Blood Reviews
Volume 22, Issue 2 , Pages 75-91 , March 2008

Supportive care, growth factors, and new therapies in myelodysplastic syndromes

  • Eva Hellström-Lindberg

      Affiliations

    • Karolinska Institutet, Department of Medicine, Division of Hematology, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
    • Corresponding Author InformationCorresponding author.
    • ,
  • Luca Malcovati

      Affiliations

    • Department of Hematology, University of Pavia Medical School, S. Matteo University Hospital, Pl.le Golgi, 2-27100 Pavia, Italy

References 

  1. Cazzola M, Malcovati L. Myelodysplastic syndromes–coping with ineffective hematopoiesis. N Engl J Med. 2005;352:536–538
  2. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982;51:189–199
  3. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100:2292–2302
  4. Germing U, Gattermann N, Strupp C, Aivado M, Aul C. Validation of the WHO proposals for a new classification of primary myelodysplastic syndromes: a retrospective analysis of 1600 patients. Leuk Res. 2000;24:983–992
  5. Malcovati L, Della Porta M, Pascutto C, et al. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria. A basis for clinical decision-making. J Clin Oncol. 2005;23:7594–7603
  6. Howe RB, Porwit-MacDonald A, Wanat R, Tehranchi R, Hellstrom-Lindberg E. The WHO classification of MDS does make a difference. Blood. 2004;103:3265–3270
  7. Verburgh E, Achten R, Maes B, et al. Additional prognostic value of bone marrow histology in patients subclassified according to the International Prognostic Scoring System for myelodysplastic syndromes. J Clin Oncol. 2003;21:273–282
  8. Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–2088
  9. de Witte T, Suciu S, Verhoef G, et al. Intensive chemotherapy followed by allogeneic or autologous stem cell transplantation for patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS. Blood. 2001;98:2326–2331
  10. Malcovati L, Germing U, Kuendgen A, et al. A WHO Classification-Based Prognostic Scoring System (WPSS) for Predicting Survival in Myelodysplastic Syndromes. Blood. 2005;106:788
  11. Bowen DT, Hellstrom-Lindberg E. Treatment of Anemia in Myelodysplastic Syndromes. In:  Bennet JM editors. The Myelodysplastic Syndromes in Pathobiology and Clinical Management. New York: Marcel Dekker Inc.; 2002;p. 345–372
  12. Maschek H, Kaloutsi V, Rodriguez-Kaiser M, et al. Hypoplastic myelodysplastic syndrome: incidence, morphology, cytogenetics, and prognosis. Ann Hematol. 1993;66:117–122
  13. Vander Heiden MG, Thompson CB. Bcl-2 proteins: regulators of apoptosis or of mitochondrial homeostasis?. Nat Cell Biol. 1999;1:E209–E216
  14. Wajant H. The Fas signaling pathway: more than a paradigm. Science. 2002;296:1635–1636
  15. De Maria R, Testa U, Luchetti L, et al. Apoptotic role of Fas/Fas ligand system in the regulation of erythropoiesis. Blood. 1999;93:796–803
  16. Claessens YE, Bouscary D, Dupont JM, et al. In vitro proliferation and differentiation of erythroid progenitors from patients with myelodysplastic syndromes: evidence for Fas-dependent apoptosis. Blood. 2002;99:1594–1601
  17. Claessens YE, Park S, Dubart-Kupperschmitt A, et al. Rescue of early-stage myelodysplastic syndrome-deriving erythroid precursors by the ectopic expression of a dominant-negative form of FADD. Blood. 2005;105:4035–4042
  18. Tehranchi R, Fadeel B, Forsblom AM, et al. Granulocyte colony-stimulating factor inhibits spontaneous cytochrome c release and mitochondria-dependent apoptosis of myelodysplastic syndrome hematopoietic progenitors. Blood. 2003;101:1080–1086
  19. Tehranchi R, Invernizzi R, Grandien A, et al. Aberrant mitochondrial iron distribution and maturation arrest characterize early erythroid precursors in low-risk myelodysplastic syndromes. Blood. 2005;106:247–253
  20. Bouscary D, De Vos J, Guesnu M, et al. Fas/Apo-1 (CD95) expression and apoptosis in patients with myelodysplastic syndromes. Leukemia. 1997;11:839–845
  21. Verhoef GE, De Schouwer P, Ceuppens JL, Van Damme J, Goossens W, Boogaerts MA. Measurement of serum cytokine levels in patients with myelodysplastic syndromes. Leukemia. 1992;6:1268–1272
