Annals of Hematology

, Volume 69, Issue 5, pp 213–221 | Cite as

Hematopoietic growth factors and the treatment of tumor-associated anemias

  • U. Dührsen
  • D. K. Hossfeld
Review Article

Summary

Erythropoietin, alone or in combination with colony-stimulating factors, is a promising agent in the treatment of patients with cancer-related ‘anemia of chronic disorders’, chemo/radiotherapy-induced anemia, or anemia due to myelodysplastic or myeloproliferative syndromes. In the first two groups, at least half of the patients can be expected to respond to erythropoietin alone, with an average response delay of about 4 weeks and maximal responses at weekly doses of approximately 1000 U/kg. In myelodysplastic syndromes, only 10–20% of patients respond to conventional doses of erythropoietin, but doses exceeding 1000 U/kg weekly in combination with granulocyte colony-stimulating factor yield response rates of about 40%. Although these results show that hematopoietic growth factors can be used successfully to treat cancer-related anemias, economic constraints preclude their use at the present time.

Key words

Anemia Cancer Colony-stimulating factors Erythropoietin Myelodysplastic syndromes 

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References

  1. 1.
    Abels RI (1992) Use of recombinant human erythropoietin in the treatment of anemia in patients who have cancer. Semin Oncol 19 [Suppl 8]: 29–35Google Scholar
  2. 2.
    Abels R, Larholt K, Nelson R, Young D (1993) Prediction of response to recombinant human erythropoietin therapy in anemic cancer patients. Blood 82 [Suppl]:92aGoogle Scholar
  3. 3.
    Adamson JW (1991) Cytokine biology: applications for transfusion medicine. Cancer 67:2708–2711PubMedGoogle Scholar
  4. 4.
    Antin JH, Smith BR, Holmes W, Rosenthal DS (1988) Phase-I/II study of recombinant human granulocyte-macrophage colony-stimulating factor in aplastic anemia and myelodys-plastic syndrome. Blood 72:705–713PubMedGoogle Scholar
  5. 5.
    Athens JW (1993) Chronic myeloid leukemia. In: Lee GR, Bithell TC, Foerster J, Athens JW, Lukens JN (eds) Wintrobe's clinical hematology, 9th edn. Lea and Febiger, Philadelphia, pp 1969–1998Google Scholar
  6. 6.
    Athens JW (1993) Myelofibrosis. In: Lee GR, Bithell TC, Foerster J, Athens JW, Lukens JN (eds) Wintrobe's clinical hematology, 9th edn. Lea and Febiger, Philadelphia, pp 2018–2033Google Scholar
  7. 7.
    Birgegard G, Wide L, Simonsson B (1989) Marked erythro-poietin increase before fall in Hb after treatment with cytostatic drugs suggests mechanism other than anaemia for stimulation. Br J Haematol 72:462–466PubMedGoogle Scholar
  8. 8.
    Bommer J, Barth H-P, Zeier M, Mandelbaum A, Bommer G, Ritz E, Reichel H, Novack R (1991) Efficacy comparison of intravenous and subcutaneous recombinant human erythropoietin administration in hemodialysis patients. In: Gurland HJ, Moran J, Samtleben W, Scigalla P, Wieczorek L (eds) Erythropoietin in renal and non-renal anemias. Karger, Basel, pp 136–143Google Scholar
  9. 9.
    Bottomley SS (1993) Sideroblastic anemias. In: Lee GR, Bithell TC, Foerster J, Athens JW, Lukens JN (eds) Wintrobe's clinical hematology, 9th edn. Lea and Febiger, Philadelphia, pp 852–871Google Scholar
  10. 10.
    Bowen DT, Jacobs A, Mary P, Cotes, Lewis TC (1990) Serum erythropoietin and erythropoiesis in patients with myelodysplastic syndromes. Eur J Haematol 44:30–32PubMedGoogle Scholar
  11. 11.
