Skip to main content Accessibility help
×
Hostname: page-component-7c8c6479df-p566r Total loading time: 0 Render date: 2024-03-28T11:57:18.721Z Has data issue: false hasContentIssue false

8 - Supportive care in myelodysplastic syndromes: hemopoietic cytokine and iron chelation therapy

Published online by Cambridge University Press:  22 August 2009

Jason Gotlib
Affiliation:
Stanford University Cancer Center, Stanford, CA, USA
Peter L. Greenberg
Affiliation:
VA Palo Alto Health Care System, Palo Alto, CA, USA
Peter L. Greenberg
Affiliation:
Stanford University School of Medicine, California
Get access

Summary

Myelodysplastic syndromes (MDS) comprise a heterogeneous spectrum of clonal myeloid hemopathies characterized by bone marrow failure, morphologic dysplasia, and a variable tendency to evolve into acute myeloid leukemia (AML). In low-risk MDS, excessive intramedullary apoptosis of hematopoietic progenitors and ineffective hematopoiesis contribute to the paradoxical finding of hypercellular marrows in the setting of chronic refractory cytopenias. Evolution to AML occurs in approximately 30% of MDS cases, and is frequently associated with reversion of marrow myeloid precursors to a leukemic phenotype. The in vitro and in vivo study of the proliferative and differentiation abnormalities involved in MDS hematopoiesis has been facilitated by the development of recombinant hemopoietic growth factors (HGFs). Refractory cytopenias are major causes of morbidity in MDS. Thus, supportive care to manage these consequences of the marrow failure in MDS is the mainstay of treatment for these individuals.

Symptomatic anemia is a critical clinical problem in MDS. Cytokine therapy with recombinant erythropoietin (rEPO) has resulted in erythroid responses in a proportion of individuals with MDS, which can be substantially increased in selected patients with addition of recombinant granulocyte colony-stimulating factor (rG-CSF). Identification of the clinical and histopathologic features which predict response to these HGFs permits tailoring of these treatments to appropriate subsets of MDS patients. Due to the combination of ineffective erythropoiesis and the relatively large amount of red blood cell (RBC) transfusions MDS patients receive to treat their hypoproductive anemia, a substantial proportion of these individuals have iron overload.

Type
Chapter
Information
Myelodysplastic Syndromes
Clinical and Biological Advances
, pp. 209 - 242
Publisher: Cambridge University Press
Print publication year: 2005

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Greenberg, P. L. (1996). Biologic and clinical implications of marrow culture studies in the myelodysplastic syndromes. Semin. Hematol., 33, 163–75Google ScholarPubMed
Greenberg, P. L. and Mara, B. (1979). The preleukemic syndrome: correlation of in vitro parameters of granulopoiesis with clinical features. Am. J. Med., 66, 951–8CrossRefGoogle ScholarPubMed
Chui, D. H. and Clarke, B. J. (1982). Abnormal erythroid progenitor cells in human preleukemia. Blood, 60, 362–7Google ScholarPubMed
Juvonen, E., Partanen, S., Knuutila, S., and Ruute, T. (1986). Megakaryocyte colony formation by bone marrow progenitors in myelodysplastic syndromes. Br. J. Haematol., 63, 331–4CrossRefGoogle ScholarPubMed
Nagler, A., Ginzton, N., Negrin, R. S.et al. (1990). In vitro differentiative and proliferative effects of human recombinant colony-stimulating factors on marrow hemopoiesis in myelodysplastic syndromes. Leukemia, 4, 193–202Google ScholarPubMed
Schipperus, M. R., Sonneveld, P., Lindemans, J.et al. (1990). The combined effects of IL-3, GM-CSF, and G-CSF on the in vitro growth of myelodysplastic myeloid progenitor cells. Leuk. Res., 14, 1019–25CrossRefGoogle ScholarPubMed
Greenberg, P. L., Mackichan, M. L., and Negrin, R. (1990). Production of granulocyte colony-stimulating factor by normal and myelodysplastic syndrome peripheral blood cells. Blood, 76 (suppl. 1), 146a (abstract)Google Scholar
