Predictive factors for response of anemia to recombinant human erythropoietin

  • Yves Beguin


Patients with solid tumors or hematological malignancies often develop anemia at diagnosis or in the course of the disease (Means et al. 1992; Beguin 1996; Moliterno et al. 1996; Groopman et al. 1999). Many studies have shown that recombinant human erythropoietin (rHEpo) therapy can ameliorate the anemia associated with cancer and chemotherapy, reduce the need for transfusions and improve quality of life as well as work capacity. However, as many as 30–50% of the patients do not respond, even to very high doses of rHEpo. It is, therefore, important to be able to recognize and correct conditions adversely affecting response to rHEpo, in particular functional iron deficiency. When no such particular condition can be identified, it would also be of great interest to have at one’s disposal predictive algorithms of response. Thereby patients can be selected on the basis of their probability to achieve a good response to treatment and prolonged ineffective use of an expensive medication can be avoided in those patients with a low probability of response. In this paper, we will review factors potentially affecting response to rHEpo and comment on the use of predictive algorithms.


Recombinant Human Erythropoietin Intravenous Iron Functional Iron Deficiency Erythropoietic Activity Serum Transferrin Receptor 
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  1. Abels RI (1992) Use of recombinant human erythropoietin in the treatment of anemia in patients who have cancer. Semin Oncol 19: 29–35PubMedGoogle Scholar
  2. Beguin Y (1996) Erythropoietin and the anemia of cancer. Acta Clin Belg 51: 36–52PubMedGoogle Scholar
  3. Beguin Y (1998) Prediction of response to treatment with recombinant human erythropoietin in anaemia associated with cancer. Med Oncol 15 (Suppl 1): 38–46Google Scholar
  4. Beguin Y, Clemons G, Pootrakul P, Fillet G (1993a) Quantitative assessment of erythropoiesis and functional classification of anemia based on measurements of serum transferrin receptor and erythropoietin. Blood 81: 1067–1076PubMedGoogle Scholar
  5. Beguin Y, Clemons GK, Oris R, Fillet G (1991) Circulating erythropoietin levels after bone marrow transplantation: Inappropriate response to anemia in allogeneic transplants. Blood 77: 868–873Google Scholar
  6. Beguin Y, Loo M, R’Zik S, Sautois B, Lejeune F, Rorive G, Fillet G (1993b) Early prediction of response to recombinant human erythropoietin in patients with the anemia of renal failure by serum transferrin receptor and fibrinogen. Blood 82: 2010–2016PubMedGoogle Scholar
  7. Beguin Y, Loo M, R’Zik S, Sautois B, Lejeune F, Rorive G, Fillet G (1995) Quantitative assessment of erythropoiesis in haemodialysis patients demonstrates gradual expansion of erythroblasts during constant treatment with recombinant human erythropoietin. Br J Haematol 89: 17–23PubMedGoogle Scholar
  8. Besarab A, Amin N, Ahsan M, Vogel SE, Zazuwa G, Frinak S, Zazra JJ, Anandan JV, Gupta A (2000) Optimization of epoetin therapy with intravenous iron therapy in hemodialysis patients. J Am Soc Nephrol 11: 530–538PubMedGoogle Scholar
  9. Biesma DH, van de Wiel A, Beguin Y, Kraaijenhagen RJ, Marx JJ (1995) Postoperative erythropoiesis is limited by the inflammatory effect of surgery on iron metabolism. Eur J Clin Invest 25: 383–389PubMedCrossRefGoogle Scholar
  10. Breymann C, Bauer C, Major A, Zimmermann R, Gautschi K, Huch A, Huch R (1996) Optimal timing of repeated rh-erythropoietin administration improves its effectiveness in stimulating erythropoiesis in healthy volunteers. Br J Haematol 92: 295–301PubMedCrossRefGoogle Scholar
  11. Brugnara C (1998) Use of reticulocyte cellular indices in the diagnosis and treatment of hematological disorders. Int J Clin Lab Res 28: 1–11PubMedCrossRefGoogle Scholar
