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Iron overload in hematopoietic cell transplantation

Bone Marrow Transplantation volume 41, pages 997–1003 (2008)Cite this article

Abstract

Iron overload, primarily related to RBC transfusions, is a relatively common complication in hematopoietic cell transplant (HCT) recipients. Iron overload increases the risk of infections, veno-occlusive disease and hepatic dysfunction post transplant. Elevated pretransplant ferritin levels have been reported to increase the risk of nonrelapse mortality following HCT and might influence the risk of acute and chronic GVHD. Serum ferritin is sensitive but not specific for iron overload and is a poor predictor of body iron burden. Estimation of hepatic iron content with a liver biopsy or magnetic resonance imaging should be considered prior to initiating therapy for post transplant iron overload. A subgroup of transplant survivors with mild iron overload and no end-organ damage may not need therapy. Phlebotomy is the treatment of choice with iron-chelation therapy reserved for patients not eligible for phlebotomy. Natural history, evolution and treatment of iron overload in transplant survivors have not been adequately investigated and more studies are needed to determine its impact on short-term and long-term morbidity and mortality.

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References

  1. Hentze MW, Muckenthaler MU, Andrews NC . Balancing acts: molecular control of mammalian iron metabolism. Cell 2004; 117: 285–297.

    Article  CAS  PubMed  Google Scholar 

  2. Andrews NC . Disorders of iron metabolism. N Engl J Med 1999; 341: 1986–1995.

    Article  CAS  PubMed  Google Scholar 

  3. Papanikolaou G, Pantopoulos K . Iron metabolism and toxicity. Toxicol Appl Pharmacol 2005; 202: 199–211.

    Article  CAS  PubMed  Google Scholar 

  4. Ganz T . Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003; 102: 783–788.

    Article  CAS  PubMed  Google Scholar 

  5. Olivieri NF, Brittenham GM . Iron-chelating therapy and the treatment of thalassemia. Blood 1997; 89: 739–761.

    CAS  PubMed  Google Scholar 

  6. Harmatz P, Butensky E, Quirolo K, Williams R, Ferrell L, Moyer T et al. Severity of iron overload in patients with sickle cell disease receiving chronic red blood cell transfusion therapy. Blood 2000; 96: 76–79.

    CAS  PubMed  Google Scholar 

  7. Olivieri NF . The beta-thalassemias. N Engl J Med 1999; 341: 99–109.

    Article  CAS  PubMed  Google Scholar 

  8. Cunningham MJ, Macklin EA, Neufeld EJ, Cohen AR . Complications of beta-thalassemia major in North America. Blood 2004; 104: 34–39.

    Article  CAS  PubMed  Google Scholar 

  9. Brittenham GM, Griffith PM, Nienhuis AW, McLaren CE, Young NS, Tucker EE et al. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med 1994; 331: 567–573.

    Article  CAS  PubMed  Google Scholar 

  10. Olivieri NF, Nathan DG, MacMillan JH, Wayne AS, Liu PP, McGee A et al. Survival in medically treated patients with homozygous beta-thalassemia. N Engl J Med 1994; 331: 574–578.

    Article  CAS  PubMed  Google Scholar 

  11. Ladis V, Chouliaras G, Berdousi H, Kanavakis E, Kattamis C . Longitudinal study of survival and causes of death in patients with thalassemia major in Greece. Ann N Y Acad Sci 2005; 1054: 445–450.

    Article  PubMed  Google Scholar 

  12. Zurlo MG, De Stefano P, Borgna-Pignatti C, Di Palma A, Piga A, Melevendi C et al. Survival and causes of death in thalassaemia major. Lancet 1989; 2: 27–30.

    Article  CAS  PubMed  Google Scholar 

  13. Marx JJ . Iron and infection: competition between host and microbes for a precious element. Best Pract Res Clin Haematol 2002; 15: 411–426.

    Article  CAS  PubMed  Google Scholar 

  14. Angelucci E, Brittenham GM, McLaren CE, Ripalti M, Baronciani D, Giardini C et al. Hepatic iron concentration and total body iron stores in thalassemia major. N Engl J Med 2000; 343: 327–331.

