Iron Overload in Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation

Authors

  • Alessandro Busca Stem Cell Transplant Center, AO Città della Salute e della Scienza, Italy
  • Chiara Dellacasa Stem Cell Transplant Center, AO Città della Salute e della Scienza, Italy
  • Clara Pecoraro Department of Oncology, AO Città della Salute e della Scienza, Italy

DOI:

https://doi.org/10.15379/2408-9877.2014.01.02.03

Keywords:

Iron overload, Stem cell transplantation, GVHD, Iron chelators, Phlebotomy

Abstract

Iron overload has been associated to a variety of post-transplant complications, including infections, sinusoidal obstructive syndrome and it is conceivable that increased hepatic iron may mimic the clinical picture of GVHD or even may contribute to the worsening of hepatic GVHD.

Objectives and Methods: aim of present review was to summarize the current knowledge about diagnosis and treatment strategies of iron overload following HSCT.

Results: serum ferritin may be considered as surrogate marker of iron overload and is widely used as an indicator of body iron status; however other noninvasive diagnostic methods, namely SQUID and MRI, may provide more precise information on iron burden in specific organs, such as liver and heart. Since there are not physiological tools to remove efficiently the excess of iron, it is of particular importance to consider iron depleting therapy. Phlebotomy should be considered as the first line treatment of iron overload, while iron chelators, such as deferasirox, may represent an alternative option for patients with an inadequate hematological recovery.

Discussion: additional prospective studies are mandatory to investigate the relationship between iron overload and the outcome of patients receiving an allogeneic stem cell transplantation.

References

Lucarelli G, Galimberti M, Polchi P, Angelucci E, Baronciani D, Giardini C, Politi P, Durazzi SM, Muretto P, Albertini F. Bone marrow transplantation in patients with thalassemia. N Engl J Med. 1990;322:417-421.

Lucarelli G, Galimberti M, Polchi P, Angelucci E, Baronciani D, Giardini C, Andreani M, Agostinelli F, Albertini F, Clift RA. Marrow transplantation in patients with thalassemia responsive to iron chelation therapy. N Engl J Med. 1993;329:840-844

Armand P, Kim HT, Cutler CS, Ho VT, Koreth J, Alyea EP, Soiffer RJ, Antin JH. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood. 2007; 109:4586-4588.

Altès A, Remacha AF, Sureda A, Martino R, Briones J, Canals C, Brunet S, Sierra J, Gimferrer E. Iron overload might increase transplant-related mortality in haematopoietic stem cell transplantation. Bone Marrow Transplant. 2002; 29:987-989.

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

Storey JA, Connor RF, Lewis ZT, Hurd D, Pomper G, Keung YK, Grover M, Lovato J, Torti SV, Torti FM, Molnár I. The transplant iron score as a predictor of stem cell transplant survival. J Hematol Oncol. 2009;2:44-53

Kamble R, Mims M. Iron-overload in long-term survivors of hematopoietic transplantation. Bone Marrow Transplant. 2006;37:805-806

Tachibana T, Tanaka M, Takasaki H, Numata A, Ito S, Watanabe R, Hyo R, Ohshima R, Hagihara M, Sakai R, Fujisawa S, Tomita N, Fujita H, Maruta A, Ishigatsubo Y, Kanamori H. Pretransplant serum ferritin is associated with bloodstream infections within 100 days of allogeneic stem cell transplantation for myeloid malignancies. Int J Hematol. 2011;93:368-374.

Pullarkat V, Blanchard S, Tegtmeier B, Dagis A, Patane K, Ito J, Forman SJ. Iron overload adversely affects outcome of allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2008;42:799-805

Deeg HJ, Spaulding E, Shulman HM Iron Overload, Hematopoietic Cell Transplantation, and Graft versus Host Disease. Leuk Lymphoma. 2009; 50: 1566–1572.

Muñoz M, Villar I, García-Erce JA. An update on iron physiology. World J Gastroenterol. 2009;15:4617-4626.

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

Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090-2093.

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

Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113:1271-1276.

Lee P, Peng H, Gelbart T, Wang L, Beutler E. Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proc Natl Acad Sci U S A. 2005;102:1906-1910.