  12. Brugnara C, Colella GM, Cremins J, Langley RC Jr, Schneider TJ, Rutherford CJ, Goldberg MA (1994) Effects of subcutaneous recombinant human erythropoietin in normal subjects: development of decreased reticulocyte hemoglobin content and iron-deficient erythropoiesis. J Lab Clin Med 123: 660–667PubMedGoogle Scholar
  13. Cascinu S, Fedeli A, Del Ferro E, Luzi Fedeli S, Catalano G (1994) Recombinant human erythropoietin treatment in cisplatin-associated anemia: a randomized, double-blind trial with placebo. J Clin Oncol 12: 1058–1062PubMedGoogle Scholar
  14. Cazzola M, Guarnone R, Cerani P, Centenara E, Rovati A, Beguin Y (1998) Red blood cell precursor mass as an independent determinant of serum erythropoietin level. Blood 91: 2139–2145PubMedGoogle Scholar
  15. Cazzola M, Messinger D, Battistel V, Bron D, Cimino R, Enller-Ziegler L, Essers U, Greil R, Grossi A, Jager G, LeMevel A, Najman A, Silingardi V, Spriano M, van Hoof A, Ehmer B (1995) Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-Hodgkin’s lymphoma: dose finding and identification of predictors of response. Blood 86: 4446–4453PubMedGoogle Scholar
  16. Cazzola M, Ponchio L, Beguin Y, Rosti V, Bergamaschi G, Liberato NL, Fregoni V, Nalli G, Barosi G, Ascari E (1992) Subcutaneous erythropoietin for treatment of refractory anemia in hematologic disorders. Results of a phase I/II clinical trial. Blood 79: 29–37Google Scholar
  17. Cazzola M, Ponchio L, Pedrotti C, Farina G, Cerani P, Lucotti C, Novella A, Rovati A, Bergamaschi G, Beguin Y (1996) Prediction of response to recombinant human erythropoietin (rHuEpo) in anemia of malignancy. Haematologica 81: 434–441PubMedGoogle Scholar
  18. Cheung W, Minton N, Gunawardena K, Frey K (2000) The pharmacokinetics and pharmacodynamics of Epoetin alpha once weekly versus Epoetin alpha 3 times weekly. Blood 96 (Suppl 1): 295a (Abstract)Google Scholar
  19. Crawford J, Blackwell S, Shoemaker D, Pupa MR, Mulhausen T, Herndon J, Winer E, Flynn J, Dempsey H (1994) Prevention of chemotherapy related anemia by recombinant human erythropoietin (EPO) in patients with small cell lung cancer (SCLC) receiving cyclophosphamide, doxorubicin, and etoposide (CAE) chemotherapy with G-CSF support. Blood 84 (Suppl 1): 129a (Abstract)Google Scholar
  20. Danielson B, Beguin Y, Bommer J, Cannata B, De Broe ME, Drueke TB, Ittel TH, Jolliffe LK, Krantz SB, Nielsen OJ, Pippard MJ, Rosenlof K, Stockenhuber B, Winearls C (1995) R-HuEPO hyporesponsiveness — who and why? Nephrol Dial Transplant 10 (Suppl 2): 69–73PubMedGoogle Scholar
  21. Drueke TB, Barany P, Cazzola M, Eschbach JW, Grutzmacher P, Kaltwasser JP, Macdougall IC, Pippard MJ, Shaldon S, van Wyck D (1997) Management of iron deficiency in renal anemia: guidelines for the optimal therapeutic approach in erythropoietin-treated patients. Clin Nephrol 48: 1–8PubMedGoogle Scholar
  22. Fillet G, Beguin Y, Baldelli L (1989) Model of reticuloendothelial iron metabolism in humans: abnormal behavior in idiopathic hemochromatosis and in inflammation. Blood 74: 844–851PubMedGoogle Scholar
  23. Fishbane S, Frei GL, Maesaka J (1995) Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis 26: 41–46PubMedCrossRefGoogle Scholar
  24. Gabrilove JL, Einhorn LH, Livingston RB, Winer E, Cleeland CS (1999) Once-weekly dosing of Epoetin alfa is similar to three-times-weekly dosing in increasing hemoglobin and quality of life. Proc Am Soc Clin Oncol 18: 574a (Abstract)Google Scholar
  25. Glimelius B, Linne T, Hoffman K, Larsson L, Svensson JH, Nasman P, Svensson B, Helmers C (1998) Epoetin beta in the treatment of anemia in patients with advanced gastrointestinal cancer. J Clin Oncol 16: 434–440PubMedGoogle Scholar
