Skip to main content
SpringerLink
Log in

Cytokines in MDS: Abnormalities and Treatment

  • Chapter
  • First Online:
The Myelodysplastic Syndromes

  • 719 Accesses

Abstract

Myelodysplastic syndromes (MDS) are associated with quantitative and qualitative hematopoietic defects. The cytokine abnormalities have led to the introduction of recombinant products into clinical practice. This chapter reviews the biology and therapeutic use of cytokines.

Erythroid defects include ineffective erythropoiesis, apoptosis and dysregulation of cytokines including TNF, TGF, interleukin-1, and vascular endothelial growth factors. Recombinant erythropoietin (rHuEPO) has been shown to increase the hemoglobin and hematocrit levels, reduce transfusion requirements and improve the quality of life in about 50% of the patients, effects lasting approximately two years. The questions about EPO safety are irrelevant for MDS. However, compliance with ASCO/ASH guidelines is mandatory.

Neutropenia and/or functional defects are found in approximately 50% of MDS patients. Apoptosis plays a significant role, and cytokines (e.g. TNF-α) are also involved. GM-CSF treatment does not provide a sustained effect and may increase the risk of leukemic transformation. G-CSF therapy is more promising.

Thrombocytopenia occurs in approximately 50% of the patients, with possible poor function and clumping of platelets as well. Recombinant thrombopoietin treatment induces antibody production and subsequent thrombocytopenia. Treatment with IL-11, IL-6 and IL-3 has demonstrated modest results, but treatment with thrombopoietin receptor agonists, romiplostim and eltrombopag, is promising. Approximately half of the patients demonstrate a sustained, durable response without formation of neutralizing antibodies or development of malignant clones.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. DeAngelo DJ, Stone RM (2005) Myelodysplastic syndromes: biology and treatment. In: Hoffman R et al (eds) Hematology—basic principles and practice, 4th edn. Elsevier, Philadelphia, pp 1195–1208

    Google Scholar 

  2. Mittelman M (1990) The myelodysplastic syndromes—1990. Isr J Med Sci 26:468–478

    PubMed  CAS  Google Scholar 

  3. Mittelman M, Lessin LS (1991) Myelodysplasia (preleukemia). In: Moossa AR, Schimpff SC, Robson MC (eds) Comprehensive textbook of oncology, 2nd edn. Williams & Wilkins, Baltimore, pp 1232–1244

    Google Scholar 

  4. Bennett JM, Catovski D, Daniel MT et al (1982) Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:189–199

    PubMed  CAS  Google Scholar 

  5. Greenberg P, Cox C, LeBeau MM et al (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2098

    PubMed  CAS  Google Scholar 

  6. Cazzola M, Beguin Y (1992) New tools for clinical evaluation of erythron function in man. Br J Haematol 80:278–284

    Article  PubMed  CAS  Google Scholar 

  7. Mittelman M (1993) Recombinant erythropoietin in myelodysplastic syndromes: whom to treat an how? More questions than answers. Acta Haematol 90:53–57

    Article  PubMed  CAS  Google Scholar 

  8. Mittelman M, Lessin LS (1994) Clinical application of recombinant erythropoietin in myelodysplasia. Hematol/Oncol Clin NAm 8:993–1009

    CAS  Google Scholar 

  9. Raza A, Gezer S, Mundle S et al (1995) Apoptosis in bone marrow biopsy sample involving stromal and hematopoietic cells in 50 patients with myelodysplastic syndromes. Blood 86:268–276

    PubMed  CAS  Google Scholar 

  10. Bowen DT, Hellström-Lindberg E (2002) Treatment of anemia in myelodysplastic syndromes. In: Bennett JM (ed) The myelodysplastic syndromes—pathobiology and clinical management. Marcel Dekker, New York, pp 345–372

    Google Scholar 

  11. Gardin C, Fenaux P (2004) Supportive care including growth factors in myelodysplastic syndromes. Rev Clin Exp Hematol 8:E3

    Google Scholar 

  12. Hellström-Lindberg E (2005) Update on supportive care and new therapies: immunomodulatory drugs, growth factors and epigenetic-acting agents. Hematol—Am Soc Hematol—Edu 2005:161–166

    Google Scholar 

  13. Katsoulidis E, Li Y, Yoon P et al (2005) Role of the p38 mitogen-activated protein kinase pathway in cytokine-mediated hematopoietic suppression in myelodysplastic syndromes. Cancer Res 65:9029–9037