Nagler, A., Binet, C., Mackichan, M. L.et al. (1990). Impact of marrow cytogenetics and morphology on in vitro hemopoiesis in the myelodysplastic syndromes: comparison between recombinant human granulocyte colony-stimulating factor and granulocyte-monocyte colony-stimulating factor. Blood, 76, 1299–307Google Scholar
Merchav, S., Nielsen, O. J., Rosenbaum, H.et al. (1990). In vitro studies of erythropoietin-dependent regulation of erythropoiesis in myelodysplastic syndromes. Leukemia, 4, 771–4Google ScholarPubMed
Greenberg, P. L., Negrin, R. S., and Ginzton, N. (1991). G-CSF synergizes with erythropoietin for enhancing erythroid colony-formation in myelodysplastic syndromes. Blood, 78 (suppl. 1), 38a (abstract)Google Scholar
Sawada, K., Sato, N., Tarumi, T.et al. (1993). Proliferation and differentiation of myelodysplastic CD34+ cells in serum-free medium: response to individual colony-stimulating factors. Br. J. Haematol., 83, 349–58CrossRefGoogle ScholarPubMed
Budel, L. M., Dong, F., Lowenberg, B., and Touw, I. P. (1995). Hematopoietic growth factor receptors: structure variations and alternatives of receptor complex formation in normal hematopoiesis and in hematopoietic disorders. Leukemia, 9, 553–61Google ScholarPubMed
Hoefsloot, L. H., Amelsvoort, M. P., Broeders, L. C.et al. (1997). Erythropoietin-induced activation of STAT5 is impaired in the myelodysplastic syndrome. Blood, 89, 1690–700Google ScholarPubMed
NCCN Myelodysplastic Syndromes Panel (2003). Myelodysplastic syndromes – clinical practice guidelines in oncology. J.N.C.C.N., 1, 456–71
Fontenay-Roupie, M., Bouscary, D., Guesnu, M.et al. (1999). Ineffective erythropoiesis in myelodysplastic syndromes: correlation with Fas expression but not with lack of erythropoietin receptor signal transduction. Br. J. Haematol., 106, 464–73CrossRefGoogle Scholar
Claessens, Y. E., Bouscary, D., Dupont, J. M.et al. (2002). In vitro proliferation and differentiation of erythroid progenitors from patients with myelodysplastic syndromes: evidence for Fas-dependent apoptosis. Blood, 99, 1594–601CrossRefGoogle ScholarPubMed
Rigolin, G. M., Della Porta, M., Bigoni, R.et al. (2002). rHuEPO administration in patients with low-risk myelodysplastic syndromes: evaluation of erythroid precursors' response by fluorescence in situ hybridization on May-Grunwald-Giemsa-stained bone marrow samples. Br. J. Haematol., 119, 652–9CrossRefGoogle ScholarPubMed
Schmidt-Mende, J., Tehranchi, R., Forsblom, A. M.et al. (2001). Granulocyte colony-stimulating factor inhibits Fas-triggered apoptosis in bone marrow cells isolated from patients with refractory anemia with ringed sideroblasts. Leukemia, 15, 742–51CrossRefGoogle ScholarPubMed
Tehranchi, R., Fadeel, B., Forsblom, A. M.et al. (2003). Granulocyte colony-stimulating factor inhibits spontaneous cytochrome c release and mitochondria-dependent apoptosis of myelodysplastic syndrome hematopoietic progenitors. Blood, 101, 1080–6CrossRefGoogle ScholarPubMed
Adamson, J. W., Schuster, M., Allen, S., and Haley, N. R. (1992). Effectiveness of recombinant human erythropoietin therapy in myelodysplastic syndromes. Acta Haematol., 87 (suppl. 1), 20–4CrossRefGoogle ScholarPubMed
Aloe Spiriti, M. A., Petti, M. C., Latagliata, R.et al. (1993). Is recombinant human erythropoietin treatment in myelodysplastic syndromes worthwhile?Leuk. Lymphoma, 9, 79–83CrossRefGoogle ScholarPubMed
Stenke, L., Wallvik, J., Celsing, F., and Hast, R. (1993). Prediction of response to treatment with human recombinant erythropoietin in myelodysplastic syndromes. Leukemia, 7, 1324–7Google ScholarPubMed
Stone, R. M., Bernstein, S. H., Demetri, G.et al. (1994). Treatment with recombinant human erythropoietin in patients with myelodysplastic syndromes. Leuk. Res., 18, 769–76CrossRefGoogle ScholarPubMed
Rose, E. H., Abels, R. I., Nelson, R. A., McCullough, O. M., and Lessin, L. (1995). The use of r-HuEPO in the treatment of anaemia related to myelodysplasia (MDS). Br. J. Haematol., 89, 831–7CrossRefGoogle Scholar
Stasi, R., Brunetti, M., Bussa, S.et al. (1997). Response to recombinant human erythropoietin in patients with myelodysplastic syndromes. Clin. Cancer Res., 3, 733–9Google ScholarPubMed