    Bowen D, Culligan D, Jacobs A (1991) The treatment of anaemia in the myelodysplastic syndromes with recombinant human erythropoietin. Br J Haematol 77:419–423PubMedGoogle Scholar
  12. 12.
    Boyd HK, Lappin TRJ (1991) Erythropoietin deficiency in the anaemia of chronic disorders. Eur J Haematol 46:198–201PubMedGoogle Scholar
  13. 13.
    Bunn HF (1990) Editorial: Recombinant erythropoietin therapy in cancer patients. J Clin Oncol 8:949–951PubMedGoogle Scholar
  14. 14.
    Case DC, Bukowski RM, Carey RW, Fishkin EH, Henry DH, Jacobson RJ, Jones SE, Keller AM, Kugler JW, Nichols CR, Salmon SE, Silver RT, Storniolo AM, Wampler GL, Dooley CM, Larholt KM, Nelson RA, Abels RI (1993) Recombinant human erythropoietin therapy for anemic cancer patients on combination chemotherapy. J Natl Cancer Inst 85:801–806PubMedGoogle Scholar
  15. 15.
    Cazzola M, Barosi G, Berzuini C, Dacco M, Orlandi E, Stefanelli M, Ascari E (1982) Quantitative evaluation of erythropoietic activity in dysmyelopoietic syndromes. Br J Haematol 50:55–62PubMedGoogle Scholar
  16. 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 79:29–37PubMedGoogle Scholar
  17. 17.
    Deiss A (1993) Non-neoplastic diseases, chemical agents, and hematologic disorders that may precede hematologic neoplasms. In: Lee GR, Bithell TC, Foerster J, Athens JW, Lukens JN (eds) Wintrobe's clinical hematology, 9th edn. Lea and Febiger, Philadelphia, pp 1946–1968Google Scholar
  18. 18.
    Dische S (1991) Radiotherapy and anemia — the clinical experience. Radiother Oncol 20:35–40PubMedGoogle Scholar
  19. 19.
    Erslev AJ (1991) Drug therapy: erythropoietin. N Engl J Med 324:1339–1344PubMedGoogle Scholar
  20. 20.
    Erslev AJ (1992) The therapeutic role of recombinant erythropoietin in anemic patients with intact endogenous production of erythropoietin. Semin Oncol 19 [Suppl 8]:14–18Google Scholar
  21. 21.
    Fischl M, Galpin JE, Levine JD, Groopman JE, Henry DH, Kennedy P, Miles S, Robbins W, Starrett B, Zalusky R, Abels RI, Tsai HC, Rudnick SA (1990) Recombinant human erythropoietin for patients with AIDS treated with zidovudine. N Engl J Med 322:1488–1493PubMedGoogle Scholar
  22. 22.
    Gale RP (1988) Myelosuppressive effects of antineoplastic chemotherapy. In: Testa NG, Gale RP (eds) Hematopoiesis. Long-term effects of chemotherapy and radiation. Marcel Dekker, New York, pp 63–73Google Scholar
  23. 23.
    Ganser A, Hoelzer D (1992) Treatment of myelodysplastic syndromes with hematopoietic growth factors. Hematol Oncol Clin North Am 6:633–653PubMedGoogle Scholar
  24. 24.
    Ganser A, Völkers B, Greher J, Ottmann OG, Walther F, Becher R, Bergmann L, Schulz G, Hoelzer D (1989) Recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes — a phase-I/II trial. Blood 73:31–37PubMedGoogle Scholar
  25. 25.
    Ganser A, Seipelt G, Lindemann A, Ottmann OG, Falk S, Eder M, Herrmann F, Becher R, Höffken K, Büchner T, Klausmann M, Frisch J, Schulz G, Mertelsmann R, Hoelzer D (1990) Effects of recombinant human interleukin-3 in patients with myelodysplastic syndromes. Blood 76:455–462PubMedGoogle Scholar
  26. 26.