    Article  PubMed  CAS  Google Scholar 

  14. Tehranchi R, Fadeel B, Forsblom AM et al (2003) Granulocyte colony-stimulating factor inhibits spontaneous cytochrome c release and mitochondria-dependent apoptosis of myelodysplastic syndrome hematopoietic progenitors. Blood 101:1080–1086

    Article  PubMed  CAS  Google Scholar 

  15. Tehranchi R, Invernizzi R, Grandien A et al (2005) Aberrant mitochondrial iron distribution and maturation arrest characterize early erythroid precursors in low-risk myelodysplastic syndromes. Blood 106:247–253

    Article  PubMed  CAS  Google Scholar 

  16. Miller C, Miller CB, Jones RJ et al (1990) Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med 322:1689–1692

    Article  PubMed  CAS  Google Scholar 

  17. Bowen D, Culligan D, Jowitt S et al (2003) Guidelines for the diagnosis and therapy of adult myelodysplastic syndromes. Br J Haematol 120:187–2000

    Article  PubMed  Google Scholar 

  18. Tefferi A, Vardiman JW (2009) Myelodysplastic syndromes. N Engl J Med 361:1872–1885

    Article  PubMed  CAS  Google Scholar 

  19. Mittelman M, Lugassy G, Merkel D et al (2008) Iron chelation therapy in patients with myelodysplastic syndromes—consensus conference guidelines (For the MDS Israel Group and The Israel Society of Hematology). Isr Med Assoc J 10:374–376

    Google Scholar 

  20. Bennett JM (2008) Consensus statement on iron overload in myelodysplastic syndromes. Am J Hematol 83:859–861

    Google Scholar 

  21. Erslev AJ (1991) Erythropoietin. N Engl J Med 324:1339–1344

    Article  PubMed  CAS  Google Scholar 

  22. Krantz S (1991) Erythropoietin. Blood 77:419–434

    PubMed  CAS  Google Scholar 

  23. Spivak JL (1986) The mechanism of action of erythropoietin. Int J Cell Cloning 4:139–166

    Article  PubMed  CAS  Google Scholar 

  24. Spivak JL, Pham T, Isaacs M, Hankins DW (1991) Erythropoietin is both a mitogen and a survival factor. Blood 77:1228–1233

    PubMed  CAS  Google Scholar 

  25. Lin F-K, Suggs S, Lin CH et al (1985) Cloning and expression of the human erythropoietin gene. Proc Natl Acad Sci U S A 82:7580–7584

    Article  PubMed  CAS  Google Scholar 

  26. Eschbach JW, Kelly MR, Haley NR et al (1987) Treatment of anemia of progressive renal failure with recombinant human erythropoietin. N Engl J Med 321:158–163

    Article  Google Scholar 

  27. Hellström E, Birgegard G, Helmers C et al (1991) Treatment of myelodysplastic syndromes with recombinant human erythropoietin. Eur J Haematol 47:355–360

    Article  PubMed  Google Scholar 

  28. Mittelman M, Floru S, Djaldetti M (1992) Subcutaneous erythropoietin for treatment of refractory anemia in hematologic disorders. Blood 80:841–842

    PubMed  CAS  Google Scholar 

  29. Rose EH, Abels RI, Nelson RA et al (1995) The use of r-HuEpo in the treatment of anaemia related to myelodysplasia (MDS). Br J Haematol 89:831–837

    Article  PubMed  CAS  Google Scholar 

  30. Hellström-Lindberg E, Negrin R, Stein R et al (1997) Erythroid response to treatment with G-CSF plus erythropoietin for the anemia of patients with myelodysplastic syndrome: proposal for a predictive model. Br J Haematol 99:344–351

    Article  PubMed  Google Scholar 

  31. 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 of on quality of life. Br J Haematol 120:1037–1046

    Article  PubMed  Google Scholar 

  32. Patton JF, Sullivan T, Mun Y et al (2005) A retrospective cohort study to assess the impact of therapeutic substitution of darbepoetin alfa for epoetin alfa in anemic patients with myelodysplastic syndrome. J Support Oncol 3:419–426

    PubMed  CAS  Google Scholar 

  33. Jadersten M, Montgomery SM, Dybedal I et al (2005) Long-term outcome of treatment of anemia in MDS with erythropoietin and G-CSF. Blood 106:803–811