Italian Cooperative Study Group for rHuEPO in Myelodysplastic Syndromes (1998). A randomized double-blind placebo-controlled study with subcutaneous recombinant human erythropoietin in patients with low-risk myelodysplastic syndromes. Br. J. Haematol., 103, 1070–4CrossRef
Terpos, E., Mougiou, A., Kouraklis, A.et al. (2002). Prolonged administration of erythropoietin increases erythroid response rate in myelodysplastic syndromes: a phase II trial in 281 patients. Br. J. Haematol., 118, 174–80CrossRefGoogle ScholarPubMed
Wallvik, J., Stenke, L., Bernell, P.et al. (2002). Serum erythropoietin (EPO) levels correlate with survival and independently predict response to EPO treatment in patients with myelodysplastic syndromes. Eur. J. Haematol., 68, 180–5CrossRefGoogle ScholarPubMed
Rodriguez, J. N., Dieguez, J. C., Muniz, R.et al. (1994). [Human recombinant erythropoietin in the treatment of myelodysplastic syndromes anemia. Meta-analytic study.]Sangre (Barc.), 39, 435–9 (in Spanish)Google Scholar
Hellström-Lindberg, E. (1995). Efficacy of erythropoietin in the myelodysplastic syndromes: a meta-analysis of 205 patients from 17 studies. Br. J. Haematol., 89, 67–71CrossRefGoogle ScholarPubMed
Hast, R., Wallvik, J., Folin Abernell, P., and Stenke, L. (2001). Long-term follow-up of 18 patients with myelodyplastic syndromes responding to recombinant erythropoietin treatment. Leuk. Res., 25, 13–18CrossRefGoogle Scholar
Musto, P., Falcone, A., Sanpaolo, G.et al. (2003). Efficacy of a single, weekly dose of recombinant erythropoietin in myelodysplastic syndromes. Br. J. Haematol., 122, 267–71CrossRefGoogle ScholarPubMed
Garypidou, V., Verrou, E., Vakalopoulou, S.et al. (2003). Efficacy of a single, weekly dose of recombinant erythropoietin in myelodysplastic syndromes. Br. J. Haematol., 123, 958CrossRefGoogle ScholarPubMed
Negrin, R. S., Haeuber, D. H., Nagler, A.et al. (1989). Treatment of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor. Ann. Intern. Med., 110, 976–84CrossRefGoogle ScholarPubMed
Negrin, R. S., Haeuber, D. H., Nagler, A.et al. (1990). Maintenance treatment of patients with myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor. Blood, 76, 36–43Google ScholarPubMed
Greenberg, P., Taylor, K., Larson, R.et al. (1993). Phase III randomized multicenter trial of recombinant human G-CSF in MDS. Blood, 82 (suppl. 1), 196a (abstract)Google Scholar
Greenberg, P. L., Negrin, R. S., and Ginzton, N. (1992). In vitro–in vivo correlations of erythroid responses to G-CSF plus erythropoietin in myelodysplastic syndromes. Exp. Hematol., 20, 733 (abstract)Google Scholar
Negrin, R. S., Stein, R., Doherty, K.et al. (1993). Treatment of the anemias of MDS using recombinant human granulocyte colony-stimulating factor in combination with erythropoietin. Blood, 82, 737–43Google ScholarPubMed
Hellström-Lindberg, E., Birgegard, G., Carlsson, M.et al. (1993). A combination of granulocyte colony-stimulating factor and erythropoietin may synergistically improve the anaemia in patients with myelodysplastic syndromes. Leuk. Lymphoma, 11, 221–8CrossRefGoogle ScholarPubMed
Negrin, R. S., Stein, R., Doherty, K.et al. (1996). Maintenance treatment of the anemia of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor and erythropoietin: evidence for in vivo synergy. Blood, 87, 4076–81Google ScholarPubMed
Hellström-Lindberg, E., Negrin, R., Stein, R.et al. (1997). Erythroid response to treatment with G-CSF plus erythropoietin for the anaemia of patients with myelodysplastic syndromes: proposal for a predictive model. Br. J. Haematol., 99, 344–51CrossRefGoogle ScholarPubMed
Hellström-Lindberg, E., Ahlgren, T., Beguin, Y.et al. (1998). Treatment of anemia in myelodysplastic syndromes with granulocyte colony-stimulating factor plus erythropoietin; results from a randomized phase II study and long-term follow-up of 71 patients. Blood, 92, 68–75Google ScholarPubMed
Hellström-Lindberg, E., Gulbrandsen, N., Lindberg, G.et al. (2003). A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life. Br. J. Haematol., 120, 1037–46CrossRefGoogle ScholarPubMed
