Seminars in Hematology
Volume 45, Issue 1 , Pages 14-22 , January 2008

Supportive Care and Use of Hematopoietic Growth Factors in Myelodysplastic Syndromes

  • Eva Hellström-Lindberg

      Affiliations

    • Karolinska Institutet, Department of Medicine, Division of Hematology, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    • Corresponding Author InformationAddress correspondence to Eva Hellström-Lindberg, MD, PhD, Karolinska Institutet, Department of Medicine, Division of Hematology, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.
    • ,
  • Luca Malcovati

      Affiliations

    • Department of Hematology, University of Pavia Medical School, S. Matteo University Hospital, 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, Flandrin G, Galton DA, Gralnick HR, 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, Invernizzi R, Boni M, Travaglino E, 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. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–2088
  8. de Witte T, Suciu S, Verhoef G, Labar B, Archimbaud E, Aul C, 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
  9. Malcovati L, Germing U, Kuendgen A, Della Porta MG, Invernizzi R, Giagounidis A, et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol. 2007;25:3503–3510
  10. 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, NY: Marcel Dekker; 2002;p. 345–372
  11. Maschek H, Kaloutsi V, Rodriguez-Kaiser M, Werner M, Choritz H, Mainzer K, et al. Hypoplastic myelodysplastic syndrome: Incidence, morphology, cytogenetics, and prognosis. Ann Hematol. 1993;66:117–122
  12. Vander Heiden MG, Thompson CB. Bcl-2 proteins: Regulators of apoptosis or of mitochondrial homeostasis?. Nat Cell Biol. 1999;1:E209–E216
  13. Wajant H. The Fas signaling pathway: More than a paradigm. Science. 2002;296:1635–1636
  14. De Maria R, Testa U, Luchetti L, Zeuner A, Stassi G, Pelosi E, et al. Apoptotic role of Fas/Fas ligand system in the regulation of erythropoiesis. Blood. 1999;93:796–803
  15. Claessens YE, Bouscary D, Dupont JM, Picard F, Melle J, Gisselbrecht S, 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
  16. Claessens YE, Park S, Dubart-Kupperschmitt A, Mariot V, Garrido C, Chretien S, 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
  17. Tehranchi R, Fadeel B, Forsblom AM, Christensson B, Samuelsson J, Zhivotovsky B, 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
  18. Tehranchi R, Invernizzi R, Grandien A, Zhivotovsky B, Fadeel B, Forsblom AM, et al. Aberrant mitochondrial iron distribution and maturation arrest characterize early erythroid precursors in low-risk myelodysplastic syndromes. Blood. 2005;106:247–253
  19. Bouscary D, De Vos J, Guesnu M, Jondeau K, Viguier F, Melle J, et al. Fas/Apo-1 (CD95) expression and apoptosis in patients with myelodysplastic syndromes. Leukemia. 1997;11:839–845
  20. 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
  21. 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
  22. 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
  23. 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
  24. van de Loosdrecht AA, Brada SJ, Blom NR, Hendriks DW, Smit JW, van den Berg E, et al. Mitochondrial disruption and limited apoptosis of erythroblasts are associated with high risk myelodysplasia (An ultrastructural analysis). Leuk Res. 2001;25:385–393
  25. 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
  26. Shin MG, Kajigaya S, Levin BC, Young NS. Mitochondrial DNA mutations in patients with myelodysplastic syndromes. Blood. 2003;101:3118–3125
  27. Cazzola M, Invernizzi R, Bergamaschi G, Levi S, Corsi B, Travaglino E, et al. Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia. Blood. 2003;101:1996–2000
  28. Della Porta MG, Malcovati L, Gallì A, Boggi S, Travaglino E, Marseglia C, et al. Mitochondrial ferritin expression and clonality of hematopoiesis in patients with refractory anemia with ringed sideroblasts. Blood. 2005;106:3444
  29. 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
  30. Saunthararajah Y, Nakamura R, Nam JM, Robyn J, Loberiza F, Maciejewski JP, 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
  31. 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
  32. Daskalakis M, Nguyen TT, Nguyen C, Guldberg P, Kohler G, Wijermans P, 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
  33. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, 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
  34. Kantarjian H, Issa JP, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: Results of a phase III randomized study. Cancer. 2006;106:1794–1803
  35. Saunthararajah Y, Hillery CA, Lavelle D, Molokie R, Dorn L, Bressler L, et al. Effects of 5-aza-2′-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. Blood. 2003;102:3865–3870
  36. Aguayo A. The role of angiogenesis in the biology and therapy of myelodysplastic syndromes. Curr Hematol Rep. 2004;3:184–191
  37. Panoskaltsis N. Dendritic cells in MDS and AML—Cause, effect or solution to the immune pathogenesis of disease?. Leukemia. 2005;19:354–357
  38. 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
  39. Kiladjian JJ, Bourgeois E, Lobe I, Braun T, Visentin G, Bourhis JH, et al. Cytolytic function and survival of natural killer cells are severely altered in myelodysplastic syndromes. Leukemia. 2006;20:463–470
  40. Izaks GJ, Westendorp RG, Knook DL. The definition of anemia in older persons. JAMA. 1999;281:1714–1717
  41. 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