Kanda J, Kawabata H, Chao NJ. Iron overload and allogeneic hematopoietic stem-cell transplantation. Expert Rev Hematol. 2011;4:71-80

Shander A, Sazama K. Clinical consequences of iron overload from chronic red blood cell transfusions, its diagnosis, and its management by chelation therapy. Transfusion 2010; 50: 1144–1155

Pullarkat V. Iron overload in patients undergoing hematopoietic stem cell transplantation. Adv Hematol. 2010;2010:1-12

Bair S, Spaulding E, Parkkinen J, Shulman HM, Lesnikov V, Beauchamp M, Canonne-Hergaux F, Kowdley KV, Deeg HJ. Transplantation of allogeneic T cells alters iron homeostasis in NOD/SCID mice. Blood. 2009;113:1841-1844.

Kanda J, Mizumoto C, Ichinohe T, Kawabata H, Saito T, Yamashita K, Kondo T, Takakura S, Ichiyama S, Uchiyama T, Ishikawa T. Pretransplant serum ferritin and C-reactive protein as predictive factors for early bacterial infection after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2011;46:208-216.

Sivgin S, Baldane S, Kaynar L, Kurnaz F, Pala C, Sivgin H, Keklik M, Demiraslan H, Cetin M, Eser B, Unal A. Pretransplant iron overload may be associated with increased risk of invasive fungal pneumonia (IFP) in patients that underwent allogeneic hematopoietic stem cell transplantation (alloHSCT). Transfus Apher Sci. 2013;48: 103-108.

Weinberg ED. Iron availability and infection. Biochim Biophys Acta. 2009;1790:600-605

Schaible UE. Iron and microbial infection. Nature reviews Microbiology. 2004;2 946-953

Ozyilmaz E, Aydogdu M, Sucak G, Aki SZ, Ozkurt ZN, Yegin ZA, Kokturk N. Risk factors for fungal pulmonary infections in hematopoietic stem cell transplantation recipients: the role of iron overload. Bone Marrow Transplant. 2010;45:1528-1533

Kontoyiannis DP, Chamilos G, Lewis RE, Giralt S, Cortes J, Raad II, Manning JT, Han X. 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.

Walker, Jr, E.M. & Walker, S.M. Effects of iron overload on the immune system. Annals of Clinical and laboratory Science 2000;30:354-365

Cunningham-Rundles S, Giardina PJ, Grady RW, Califano C, McKenzie P, De Sousa M. Effect of transfusional iron overload on immune response. J Infect Dis. 2000;182 Suppl 1:S115-121.

Piperno A. Classification and diagnosis of iron overload. Haematologica 1998;83: 447-455

Olivé A, Juncà J. Elevated serum ferritin levels: associated diseases and clinical significance. Am J Med. 1996;101:120-122.

Sucak GT, Yegin ZA, Ozkurt ZN, Aki SZ, Karakan T, Akyol G. The role of liver biopsy in the workup of liver dysfunction late after SCT: is the role of iron overload underestimated? Bone Marrow Transplant. 2008;42:461-467

Ali S, Pimentel JD, Munoz J, Shah V, McKinnon R, Divine G, Janakiraman N. Iron overload in allogeneic hematopoietic stem cell transplant recipients. Arch Pathol Lab Med. 2012;136:532-538

Sheth S. SQUID biosusceptometry in the measurement of hepatic iron. Pediatr Radiol. 2003;33:373-377.

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.

Busca A, Falda M, Manzini P, D'Antico S, Valfrè A, Locatelli F, Calabrese R, Chiappella A, D'Ardia S, Longo F, Piga A. Iron overload in patients receiving allogeneic hematopoietic stem cell transplantation: quantification of iron burden by a superconducting quantum interference device (SQUID) and therapeutic effectiveness of phlebotomy. Biol Blood Marrow Transplant. 2010;16:115-122.

Hankins JS, McCarville MB, Loeffler RB, Smeltzer MP, Onciu M, Hoffer FA, Li CS, Wang WC, Ware RE, Hillenbrand CM. R2* magnetic resonance imaging of the liver in patients with iron overload. Blood. 2009;113:4853-4855.

Armand P, Sainvil MM, Kim HT, Rhodes J, Cutler C, Ho VT, Koreth J, Alyea EP, Neufeld EJ, Kwong RY, Soiffer RJ, Antin JH. Does iron overload really matter in stem cell transplantation? Am J Hematol. 2012;87:569-572.