    Article  PubMed  CAS  Google Scholar 

  34. Mannone L, Gardin C, Quarre MC et al (2006) High-dose darbepoetin alpha in the treatment of anaemia of lower risk myelodysplastic syndrome results of a phase II study. Br J Haematol 133:513–519

    Article  PubMed  CAS  Google Scholar 

  35. Giraldo P, Nomdedeu B, Loscertales J et al (2006) Darbepoetin alpha for the treatment of anemia in patients with myelodysplastic syndromes. Cancer 107:2807–2816

    Article  PubMed  CAS  Google Scholar 

  36. Gabrilove J, Paquette R, Lyons RM et al (2008) Phase 2, single-arm trial to evaluate the effectiveness of darbepoetin alfa for correcting anaemia in patients with myelodysplastic syndromes. Br J Haematol 142:379–393

    Article  PubMed  CAS  Google Scholar 

  37. Hellström-Lindberg E (1995) Efficacy of erythropoietin in the myelodysplastic syndromes: a meta-analysis of 205 patients from 17 studies. Br J Haematol 89(1):67–71

    Article  PubMed  Google Scholar 

  38. Ross SD, Allen IE, Probst CA et al (2007) Efficacy and safety of erythropoiesis-stimulating proteins in myelodysplastic syndrome: a systematic review and meta-analysis. Oncologist 12:1264–1273

    Article  PubMed  CAS  Google Scholar 

  39. Park S, Grabar S, Kelaidi C et al (2008) Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: the GFM experience. Blood 111:574–582

    Article  PubMed  CAS  Google Scholar 

  40. Moyo V, Lefebvre P, Duh MS et al (2008) Erythropoiesis-stimulating agents in the treatment of anemia in myelodysplastic syndromes: a meta-analysis. Ann Hematol 87:527–536

    Article  PubMed  CAS  Google Scholar 

  41. Mufti GJ (2004) Emerging therapeutic and supportive care approaches for the myelodysplastic syndromes. Rev Clin Exp Hematol 8:E4

    Google Scholar 

  42. Stasi R, Abruzzese E, Lanzetta G et al (2005) Darbepoetin alfa for the treatment of anemic patients with low- and intermediate-1-risk myelodysplastic syndromes. Ann Oncol 16(12):1921–1927

    Article  PubMed  CAS  Google Scholar 

  43. Balleari E, Rossi E, Clavio M et al (2006) 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 85:174–180

    Article  PubMed  CAS  Google Scholar 

  44. Spiriti MA, Latagliata R, Niscola P et al (2005) Impact of a new dosing regimen of epoetin alfa on quality of life and anemia in patients with low-risk myelodysplastic syndrome. Ann Hematol 84:167–176

    Article  PubMed  CAS  Google Scholar 

  45. Marsh JC, Ganser A, Stadler M (2007) Hematopoietic growth factors in the treatment of acquired bone marrow failure states. Semin Hematol 44:138–147

    Article  PubMed  CAS  Google Scholar 

  46. Cheson BD, Bennett JM, Kantarjian H et al (2000) Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 96:3671–3674

    PubMed  CAS  Google Scholar 

  47. Cheson BD, Greenberg PL, Bennett JM et al (2006) Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 108:419–425

    Article  PubMed  CAS  Google Scholar 

  48. Walvik 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 68:180–185

    Article  Google Scholar 

  49. Musto P, Falcone A, Sanpaolo G et al (2003) Efficacy of a single, weekly dose of recombinant erythropoietin in myelodysplastic syndromes. Br J Haematol 122:269–271

    Article  PubMed  CAS  Google Scholar 

  50. Gotlib J, Lavori P, Quesada S et al (2009) A phase II intra-patient dose-escalation trial of weight-bases darbepoetin alfa with or without granulocyte-colony stimulating factor in myelodysplastic syndromes. Am J Hematol 84:15–20

    Article  PubMed  CAS  Google Scholar 

  51. 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 92:68–75

    PubMed  Google Scholar 

  52. Musto P, Lanza F, Balleari E et al (2005) Darbepoetin alpha for the treatment of anaemia in low-intermediate risk myelodysplastic syndromes. Br J Haematol 128:204–209

    Article  PubMed  CAS  Google Scholar 

  53. Sekeres MA, Fu AZ, Maciejewski JP, Golshayan AR et al (2007) A Decision analysis to determine the appropriate treatment for low-risk myelodysplastic syndromes. Cancer 109:1125–1132

    Article  PubMed  Google Scholar 

  54. Bowen D, Hyslop A, Keenan N et al (2006) Predicting erythroid response to recombinant erythropoietin plus granulocyte colony-stimulating factor therapy following a single subcutaneous bolus in patients with myelodysplasia. Haematologica 91:709–710

    PubMed  Google Scholar 

  55. Cortelezzi A, Colombo G, Pellegrini C et al (2008) Bone marrow glycophorin-positive erythroid cells of myelodysplastic patients responding to high-dose rHuEPO therapy have a different gene expression pattern from those of nonresponders. Am J Hematol 83:531–539.