  42. 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
  43. Alessandrino EP, Amadori S, Barosi G, Cazzola M, Grossi A, Liberato LN, 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
  44. Bowen D, Culligan D, Jowitt S, Kelsey S, Mufti G, Oscier D, et al. Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes. Br J Haematol. 2003;120:187–200
  45. Hellstrom-Lindberg E, Gulbrandsen N, Lindberg G, Ahlgren T, Dahl IM, Dybedal I, 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
  46. Armand P, Kim HT, Cutler CS, Ho VT, Koreth J, Alyea E, et al. Prognostic impact of elevated pre-transplant serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood. 2007;109:4586–4588
  47. Angelucci E, Muretto P, Nicolucci A, Baronciani D, Erer B, Gaziev J, 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
  48. 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
  49. Cappellini MD, Cohen A, Piga A, Bejaoui M, Perrotta S, Agaoglu L, 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
  50. Testa U. Apoptotic mechanisms in the control of erythropoiesis. Leukemia. 2004;18:1176–1199
  51. 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
  52. 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
  53. 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
  54. Hellstrom-Lindberg E, Negrin R, Stein R, Krantz S, Lindberg G, Vardiman J, 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
  55. Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD, et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000;96:3671–3674
  56. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108:419–425
  57. Terpos E, Mougiou A, Kouraklis A, Chatzivassili A, Michalis E, Giannakoulas N, 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
  58. 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
  59. Rigolin GM, Porta MD, Ciccone M, Bugli AM, Bragotti LZ, Mauro E, 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
  60. 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
  61. Bennett CL, Luminari S, Nissenson AR, Tallman MS, Klinge SA, McWilliams N, et al. Pure red-cell aplasia and epoetin therapy. N Engl J Med. 2004;351:1403–1408
  62. Mannone L, Gardin C, Quarre MC, Bernard JF, Vassilieff D, Ades L, 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
  63. Musto P, Lanza F, Balleari E, Grossi A, Falcone A, Sanpaolo G, et al. Darbepoetin alpha for the treatment of anaemia in low-intermediate risk myelodysplastic syndromes. Br J Haematol. 2005;128:204–209
  64. 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
  65. Osterborg A, Steegmann JL, Hellmann A, Couban S, Mayer J, Eid JE. Phase II study of three dose levels of continuous erythropoietin receptor activator (C.E.R.A.) in anaemic patients with aggressive non-Hodgkin’s lymphoma receiving combination chemotherapy. Br J Haematol. 2007;136:736–744
  66. Dmoszynska A, Kloczko J, Rokicka M, Hellmann A, Spicka I, Eid JE. A dose exploration, phase I/II study of administration of continuous erythropoietin receptor activator once every 3 weeks in anemic patients with multiple myeloma receiving chemotherapy. Haematologica. 2007;92:493–501
  67. Negrin RS, Stein R, Doherty K, Cornwell J, Vardiman J, Krantz S, 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
  68. Hellstrom-Lindberg E, Ahlgren T, Beguin Y, Carlsson M, Carneskog J, Dahl IM, 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
  69. Casadevall N, Durieux P, Dubois S, Hemery F, Lepage E, Quarre MC, 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
  70. Balleari E, Rossi E, Clavio M, Congiu A, Gobbi M, Grosso 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
  71. Remacha AF, Arrizabalaga B, Villegas A, Manteiga R, Calvo T, Julia A, et al. The Spanish Erythropathology Group Erythropoietin plus granulocyte colony-stimulating factor in the treatment of myelodysplastic syndromes (Identification of a subgroup of responders). Haematologica. 1999;84:1058–1064
  72. Bowen D, Hyslop A, Keenan N, Groves M, Culligan D, Johnson P, 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
  73. Henke M, Laszig R, Rube C, Schafer U, Haase KD, Schilcher B, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebo-controlled trial. Lancet. 2003;362:1255–1260
  74. Temkin SM, Hellmann M, Serur E, Lee YC, Abulafia O. Erythropoietin administration during primary treatment for locally advanced cervical carcinoma is associated with poor response to radiation. Int J Gynecol Cancer. 2006;16:1855–1861
  75. Leyland-Jones B, Semiglazov V, Pawlicki M, Pienkowski T, Tjulandin S, Manikhas G, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: A survival study. J Clin Oncol. 2005;23:5960–5972
  76. 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
  77. Jädersten M, Malcovati L, Dybedal I, Della Porta M, Invernizzi R, Montgomery S, et al. Treatment with erythropoietin and G-CSF improves survival in MDS patients with low transfusion need. Blood. 2006;106:172;(abstr)
  78. Kaushansky K, Lok S, Holly RD, Broudy VC, Lin N, Bailey MC, et al. Promotion of megakaryocyte progenitor expansion and differentiation by the c-Mpl ligand thrombopoietin. Nature. 1994;369:568–571
  79. Newland A, Caulier MT, Kappers-Klunne M, Schipperus MR, Lefrere F, Zwaginga JJ, 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: S0037-1963(07)00155-2

doi: 10.1053/j.seminhematol.2007.10.004

Seminars in Hematology
Volume 45, Issue 1 , Pages 14-22 , January 2008

Article Tools

* Image Usage & Resolution