Remacha, A. F., Arrizabalaga, B., Villegas, A.et al. (1999). Erythropoietin plus granulocyte colony-stimulating factor in the treatment of myelodysplastic syndromes. Identification of a subgroup of responders. Haematologica, 84, 1058–64Google ScholarPubMed
Mantovani, L., Lentini, G., Hentschel, B.et al. (2000). Treatment of anaemia in myelodysplastic syndromes with prolonged administration of recombinant human granulocyte colony-stimulating factor and erythropoietin. Br. J. Haematol., 109, 367–75CrossRefGoogle ScholarPubMed
Casadevall, N., Durieux, P., Dubois, S.et al. (2004). Health, economic, and quality-of-life effects of erythropoietin and granulocyte colony-stimulating factor for the treatment of myelodysplastic syndromes: a randomized, controlled trial. Blood, 104, 321–7CrossRefGoogle ScholarPubMed
Jadersten, M., Montgomery, S. M., Astermark, J.et al. (2003). Treatment of anemia in myelodysplastic syndromes with granulocyte colony-stimulating factor and erythropoietin: response and impact on survival in a long-term follow-up of 129 patients. Blood, 102 (suppl. 1), 184a–5a (abstract)Google Scholar
Greenberg, P., Cox, C., Beau, M. M.et al. (1997). International scoring system (IPSS) for evaluating prognosis in myelodysplastic syndrome. Blood, 89, 2079–88Google Scholar
Vadhan-Raj, S., Keating, M., LeMaistre, A.et al. (1987). Effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes. N. Engl. J. Med., 317, 1545–52CrossRefGoogle ScholarPubMed
Antin, J. H., Weinberg, D. S., and Rosenthal, D. S. (1990). Variable effect of recombinant human granulocyte-macrophage colony-stimulating factor on bone marrow fibrosis in patients with myelodysplasia. Exp. Hematol., 18, 266–70Google Scholar
Ganser, A., Volkers, B., Greher, J.et al. (1989). Recombinant human-granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes – a phase I/II trial. Blood, 73, 31–7Google ScholarPubMed
Hermann, F., Lindemann, A., Klein, H.et al. (1989). Effect of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndrome with excess blasts. Leukemia, 3, 335–8Google Scholar
Hoelzer, D., Ganser, A., Greher, J., Volkers, B., and Walther, F. (1988). Phase I/II study with GM-CSF in patients with myelodysplastic syndromes. Behring Inst. Mitt., 83, 134–8Google Scholar
Thompson, J. A., Douglas, J. L., Kidd, P.et al. (1989). Subcutaneous granulocyte macrophage colony-stimulating factor in patients with myelodysplastic syndrome: toxicity, pharmacokinetics, and hematological effects. J. Clin. Oncol., 7, 629–37CrossRefGoogle ScholarPubMed
Estey, E. H., Kurzrock, R., Talpaz, M.et al. (1991). Effects of low doses of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with myelodysplastic syndromes. Br. J. Haematol., 77, 291–5CrossRefGoogle ScholarPubMed
Rosenfeld, C. S., Sulecki, M., Evans, C., and Shadduck, R. K. (1991). Comparison of intravenous versus subcutaneous recombinant human granulocyte-macrophage colony-stimulating factor in patients with primary myelodysplasia. Exp. Hematol., 19, 273–7Google ScholarPubMed
Gradishar, W. J., Beau, M. M., O'Laughlin, R., Vardiman, J. W., and Larson, R. A. (1992). Clinical and cytogenetic responses to granulocyte-macrophage colony-stimulating factor in therapy-related myelodysplasia. Blood, 80, 2463–70Google ScholarPubMed
Takahashi, M., Yoshida, Y., Kaku, K.et al. (1993). Phase II study of recombinant granulocyte-macrophage colony-stimulating factor in myelodysplastic syndrome and aplastic anemia. Acta Haematol., 89, 189–94CrossRefGoogle ScholarPubMed
Rose, C., Wattel, E., Bastion, Y.et al. (1994). Treatment with very low-dose GM-CSF in myelodysplastic syndromes with neutropenia. A report on 28 cases. Leukemia, 8, 1458–62Google ScholarPubMed
Willemze, R., Lely, N., Zwierzina, H.et al. (1992). A randomized phase-I/II multicenter study of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy for patients with myelodysplastic syndromes and a relatively low risk of acute leukemia. Ann. Hematol., 64, 173–80CrossRefGoogle Scholar