Wermke M, Schmidt A, Middeke JM, Sockel K, von Bonin M, Schönefeldt C, Mair S, Plodeck V, Laniado M, Weiss G, Schetelig J,Ehninger G, Theurl I, Bornhäuser M, Platzbecker U. MRI-based liver iron content predicts for nonrelapse mortality in MDS and AML patients undergoing allogeneic stem cell transplantation. Clin Cancer Res. 2012;18:6460-6468

Rose C, Ernst O, Hecquet B, Maboudou P, Renom P, Noel MP, Yakoub-Agha I, Bauters F, Jouet JP. Quantification by magnetic resonance imaging and liver consequences of post-transfusionaliron overload alone in long term survivors after allogeneic hematopoietic stem cell transplantation (HSCT). Haematologica. 2007; 92:850-853.

Majhail NS, Lazarus HM, Burns LJ. Iron overload in hematopoietic cell transplantation. Bone Marrow Transplant. 2008; 41:997-1003.

Mahindra A, Bolwell B, Sobecks R, Rybicki L, Pohlman B, Dean R, Andresen S, Sweetenham J, Kalaycio M, Copelan E. Elevated ferritin is associated with relapse after autologous hematopoietic stem cell transplantation for lymphoma. Biol Blood Marrow Transplant. 2008; 14:1239-1244.

Mahindra A, Bolwell B, Sobecks R, Rybicki L, Pohlman B, Dean R, Andresen S, Sweetenham J, Kalaycio M, Copelan E. Elevated pretransplant ferritin is associated with a lower incidence of chronic graft-versus-host disease and inferior survival after myeloablative allogeneic haematopoietic stem cell transplantation. Br J Haematol. 2009;146:310-316.

Mahindra A, Sobecks R, Rybicki L, Pohlman B, Dean R, Andresen S, Kalaycio M, Sweetenham J, Bolwell B, Copelan E. Elevated pretransplant serum ferritin is associated with inferior survival following nonmyeloablative allogeneic transplantation. Bone Marrow Transplant 2009;44:767-768.

Kataoka K, Nannya Y, Hangaishi A, Imai Y, Chiba S, Takahashi T, Kurokawa M. Influence of pretransplantation serum ferritin on nonrelapse mortality after myeloablative and nonmyeloablative allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009;15:195-204

Barba P, Valcárcel D, Pérez-Simón JA, Fernández-Avilés F, Piñana JL, Martino R, López-Anglada L, Rovira M, Garcia-Cadenas I, Novelli S, Carreras E, López Corral L, Sierra J. Impact of hyperferritinemia on the outcome of reduced-intensity conditioning allogeneic hematopoietic cell transplantation for lymphoid malignancies. Biol Blood Marrow Transplant. 2013;19:597-601

Platzbecker U, Ehninger G, Bornhäuser M. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem-cell transplantation. Blood. 2007;110:3083

Tachibana T, Tanaka M, Numata A, Takasaki H, Ito S, Ohshima R, Hagihara M, Yamazaki E, Tomita N, Fujimaki K, Taguchi J, Sakai R, Fujita H, Fujisawa S, Maruta A, Ishigatsubo Y, Kanamori H. Pretransplant serum ferritin has a prognostic influence on allogeneic transplant regardless of disease risk. Leuk Lymphoma. 2012;53:456-461.

Alessandrino EP, Della Porta MG, Bacigalupo A, Van Lint MT, Falda M, Onida F, Bernardi M, Iori AP, Rambaldi A, Cerretti R, Marenco P,Pioltelli P, Malcovati L, Pascutto C, Oneto R, Fanin R, Bosi A; Gruppo Italiano Trapianto di Midollo Osseo (GITMO). WHO classification and WPSS predict posttransplantation outcome in patients with myelodysplastic syndrome: a study from the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Blood. 2008;112:895-902

Alessandrino EP, Della Porta MG, Bacigalupo A, Malcovati L, Angelucci E, Van Lint MT, Falda M, Onida F, Bernardi M, Guidi S, Lucarelli B, Rambaldi A, Cerretti R, Marenco P, Pioltelli P, Pascutto C, Oneto R, Pirolini L, Fanin R, Bkosi A. Prognostic impact of pre-transplantation transfusion history and secondary iron overload in patients with myelodysplastic syndrome undergoing allogeneic stem cell transplantation: a GITMO study. Haematologica. 2010;95:476-484

