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The issue of iron overload in hemopoietic cell transplantation has been first discussed in the field of transplantation for thalassemia. Thalassemia major is characterized by ineffective erythropoiesis and hemolysis leading to anemia in the majority of patients. Patients require regular blood transfusion therefore they develop iron overload causing organ damage and hematopoietic cell transplantation (HCT) is a consolidated reliably curative option.
In this category of patients an important issue for transplant outcome is the iron burden before transplant and in the long-life post-transplant. Nevertheless, today the concept of the impact of iron overload / toxicity on the outcome of HCT) has been extended to other diseases characterized by periods of variable duration of transfusion dependence
Recent preclinical data has shown how increased production of reactive oxygen species (ROS) resulting under iron overload condition, could impair the stem cells clonality capacity, proliferation and maturation. Also, microenvironment cells could be affected through this mechanism. For this reason, iron overload is becoming an important issue also in the engraftment period post-transplant
The aim of this review is to update consolidated knowledge about the role of iron overload/iron toxicity in the HCT setting in non-malignant and in malignant diseases introducing the concept of exposition of free toxic iron forms and related cellular damage in the different stage of transplant.
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1. Olivieri NF, Nathan DG, MacMillan JH, Wayne AS, Liu PP, McGee A, Martin M, Koren G and Cohen AR. Survival in medically treated patients with homozygous beta-thalassemia. N Engl J Med. 1994; 331: 574–8.
2. Angelucci E. Hematopoietic stem cell transplantation in thalassemia. Hematology. Am Soc Hematol Educ Program. 2010; 2010: 456–62.
3. Finotti A, Breda L, Lederer CW, Bianchi N, Zuccato C, Kleanthous M, Rivella S and Gambari R. Recent trends in the gene therapy of beta-thalassemia. J Blood Med; 2015; 6: 69–85.
4. Armand P, Kim HT, Cutler CS, Ho VT, Koreth J, Alyea EP, Soiffer RJ and Antin JH. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood 2007; 109: 4586–8.
5. Pullarkat V, Blanchard S, Tegtmeier B, Dagis A, Patane K, Ito J and Forman SJ.. Iron overload adversely affects outcome of allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2008; 42: 799–805.
6. Schaible UE, Kaufmann SHE. Iron and microbial infection. Nat Rev Microbiol 2004; 2: 946–53.
7. Pilo F, Angelucci E. A storm in the niche: Iron, oxidative stress and haemopoiesis. Blood Rev. Blood Rev. 2018; 32: 29-35
8. Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to Tango: Regulation of Mammalian Iron Metabolism. Cell 2010; 142: 24-38
9. Sajadimajd S, Khazaei M. Oxidative Stress and Cancer: The Role of Nrf2. Curr Cancer Drug Targets 2018; 18: 538–57.
10. Coates TD. Physiology and pathophysiology of iron in hemoglobin-associated diseases. Free Radic Biol Med 2014; 72: 23–40.
11. 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: 417–21.
12. Angelucci E, Pilo F, Coates TD. Transplantation in thalassemia: Revisiting the Pesaro risk factors 25 years later. Am J Hematol 2017; ;92: 411-413
13. Angelucci E, Pilo F. Management of iron overload before, during, and after hematopoietic stem cell transplantation for thalassemia major. Ann N Y Acad Sci 2016; 1368:115–21.
14. 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, Bosi 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: 476–84.
15. 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: 1217–25.
16. Kataoka K, Nannya Y, Hangaishi A, Imai Y, Chiba S, Takahashi T and 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.
17. Wermke M, Eckoldt J, Gotze KS, Klein SA, Bug G, de Wreede LC, Kramer M, Stölzel F, von Bonin M, Schetelig J, Laniado M, Plodeck V, Hofmann WK, Ehninger G, Bornhäuser M, Wolf D, Theurl I, Platzbecker U. Enhanced labile plasma iron and outcome in acute myeloid leukaemia and myelodysplastic syndrome after allogeneic haemopoietic cell transplantation (ALLIVE): a prospective, multicentre, observational trial. Lancet Haematol 2018; 5: e201–10.
18. Pullarkat V. Iron toxicity in hematopoietic stem cell transplantation: Strike while the iron is labile. Acta Haematol 2014; 131: 220-1
19. Naoum FA, Esposito BP, Ruiz LP, Ruiz MA, Tanaka PY, Sobreira JT, Cancado RD, de Barros JC. Assessment of labile plasma iron in patients who undergo hematopoietic stem cell transplantation. Acta Haematol 2014; 131: 222–6.