Schuster, M. W., Thompson, J. A., Larson, R.et al. (1995). Randomized phase II study of recombinant granulocyte macrophage-colony stimulating factor (rGM-CSF) in patients with neutropenia secondary to myelodysplastic syndrome (MDS). Blood, 86 (suppl. 1), 338a (abstract)Google Scholar
Yoshida, Y., Nakahata, T., Shibata, A.et al. (1995). Effects of long-term treatment with recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndrome. Leuk. Lymphoma, 18, 457–63CrossRefGoogle ScholarPubMed
Runde, V., Aul, C., Ebert, A., Grabenhorst, U., and Schneider, W. (1995). Sequential administration of recombinant human granulocyte-macrophage colony-stimulating factor and human erythropoietin for treatment of myelodysplastic syndromes. Eur. J. Haematol., 54, 39–45CrossRefGoogle ScholarPubMed
Hansen, P. B., Johnsen, H. E., Hippe, E., Hellstrom-Lindberg, E., and Ralfkiaer, E. (1993). Recombinant human granulocyte-macrophage colony-stimulting factor plus recombinant human erythropoietin may improve anemia in selected patients with myelodysplastic syndromes. Am. J. Hematol., 44, 229–36CrossRefGoogle Scholar
Bernell, P., Stenke, L., Wallvik, J., Hippe, E., and Hast, R. (1996). A sequential erythropoietin and GM-CSF schedule offers clinical benefits in the treatment of anemia in myelodysplastic syndromes. Leuk. Res., 20, 693–9CrossRefGoogle ScholarPubMed
Stasi, R., Pagano, A., Terzoli, E., and Amadori, S. (1999). Recombinant human granulocyte-macrophage colony-stimulating factor plus erythropoietin for the treatment of cytopenias in patients with myelodysplastic syndromes. Br. J. Haematol., 105, 141–8CrossRefGoogle ScholarPubMed
Thompson, J., Gilliland, G., Prchal, J.et al. (1995). The use of GM-CSF+ r-HuEPO for the treatment of cytopenias associated with myelodysplastic syndromes. Blood, 86 (suppl. 1), 337a (abstract)Google Scholar
Economopoulos, T., Mellou, S., Papageorgiou, E.et al. (1999). Treatment of anemia in low risk myelodysplastic syndromes with granulocyte-macrophage colony-stimulating factor plus recombinant human erythropoietin. Leukemia, 13, 1009–12CrossRefGoogle ScholarPubMed
Tefferi, A., Elliott, M. A., Steensma, D. P.et al. (2001). Amifostine alone and in combination with erythropoietin for the treatment of favorable myelodysplastic syndrome. Leuk. Res., 25, 183–5CrossRefGoogle ScholarPubMed
Neumeister, P., Jaeger, G., Eibl, M.et al. (2001). Amifostine in combination with erythropoietin and G-CSF promotes multilineage hematopoiesis in patients with myelodysplastic syndrome. Leuk. Lymphoma, 40, 345–9CrossRefGoogle ScholarPubMed
Tsiara, S. N., Kapsali, H. D., Panteli, K., Christou, L., and Bourantas, K. L. (2001). Preliminary results of amifostine administration in combination with recombinant human erythropoietin in patients with myelodysplastic syndromes. J. Exp. Clin. Cancer Res., 20, 35–8Google ScholarPubMed
Grossi, A., Musto, P., Santini, V.et al. (2002). Combined therapy with amifostine plus erythropoietin for the treatment of myelodysplastic syndromes. Haematologica, 87, 322–3Google ScholarPubMed
Stasi, R., Brunetti, M., Terzoli, E., and Amadori, S. (2002). Sustained response to recombinant human erythropoietin and intermittent all-trans retinoic acid in patients with myelodysplastic syndromes. Blood, 99, 1578–84CrossRefGoogle ScholarPubMed
Ganser, A., Seipelt, G., Lindemann, A.et al. (1990). Effects of recombinant human interleukin-3 in patients with myelodysplastic syndromes. Blood, 76, 455–62Google ScholarPubMed
Kurzrock, R., Talpaz, M., Estrov, Z., Rosenblum, M. G., and Gutterman, J. U. (1991). Phase I study of recombinant human interleukin-3 in patients with bone marrow failure. J. Clin. Oncol., 9, 1241–50CrossRefGoogle ScholarPubMed
Nimer, S. D., Paquette, R. L., Ireland, P.et al. (1994). A phase I/II study of interleukin-3 in patients with aplastic anemia and myelodysplasia. Exp. Hematol., 22, 875–80Google ScholarPubMed
Ganser, A., Ottmann, O. G., Seipelt, G.et al. (1993). Effect of long-term treatment with recombinant human interleukin-3 in patients with myelodysplastic syndromes. Leukemia, 7, 696–701Google ScholarPubMed
