Dio Hospital
80027 Naples, Italy
Giovannella Palmieri, M.D.
University Federico II
80131 Naples, Italy
References
Buchdunger E, Cioffi CL, Law N, et al. ABL protein-tyrosine kinase inhibitor STI 571 inhibits in vitro signal transduction mediated by c-kit and platelet-driven growth factor receptors. J Pharmacol Exp Ther 2000;295:139-145.
Uebelhoer M, Bewig B, Kreipe H, Nowak D, Magnussen H, Barth J. Modulation of fibroblast activity in histiocytosis X by platelet-derived growth factor. Chest 1995;107:701-705.
Martinet Y, Bitterman PB, Mornex JF, Grotendorst GR, Martin GR, Crystal RG. Activated human monocytes express the c-sis proto-oncogene and release a mediator showing PDGF-like activity. Nature 1986;319:158-160.
Appel S, Boehmler AM, Grunebach F, et al. Imatinib mesylate affects the development and function of dendritic cells generated from CD34+ peripheral blood progenitor cells. Blood 2004;103:538-544.