  26. Groopman JE, Itri LM (1999) Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst 91: 1616–1634PubMedCrossRefGoogle Scholar
  27. Henry D, Abels R, Larholt K (1995) Prediction of response to recombinant human erythropoietin (r-HuEPO/epoetin-alpha) therapy in cancer patients [letter]. Blood 85: 1676–1678PubMedGoogle Scholar
  28. Henry DH, Abels RI (1994) Recombinant human erythropoietin in the treatment of cancer and chemotherapy-induced anemia: Results of double-blind and open-label follow-up studies. Semin Oncol 21 (Suppl 3): 21–28PubMedGoogle Scholar
  29. Huebers HA, Beguin Y, Pootrakul P, Einspahr D, Finch CA (1990) Intact transferrin receptors in human plasma and their relation to erythropoiesis. Blood 75: 102–107PubMedGoogle Scholar
  30. Kooistra MP, van Es A, Struyvenberg A, Marx JJ (1991) Iron metabolism in patients with the anaemia of end-stage renal disease during treatment with recombinant human erythropoietin. Br J Haemato179: 634–639Google Scholar
  31. Leon MP, Jimenez MM, Barona ZP, Riol DM, Castro PL, Sierrasesumaga AL (1998) [Recombinant human erythropoietin in anemia associated with pediatric cancer: study of the identification of predictors of response]. An Esp Pediatr 49: 17–22Google Scholar
  32. Link H, Boogaerts MA, Fauser AA, Slavin S, Reiffers J, Gorin NC, Carella AM, Mandelli F, Burdach S, Ferrant A, Linkesch W, Tura S, Bacigalupo A, Schindel F, Heinrichs H (1994) A controlled trial of recombinant human erythropoietin after bone marrow transplantation. Blood 84: 3327–3335PubMedGoogle Scholar
  33. Ludwig H, Fritz E, Leitgeb C, Kramer M, Kuhrer I, Sagaster P, Umek H (1993a) Erythropoietin treatment for chronic anemia of selected hematological malignancies and solid tumors. Ann Oncol 4: 161–167PubMedGoogle Scholar
  34. Ludwig H, Fritz E, Leitgeb C, Pecherstorfer M, Samonigg L, Schuster J (1994) Prediction of response to erythropoietin treatment in chronic anemia of cancer. Blood 84: 1056–1063PubMedGoogle Scholar
  35. Ludwig H, Pecherstorfer M, Leitgeb C, Fritz E (1993b) Recombinant human erythropoietin for the treatment of chronic anemia in multiple myeloma and squamous cell carcinoma. Stem Cells 11: 348–355PubMedCrossRefGoogle Scholar
  36. Macdougall IC (1999) Strategies for iron supplementation: oral versus intravenous. Kidney Int (Suppl) 69: S61 - S66CrossRefGoogle Scholar
  37. Macdougall IC (2000) Novel erythropoiesis stimulating protein. Semin Nephrol 20: 375–381PubMedGoogle Scholar
  38. Macdougall IC, Cavill I, Hulme B, Bain B, McGregor E, McKay P, Sanders E, Coles GA, Williams JD (1992) Detection of functional iron deficiency during erythropoietin treatment: a new approach. Br Med J 304: 225–226CrossRefGoogle Scholar
  39. Macdougall IC, Roberts DE, Neubert P, Dharmasena AD, Coles GA, Williams JD (1989) Pharmacokinetics of recombinant human erythropoietin in patients on continuous ambulatory peritoneal dialysis. Lancet 1: 425–427PubMedCrossRefGoogle Scholar
  40. Macdougall IC, Tucker B, Thompson J, Tomson CR, Baker LR, Raine AE (1996) A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int 50: 1694–1699PubMedCrossRefGoogle Scholar
  41. Markman M, Reichman B, Hakes T, Rubin S, Jones W, Lewis JL, Jr., Curtin J, Almadrones L, Hoskins W (1993) The use of recombinant human erythropoietin to prevent carboplatin-induced anemia. Gynecol Oncol 49: 172–176PubMedCrossRefGoogle Scholar
  42. Martini A, Ravelli A, Di Fuccia G, Rosti V, Cazzola M, Barosi G (1994) Intravenous iron therapy for severe anaemia in systemic-onset juvenile chronic arthritis. Lancet 344: 1052–1054PubMedCrossRefGoogle Scholar
  43. Matsumoto T, Endoh K, Kamisango K, Akamatsu K, Koizumi K, Higuchi M, Imai N, Mitsui H, Kawaguchi T (1990) Effect of recombinant human erythropoietin on anticancer drug-induced anaemia. Br J Haematol 75: 463–468PubMedCrossRefGoogle Scholar