Platzbecker U, Bornhäuser M, Germing U, Stumpf J, Scott BL, Kröger N, Schwerdtfeger R, Böhm A, Kobbe G, Theuser C, Rabitsch W, Valent P, Sorror ML, Ehninger G, Deeg HJ. Red blood cell transfusion dependence and outcome after allogeneic peripheral blood stem cell transplantation in patients with de novo myelodysplastic syndrome (MDS). Biol Blood Marrow Transplant. 2008;14:1217-1225

Pastore D. et al. Elevated serum ferritin and major transplant-related complications after hematopoietic stem cell transplantation. Haematologica 2010, Suppl 2, Abs 1075

Trottier BJ, Defor TE, Burns LJ et al. Association of iron overload with survival and complications in allogeneic hematopoietic cell transplant recipients: prospective cohort study using R2-MRI measured liver iron content. Blood 2013;122:1678-1684.

Armand P, Kim HT, Virtanen JM, et al. Iron overload in allogeneic hematopoietic cell transplantation outcome : a meta-analysis. Biol Blood Marrow Transplant 2014 in press

Altes A, Remacha AF, Sarda P, Baiget M, Sureda A, Martino R, Briones J, Brunet S, Canals C, Sierra J. Early clinical impact of iron overload in stem cell transplantation. A prospective study. Ann Hematol. 2007;86:443-447

Virtanen JM, Itala-Remes MA, Remes KJ et al. Prognostic impact of pretransplant iron overload measured with magnetic resonance imaging on severe infections in allogeneic stem cell transplantation. Europ J Haematol 2013;91:85-93

Kanda J, Mizumoto C, Kawabata H, Ichinohe T, Tsuchida H, Tomosugi N, Matsuo K, Yamakshita K, Kondo T, Ishikawa T, Uchiyama T. Clinical significance of serum hepcidin levels on early infectious complications in allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009;15:956-962.

Maertens J, Demunynck H, Verbeken EK, et al. Mucormycosis in allogeneic bone marrow recipients: report of five cases and review of the role of iron overload in the pathogenesis. Bone Marrow Transplant 1999; 24: 307-312

Garcia-Vidal C, Upton A, Kirby KA, Marr KA. Epidemiology of invasive mold infections in allogeneic stem cell transplant recipients: biological risk factors for infection according to time after transplantation. Clin Infect Dis. 2008;47:1041-1050

Ferrara JLM, Deeg HJ. Graft-versus-host disease. New Engl J Med 1991;324:667–674.

Wahlin A, Lorenz F, Fredriksson M, Remberger M, Wahlin BE, Hagglund H. Hyperferritinemia is associated with low incidence of graft versus host disease, high relapse rate, and impaired survival in patients with blood disorders receiving allogeneic hematopoietic stem cell grafts. Med Oncol. 2011;28:552–558.

Matzner Y, Hershko C, Polliack A, Konijn AM, Izak G. Suppressive effect of ferritin on in vitro lymphocyte function. Br J Haematol. 1979;42:345-353.

McDonald GB. Hepatobiliary complications of hematopoietic cell transplantation, 40 years on. Hepatology. 2010;51:1450-1460.

Rubbia-Brandt L. Sinusoidal obstruction syndrome. Clin Liver Dis. 2010;14:651-668

Maradei SC, Maiolino A, de Azevedo AM, Colares M, Bouzas LF, Nucci M. Serum ferritin as risk factor for sinusoidal obstruction syndrome of the liver in patients undergoing hematopoietic stem cell transplantation, Blood 2009;114:1270–1275.

Morado M, Ojeda E, Garcia-Bustos J, et al. Serum ferritin as risk factor for veno-occlusive disease of the liver. Prospective cohort study. Hematology. 2000;4:505-512

Majhail NS, DeFor T, Lazarus HM, Burns LJ. High prevalence of iron overload in adult allogeneic hematopoietic cell transplant survivors. Biol Blood Marrow Transplant. 2008;14:790-794.