    Ganser A, Ottmann OG, Schadeck-Gressel C, Kolbe K, Haas R, Seipelt G, Maurer A, Zander C, Reutzel R, Hoelzer D (1993) Combination therapy with all-trans retinoic acid (ATRA), granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO) and vitamin E in patients with myelo-dysplastic syndromes (MDS). Blood 82 [Suppl]:377aGoogle Scholar
  27. 27.
    Ganser A, Ottmann OG, Seipelt G, Lindemann A, Hess U, Geissler G, Maurer A, Frisch F, Schulz G, Mertelsmann R, Hoelzer D (1993) Effect of long-term treatment with recom-binant human interleukin-3 in patients with myelodysplastic syndromes. Leukemia 7:696–701PubMedGoogle Scholar
  28. 28.
    Hansen PB, Johnsen HE, Hippe E, Hellström-Lindberg E, Ralfkiaer E (1993) Recombinant human granulocyte-macro-phage colony-stimulating factor plus recombinant human erythropoietin may improve anemia in selected patients with myelodysplastic syndromes. Am J Hematol 44:229–236PubMedGoogle Scholar
  29. 29.
    Hellström E, Birgegard G, Lockner D, Helmers C, Öst A, Wide L (1991) Treatment of myelodysplastic syndromes with recombinant human erythropoietin. Eur J Haematol 47:355–360PubMedGoogle Scholar
  30. 30.
    Hellström-Lindberg E, Birgegard G, Carlsson M, Carneskog J, Dahl IM, Dybedal I, Grimfors G, Merk K, Tangen JM, Winqvist I, Öst A (1993) A combination of granulocyte colony-stimulating factor and erythropoietin may synergistically improve anaemia in patients with myelodysplastic syndromes. Leuk Lymph 11:221–228Google Scholar
  31. 31.
    Hellström-Lindberg E, Carlsson M, Grimfors G, Lindemalm C, Löfvenberg E, Tangen JM, Öst A (1993) The combination of granulocyte-CSF and erythropoietin (EPO) may significantly increase the hemoglobin levels in MDS patients with no response to EPO alone. Report from a randomized phase-II trial. Blood 82 [Supp]:376aGoogle Scholar
  32. 32.
    Henry DH (1992) Changing patterns of care in the management of anemia. Semin Oncol 19 [Suppl 8]:3–7Google Scholar
  33. 33.
    Hörl WH (1992) Optimal route of administration of erythropoietin in chronic renal failure patients: intravenous versus subcutaneous. Acta Haematol 87 [Suppl 1]:16–19Google Scholar
  34. 34.
    Iki S, Yagisawa M, Ohbayashi Y, Sato H, Urabe A (1991) Adverse effect of erythropoietin in myeloproliferative disorders. Lancet 337:187–188Google Scholar
  35. 35.
    Jacobs A (1985) Myelodysplastic syndromes: pathogenesis, functional abnormalities, and clinical implications. J Clin Pathol 38:1201–1217PubMedGoogle Scholar
  36. 36.
    Jacobs A, Janowska-Wieczorek A, Caro J, Bowen DT, Lewis T (1989) Circulating erythropoietin in patients with myelodysplastic syndromes. Br J Haematol 73:36–39PubMedGoogle Scholar
  37. 37.
    Koeffler HP (1986) Myelodysplastic syndromes (preleukemia). Semin Hematol 23:284–299PubMedGoogle Scholar
  38. 38.
    Krantz SB (1991) Erythropoietin. Blood 77:419–434PubMedGoogle Scholar
  39. 39.
    Kurzrock R, Talpaz M, Estey E, O'Brien S, Estrov Z, Gutterman JU (1991) Erythropoietin treatment in patients with myelodysplastic syndromes and anemia. Leukemia 5:985–990PubMedGoogle Scholar
  40. 40.