    Article  CAS  PubMed  Google Scholar 

  15. Iqbal M, Creger RJ, Fox RM, Cooper BW, Jacobs G, Stellato TA et al. Laparoscopic liver biopsy to evaluate hepatic dysfunction in patients with hematologic malignancies: a useful tool to effect changes in management. Bone Marrow Transplant 1996; 17: 655–662.

    CAS  PubMed  Google Scholar 

  16. Kamble RT, Selby GB, Mims M, Kharfan-Dabaja MA, Ozer H, George JN . Iron overload manifesting as apparent exacerbation of hepatic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2006; 12: 506–510.

    Article  CAS  PubMed  Google Scholar 

  17. McKay PJ, Murphy JA, Cameron S, Burnett AK, Campbell M, Tansey P et al. Iron overload and liver dysfunction after allogeneic or autologous bone marrow transplantation. Bone Marrow Transplant 1996; 17: 63–66.

    CAS  PubMed  Google Scholar 

  18. Smith TP, Presson TL, Heneghan MA, Ryan JM . Transjugular biopsy of the liver in pediatric and adult patients using an 18-gauge automated core biopsy needle: a retrospective review of 410 consecutive procedures. AJR Am J Roentgenol 2003; 180: 167–172.

    Article  PubMed  Google Scholar 

  19. Brittenham GM, Farrell DE, Harris JW, Feldman ES, Danish EH, Muir WA et al. Magnetic-susceptibility measurement of human iron stores. N Engl J Med 1982; 307: 1671–1675.

    Article  CAS  PubMed  Google Scholar 

  20. Brittenham GM, Badman DG . Noninvasive measurement of iron: report of an NIDDK workshop. Blood 2003; 101: 15–19.

    Article  CAS  PubMed  Google Scholar 

  21. Gandon Y, Olivie D, Guyader D, Aube C, Oberti F, Sebille V et al. Non-invasive assessment of hepatic iron stores by MRI. Lancet 2004; 363: 357–362.

    Article  CAS  PubMed  Google Scholar 

  22. Voskaridou E, Douskou M, Terpos E, Papassotiriou I, Stamoulakatou A, Ourailidis A et al. Magnetic resonance imaging in the evaluation of iron overload in patients with beta thalassaemia and sickle cell disease. Br J Haematol 2004; 126: 736–742.

    Article  CAS  PubMed  Google Scholar 

  23. St Pierre TG, Clark PR, Chua-anusorn W, Fleming AJ, Jeffrey GP, Olynyk JK et al. Noninvasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood 2005; 105: 855–861.

    Article  CAS  PubMed  Google Scholar 

  24. Wood JC, Enriquez C, Ghugre N, Tyzka JM, Carson S, Nelson MD et al. MRI R2 and R2* mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients. Blood 2005; 106: 1460–1465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Carneiro AA, Fernandes JP, de Araujo DB, Elias Jr J, Martinelli AL, Covas DT et al. Liver iron concentration evaluated by two magnetic methods: magnetic resonance imaging and magnetic susceptometry. Magn Reson Med 2005; 54: 122–128.

    Article  CAS  PubMed  Google Scholar 

  26. Brittenham GM, Cohen AR, McLaren CE, Martin MB, Griffith PM, Nienhuis AW et al. Hepatic iron stores and plasma ferritin concentration in patients with sickle cell anemia and thalassemia major. Am J Hematol 1993; 42: 81–85.

    Article  CAS  PubMed  Google Scholar 

  27. Karam LB, Disco D, Jackson SM, Lewin D, McKie V, Baker RD et al. Liver biopsy results in patients with sickle cell disease on chronic transfusions: poor correlation with ferritin levels. Pediatr Blood Cancer 2008; 50: 62–65.

    Article  PubMed  Google Scholar 

  28. Nielsen P, Gunther U, Durken M, Fischer R, Dullmann J . Serum ferritin iron in iron overload and liver damage: correlation to body iron stores and diagnostic relevance. J Lab Clin Med 2000; 135: 413–418.