    Article  PubMed  CAS  Google Scholar 

  56. Di Raimondo F, Longo G, Cacciola E Jr et al (1996) A good response rate to recombinant erythropoietin alone may be expected in selected myelodysplastic patients. A preliminary clinical study. Eur J Haematol 56:7–11

    Article  PubMed  CAS  Google Scholar 

  57. Hedenus M, Birgegård G, Näsman P et al (2007) Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study. Leukemia 21:627–632

    PubMed  CAS  Google Scholar 

  58. Bastit L, Vandebroek A, Altintas S et al (2008) Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. J Clin Oncol 26:1611–1618

    Article  PubMed  CAS  Google Scholar 

  59. Jädersten M, Hellström-Lindberg E (2009) Myelodysplastic syndromes: biology and treatment. J Intern Med 265:307–328

    Article  PubMed  Google Scholar 

  60. Rizzo JD, Somerfield MR, Hagerty KL et al (2008) Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update. J Clin Oncol 26:132–149

    Article  PubMed  CAS  Google Scholar 

  61. Glaspy JA (2009) Erythropoietin in cancer patients. Annu Rev Med 60:181–192

    Article  PubMed  CAS  Google Scholar 

  62. Casadevall N, Dupuy E, Molho-Sabatier P et al (1996) Autoantibodies against erythropoietin in a patient with pure red-cell aplasia. N Engl J Med 334:630–633

    Article  PubMed  CAS  Google Scholar 

  63. Mundle S, Lefebvre P, Vekeman F et al (2009) An assessment of erythroid response to epoetin alpha as a single agent versus in combination with granulocyte- or granulocyte-macrophage-colony-stimulating factor in myelodysplastic syndromes using a meta-analysis approach. Cancer 115:706–715

    Article  PubMed  CAS  Google Scholar 

  64. Garypidou V, Verrou E, Vakalopoulou S et al (2003) Efficacy of a single, weekly dose of recombinant erythropoietin in myelodysplastic syndromes. Br J Haematol 123:958

    Article  PubMed  Google Scholar 

  65. Gabrilove JL, Cleeland CS, Livingston RB et al (2001) Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol 19:2875–2882

    PubMed  CAS  Google Scholar 

  66. Cazzola M, Beguin Y, Kloczko J et al (2003) Once-weekly epoetin beta is highly effective in treating anaemic patients with lymphoproliferative malignancy and defective endogenous erythropoietin production. Br J Haematol 122:386–393

    Article  PubMed  CAS  Google Scholar 

  67. Bokemeyer C, Aapro MS, Courdi A et al (2004) EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 40:2201–2216

    Article  PubMed  CAS  Google Scholar 

  68. Bohlius J, Wilson J, Seidenfeld J (2006) Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 98(10):708–714

    Article  PubMed  CAS  Google Scholar 

  69. Malcovati L, Della Porta MG, Cazzola M (2006) Predicting survival and leukemic evolution in patients with myelodysplastic syndrome. Haematologica 91:1588–1590

    PubMed  Google Scholar 

  70. Malcovati L, de La Porta MG, Pascutto C et al (2005) 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

    Article  Google Scholar 

  71. Silverberg DS, Wexler D, Sheps D et al (2001) The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study. J Am Coll Cardiol 37:1775–1780

    Article  PubMed  CAS  Google Scholar 

  72. Zeidman A, Fradin Z, Blecher A, Oster HS, Avrahami Y, Mittelman M (2004) Anemia as a risk factor for ischemic heart disease. Isr Med Assoc J 6:16–18

    PubMed  Google Scholar 

  73. Vaupel P, Dunst J, Engert A et al (2005) Effects of recombinant human erythropoietin (rHuEPO) on tumor control in patients with cancer-induced anemia. Onkologie 28:216–221