  22. Otsuki T, Nagakura S, Wang J, Bloom M, Grompe M, Liu JM. Tumor necrosis factor-alpha and CD95 ligation suppress erythropoiesis in Fanconi anemia C gene knockout mice. J Cell Physiol. 1999;179:79–86
  23. Hellstrom-Lindberg E, Schmidt-Mende J, Forsblom AM, Christensson B, Fadeel B, Zhivotovsky B. Apoptosis in refractory anaemia with ringed sideroblasts is initiated at the stem cell level and associated with increased activation of caspases. Br J Haematol. 2001;112:714–726
  24. May A, de Souza P, Barnes K, Kaaba S, Jacobs A. Erythroblast iron metabolism in sideroblastic marrows. Br J Haematol. 1982;52:611–621
  25. Sakura T, Murakami H, Saitoh T, Naruse T, Tsuchiya J. Ultrastructural abnormalities of bone marrow erythroblasts in refractory anemia. Ultrastruct Pathol. 1998;22:173–180
  26. van de Loosdrecht AA, Brada SJ, Blom NR, et al. Mitochondrial disruption and limited apoptosis of erythroblasts are associated with high risk myelodysplasia. An ultrastructural analysis. Leuk Res. 2001;25:385–393
  27. Gattermann N, Wulfert M, Junge B, Germing U, Haas R, Hofhaus G. Ineffective hematopoiesis linked with a mitochondrial tRNA mutation (G3242A) in a patient with myelodysplastic syndrome. Blood. 2004;103:1499–1502
  28. Shin MG, Kajigaya S, Levin BC, Young NS. Mitochondrial DNA mutations in patients with myelodysplastic syndromes. Blood. 2003;101:3118–3125
  29. Cazzola M, Invernizzi R, Bergamaschi G, et al. Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia. Blood. 2003;101:1996–2000
  30. Della Porta MG, Malcovati L, Gallı` A, et al. Mitochondrial Ferritin Expression and Clonality of Hematopoiesis in Patients with Refractory Anemia with Ringed Sideroblasts. Blood. 2005;106:3444
  31. Parker JE, Mufti GJ. The myelodysplastic syndromes: a matter of life or death. Acta Haematol. 2004;111:78–99
  32. Barrett J, Saunthararajah Y, Molldrem J. Myelodysplastic syndrome and aplastic anemia: distinct entities or diseases linked by a common pathophysiology?. Semin Hematol. 2000;37:15–29
  33. Saunthararajah Y, Nakamura R, Nam JM, et al. HLA-DR15 (DR2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome. Blood. 2002;100:1570–1574
  34. Molldrem JJ, Caples M, Mavroudis D, Plante M, Young NS, Barrett AJ. Antithymocyte globulin for patients with myelodysplastic syndrome. Br J Haematol. 1997;99:699–705
  35. Aguayo A. The role of angiogenesis in the biology and therapy of myelodysplastic syndromes. Curr Hematol Rep. 2004;3:184–191
  36. Panoskaltsis N. Dendritic cells in MDS and AML–cause, effect or solution to the immune pathogenesis of disease?. Leukemia. 2005;19:354–357
  37. Delforge M, Raets V, Van Duppen V, Vandenberghe P, Boogaerts M. CD34+ marrow progenitors from MDS patients with high levels of intramedullary apoptosis have reduced expression of alpha4beta1 and alpha5beta1 integrins. Leukemia. 2005;19:57–63
  38. Kiladjian JJ, Bourgeois E, Lobe I, et al. Cytolytic function and survival of natural killer cells are severely altered in myelodysplastic syndromes. Leukemia. 2006;20:463–470
  39. Lai JL, Preudhomme C, Zandecki M, et al. Myelodysplastic syndromes and acute myeloid leukemia with 17p deletion. An entity characterized by specific dysgranulopoiesis and a high incidence of P53 mutations. Leukemia. 1995;9:370–381
  40. Christiansen DH, Andersen MK, Pedersen-Bjergaard J. Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly associated with deletion or loss of 5q, a complex karyotype, and a poor prognosis. J Clin Oncol. 2001;19:1405–1413
  41. Parker JE, Fishlock KL, Mijovic A, Czepulkowski B, Pagliuca A, Mufti A. ‘Low-risk’ myelodysplastic syndrome is associated with excessive apoptosis and an increased ratio of pro- versus anti-apoptotic bcl-2-related proteins. Br J Haematol. 1998;103:1075–1082
  42. Parker JE, Mufti GJ, Rasool F, Mijovic A, Devereux S, Pagliuca A. The role of apoptosis, proliferation, and the Bcl-2-related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS. Blood. 2000;96:3932–3938