Miller, A. M., Noyes, W. E., Taetle, R., and List, A. F. (1999). Limited erythropoietic response to combined treatment with recombinant human interleukin 3 and erythropoietin in myelodysplastic syndrome. Leuk. Res., 23, 77–83CrossRefGoogle ScholarPubMed
Gordon, M. S., Nemunaitis, J., Hoffman, R.et al. (1995). A phase I trial of recombinant human interleukin-6 in patients with myelodysplastic syndromes and thrombocytopenia. Blood, 85, 3066–76Google ScholarPubMed
Kurzrock, R., Cortes, J., Thomas, D. A.et al. (2001). Pilot study of low-dose interleukin-II in patients with bone marrow failure. J. Clin. Oncol., 19, 4165–72CrossRefGoogle Scholar
Lok, S., Kaushansky, K., Holly, R. D.et al. (1994). Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature, 369, 565–8CrossRefGoogle ScholarPubMed
Sauvage, F. J., Hass, P. E., Spencer, S. D.et al. (1994). Stimulation of megakaryocytopoiesis and thrombopoiesis by the c-mpl ligand. Nature, 369, 533–8CrossRefGoogle ScholarPubMed
Kaushansky, K., Lok, S., Holly, R. D.et al. (1994). Promotion of megakaryocyte progenitor expansion and differentiation by the c-mpl ligand thrombopoietin. Nature, 369, 568–71CrossRefGoogle ScholarPubMed
Wendling, F., Maraskovsky, E., Debili, N.et al. (1994). cMpl ligand is a humoral regulator of megakaryocytopoieisis. Nature, 369, 571–4CrossRefGoogle Scholar
Bartley, T. D., Bogenberger, J., Hunt, P.et al. (1994). Identification and cloning of a megakaryocyte and development factor that is a ligand for the cytokine receptor mpl. Cell, 77, 1117–24CrossRefGoogle ScholarPubMed
Debili, N., Wendling, F., Katz, A.et al. (1995). The Mpl-ligand or thrombopoietin of megakaryocyte growth and differentiative factor has both direct proliferative and differentiative activities on human megakaryocyte progenitors. Blood, 86, 2516–25Google ScholarPubMed
Sitnicka, E., Lin, N., Priestley, G. V.et al. (1996). The effect of thrombopoietin on the proliferation and differentiation of murine hematopoietic stem cells. Blood, 87, 4998–5005Google ScholarPubMed
Katayama, N., Itoh, R., Kato, T.et al. (1997). Role for C-MPL and its ligand thrombopoietin in early hematopoiesis. Leuk. Lymphoma, 28, 51–6CrossRefGoogle ScholarPubMed
Molineaux, G., Hartley, C., McElroy, P., McCrea, C., and McNiece, I. K. (1996). Megakaryocyte growth and development factor accelerates platelet recovery in peripheral blood progenitor cell transplant recipients. Blood, 88, 366–76Google Scholar
Farese, A. M., Hunt, P., Grab, L. B., and MacVittie, T. J. (1996). Combined administration of recombinant human megakaryocyte growth and development factor and granulocyte colony-stimulating factor enhances multilineage hematopoietic reconstitution in non-human primates after radiation-induced marrow aplasia. J. Clin. Invest., 97, 2145–51CrossRefGoogle Scholar
Basser, R. L., Rasko, J. E., Clarke, K.et al. (1996). Thrombopoietic effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) in patients with advanced cancer. Lancet, 348, 1279–81CrossRefGoogle Scholar
Vadhan-Raj, S., Murray, L. J., Bueso-Ramos, C.et al. (1997). Stimulation of megakaryocyte and platelet production by a single dose of recombinant human thrombopoietin in patients with cancer. Ann. Intern. Med., 126, 673–81CrossRefGoogle ScholarPubMed
Basser, R. L., Rasko, J. E., Clarke, K.et al. (1997). Randomized, blinded, placebo-controlled phase I trial of pegylated recombinant human megakaryocyte growth and development factor with filgrastim after dose-intensive chemotherapy in patients with advanced cancer. Blood, 89, 3118–28Google ScholarPubMed
Fanucchi, M., Glaspy, J., Crawford, J.et al. (1997). Effects of polyethylene glycol-conjugated recombinant human megakaryocyte growth and development factor on platelet counts after chemotherapy for lung cancer. N. Engl. J. Med., 336, 404–9CrossRefGoogle ScholarPubMed
Emmons, R. V., Reid, D. M., Cohen, R. L.et al. (1996). Human thrombopoietin levels are high when thrombocytopenia is due to megakaryocyte deficiency and low when due to increased platelet destruction. Blood, 87, 4068–71Google ScholarPubMed
Wang, W., Matsuo, T., Yoshida, S.et al. (2000). Colony-forming unit-megakaryocyte (CFR-meg) numbers and serum thrombopoietin concentrations in thrombocytopenic disorders: an inverse correlation in myelodysplastic syndromes. Leukemia, 14, 1751–6CrossRefGoogle ScholarPubMed