    Article  CAS  PubMed  Google Scholar 

  29. Majhail NS, Defor TE, Kang B, Paley C, Lazarus HM, Burns LJ . High prevalence of iron overload in adult survivors of allogeneic hematopoieitic cell transplantation. Biol Blood Marrow Transplant 2008; 14 (Suppl 1): Abstract 142.

  30. Rose C, Ernst O, Hecquet B, Maboudou P, Renom P, Noel MP et al. Quantification by magnetic resonance imaging and liver consequences of post-transfusional iron overload alone in long term survivors after allogeneic hematopoietic stem cell transplantation (HSCT). Haematologica 2007; 92: 850–853.

    Article  CAS  PubMed  Google Scholar 

  31. Au WY, Lam WM, Chu WC, Tam S, Wong WK, Pennell DJ et al. A magnetic resonance imaging study of iron overload in hemopoietic stem cell transplant recipients with increased ferritin levels. Transplant Proc 2007; 39: 3369–3374.

    Article  CAS  PubMed  Google Scholar 

  32. Durken M, Nielsen P, Knobel S, Finckh B, Herrnring C, Dresow B et al. Nontransferrin-bound iron in serum of patients receiving bone marrow transplants. Free Radic Biol Med 1997; 22: 1159–1163.

    Article  CAS  PubMed  Google Scholar 

  33. Gordon LI, Brown SG, Tallman MS, Rademaker AW, Weitzman SA, Lazarus HM et al. Sequential changes in serum iron and ferritin in patients undergoing high-dose chemotherapy and radiation with autologous bone marrow transplantation: possible implications for treatment related toxicity. Free Radic Biol Med 1995; 18: 383–389.

    Article  CAS  PubMed  Google Scholar 

  34. Sahlstedt L, Ebeling F, von Bonsdorff L, Parkkinen J, Ruutu T . Non-transferrin-bound iron during allogeneic stem cell transplantation. Br J Haematol 2001; 113: 836–838.

    Article  CAS  PubMed  Google Scholar 

  35. Evens AM, Mehta J, Gordon LI . Rust and corrosion in hematopoietic stem cell transplantation: the problem of iron and oxidative stress. Bone Marrow Transplant 2004; 34: 561–571.

    Article  CAS  PubMed  Google Scholar 

  36. Altes A, Remacha AF, Sureda A, Martino R, Briones J, Canals C et al. Iron overload might increase transplant-related mortality in haematopoietic stem cell transplantation. Bone Marrow Transplant 2002; 29: 987–989.

    Article  CAS  PubMed  Google Scholar 

  37. Strasser SI, Kowdley KV, Sale GE, McDonald GB . Iron overload in bone marrow transplant recipients. Bone Marrow Transplant 1998; 22: 167–173.

    Article  CAS  PubMed  Google Scholar 

  38. Butt NM, Clark RE . Autografting as a risk factor for persisting iron overload in long-term survivors of acute myeloid leukaemia. Bone Marrow Transplant 2003; 32: 909–913.

    Article  CAS  PubMed  Google Scholar 

  39. Harrison P, Neilson JR, Marwah SS, Madden L, Bareford D, Milligan DW . Role of non-transferrin bound iron in iron overload and liver dysfunction in long term survivors of acute leukaemia and bone marrow transplantation. J Clin Pathol 1996; 49: 853–856.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Azar N, Valla D, Abdel-Samad I, Hoang C, Fretz C, Sutton L et al. Liver dysfunction in allogeneic bone marrow transplantation recipients. Transplantation 1996; 62: 56–61.

    Article  CAS  PubMed  Google Scholar 

  41. Altes A, Remacha AF, Sarda P, Sancho FJ, Sureda A, Martino R et al. Frequent severe liver iron overload after stem cell transplantation and its possible association with invasive aspergillosis. Bone Marrow Transplant 2004; 34: 505–509.

    Article  CAS  PubMed  Google Scholar 

  42. Gaziev D, Baronciani D, Galimberti M, Polchi P, Angelucci E, Giardini C et al. Mucormycosis after bone marrow transplantation: report of four cases in thalassemia and review of the literature. Bone Marrow Transplant 1996; 17: 409–414.