  43. Rajapaksa R, Ginzton N, Rott LS, Greenberg PL. Altered oncoprotein expression and apoptosis in myelodysplastic syndrome marrow cells. Blood. 1996;88:4275–4287
  44. Reuter CW, Morgan MA, Bergmann L. Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies?. Blood. 2000;96:1655–1669
  45. Shih LY, Huang CF, Wang PN, et al. Acquisition of FLT3 or N-ras mutations is frequently associated with progression of myelodysplastic syndrome to acute myeloid leukemia. Leukemia. 2004;18:466–475
  46. Gallagher A, Darley R, Padua RA. RAS and the myelodysplastic syndromes. Pathol Biol (Paris). 1997;45:561–568
  47. List AF, Vardiman J, Issa JP, DeWitte TM. Myelodysplastic syndromes. Hematology (Am Soc Hematol Educ Program). 2004;297–317
  48. Kamb A, Gruis NA, Weaver-Feldhaus J, et al. A cell cycle regulator potentially involved in genesis of many tumor types. Science. 1994;264:436–440
  49. Hirama T, Koeffler HP. Role of the cyclin-dependent kinase inhibitors in the development of cancer. Blood. 1995;86:841–854
  50. Uchida T, Kinoshita T, Nagai H, et al. Hypermethylation of the p15INK4B gene in myelodysplastic syndromes. Blood. 1997;90:1403–1409
  51. Quesnel B, Guillerm G, Vereecque R, et al. Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression. Blood. 1998;91:2985–2990
  52. Daskalakis M, Nguyen TT, Nguyen C, et al. Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2’-deoxycytidine (decitabine) treatment. Blood. 2002;100:2957–2964
  53. Batova A, Shao LE, Diccianni MB, et al. The histone deacetylase inhibitor AN-9 has selective toxicity to acute leukemia and drug-resistant primary leukemia and cancer cell lines. Blood. 2002;100:3319–3324
  54. Kuendgen A, Strupp C, Aivado M, et al. Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood. 2004;104:1266–1269
  55. Izaks GJ, Westendorp RG, Knook DL. The definition of anemia in older persons. Jama. 1999;281:1714–1717
  56. Penninx BW, Guralnik JM, Onder G, Ferrucci L, Wallace RB, Pahor M. Anemia and decline in physical performance among older persons. Am J Med. 2003;115:104–110
  57. Wu WC, Rathore SS, Wang Y, Radford MJ, Krumholz HM. Blood transfusion in elderly patients with acute myocardial infarction. N Engl J Med. 2001;345:1230–1236
  58. Hellstrom-Lindberg E, Gulbrandsen N, Lindberg G, et al. 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. 2003;120:1037–1046
  59. Jansen AJ, Essink-Bot ML, Beckers EA, Hop WC, Schipperus MR, Van Rhenen DJ. Quality of life measurement in patients with transfusion-dependent myelodysplastic syndromes. Br J Haematol. 2003;121:270–274
  60. Alessandrino EP, Amadori S, Barosi G, et al. Evidence- and consensus-based practice guidelines for the therapy of primary myelodysplastic syndromes. A statement from the Italian Society of Hematology. Haematologica. 2002;87:1286–1306
  61. Bowen D, Culligan D, Jowitt S, et al. Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes. Br J Haematol. 2003;120:187–200
  62. Cutler CS, Lee SJ, Greenberg P, et al. A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood. 2004;104:579–585
  63. Angelucci E, Muretto P, Nicolucci A, et al. Effects of iron overload and hepatitis C virus positivity in determining progression of liver fibrosis in thalassemia following bone marrow transplantation. Blood. 2002;100:17–21
  64. Franchini M, Gandini G, de Gironcoli M, Vassanelli A, Borgna-Pignatti C, Aprili G. Safety and efficacy of subcutaneous bolus injection of deferoxamine in adult patients with iron overload. Blood. 2000;95:2776–2779
  65. Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia. Blood. 2006;107:3455–3462
  66. Cantor AB, Orkin SH. Transcriptional regulation of erythropoiesis: an affair involving multiple partners. Oncogene. 2002;21:3368–3376
  67. Testa U. Apoptotic mechanisms in the control of erythropoiesis. Leukemia. 2004;18:1176–1199
  68. Aul C, Arning M, Runde V, Schneider W. Serum erythropoietin concentrations in patients with myelodysplastic syndromes. Leuk Res. 1991;15:571–575
  69. Hellstrom E, Birgegard G, Lockner D, Helmers C, Ost A, Wide L. Treatment of myelodysplastic syndromes with recombinant human erythropoietin. Eur J Haematol. 1991;47:355–360