    Kurzrock R, Talpaz M, Estrov Z, Rosenblum MG, Gutterman JU (1991) Phase-I study of recombinant human interleukin-3 in patients with bone marrow failure. J Clin Oncol 9:1241–1250PubMedGoogle Scholar
  41. 41.
    Lavey RS, Dempsey WH (1993) Erythropoietin increases hemoglobin in cancer patients during radiation therapy. Int J Radiat Oncol Biol Phys 27:1147–1152PubMedGoogle Scholar
  42. 42.
    Lee GR (1983) The anemia of chronic disease. Semin Hematol 20:61–80PubMedGoogle Scholar
  43. 43.
    Lee GR (1993) The anemia of chronic disorders. In: Lee GR, Bithell TC, Foerster J, Athens JW, Lukens JN (eds) Wintrobe's clinical hematology, 9th edn. Lea and Febiger, Philadelphia, pp 840–851Google Scholar
  44. 44.
    Lieschke GJ, Burgess AW (1992) Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (first of two parts). N Engl J Med 327:28–35PubMedGoogle Scholar
  45. 45.
    Lieschke GJ, Burgess AW (1992) Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (second of two parts). N Engl J Med 327:99–106PubMedGoogle Scholar
  46. 46.
    List AL, Noyes W, Power J, Thomas T, Glinsman-Gibson B, Taetle R, Miller-McCauley V, Gross M, Miller AM (1993) Combined treatment of myelodysplastic syndromes (MDS) with recombinant human interleukin-3 (IL-3) and erythropoietin (EPO). Blood 82 [Suppl]:377aGoogle Scholar
  47. 47.
    Ludwig H, Fritz E, Kotzmann H, Höcker P, Gisslinger H, Bamas U (1990) Erythropoietin treatment of anemia associated with multiple myeloma. N Engl J Med 322:1693–1699PubMedGoogle Scholar
  48. 48.
    Ludwig H, Fritz E, Leitgeb C, Krainer M, Kührer I, Sagaster P, Umek H (1993) Erythropoietin treatment for chronic anemia of selected hematological malignancies and solid tumors. Ann Oncol 4:161–167PubMedGoogle Scholar
  49. 49.
    Markman M, Reichman B, Hakes T, Rubin S, Jones W, Lewis JL, Barakat R, Curtin J, Almadrones L, Hoskins W (1993) The use of recombinant human erythropoietin to prevent carboplatin-induced anemia. Gynecol Oncol 49:172–176PubMedGoogle Scholar
  50. 50.
    Merchav S, Nielsen OJ, Rosenbaum H, Sharon R, Brenner B, Tatarsky I, Scigalla P, Wieczorek L (1990) In vitro studies of erythropoietin-dependent regulation of erythropoiesis in myelodysplastic syndromes. Leukemia 4:771–774PubMedGoogle Scholar
  51. 51.
    Metcalf D (1984) The hemopoietic colony-stimulating factors. Elsevier, AmsterdamGoogle Scholar
  52. 52.
    Metcalf D (1989) The molecular control of cell division, differentiation commitment and maturation in haemopoietic cells. Nature 339:27–30PubMedGoogle Scholar
  53. 53.
    Miller CB, Jones RJ, Piantadosi S, Abeloff MD, Spivak JL (1990) Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med 322:1689–1692PubMedGoogle Scholar
  54. 54.
    Miller CB, Platanias LC, Mills SR, Zahurak ML, Ratain MJ, Ettinger DS, Jones RJ (1992) Phase I–II trial of erythropoietin in the treatment of cisplatin-associated anemia. J Natl Cancer Inst 84:98–103PubMedGoogle Scholar
  55. 55.
    Negrin RS, Haeuber DH, Nagler A, Kobayashi Y, Sklar J, Donlon T, Vincent M, Greenberg PL (1990) Maintenance treatment of patients with myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor. Blood 76:36–43PubMedGoogle Scholar
  56. 56.