    Article  PubMed  CAS  Google Scholar 

  74. Leyland-Jones B (2003) BEST Investigators and study group. Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol 4:459–460

    Article  PubMed  Google Scholar 

  75. Leyland-Jones B, Semiglazov V, Pawlicki M et al (2005) 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 23:5960–5972

    Article  PubMed  CAS  Google Scholar 

  76. Henke M, Laszig R, Rübe C et al (2003) Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 362:1255–1260

    Article  PubMed  CAS  Google Scholar 

  77. Wright JR, Ung YC, Julian JA et al (2007) Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol 25:1027–1032

    Article  PubMed  CAS  Google Scholar 

  78. Smith RE Jr, Aapro MS, Ludwig H et al (2008) Darbepoetin alpha for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. J Clin Oncol 26:1040–1050

    Google Scholar 

  79. Overgaard J, Hoff CM, Hansen HS, et al (2009) Randomized study of darbepoetin alfa as modifier of radiotherapy in patients with primary squamous cell carcinoma of the head and neck (HNSCC): Final outcome of the DAHANCA 10 trial. J Clin Oncol 27:15s, (suppl; abstr 6007)

    Google Scholar 

  80. Hedenus M, Adriansson M, San Miguel J et al (2003) Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study. Br J Haematol 122:394–403

    Article  PubMed  CAS  Google Scholar 

  81. Thomas G, Ali S, Hoebers FJ et al (2008) Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs above 10.0 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer. Gynecol Oncol 108:317–325

    Article  PubMed  CAS  Google Scholar 

  82. Untch M, Fasching PA, Bauerfeind I et al (2008) PREPARE trial. A randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel and CMF with a standard dosed epirubicin/cyclophosphamide followed by paclitaxel ± darbepoetin alfa in primary breast cancer: A preplanned interim analysis of efficacy at surgery. J Clin Oncol 26:(May 20 suppl; abstr 517)

    Google Scholar 

  83. Takeshita A, Shinjo K, Higuchi M et al (2000) Quantitative expression of erythropoietin receptor (EPO-R) on acute leukaemia cells: relationships between the amount of EPO-R and CD phenotypes, in vitro proliferative response, the amount of other cytokine receptors and clinical prognosis. Japan Adult Leukaemia Study Group. Br J Haematol 108:55–63

    Article  PubMed  CAS  Google Scholar 

  84. Nowrousian MR, Dunst J, Vaupel P (2008) Erythropoiesis-stimulating agents: favorable safety profile when used as indicated. Strahlenther Onkol 184:121–136

    Article  PubMed  Google Scholar 

  85. Longmore GD (2007) Do cancer cells express functional erythropoietin receptors? N Engl J Med 356:2447

    Article  PubMed  CAS  Google Scholar 

  86. Jelkman W (2010) Erythropoietin: back to basics. Blood 115:4151–4152

    Article  Google Scholar 

  87. Mittelman M, Zeidman A, Kanter P, Katz O, Oster H, Rund D, Neumann D (2004) Erythropoietin has an anti-myeloma effect—a clinical observation supported by animal studies. Eur J Haematol 72:155–165

    Article  PubMed  CAS  Google Scholar 

  88. Mittelman M, Neumann D, Peled A, Kanter P, Haran-Ghera N (2001) Erythropoietin induces tumor regression and anti-tumor immune responses in murine myeloma models. Proc Natl Acad Sci U S A 98:5181–5186

    Article  PubMed  CAS  Google Scholar 

  89. Dunst J (2001) The use of epoetin alfa to increase and maintain hemoglobin levels during radiotherapy. Semin Oncol 28(2 Suppl 8):42–48

    Article  PubMed  CAS  Google Scholar 

  90. Littlewood TJ, Bajetta E, Nortier JW et al (2001) Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 19:2865–2874

    PubMed  CAS  Google Scholar 

  91. Baz R, Walker E, Choueiri TK et al (2007) Recombinant human erythropoietin is associated with increased overall survival in patients with multiple myeloma. Acta Haematol 117:162–167

    Article  PubMed  CAS  Google Scholar 

  92. Aapro M, Scherhag A, Burger HU (2008) Effect of treatment with epoetin-beta on survival, tumour progression and thromboembolic events in patients with cancer: an updated meta-analysis of 12 randomised controlled studies including 2301 patients. Br J Cancer 99:14–22

    Article  PubMed  CAS  Google Scholar 

  93. Bohlius J, Langensiepen S, Schwarzer G et al (2005) Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive meta-analysis. J Natl Cancer Inst 97:489–498