  70. Bowen D, Culligan D, Jacobs A. The treatment of anaemia in the myelodysplastic syndromes with recombinant human erythropoietin. Br J Haematol. 1991;77:419–423
  71. Aloe Spiriti MA, Petti MC, Latagliata R, et al. Recombinant human erythropoietin in the treatment of myelodysplastic syndromes. An interim report. Haematologica. 1993;78:123–126
  72. Hellstrom-Lindberg E. Efficacy of erythropoietin in the myelodysplastic syndromes: a meta-analysis of 205 patients from 17 studies. Br J Haematol. 1995;89:67–71
  73. Stein RS, Abels RI, Krantz SB. Pharmacologic doses of recombinant human erythropoietin in the treatment of myelodysplastic syndromes. Blood. 1991;78:1658–1663
  74. A randomized double-blind placebo-controlled study with subcutaneous recombinant human erythropoietin in patients with low-risk myelodysplastic syndromes. Italian Cooperative Study Group for rHuEpo in Myelodysplastic Syndromes. Br J Haematol 1998;103:1070–1074.
  75. Hellstrom-Lindberg E, Negrin R, Stein R, et al. 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. 1997;99:344–351
  76. Cheson BD, Bennett JM, Kantarjian H, et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000;96:3671–3674
  77. Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the international working group (IWG) response criteria in myelodysplasia. Blood. 2006;
  78. Terpos E, Mougiou A, Kouraklis A, et al. Prolonged administration of erythropoietin increases erythroid response rate in myelodysplastic syndromes: a phase II trial in 281 patients. Br J Haematol. 2002;118:174–180
  79. Verhoef G, Van den Berghe H, Boogaerts M. Cytogenetic effects on cells derived from patients with myelodysplastic syndromes during treatment with hemopoietic growth factors. Leukemia. 1992;6:766–769
  80. Rigolin GM, Porta MD, Ciccone M, et al. In patients with myelodysplastic syndromes response to rHuEPO and G-CSF treatment is related to an increase of cytogenetically normal CD34 cells. Br J Haematol. 2004;126:501–507
  81. Ljung T, Back R, Hellstrom-Lindberg E. Hypochromic red blood cells in low-risk myelodysplastic syndromes: effects of treatment with hemopoietic growth factors. Haematologica. 2004;89:1446–1453
  82. Bennett CL, Luminari S, Nissenson AR, et al. Pure red-cell aplasia and epoetin therapy. N Engl J Med. 2004;351:1403–1408
  83. Mannone L, Gardin C, Quarre MC, et al. High-dose darbepoetin alpha in the treatment of anaemia of lower risk myelodysplastic syndrome results of a phase II study. Br J Haematol. 2006;133:513–519
  84. Musto P, Lanza F, Balleari E, et al. Darbepoetin alpha for the treatment of anaemia in low-intermediate risk myelodysplastic syndromes. Br J Haematol. 2005;128:204–209
  85. Stasi R, Abruzzese E, Lanzetta G, Terzoli E, Amadori S. Darbepoetin alfa for the treatment of anemic patients with low- and intermediate-1-risk myelodysplastic syndromes. Ann Oncol. 2005;16:1921–1927
  86. Negrin RS, Stein R, Vardiman J, et al. Treatment of the anemia of myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor in combination with erythropoietin. Blood. 1993;82:737–743
  87. Negrin RS, Stein R, Doherty K, et al. Maintenance treatment of the anemia of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor and erythropoietin: evidence for in vivo synergy. Blood. 1996;87:4076–4081
  88. Hellstrom-Lindberg E, Ahlgren T, Beguin Y, et al. 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. 1998;92:68–75
  89. Remacha AF, Arrizabalaga B, Villegas A, et al. Erythropoietin plus granulocyte colony-stimulating factor in the treatment of myelodysplastic syndromes. Identification of a subgroup of responders. The Spanish Erythropathology Group. Haematologica. 1999;84:1058–1064
  90. Casadevall N, Durieux P, Dubois S, et al. 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. 2004;104:321–327
  91. Balleari E, Rossi E, Clavio M, et al. Erythropoietin plus granulocyte colony-stimulating factor is better than erythropoietin alone to treat anemia in low-risk myelodysplastic syndromes: results from a randomized single-centre study. Ann Hematol. 2006;85:174–180