    CAS  PubMed  Google Scholar 

  43. Maertens J, Demuynck H, Verbeken EK, Zachee P, Verhoef GE, Vandenberghe P et al. Mucormycosis in allogeneic bone marrow transplant recipients: report of five cases and review of the role of iron overload in the pathogenesis. Bone Marrow Transplant 1999; 24: 307–312.

    Article  CAS  PubMed  Google Scholar 

  44. Kontoyiannis DP, Chamilos G, Lewis RE, Giralt S, Cortes J, Raad II et al. Increased bone marrow iron stores is an independent risk factor for invasive aspergillosis in patients with high-risk hematologic malignancies and recipients of allogeneic hematopoietic stem cell transplantation. Cancer 2007; 110: 1303–1306.

    Article  PubMed  Google Scholar 

  45. Lee AC, Ha SY, Yuen KY, Lau YL . Listeria septicemia complicating bone marrow transplantation for diamond-blackfan syndrome. Pediatr Hematol Oncol 1995; 12: 295–299.

    Article  CAS  PubMed  Google Scholar 

  46. Miceli MH, Dong L, Grazziutti ML, Fassas A, Thertulien R, Van Rhee F et al. Iron overload is a major risk factor for severe infection after autologous stem cell transplantation: a study of 367 myeloma patients. Bone Marrow Transplant 2006; 37: 857–864.

    Article  CAS  PubMed  Google Scholar 

  47. Pullarkat V, Blanchard S, Tegtmeier B, Dagis A, Patane K, Ito J et al. Iron overload adversely affects survival and increases risk of graft-versus-host disease and blood stream infections after allogeneic hematopoietic stem cell transplantation. Blood 2007; 110: Abstract 2981.

  48. Morado M, Ojeda E, Garcia-Bustos J, Aguado MJ, Arrieta R, Quevedo E et al. BMT: serum ferritin as risk factor for veno-occlusive disease of the liver. Prospective cohort study. Hematology 2000; 4: 505–512.

    Article  CAS  PubMed  Google Scholar 

  49. Jastaniah W, Harmatz P, Pakbaz Z, Fischer R, Vichinsky E, Walters MC . Transfusional iron burden and liver toxicity after bone marrow transplantation for acute myelogenous leukemia and hemoglobinopathies. Pediatr Blood Cancer 2008; 50: 319–324.

    Article  PubMed  Google Scholar 

  50. Armand P, Kim HT, Cutler CS, Ho VT, Koreth J, Alyea EP et al. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood 2007; 109: 4586–4588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mahindra A, Bolwell B, Sobecks R, Rybicki L, Brown S, Pohlman B et al. Elevated pretransplant serum ferritin in autologous stem cell transplant. Blood 2007; 110: Abstract 606.

  52. Mahindra A, Bolwell B, Sobecks R, Rybicki L, Brown S, Pohlman B et al. Prognostic impact of elevated pretransplant serum ferritin in allogeneic hematopoietic stem cell transplantation. Blood 2007; 110: Abstract 1109.

  53. Mahindra A, Sobecks R, Rybicki L, Brown S, Pohlman B, Kalaycio M et al. Elevated ferritin is associated with poorer survival following nonablative allogeneic transplantation. Blood 2007; 110: Abstract 1986.

  54. Storey JA, Connor R, Lewis ZT, Lovato J, Hurd D, Torti FM et al. The transfusion iron overload score is a potential predictor of survival in stem cell transplant patients. Blood 2007; 110: Abstract 1108.

  55. 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.

    Article  CAS  PubMed  Google Scholar 

  56. Muretto P, Angelucci E, Lucarelli G . Reversibility of cirrhosis in patients cured of thalassemia by bone marrow transplantation. Ann Intern Med 2002; 136: 667–672.

    Article  PubMed  Google Scholar 

  57. Mariotti E, Angelucci E, Agostini A, Baronciani D, Sgarbi E, Lucarelli G . Evaluation of cardiac status in iron-loaded thalassaemia patients following bone marrow transplantation: improvement in cardiac function during reduction in body iron burden. Br J Haematol 1998; 103: 916–921.