Meyer SC, O'Meara A, Buser AS, Tichelli A, Passweg JR, Stern M. Prognostic impact of posttransplantation iron overload after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2013;19:440-444

Großekatthöfer M, Güclü ED, Lawitschka A, Matthes-Martin S, Mann G, Minkov M, Peters C, Seidel MG. . Ferritin concentrations correlate to outcome of hematopoietic stem cell transplantation but do not serve as biomarker of graft-versus-host disease. Ann Hematol. 2013;92:1121-1128

Bennett JM; MDS Foundation's Working Group on Transfusional Iron Overload. Consensus statement on iron overload in myelodysplastic syndromes. Am J Hematol. 2008 ;83):858-861.

Gattermann N. Overview of guidelines on iron chelation therapy in patients with myelodysplastic syndromes and transfusional iron overload. Int J Hematol. 2008;88:24-29

Wells RA, Leber B, Buckstein R, Lipton JH, Hasegawa W, Grewal K, Yee K, Olney HJ, Larratt L, Vickars L, Tinmouth A. Iron overload in myelodysplastic syndromes: a Canadian consensus guideline. Leuk Res. 2008;32:1338-1353.

Alessandrino EP, Angelucci E, Cazzola M, Porta MG, Di Bartolomeo P, Gozzini A, Malcovati L, Pioltelli P, Sica S, Bosi A. Iron overload and iron chelation therapy in patients with myelodysplastic syndrome treated by allogeneic stem-cell transplantation: report from the working conference on iron chelation of the Gruppo Italiano Trapianto di Midollo Osseo. Am J Hematol. 2011;86:897-902.

Rizzo JD, Wingard JR, Tichelli A, Lee SJ, Van Lint MT, Burns LJ, Davies SM, Ferrara JL, Socié G. Recommended screening and preventive practices for long-term survivors after hematopoietic cell transplantation: joint recommendations of the European Group for Blood and Marrow Transplantation, Center for International Blood and Marrow Transplant Research, and the American Society for Blood and Marrow Transplantation (EBMT/CIBMTR/ASBMT). Bone Marrow Transplant. 2006;37:249-261.

Majhail NS, Rizzo JD, Lee SJ, Aljurf M, Atsuta Y, Bonfim C, Burns LJ, Chaudhri N, Davies S, Okamoto S, Seber A, Socie G, Szer J, Van Lint MT, Wingard JL, Tichelli A. Recommended screening and preventive practices for long term survivors after hematopoietic cell transplantation. Bone Marrow Transplant. 2012; 47: 337–341

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

Majhail NS, Lazarus HM, Burns LJ. A prospective study of iron overload management in allogeneic hematopoietic cell transplantation survivors. Biol Blood Marrow Transplant. 2010;16:832-837.

Sivgin S, Baldane S, Akyol G, Keklik M, Kaynar L, Kurnaz F, Pala C, Zararsiz G, Cetin M, Eser B, Unal A. The oral iron chelator deferasirox might improve survival in allogeneic hematopoietic cell transplant (alloHSCT) recipients with transfusional iron overload. Transfus Apher Sci. 2013 ;49 :295-301.

Lee JW, Kang HJ, Kim EK et al. Effect of iron overload and iron-chelating therapy on allogeneic hematopoietic SCT in children. Bone Marrow Transplant 2009 ;44 :793-797

Gaziev D, Giardini C, Angelucci E et al. Intravenous chelation therapy during transplantation for thalassemia. Haematol 1995 ; 80 :300-304

Maertens J, Demuynck H, Verbeken EK et al. Mucomycosis 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

Kim YR, Kim JS, Cheong JW, Song JW, Min YH. Transfusion-associated iron overload as an adverse risk factor for transplantation outcome in patients undergoing reduced-intensity stem cell transplantation for myeloid malignancies. Acta Haematol. 2008;120:182-189.

Sucak GT, Yegin ZA, Ozkurt ZN, Aki SZ, Ya?ci M. Iron overload: predictor of adverse outcome in hematopoietic stem cell transplantation. Transplant Proc. 2010;42:1841-1848.

Tachibana T, Takasaki H, Tanaka M, Maruta A, Hyo R, Ishigatsubo Y, Kanamori H. Serum ferritin and disease status at transplantation predict the outcome of allo-SCT in patients with AML or myelodysplastic syndrome. Bone Marrow Transplant. 2011;46:150-151.

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2014-11-20

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