The anemia of inflammation/malignancy: mechanisms and management.

Anemia is a common complication in patients with inflammatory diseases of many kinds, including cancer. The mechanisms that have captured the most attention include cytokine-mediated changes in both the production of and the response to erythropoietin (Epo), as well as important alterations in iron metabolism. The last is brought about by the relatively recently recognized peptide hormone, hepcidin. The availability of recombinant human Epo and its derivatives (known by class as Erythropoietic Stimulating Agents, ESAs) has dramatically changed anemia management in patients with cancer but, in the process, has raised as many issues as have been answered. This chapter reviews the mechanisms resulting in anemia in inflammation, including cancer, and focuses on the controversies around management with the ESAs and the adjuvant use of iron in anemia management.

[1]  M. Auerbach.  Should intravenous iron be the standard of care in oncology? , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  R. Labianca,et al.  Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alpha. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  T. Pintér,et al.  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. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  F. Carvalho,et al.  Erythropoietin mediates hepcidin expression in hepatocytes through EPOR signaling and regulation of C/EBPα , 2008, Blood.

[5]  D. Dorr,et al.  Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. , 2008, JAMA.

[6]  H. Niederegger,et al.  Autocrine formation of hepcidin induces iron retention in human monocytes. , 2008, Blood.

[7]  N. Andrews,et al.  Hepcidin antimicrobial peptide transgenic mice exhibit features of the anemia of inflammation. , 2007, Blood.

[8]  Wilson Roa,et al.  Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  N. Dahl,et al.  Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. , 2007, The oncologist.

[10]  N. Andrews,et al.  Interleukin-6 induces hepcidin expression through STAT3. , 2006, Blood.

[11]  V. Nizet,et al.  TLR4-dependent hepcidin expression by myeloid cells in response to bacterial pathogens. , 2006, Blood.

[12]  Raymond T Chung,et al.  Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression , 2006, Nature Genetics.

[13]  R. Means,et al.  Hepcidin inhibits in vitro erythroid colony formation at reduced erythropoietin concentrations. , 2006, Blood.

[14]  J. Baselga,et al.  Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  P. Novotny,et al.  Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  L. Goodnough,et al.  Anemia of chronic disease. , 2005, The New England journal of medicine.

[17]  Elizabeta Nemeth,et al.  IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. , 2004, The Journal of clinical investigation.

[18]  M. Auerbach,et al.  Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  C. Rübe,et al.  Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial , 2003, The Lancet.

[20]  C. Beaumont,et al.  Hepcidin, a new iron regulatory peptide. , 2002, Blood cells, molecules & diseases.

[21]  H. Papadaki,et al.  Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor-alpha antibody therapy. , 2002, Blood.

[22]  H. Papadaki,et al.  Bone marrow progenitor cell reserve and function and stromal cell function are defective in rheumatoid arthritis: evidence for a tumor necrosis factor alpha-mediated effect. , 2002, Blood.

[23]  J. Nortier,et al.  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. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  M. Cazzola,et al.  Defective iron supply for erythropoiesis and adequate endogenous erythropoietin production in the anemia associated with systemic-onset juvenile chronic arthritis. , 1996, Blood.

[25]  S. Krantz,et al.  Inhibition of human erythroid colony-forming units by interferons alpha and beta: differing mechanisms despite shared receptor. , 1996, Experimental hematology.

[26]  W. Hrushesky,et al.  Cisplatin-associated anemia: an erythropoietin deficiency syndrome. , 1995, The Journal of clinical investigation.

[27]  D. Henry,et al.  Recombinant human erythropoietin in the treatment of cancer and chemotherapy-induced anemia: results of double-blind and open-label follow-up studies. , 1994, Seminars in oncology.

[28]  S. Marsters,et al.  Inhibition of murine erythroid colony formation in vitro by interferon gamma and correction by interferon receptor immunoadhesin. , 1994, Blood.

[29]  S. Krantz,et al.  Inhibition of human erythroid colony-forming units by tumor necrosis factor requires beta interferon. , 1993, The Journal of clinical investigation.

[30]  L. Paddock,et al.  The Frequency of Red Cell Transfusion for Anemia in Patients Receiving Chemotherapy A Retrospective Cohort Study , 1993, American journal of clinical oncology.

[31]  R. Hillman,et al.  Red cell manual , 1974 .

[32]  Abels Ri.  Use of recombinant human erythropoietin in the treatment of anemia in patients who have cancer. , 1992 .

[33]  M. Goldberg,et al.  EFFECT OF INFLAMMATORY CYTOKINES ON HYPOXIA-INDUCED ERYTHROPOIETIN PRODUCTION , 1992 .

[34]  E. Dessypris,et al.  Inhibition of human erythroid colony‐forming units by interleukin‐1 is mediated by gamma interferon , 1992, Journal of cellular physiology.

[35]  E. Dessypris,et al.  Inhibition of human colony-forming-unit erythroid by tumor necrosis factor requires accessory cells. , 1990, The Journal of clinical investigation.

[36]  S. Piantadosi,et al.  Decreased erythropoietin response in patients with the anemia of cancer. , 1990, The New England journal of medicine.

[37]  J. Caro,et al.  Chronic exposure to tumor necrosis factor in vivo preferentially inhibits erythropoiesis in nude mice. , 1989, Blood.

[38]  P. Furmanski,et al.  In vivo hematopoietic effects of recombinant interleukin-1 alpha in mice: stimulation of granulocytic, monocytic, megakaryocytic, and early erythroid progenitors, suppression of late-stage erythropoiesis, and reversal of erythroid suppression with erythropoietin. , 1989, Blood.

[39]  M A Goldberg,et al.  The regulated expression of erythropoietin by two human hepatoma cell lines. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[40]  J. Adamson,et al.  Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. , 1987, The New England journal of medicine.

[41]  D. Williams,et al.  The suppressive influences of human tumor necrosis factors on bone marrow hematopoietic progenitor cells from normal donors and patients with leukemia: synergism of tumor necrosis factor and interferon-gamma. , 1986, Journal of immunology.

[42]  G. Roodman,et al.  Inhibition of erythroid colony formation by autologous bone marrow adherent cells from patients with the anemia of chronic disease. , 1983, Blood.

[43]  Lee Gr.  The anemia of chronic disease. , 1983, Seminars in hematology.

[44]  G. Sarosi,et al.  In vitro suppression of erythropoiesis by bone marrow adherent cells from some patients with fungal infection , 1982, British journal of haematology.

[45]  G. Birgegard,et al.  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 , 2008, Leukemia.

[46]  Y. Brandberg,et al.  Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy , 2003, Cancer.

[47]  M. Buyse,et al.  Anemia in children with cancer is associated with decreased erythropoietic activity and not with inadequate erythropoietin production. , 1998, Blood.

[48]  R. Means.  Pathogenesis of the anemia of chronic disease: A cytokine‐mediated anemia , 1995, Stem cells.

[49]  W. Jelkmann,et al.  Monokines inhibiting erythropoietin production in human hepatoma cultures and in isolated perfused rat kidneys. , 1992, Life sciences.

[50]  Abels Ri,et al.  Use of recombinant human erythropoietin in the treatment of anemia in patients who have cancer. , 1992, Seminars in oncology.

[51]  S. Wolff,et al.  Effect of induced fever on serum iron and ferritin concentrations in man. , 1977, Blood.