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Previous Volume 347:481-487 August 15, 2002 Number 7 Next

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ABSTRACT

Background A small proportion of patients with chronic myeloproliferative diseases have constitutive activation of the gene for platelet-derived growth factor receptor beta (PDGFRB), which encodes a receptor tyrosine kinase. The gene is located on chromosome 5q33, and the activation is usually caused by a t(5;12)(q33;p13) translocation associated with an ETV6-PDGFRB fusion gene. The tyrosine kinase inhibitor imatinib mesylate specifically inhibits ABL, PDGFR, and KIT kinases and has impressive clinical efficacy in BCR-ABL–positive chronic myeloid leukemia.

Methods We treated four patients who had chronic myeloproliferative diseases and chromosomal translocations involving 5q33 with imatinib mesylate (400 mg daily). Three of the four patients presented with leukocytosis and eosinophilia; their leukemia cells carried the ETV6-PDGFRB fusion gene. The fourth patient had leukocytosis, eosinophilia, and a t(5;12) translocation involving PDGFRB and an unknown partner gene; he also had extensive raised, ulcerated skin lesions that had been present for a long time.

Results In all four patients, a normal blood count was achieved within four weeks after treatment began. In the patient with skin disease, the lesions began to resolve shortly after treatment began. The t(5;12) translocation was undetectable by 12 weeks in three patients and by 36 weeks in the fourth patient. In the three patients with the ETV6-PDGFRB fusion gene, the transcript level decreased, and in one patient, it became undetectable by 36 weeks. All responses were durable at 9 to 12 months of follow-up.

Conclusions Imatinib mesylate induces durable responses in patients with chronic myeloproliferative diseases associated with activation of PDGFRB.

Source Information

From the Department of Haematology, Faculty of Medicine, Imperial College, London (J.F.A., J.V.M., B.J.B., D.M., E.O., B.S., J.M.G.); the Department of Hematology, Centre Hospitalier Universitaire Angers, Angers, France (M.G.); the Skin Tumour Unit, St. John's Institute of Dermatology, St. Thomas' Hospital, London (R.R.-J.); Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, United Kingdom (E.J.B., A.C., N.C.P.C.); the Department of Haematology, Great Ormond Street Hospital for Children, London (J.M.C.); the Department of Hematology, Centre Hospitalier Universitaire Bordeaux, Pessac, France (M.C., F.-X.M.); the Department of Haematology, St. George's Hospital, London (C.E.D.); and Novartis Oncology, Basel, Switzerland (S.D., Z.N., S.S.).

Address reprint requests to Prof. Apperley at the Department of Haematology, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, Du Cane Rd., London W12 0NN, United Kingdom, or at j.apperley{at}ic.ac.uk.