    Negrin RS, Stein R, Vardiman J, Doherty K, Cornwell J, Krantz S, Greenberg PL (1993) Treatment of the anemia of myelodysplastic syndromes using human granulocyte colonystimulating factor in combination with erythropoietin. Blood 82:737–743PubMedGoogle Scholar
  57. 57.
    Oster W, Herrmann F, Gamm H, Zeile G, Lindemann A, Müller G, Brune T, Kraemer H-P, Mertelsmann R (1990) Erythropoietin for the treatment of anemia associated with neoplastic bone marrow infiltration. J Clin Oncol 8:956–962PubMedGoogle Scholar
  58. 58.
    Pangalis GA, Poziopoulos C, Panayiotidis P, Angelopoulou M (1993) Treatment of anaemia in B-chronic lymphocytic leukemia (B-CLL) with recombinant human erythropoietin (r-HuEPO). Blood 82 [Suppl]:574aGoogle Scholar
  59. 59.
    Platanias LC, Miller CB, Mick R, Hart RD, Ozer H, McEvilly J-M, Jones RJ, Ratain MJ (1991) Treatment of chemotherapy-induced anemia with recombinant human erythropoietin in cancer patients. J Clin Oncol 9:2021–2026PubMedGoogle Scholar
  60. 60.
    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 anemia. Haematologica (Pavia) 77:494–501Google Scholar
  61. 61.
    Rafanelli D, Grossi A, Longo G, Vannucchi AM, Bacci P, Ferrini PR (1992) Recombinant human erythropoietin for the treatment of myelodysplastic syndromes. Leukemia 6:323–327PubMedGoogle Scholar
  62. 62.
    Sawyers CL, Denny CT, Witte ON (1991) Leukemia and the disruption of normal hemopoiesis. Cell 64:337–350PubMedGoogle Scholar
  63. 63.
    Schapira L, Antin JH, Ransil BJ, Antman KH, Eder JP, McGarigle CJ, Goldberg MA (1990) Serum erythropoietin levels in patients receiving intensive chemotherapy and radiotherapy. Blood 76:2354–2359PubMedGoogle Scholar
  64. 64.
    Schilling RF (1991) Anemia of chronic disease: a misnomer. Ann Intern Med 115:572–573PubMedGoogle Scholar
  65. 65.
    Schouten HC, Vellenga E, Van Rhenen DJ, De Wolf JTM, Coppens PJW, Blijham GH (1991) Recombinant human erythropoietin in patients with myelodysplastic syndromes. Leukemia 5:432–436PubMedGoogle Scholar
  66. 66.
    Seipelt G, Ganser A, Duranceyk H, Maurer A, Ottmann OG, Hoelzer D (1993) Induction of TNF-α in patients with myelodysplastic syndromes undergoing treatment with interleukin-3. Br J Haematol 84:749–751PubMedGoogle Scholar
  67. 67.
    Skikne BS, Ahluwalia N, Savin V, Chonko A, Cook JD (1993) Serum transferrin receptor (TfR) and automated reticulocyte counts are early markers of marrow response to recombinant human erythropoietin (rHuEPO). Blood 82 [Suppl]:93aGoogle Scholar
  68. 68.
    Skillings JR, Sridhar FG, Wong C, Paddock L (1993) The frequency of red cell transfusion for anemia in patients receiving chemotherapy. Am J Clin Oncol (CCT) 16:22–25Google Scholar
  69. 69.
    Stein RS, Abels RI, Krantz SB (1991) Pharmacologic doses of recombinant human erythropoietin in the treatment of myelodysplastic syndromes. Blood 78:1658–1663PubMedGoogle Scholar
  70. 70.
    Suciu S, Zeller W, Weh HJ, Hossfeld DK (1993) Immunophe-notype of mitotic cells with clonal chromosome abnormalities demonstrating multilineage involvement in acute myeloid leukemia. Cancer Genet Cytogenet 70:1–5PubMedGoogle Scholar
  71. 71.