    Article  PubMed  CAS  Google Scholar 

  94. Bohlius J, Schmidlin K, Brillant C et al (2009) Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet 373:1532–1542

    Article  PubMed  CAS  Google Scholar 

  95. Jadersten M, Malcovati L, Dybedal I et al (2008) Erythropoietin and granulocyte-colony stimulating factor treatment associated with improved survival in myelodysplastic syndrome. J Clin Oncol 26:3607–3613

    Article  PubMed  Google Scholar 

  96. Cermák J (2006) Erythropoietin administration may potentiate mobilization of storage iron in patients on oral iron chelation therapy. Hemoglobin 30:105–112

    Article  PubMed  CAS  Google Scholar 

  97. Brines ML, Ghezzi P, Keenan S et al (2000) Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 97:10526–10531

    Article  PubMed  CAS  Google Scholar 

  98. Katz O, Barzilay E, Skaat A et al (2005) Erythropoietin induced tumour mass reduction in murine lymphoproliferative models. Acta Haematol 114:177–179

    Article  PubMed  Google Scholar 

  99. Prutchi Sagiv S, Lifshitz L, Orkin R et al (2008) Erythropoietin effects on dendritic cells: potential mediators in its function as an immunomodulator? Exp Hematol 36:1682–1690

    Article  PubMed  CAS  Google Scholar 

  100. Katz O, Gil L, Lifshitz L et al (2007) Erythropoietin enhances immune responses in mice. Eur J Immunol 37:1584–1593

    Article  PubMed  CAS  Google Scholar 

  101. Lifshitz L, Tabak G, Mittelman M, Gassmann M, Neumann D (2010) Macrophages as novel targets for erythropoietin. Haematologica 95(11):1823–1831

    Article  PubMed  CAS  Google Scholar 

  102. Prutchi-Sagiv S, Golishevsky N, Oster HS, Katz O, Cohen A, Naparstek E, Neumann D, Mittelman M (2006) Erythropoietin treatment in advanced multiple myeloma is associated with improved immunological functions: could it be beneficial in early disease? Br J Haematol 135:660–672

    Article  PubMed  CAS  Google Scholar 

  103. Prutchi-Sagiv S, Golishevski N, Katz O, Oster HS, Naparstek E, Hoffman M, Neumann D, Mittelman M (2006) T-cell abnormalities in patients with myelodysplastic syndromes: improved immunological functions in patients treated with recombinant erythropoietin. Blood 108:756a (Abstr No. 2675)

    Article  CAS  Google Scholar 

  104. 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 104:321–327

    Article  PubMed  CAS  Google Scholar 

  105. Greenberg PL, Young NS, Gattermann N (2002) Myelodysplastic syndromes. Hematology 2002:136–161 (educational book)

    Article  Google Scholar 

  106. Martin S, Baldock SC, Ghoneim AT et al (1983) Defective neutrophil function and microbicidal mechanisms in the myelodysplastic disorders. J Clin Pathol 36:1120–1128

    Article  PubMed  CAS  Google Scholar 

  107. Ohmori M, Ohmori S, Ueda Y (1991) Ineffective hemopoiesis in the myelodysplastic syndromes (MDS) as studied by daily in situ observation of colony-cluster formation. Int J Cell Cloning 9:521–530

    Article  PubMed  CAS  Google Scholar 

  108. Dar S, Mundle S, Andric T et al (1999) Biological characteristics of myelodysplastic syndrome patients who demonstrated high versus no intramedullary apoptosis. Eur J Haematol 62:90–94

    Article  PubMed  CAS  Google Scholar 

  109. Rajapaska R, Ginzton N, Rott LS et al (1996) Altered oncoprotein expression and apoptosis in myelodysplastic syndrome marrow cells. Blood 88:4275–4287

    Google Scholar 

  110. Nimer SD (2008) Myelodysplastic syndromes. Blood 111(10):4841–4851

    Article  PubMed  CAS  Google Scholar 

  111. Gradishar WJ, Le Beau MM, O’Laughlin R et al (1992) Clinical and cytogenetic responses to granulocyte-macrophage colony-stimulating factor in therapy-related myelodysplasia. Blood 80(10):2463–2470

    PubMed  CAS  Google Scholar 

  112. 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 317:1545–1552

    Article  PubMed  CAS  Google Scholar 

  113. Lieschke GJ, Ramenghi U, O’Connor MP et al (1992) Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. N Engl J Med 327:99–106