  92. Bowen D, Hyslop A, Keenan N, et al. Predicting erythroid response to recombinant erythropoietin plus granulocyte colony-stimulating factor therapy following a single subcutaneous bolus in patients with myelodysplasia. Haematologica. 2006;91:709–710
  93. Jadersten M, Montgomery SM, Dybedal I, Porwit-MacDonald A, Hellstrom-Lindberg E. Long-term outcome of treatment of anemia in MDS with erythropoietin and G-CSF. Blood. 2005;106:803–811
  94. Jädersten M, Malcovati L, Dybedal I, et al. Treatment with Erythropoietin and G-CSF Improves Survival in MDS Patients with Low Transfusion Need. Blood. 2006;106:172
  95. Park S, Grabar S, Kelaidi C, Beyne-Rauzy O, Picard F, Bardet V et al. Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: the GFM experience. Blood Available online 16 October 2007.
  96. Molldrem JJ, Jiang YZ, Stetler-Stevenson M, Mavroudis D, Hensel N, Barrett AJ. Haematological response of patients with myelodysplastic syndrome to antithymocyte globulin is associated with a loss of lymphocyte-mediated inhibition of CFU-GM and alterations in T-cell receptor Vbeta profiles. Br J Haematol. 1998;102:1314–1322
  97. Killick SB, Mufti G, Cavenagh JD, et al. A pilot study of antithymocyte globulin (ATG) in the treatment of patients with ‘low-risk’ myelodysplasia. Br J Haematol. 2003;120:679–684
  98. Stadler M, Germing U, Kliche KO, et al. A prospective, randomised, phase II study of horse antithymocyte globulin vs rabbit antithymocyte globulin as immune-modulating therapy in patients with low-risk myelodysplastic syndromes. Leukemia. 2004;18:460–465
  99. Aivado M, Rong A, Stadler M, et al. Favourable response to antithymocyte or antilymphocyte globulin in low-risk myelodysplastic syndrome patients with a ‘non-clonal’ pattern of X-chromosome inactivation in bone marrow cells. Eur J Haematol. 2002;68:210–216
  100. Steensma DP, Dispenzieri A, Moore SB, Schroeder G, Tefferi A. Antithymocyte globulin has limited efficacy and substantial toxicity in unselected anemic patients with myelodysplastic syndrome. Blood. 2003;101:2156–2158
  101. Broliden PA, Dahl IM, Hast R, et al. Antithymocyte globulin and cyclosporine A as combination therapy for low-risk non-sideroblastic myelodysplastic syndromes. Haematologica. 2006;91:667–670
  102. Jonasova A, Neuwirtova R, Cermak J, et al. Cyclosporin A therapy in hypoplastic MDS patients and certain refractory anaemias without hypoplastic bone marrow. Br J Haematol. 1998;100:304–309
  103. Shimamoto T, Tohyama K, Okamoto T, et al. Cyclosporin A therapy for patients with myelodysplastic syndrome: multicenter pilot studies in Japan. Leuk Res. 2003;27:783–788
  104. D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A. 1994;91:4082–4085
  105. Raza A, Meyer P, Dutt D, et al. Thalidomide produces transfusion independence in long-standing refractory anemias of patients with myelodysplastic syndromes. Blood. 2001;98:958–965
  106. Musto P, Falcone A, Sanpaolo G, Bisceglia M, Matera R, Carella AM. Thalidomide abolishes transfusion-dependence in selected patients with myelodysplastic syndromes. Haematologica. 2002;87:884–886
  107. Strupp C, Germing U, Aivado M, Misgeld E, Haas R, Gattermann N. Thalidomide for the treatment of patients with myelodysplastic syndromes. Leukemia. 2002;16:1–6
  108. List A, Kurtin S, Roe DJ, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005;352:549–557
  109. List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355:1456–1465
  110. Raza A, Reeves JA, Feldman EJ, Dewald GW, Bennett JM, Deeg HJ et al. Phase II study of lenalidomide in transfusion-dependent, low- and intermediate-1-risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood Available online 24 September 2007.
  111. Gersuk GM, Beckham C, Loken MR, et al. A role for tumour necrosis factor-alpha, Fas and Fas-Ligand in marrow failure associated with myelodysplastic syndrome. Br J Haematol. 1998;103:176–188