    Thompson JA, Lee DJ, Kidd P, Rubin E, Kaufmann J, Bonnem EM, Fefer A (1989) Subcutaneous granulocyte-macro-phage colony-stimulating factor in patients with myelodys-plastic syndrome: toxicity, pharmakokinetics, and hematological effects. J Clin Oncol 7:629–637PubMedGoogle Scholar
  72. 72.
    Tsukuda M, Mochimatsu I, Nagahara T, Kokatsu T, Sawaki S, Kubota A, Furkawa M, Arai Y (1993) Clinical application of recombinant human erythropoietin for treatments in patients with head and neck cancer. Cancer Immunol Immunother 36:52–56PubMedGoogle Scholar
  73. 73.
    Vadhan-Raj S, Keating M, LeMaistre A, Hittelman WN, McCredie K, Trujillo JM, Broxmeyer HE, Henney C, Gutterman JU (1987) Effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes. N Engl J Med 317:1545–1552PubMedGoogle Scholar
  74. 74.
    Vadhan-Raj S, Hittelman WN, Lepe-Zuniga JL, Gutterman JU, Broxmeyer HE (1990) Regulation of endogenous erythropoietin levels in anemia associated with myelodysplastic syndromes. Blood 75:1749–1750PubMedGoogle Scholar
  75. 75.
    Van Kamp H, Prinsze-Postema TC, Kluin PM, Den Ottolander GJ, Beverstock GC, Willemze R, Fibbe WE (1991) Effect of subcutaneously administered human recombinant erythro-poietin on erythropoiesis in patients with myelodysplasia. Br J Haematol 78:488–493PubMedGoogle Scholar
  76. 76.
    Verhoef GEG, Zachée P, Ferrant A, Demuynck H, Selleslag D, Van Hove L, Deckers F, Boogaerts MA (1992) Recombinant human erythropoietin for the treatment of anemia in the myelodysplastic syndromes: a clinical and erythrokinetic assessment. Ann Hematol 64:16–21PubMedGoogle Scholar
  77. 77.
    Verhoef G, Demuynck H, Zachée P, Ceuppens J, Dewitte M, Boogaerts M (1993) Treatment of myelodysplastic syndromes (MDS) with the combination of interleukin-3 and erythro-poietin. Blood 82 [Suppl]: 377aGoogle Scholar
  78. 78.
    Vijayakumar S, Roach M, Wara W, Chan SK, Ewing C, Rubin S, Sutton H, Halpern H, Awan A, Houghton A, Quiet C, Weichselbaum R (1993) Effect of subcutaneous recombinant human erythropoietin in cancer patients receiving radiotherapy: preliminary results of a randomized, open-label phase-II trial. Int J Radiat Oncol Biol Phys 26:721–729PubMedGoogle Scholar
  79. 79.
    Yoshida Y, Hirashima K, Asano S, Takaku F (1991) A phase-II trial of recombinant human granulocyte colony-stimulating factor in the myelodysplastic syndromes. Br J Haematol 78:378–384PubMedGoogle Scholar
  80. 80.
    Yoshida Y, Anzai N, Kawabata H, Kohsaka Y, Okuma M (1993) Serial changes in endogenous erythropoietin levels in patients with myelodysplastic syndromes and aplastic anemia undergoing erythropoietin treatment. Ann Hematol 66:175–180PubMedGoogle Scholar
  81. 81.
    Zeigler ZR, Rosenfeld CS, Shadduck RK (1993) Resolution of transfusion dependence by recombinant human erythro-poietin (rHuEPO) in acquired pure red cell aplasia (PRCA) associated with myeloid metaplasia. Br J Haematol 83:28–29PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • U. Dührsen
    • 1
  • D. K. Hossfeld
    • 1
  1. 1.Medizinische Klinik, Abteilung für Onkologie und HämatologieUniversitätskrankenhaus EppendorfHamburgGermany

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