    Article  PubMed  CAS  Google Scholar 

  114. Negrin RS, Haeuber DH, Nagler A et al (1989) Treatment of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor: a phase I-II trial. Ann Intern Med 110:976–984

    PubMed  CAS  Google Scholar 

  115. Negrin RS, Haeuber DH, Nagler A et al (1990) Maintenance treatment of patients with myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor. Blood 76:36–43

    PubMed  CAS  Google Scholar 

  116. Greenberg P, Taylor K, Larson R et al (1993) Phase III randomized multicenter trial of G-CSF vs. observation for myelodysplastic syndromes (MDS). Blood (Abstr) 82(Suppl 1):196a

    Google Scholar 

  117. Chuncharunee S, Intragumtornchai T, Chaimongkol B et al (2001) Treatment of myelodysplastic syndrome with low-dose human granulocyte colony–stimulating factor: a multicenter study. Int J Hematol 74:144–146

    Article  PubMed  CAS  Google Scholar 

  118. Zeidman A, Sokolover N, Fradin Z, Cohen A, Redlich O, Mittelman M (2004) Platelet function and its clinical significance in the myelodysplastic syndromes. Hematol J 5:234–238

    Article  PubMed  CAS  Google Scholar 

  119. Bryan J, Jabbour E, Prescott H et al (2010) Thrombocytopenia in patients with myelodysplastic syndromes. Semin Hematol 47:274–280

    Article  PubMed  CAS  Google Scholar 

  120. TRAP study group (1997) Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. N Engl J Med 337:1861–1869

    Google Scholar 

  121. Kaushansky K (2008) Historical review: megakaryopoiesis and thrombopoiesis. Blood. 111:981–986

    Article  PubMed  CAS  Google Scholar 

  122. Li J, Yang C, Xia Y et al (2001) Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood 98:3241–3248

    Article  PubMed  CAS  Google Scholar 

  123. Tsimberidou AM, Giles FJ, Khouri I et al (2005) Low-dose interleukin-11 in patients with bone marrow failure: update of the MD Anderson cancer center experience. Ann Oncol 16:139–145

    Article  PubMed  Google Scholar 

  124. Kurzrock R, Cortes J, Thomas DA et al (2001) Pilot study of low-dose interleukin-11 in patients with bone marrow failure. J Clin Oncol 19:4165–4172

    PubMed  CAS  Google Scholar 

  125. Gordon MS, Nemunaitis J, Hoffman R et al (1995) A phase I trial of recombinant human interleukin-6 in patients with myelodysplastic syndromes and thrombocytopenia. Blood 85:3066–3076

    PubMed  CAS  Google Scholar 

  126. Ganser A, Seipelt G, Lindemann A et al (1990) Effects of recombinant human interleukin-3 in patients with myelodysplastic syndromes. Blood 76(3):455–462

    PubMed  CAS  Google Scholar 

  127. Kantarjian H, Fenaux P, Sekeres MA et al (2009) Safety and efficacy of Romiplostim in patients with lower-risk myelodysplastic syndrome and thrombocytopenia. J Clin Oncol 28:437–444

    Article  PubMed  CAS  Google Scholar 

  128. Will B, Kawahara M, Luciano JP et al (2009) Effect of the nonpeptide thrombopoietin receptor agonist Eltrombopag on bone marrow cells from patients with acute myeloid leukemia and myelodysplastic syndrome. Blood 114:3899–3908

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Tel Aviv Sourasky Medical Center, 6 Weizmann St., 64239, Tel Aviv, Israel

    Howard S. Oster & Moshe Mittelman

  2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Howard S. Oster, Drorit Neumann & Moshe Mittelman

Authors
  1. Howard S. Oster
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Drorit Neumann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Moshe Mittelman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Moshe Mittelman .

Editor information

Editors and Affiliations

  1. , 3rd Department of Internal Medicine, Semmelweis University, Kútvölgyi út 4, Budapest, 1125, Hungary

    Judit Várkonyi

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media B.V.

About this chapter

Cite this chapter

Oster, H.S., Neumann, D., Mittelman, M. (2011). Cytokines in MDS: Abnormalities and Treatment. In: Várkonyi, J. (eds) The Myelodysplastic Syndromes. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-0440-4_13

Download citation

Publish with us

Policies and ethics

Search

Navigation