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• Appel, S., Boehmler, A. M., Grunebach, F., Muller, M. R., Rupf, A., Weck, M. M., Hartmann, U., Reichardt, V. L., Kanz, L., Brummendorf, T. H., Brossart, P. (2004). Imatinib mesylate affects the development and function of dendritic cells generated from CD34+ peripheral blood progenitor cells. Blood 103: 538-544 [Abstract] [Full Text]  
• List, A. F., Vardiman, J., Issa, J.-P. J., DeWitte, T. M. (2004). Myelodysplastic Syndromes. ASH Education Book 2004: 297-317 [Abstract] [Full Text]  
• Sawyers, C. L. (2003). Opportunities and challenges in the development of kinase inhibitor therapy for cancer. Genes Dev. 17: 2998-3010 [Full Text]  
• Heinrich, M. C., Corless, C. L., Demetri, G. D., Blanke, C. D., von Mehren, M., Joensuu, H., McGreevey, L. S., Chen, C.-J., Van den Abbeele, A. D., Druker, B. J., Kiese, B., Eisenberg, B., Roberts, P. J., Singer, S., Fletcher, C. D.M., Silberman, S., Dimitrijevic, S., Fletcher, J. A. (2003). Kinase Mutations and Imatinib Response in Patients With Metastatic Gastrointestinal Stromal Tumor. JCO 21: 4342-4349 [Abstract] [Full Text]  
• Johnson, B. E., Fischer, T., Fischer, B., Dunlop, D., Rischin, D., Silberman, S., Kowalski, M. O., Sayles, D., Dimitrijevic, S., Fletcher, C., Hornick, J., Salgia, R., Le Chevalier, T. (2003). Phase II Study of Imatinib in Patients with Small Cell Lung Cancer. Clin. Cancer Res. 9: 5880-5887 [Abstract] [Full Text]  
• Druker, B. J. (2003). Imatinib As a Paradigm of Targeted Therapies. JCO 21: 239s-245 [Full Text]  
• Wilkinson, K., Velloso, E. R. P., Lopes, L. F., Lee, C., Aster, J. C., Shipp, M. A., Aguiar, R. C. T. (2003). Cloning of the t(1;5)(q23;q33) in a myeloproliferative disorder associated with eosinophilia: involvement of PDGFRB and response to imatinib. Blood 102: 4187-4190 [Abstract] [Full Text]  
• Mauro, M. J. (2003). HES and SMCD-eos: birds of a FIP1L1-PDGFRA feather. Blood 102: 3082-3082 [Full Text]  
• Pardanani, A., Ketterling, R. P., Brockman, S. R., Flynn, H. C., Paternoster, S. F., Shearer, B. M., Reeder, T. L., Li, C.-Y., Cross, N. C. P., Cools, J., Gilliland, D. G., Dewald, G. W., Tefferi, A. (2003). CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood 102: 3093-3096 [Abstract] [Full Text]  
• Heinrich, M. C., Corless, C. L. (2003). In Reply:. JCO 21: 3886-3887 [Full Text]  
• Oehler, L., Jaeger, E., Eser, A., Sillaber, C., Gisslinger, H., Geissler, K. (2003). Imatinib mesylate inhibits autonomous erythropoiesis in patients with polycythemia vera in vitro. Blood 102: 2240-2242 [Abstract] [Full Text]  
• Pietras, K., Stumm, M., Hubert, M., Buchdunger, E., Rubin, K., Heldin, C.-H., McSheehy, P., Wartmann, M., Ostman, A. (2003). STI571 Enhances the Therapeutic Index of Epothilone B by a Tumor-selective Increase of Drug Uptake. Clin. Cancer Res. 9: 3779-3787 [Abstract] [Full Text]  
• Deininger, M. W. N., Druker, B. J. (2003). Specific Targeted Therapy of Chronic Myelogenous Leukemia with Imatinib. Pharmacol. Rev. 55: 401-423 [Abstract] [Full Text]  
• Antin, J. H. (2003). A 41-Year-Old Woman With Chronic Myelogenous Leukemia. JAMA 290: 1083-1090 [Full Text]  
• Griffin, J. H., Leung, J., Bruner, R. J., Caligiuri, M. A., Briesewitz, R. (2003). Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome. Proc. Natl. Acad. Sci. USA 100: 7830-7835 [Abstract] [Full Text]  
• Kurzrock, R., Kantarjian, H. M., Druker, B. J., Talpaz, M. (2003). Philadelphia Chromosome-Positive Leukemias: From Basic Mechanisms to Molecular Therapeutics. ANN INTERN MED 138: 819-830 [Abstract] [Full Text]  
• Pardanani, A., Reeder, T., Porrata, L. F., Li, C.-Y., Tazelaar, H. D., Baxter, E. J., Witzig, T. E., Cross, N. C. P., Tefferi, A. (2003). Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders. Blood 101: 3391-3397 [Abstract] [Full Text]  
• Sohal, J., Phan, V. T., Chan, P. V., Davis, E. M., Patel, B., Kelly, L. M., Abrams, T. J., O'Farrell, A. M., Gilliland, D. G., Le Beau, M. M., Kogan, S. C. (2003). A model of APL with FLT3 mutation is responsive to retinoic acid and a receptor tyrosine kinase inhibitor, SU11657. Blood 101: 3188-3197 [Abstract] [Full Text]  
• Hirai, H. (2003). Molecular Mechanisms of Myelodysplastic Syndrome. Jpn J Clin Oncol 33: 153-160 [Abstract] [Full Text]  
• Cools, J., DeAngelo, D. J., Gotlib, J., Stover, E. H., Legare, R. D., Cortes, J., Kutok, J., Clark, J., Galinsky, I., Griffin, J. D., Cross, N. C.P., Tefferi, A., Malone, J., Alam, R., Schrier, S. L., Schmid, J., Rose, M., Vandenberghe, P., Verhoef, G., Boogaerts, M., Wlodarska, I., Kantarjian, H., Marynen, P., Coutre, S. E., Stone, R., Gilliland, D. G. (2003). A Tyrosine Kinase Created by Fusion of the PDGFRA and FIP1L1 Genes as a Therapeutic Target of Imatinib in Idiopathic Hypereosinophilic Syndrome. NEJM 348: 1201-1214 [Abstract] [Full Text]  
• O'Brien, S. G., Guilhot, F., Larson, R. A., Gathmann, I., Baccarani, M., Cervantes, F., Cornelissen, J. J., Fischer, T., Hochhaus, A., Hughes, T., Lechner, K., Nielsen, J. L., Rousselot, P., Reiffers, J., Saglio, G., Shepherd, J., Simonsson, B., Gratwohl, A., Goldman, J. M., Kantarjian, H., Taylor, K., Verhoef, G., Bolton, A. E., Capdeville, R., Druker, B. J., the IRIS Investigators, (2003). Imatinib Compared with Interferon and Low-Dose Cytarabine for Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia. NEJM 348: 994-1004 [Abstract] [Full Text]  
• Nahta, R., Hortobagyi, G. N., Esteva, F. J. (2003). Growth Factor Receptors in Breast Cancer: Potential for Therapeutic Intervention. The Oncologist 8: 5-17 [Abstract] [Full Text]  
• Mufti, G., List, A. F., Gore, S. D., Ho, A. Y.L. (2003). Myelodysplastic Syndrome. ASH Education Book 2003: 176-199 [Abstract] [Full Text]  
• Ebos, J. M.L., Tran, J., Master, Z., Dumont, D., Melo, J. V., Buchdunger, E., Kerbel, R. S. (2002). Imatinib Mesylate (STI-571) Reduces Bcr-Abl-Mediated Vascular Endothelial Growth Factor Secretion in Chronic Myelogenous Leukemia. Mol Cancer Res 1: 89-95 [Abstract] [Full Text]  
• Arceci, R. J., Longley, B. J., Emanuel, P. D. (2002). Atypical Cellular Disorders. ASH Education Book 2002: 297-314 [Abstract] [Full Text]