  44. Means RT Jr, Krantz SB (1992) Progress in understanding the pathogenesis of the anemia of chronic disease. Blood 80: 1639–1647PubMedGoogle Scholar
  45. Moliterno AR, Spivak JL (1996) Anemia of cancer. Hematol Oncol Clin North Am 10: 345–363PubMedCrossRefGoogle Scholar
  46. Oberhoff C, Neri B, Amadori D, Petry KU, Gamucci T, Rebmann U, Nowrousian MR, Voigtmann R, Monfardini S, Armand JP, Herrmann R, Netter-Pinon J, Tubiana-Mathieu N, Zwierzina H (1998) Recombinant human erythropoietin in the treatment of chemotherapy-induced anemia and prevention of transfusion requirement associated with solid tumors: a randomized, controlled study. Ann Oncol 9: 255–260PubMedCrossRefGoogle Scholar
  47. Oster W, Herrmann F, Gamm H, Zeile G, Lindemann A, Muller G, Brune T, Kraemer HP, Mertelsmann R (1990) Erythropoietin for the treatment of anemia of malignancy associated with neoplastic bone marrow infiltration. J Clin Oncol 8: 956–962PubMedGoogle Scholar
  48. Österborg A, Boogaerts MA, Cimino R, Essers U, Holowiecki J, Juliusson G, Jager G, Najman A, Peest D (1996) Recombinant human erythropoietin in transfusion-dependent anemic patients with multiple myeloma and non-Hodgkin’s lymphoma. A randomized multicenter study. Blood 87: 2675–2682Google Scholar
  49. Paganini EP, Eschbach JW, Lazarus JM, Van Stone JC, Gimenez LF, Graber SE, Egrie JC, Okamoto DM, Goodkin DA (1995) Intravenous versus subcutaneous dosing of epoetin alfa in hemodialysis patients. Am J Kidney Dis 26: 331–340PubMedCrossRefGoogle Scholar
  50. Pawlicki M, Jassem J, Bosze P, Lotan C, Kurteva GP, Siddiqui M, Kosmidis PA, Rigatos GA, Kansu E, Durkovic P, Aziz Z, Al Idrissi H, Roth A, Cozma G (1997) A multicenter study of recombinant human erythropoietin (epoetin alpha) in the management of anemia in cancer patients receiving chemotherapy. Anticancer Drugs 8: 949–957PubMedCrossRefGoogle Scholar
  51. Platanias LC, Miller CB, Mick R, Hart RD, Ozer H, McEvilly JM, Jones RJ, Ratain MJ (1991) Treatment of chemotherapy-induced anemia with recombinant human erythropoietin in cancer patients. J Clin Oncol 9: 2021–2026PubMedGoogle Scholar
  52. Ponchio L, Beguin Y, Farina G, Pedrazzoli P, Pedrotti C, Poggi G, Rosti V, Bergamaschi G, Battistel V, Cazzola M (1992) Evaluation of erythroid marrow response to recombinant human erythropoietin in patients with cancer anaemia. Haematologica 77: 494–501PubMedGoogle Scholar
  53. Sears D (1992) Anemia of chronic disease. Med Clin North Am 76: 567–579PubMedGoogle Scholar
  54. Skikne BS, Flowers CH, Cook JD (1990) Serum transferrin receptor: a quantitative measure of tissue iron deficiency. Blood 75: 1870–1876PubMedGoogle Scholar
  55. Sunder-Plassmann G, Horl WH (1997) Safety aspects of parenteral iron in patients with end-stage renal disease. Drug Safety 17: 241–250PubMedCrossRefGoogle Scholar
  56. ten Bokkel Huinink WW, de Swart CA, van Toorn DW, Morack G, Breed WP, Hillen HF, van der Hoeven JJ, Reed NS, Fairlamb DJ, Chan SY, Godfrey KA, Kristensen GB, van Tinteren H, Ehmer B (1998) Controlled multicentre study of the influence of subcutaneous recombinant human erythropoietin on anaemia and transfusion dependency in patients with ovarian carcinoma treated with platinum-based chemotherapy. Med Oncol 15: 174–182PubMedCrossRefGoogle Scholar
  57. Weinberg ED (1996) The role of iron in cancer. Eur J Cancer Prey 5: 19–36Google Scholar
  58. Wood PA, Hrushesky WJ (1995) Cisplatin-associated anemia: an erythropoietin deficiency syndrome. J Clin Invest 95: 1650–1659PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag/Wien 2002

Authors and Affiliations

  1. 1.Department of Medicine, Division of HematologyUniversity of LiègeLiègeBelgium

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