Zwierzina, H., Rollinger-Holzinger, I., Nuessler, V., Herold, M., and Meng, Y. G. (1998). Endogenous serum thrombopoietin concentrations in patients with myelodysplastic syndromes. Leukemia, 12, 59–64CrossRefGoogle ScholarPubMed
Tamura, H., Ogata, K., Luo, S.et al. (1998). Plasma thrombopoietin (TPO levels) and expression of TPO receptor on platelets in patients with myelodysplastic syndromes. Br. J. Haematol., 103, 778–84CrossRefGoogle ScholarPubMed
Fontenay-Roupie, M., Dupont, J. M., Picard, F.et al. (1998). Analysis of megakaryocyte growth and development factor (thrombopoietin) effects on blast cell and megakaryocyte growth in myelodysplasia. Leuk. Res., 22, 527–35CrossRefGoogle ScholarPubMed
Luo, S. S., Ogata, K., Yokose, N., Kato, T., and Dan, K. (2000). Effect of thrombopoietin on proliferation of blasts from patients with myelodysplastic syndromes. Stem Cells, 18, 112–19CrossRefGoogle ScholarPubMed
Adams, J. A., Liu Yin, J. A., Brereton, M. L.et al. (1997). The in vitro effect of pegylated recombinant human megakaryocyte growth and development factor (PEG rHuMGDF) on megakarypoiesis in normal subjects and patients with myelodysplasia and acute myeloid leukemia. Br. J. Haematol., 99, 139–46CrossRefGoogle Scholar
Liu Yin, J. A., Adams, J. A., Brereton, M. L.et al. (2000). Megakaryopoiesis in vitro in myelodysplastic syndromes and acute myeloid leukemia: effect of pegylated recombinant human megakaryocyte growth and development factor in combination with other growth factors. Br. J. Haematol., 108, 743–6CrossRefGoogle ScholarPubMed
Ferrajoli, A., Talpaz, M., Kurzrock, R.et al. (1998). Thrombopoietin stimulates myelodysplastic syndrome granulocyte-macrophage and erythroid progenitor proliferation. Leuk. Lymphoma, 30, 279–92CrossRefGoogle ScholarPubMed
Komatsu, N., Okamoto, T., Yoshida, T.et al. (2000). Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) increased platelet counts (PLT) in patients (pts) with aplastic anemia (AA) and myelodysplastic syndrome (MDS). Blood, 96, 296a (abstract)Google Scholar
Kizaki, M., Yoshitaka, M., and Ikeda, Y. (2003). Long-term administration of pegylated recombinant human megakaryocyte growth and development factor dramatically improved cytopenias in a patient with myelodysplastic syndrome. Br. J. Haematol., 122, 764–7CrossRefGoogle Scholar
Olivieri, N. F. (1999). The beta-thalassemias. N. Engl. J. Med., 341, 99–109CrossRefGoogle ScholarPubMed
Hershko, C., Graham, G., Bates, G. W., and Rachmilewitz, E. A. (1978). Non-specific serum iron in thalassemia: an abnormal serum iron fraction of potential toxicity. Br. J. Haematol., 40, 255–63CrossRefGoogle ScholarPubMed
Farquhar, M. J. and Bowen, D. T. (2003). Oxidative stress and the myelodysplastic syndromes. Int. J. Hematol., 77, 342–50CrossRefGoogle ScholarPubMed
Gotlib, J. and Greenberg, P. L. (2002). Myelodysplastic syndromes. In Leukemia, 7th Edn, ed. , E. Henderson, , T. Lister, , M. F. Greaves. New York: Churchill Livingstone, pp. 545–82Google Scholar
Olivieri, N. F., Nathan, D. G., MacMillan, J. H.et al. (1994). Survival in medically treated patients with homozygous beta-thalassemia. N. Engl. J. Med., 331, 574–8CrossRefGoogle ScholarPubMed
Brittenham, G. M., Griffith, P. M., Nienhuis, A. W.et al. (1994). Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N. Engl. J. Med., 331, 567–73CrossRefGoogle ScholarPubMed
Olivieri, N. F. and Brittenham, G. M. (1997). Iron-chelating therapy and the treatment of thalassemia. Blood, 89, 739–61Google ScholarPubMed
Jensen, P. D., Heickendorff, L., Bendix-Hansen, K.et al. (1996). The effect of iron chelation on haemopoiesis in MDS patients with transfusional iron overload. Br. J. Haematol., 94, 288–99CrossRefGoogle ScholarPubMed
Franchini, M., Gandini, G., Gironcoli, M.et al. (2000). Safety and efficacy of subcutaneous bolus injection of deferoxamine in adult patients with iron overload. Blood, 95, 2776–9Google ScholarPubMed