  112. Maciejewski JP, Risitano AM, Sloand EM, et al. A pilot study of the recombinant soluble human tumour necrosis factor receptor (p75)-Fc fusion protein in patients with myelodysplastic syndrome. Br J Haematol. 2002;117:119–126
  113. Raza A, Candoni A, Khan U, et al. Remicade as TNF suppressor in patients with myelodysplastic syndromes. Leuk Lymphoma. 2004;45:2099–2104
  114. Bellamy WT, Richter L, Sirjani D, et al. Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes. Blood. 2001;97:1427–1434
  115. Giles FJ, Stopeck AT, Silverman LR, et al. SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Blood. 2003;102:795–801
  116. List AF, Kurtin SE, Callander N, et al. Randomized, Double-Blind Phase II Study of the Matrix Metalloprotease (MMP) Inhibitor, AG3340 (PrinomastatTM) in Patients with Myelodysplastic Syndrome (MDS). Blood. 2002;100:3119a
  117. Bonati A, Rizzoli V, Lunghi P. Arsenic trioxide in hematological malignancies: the new discovery of an ancient drug. Curr Pharm Biotechnol. 2006;7:397–405
  118. Schiller GJ, Slack J, Hainsworth JD, et al. Phase II multicenter study of arsenic trioxide in patients with myelodysplastic syndromes. J Clin Oncol. 2006;24:2456–2464
  119. Vey N, Bosly A, Guerci A, et al. Arsenic trioxide in patients with myelodysplastic syndromes: a phase II multicenter study. J Clin Oncol. 2006;24:2465–2471
  120. Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20:2429–2440
  121. Wijermans P, Lubbert M, Verhoef G, et al. Low-dose 5-aza-2’-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol. 2000;18:956–962
  122. Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794–1803
  123. Graef T, Kuendgen A, Fenk R, Zohren F, Haas R, Kobbe G. Successful treatment of relapsed AML after allogeneic stem cell transplantation with azacitidine. Leuk Res. 2007;31:257–259
  124. Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 2007;109:52–57
  125. Khan R, Aggerholm A, Hokland P, Hassan M, Hellstrom-Lindberg E. A pharmacodynamic study of 5-azacytidine in the P39 cell line. Exp Hematol. 2006;34:35–43
  126. Bhalla K, List A. Histone deacetylase inhibitors in myelodysplastic syndrome. Best Pract Res Clin Haematol. 2004;17:595–611
  127. Kuendgen A, Knipp S, Fox F, et al. Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia. Ann Hematol. 2005;84(Suppl 13):61–66
  128. Germing U, Strupp C, Kuendgen A, et al. Prospective validation of the WHO proposals for the classification of myelodysplastic syndromes. Haematologica/the Hematology Journal. 2006;91:1596–1604
  129. Kurzrock R, Kantarjian HM, Cortes JE, et al. Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting. Blood. 2003;102:4527–4534
  130. Kurzrock R, Albitar M, Cortes JE, et al. Phase II study of R115777, a farnesyl transferase inhibitor, in myelodysplastic syndrome. J Clin Oncol. 2004;22:1287–1292
  131. Apperley JF, Gardembas M, Melo JV, et al. Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med. 2002;347:481–487
  132. Navas TA, Mohindru M, Estes M, et al. Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors. Blood. 2006;108:4170–4177
  133. Stofega MR, Cheng M, Ma H, et al. TelintraTM (TLK199) Enhances Granulocyte Colony-Stimulating Factor Production. Blood. 2006;108:1161a
  134. Chan G, DiVenuti G, Miller K. Danazol for the treatment of thrombocytopenia in patients with myelodysplastic syndrome. Am J Hematol. 2002;71:166–171
  135. Yamada T, Tsurumi H, Kasahara S, Hara T, Sawada M, Moriwaki H. Immunosuppressive therapy for myelodysplastic syndrome: efficacy of methylprednisolone pulse therapy with or without cyclosporin A. J Cancer Res Clin Oncol. 2003;129:485–491
  136. Kaushansky K, Lok S, Holly RD, et al. Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature. 1994;369:568–571
  137. Newland A, Caulier MT, Kappers-Klunne M, et al. An open-label, unit dose-finding study of AMG 531, a novel thrombopoiesis-stimulating peptibody, in patients with immune thrombocytopenic purpura. Br J Haematol. 2006;135:547–553

PII: S0268-960X(07)00069-0

doi: 10.1016/j.blre.2007.10.003

Blood Reviews
Volume 22, Issue 2 , Pages 75-91 , March 2008

Article Tools

* Image Usage & Resolution