    Article  CAS  PubMed  Google Scholar 

  58. Lucarelli G, Angelucci E, Giardini C, Baronciani D, Galimberti M, Polchi P et al. Fate of iron stores in thalassaemia after bone-marrow transplantation. Lancet 1993; 342: 1388–1391.

    Article  CAS  PubMed  Google Scholar 

  59. Rizzo JD, Wingard JR, Tichelli A, Lee SJ, Van Lint MT, Burns LJ et al. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European group for blood and marrow transplantation, the center for international blood and marrow transplant research, and the american society of blood and marrow transplantation. Biol Blood Marrow Transplant 2006; 12: 138–151.

    Article  PubMed  Google Scholar 

  60. Li CK, Lai DH, Shing MM, Chik KW, Lee V, Yuen PM . Early iron reduction programme for thalassaemia patients after bone marrow transplantation. Bone Marrow Transplant 2000; 25: 653–656.

    Article  CAS  PubMed  Google Scholar 

  61. Gaziev D, Giardini C, Angelucci E, Polchi P, Galimberti M, Baronciani D et al. Intravenous chelation therapy during transplantation for thalassemia. Haematologica 1995; 80: 300–304.

    CAS  PubMed  Google Scholar 

  62. Giardini C, Galimberti M, Lucarelli G, Polchi P, Angelucci E, Baronciani D et al. Desferrioxamine therapy accelerates clearance of iron deposits after bone marrow transplantation for thalassaemia. Br J Haematol 1995; 89: 868–873.

    Article  CAS  PubMed  Google Scholar 

  63. Angelucci E, Muretto P, Lucarelli G, Ripalti M, Baronciani D, Erer B et al. Phlebotomy to reduce iron overload in patients cured of thalassemia by bone marrow transplantation. Italian cooperative group for phlebotomy treatment of transplanted thalassemia patients. Blood 1997; 90: 994–998.

    CAS  PubMed  Google Scholar 

  64. Cho SJ, Lee SJ, Yoo ES, Ryu KH, Seoh JY, Hong KS et al. Iron removal with phlebotomy and recombinant human erythropoietin in secondary hemochromatosis after allogeneic bone marrow transplantation. Pediatr Int 2006; 48: 174–177.

    Article  CAS  PubMed  Google Scholar 

  65. Rizzo JD, Somerfield MR, Hagerty KL, Seidenfeld J, Bohlius J, Bennett CL et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update. Blood 2008; 111: 25–41.

    Article  CAS  PubMed  Google Scholar 

  66. Bokemeyer C, Aapro MS, Courdi A, Foubert J, Link H, Osterborg A et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update. Eur J Cancer 2007; 43: 258–270.

    Article  CAS  PubMed  Google Scholar 

  67. Cappellini MD, Cohen A, Piga A, Bejaoui M, Perrotta S, Agaoglu L et al. A Phase III study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with {beta}-thalassemia. Blood 2006; 107: 3455–3462.

    Article  CAS  PubMed  Google Scholar 

  68. Vichinsky E, Onyekwere O, Porter J, Swerdlow P, Eckman J, Lane P et al. A randomised comparison of deferasirox versus deferoxamine for the treatment of transfusional iron overload in sickle cell disease. Br J Haematol 2007; 136: 501–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Piga A, Galanello R, Forni GL, Cappellini MD, Origa R, Zappu A et al. Randomized phase II trial of deferasirox (Exjade, ICL670), a once-daily, orally-administered iron chelator, in comparison to deferoxamine in thalassemia patients with transfusional iron overload. Haematologica 2006; 91: 873–880.

    CAS  PubMed  Google Scholar 

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  1. Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN, USA

    N S Majhail & L J Burns

  2. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA

    H M Lazarus

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Correspondence to N S Majhail.

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Majhail, N., Lazarus, H. & Burns, L. Iron overload in hematopoietic cell transplantation. Bone Marrow Transplant 41, 997–1003 (2008). https://doi.org/10.1038/bmt.2008.99

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