Franchini, M., Gandini, G., Veneri, D., and Aprili, G. (2004). Safety and efficacy of subcutaneous bolus injection of deferoxamine in adult patients with iron overload: an update. Blood, 103, 747–8CrossRefGoogle ScholarPubMed
Hoffbrand, A. V., Cohen, A., and Hershko, C. (2003). Role of deferiprone in chelation therapy for transfusional iron overload. Blood, 102, 17–24CrossRefGoogle ScholarPubMed
Cohen, A. R., Galanello, R., Piga, A., Sanctis, V., and Tricta, F. (2003). Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone. Blood, 102, 1583–7CrossRefGoogle ScholarPubMed
Olivieri, N. F., Brittenham, G. M., McLaren, C. E.et al. (1998). Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major. N. Engl. J. Med., 339, 417–23CrossRefGoogle ScholarPubMed
Hoffbrand, A. V., Al-Refaie, F., Davis, B.et al. (1998). Long-term trial of deferiprone in 51-transfusion-dependent iron overloaded patients. Blood, 91, 295–300Google ScholarPubMed
Stella, M., Pinzello, G., and Maggio, A. (1998). Iron chelation with oral deferiprone in patients with thalassemia. N. Engl. J. Med., 339, 1710–11Google ScholarPubMed
Tondury, P., Zimmermann, A., Nielsen, P., and Hirt, A. (1998). Liver iron and fibrosis during long-term treatment with deferiprone in Swiss thalassaemic patients. Br. J. Haematol., 101, 413–15CrossRefGoogle ScholarPubMed
Berdoukas, V., Bohane, T., Eagle, C.et al. (2000). The Sidney Children's Hospital experience with the oral iron chelator deferiprone (L1). Transfus. Sci., 23, 239–40CrossRefGoogle Scholar
Wanless, I. R., Sweeney, G., Dhillon, A. P.et al. (2002). Lack of progressive hepatic fibrosis during long-term therapy with deferiprone in subjects with transfusion-dependent beta-thalassemia. Blood, 100, 1566–9CrossRefGoogle ScholarPubMed
Addis, A., Loebstein, R., Koren, G., and Einarson, T. R. (1999). Meta-analytic review of the clinical effectiveness of oral deferiprone (L1). Eur. J. Clin. Pharmacol., 55, 1–6CrossRefGoogle Scholar
Barman Balfour, J. A. and Foster, R. H. (1999). Deferiprone: a review of its clinical potential in iron overload in beta-thalassaemia major and other transfusion-dependent diseases. Drugs, 58, 553–78CrossRefGoogle ScholarPubMed
Kersten, M. J., Lange, R., Smeets, M. E.et al. (1996). Long-term treatment of transfusional iron overload with the oral iron chelator deferiprone (L1): a Dutch multicenter trial. Ann. Hematol., 73, 247–52CrossRefGoogle ScholarPubMed
Pootrakul, P., Sirankapracha, P., Sankote, J.et al. (2003). Clinical trial of deferiprone iron chelation therapy in beta-thalassaemia/haemoglobin E patients in Thailand. Br. J. Haematol., 122, 305–10CrossRefGoogle Scholar
Nick, H., Acklin, P., Lattmann, R.et al. (2003). Development of tridentate iron chelators: from desferrithiocin to ICL670. Curr. Med. Chem., 10, 1065–76CrossRefGoogle ScholarPubMed
Nisbet-Brown, E., Olivieri, N. F., Giardina, P. J.et al. (2003). Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet, 361, 1597–602CrossRefGoogle ScholarPubMed
Piga, A., Galanello, R., Cappellini, M. D.et al. (2002). Phase II study of oral chelator ICL670 in thalassaemia patients with transfusional iron overload: efficacy, safety, pharmacokinetics (PK) and pharmacodynamics (PD) after 6 months of therapy. Blood, 100 (suppl. 1), 5a (abstract)Google Scholar
Piga, A., Galanello, R., Cappellini, M. D.et al. (2003). Phase II study of ICL670, an oral chelator, in adult thalassaemia patients with transfusional iron overload: efficacy, safety, pharmacokinetics (PK) and pharmacodynamics (PD) after 18 months of therapy. Blood, 102 (suppl. 1), 121a (abstract)Google Scholar
Cheson, B. D., Bennett, J. M., Kantarjian, H.et al. (2000). Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood, 96, 3671–4Google Scholar
Bowen, D. T. and Hellstrom-Lindberg, E. (2001). Best supportive care for the anaemia of myelodysplasia: inclusion of recombinant erythropoietin therapy?Leuk. Res., 25, 19–21CrossRefGoogle ScholarPubMed
Nicolas, G., Bennoun, M., Devaux, I.et al. (2001). Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice. Proc. Natl Acad. Sci. U.S.A., 98, 8780–5CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×