20. Kautz L, Jung G, Valore E V, Rivella S, Nemeth E, Ganz T. Identification of erythroferrone as an erythroid regulator of iron metabolism. Nat Genet 2014; 46: 678–84.
21. Naoum FA, Esposito BP, Cancado RD. Impact of conditioning and engraftment on iron status in hematopoietic stem cell transplantation: Contribution of labile plasma iron. Hematology/oncology and stem cell therapy Hematol Oncol Stem Cell Ther. 2016; 9: 165-167
22. Duca L, Cappellini MD, Baronciani D, Pilo F, Targhetta C, Visani G and Angelucci E. Non-transferrin-bound iron and oxidative stress during allogeneic hemopoietic stem cell transplantation in patients with or without iron overload. Am J Hematol. 2018; 93: E250-E252
23. Bigarella CL, Liang R, Ghaffari S. Stem cells and the impact of ROS signaling. Development 2014; 141: 4206–18.
24. Ludin A, Gur-Cohen S, Golan K, Kaufmann KB, Itkin T, Medaglia C, Lu XJ, Ledergor G, Kollet O, Lapidot T. Reactive oxygen species regulate hematopoietic stem cell self-renewal, migration and development, as well as their bone marrow microenvironment. Antioxid Redox Signal 2014; 21: 1605–19.
25. Chai X, Li D, Cao X, Zhang Y, Mu J, Lu W,. Xiao X, Li C, Meng J, Chen J, Li Q, Wang J, Meng A, Zhao M. ROS-mediated iron overload injures the hematopoiesis of bone marrow by damaging hematopoietic stem/progenitor cells in mice. Sci Rep. 2015; 5: 10181.
26. Okabe H, Suzuki T, Uehara E, Ueda M, Nagai T, Ozawa K. The bone marrow hematopoietic microenvironment is impaired in iron-overloaded mice. Eur J Haematol 2014; 93: 118–28.
27. Zhang Y, Zhai W, Zhao M, Li D, Chai X, Cao X, Meng J, Chen J, Xiao X, Li Q, Mu J, Shen J and Meng A. Effects of iron overload on the bone marrow microenvironment in mice. PLoS One 2015; 10: e0120219.
28. Gaziev D, Giardini C, Angelucci E, Polchi P, Galimberti M, Baronciani D, Erer B, Maiello A, Lucarelli G. Intravenous chelation therapy during transplantation for thalassemia. Haematologica 1995; 80: 300–4.
29. Fritsch A, Langebrake C, Nielsen P, Bacher U, Baehr M, Dartsch DC, Kroeger N. Deferasirox (Exjade®) Given During Conditioning Regimen (FLAMSA/Busulfan/ATG) Reduces the Appearance of Labile Plasma Iron in Patients Undergoing Allogeneic Stem Cell Transplantation. Blood 2011; 118: 3023
30. Naoum FA, Esposito BP, Zotarelli Filho IJ. Impact of labile plasma iron and iron chelation on the viability of cultured mononuclear cells from patients undergoing autologous hematopoietic stem cell transplantation. Blood Res 2017; 52: 135–6.
31. Lucarelli G, Angelucci E, Giardini C, Baronciani D, Galimberti M, Polchi P, Bartolucci M, Muretto P, Albertini F. Fate of iron stores in thalassaemia after bone-marrow transplantation. Lancet 1993; 342: 1388–91.
32. Angelucci E, Muretto P, Nicolucci A, Baronciani D, Erer B, Gaziev J, Ripalti M, Sodani P, Tomassoni S, Visani G, Lucarelli G. 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.
33. Medvedev R, Ploen D, Spengler C, Elgner F, Ren H, Bunten S, Hildt E.. HCV-induced oxidative stress by inhibition of Nrf2 triggers autophagy and favors release of viral particles. Free Radic Biol Med. 2017; 110: 300–15.
34. Atilla E, Toprak SK, Demirer T. Current Review of Iron Overload and Related Complications in Hematopoietic Stem Cell Transplantation. Turkish J Haematol 2017; 34: 1–9.
35. Hamidieh AA, Tayebi S, Moeininia F, Shamshiri AR, Behfar M, Alimoghaddam K and Ghavamzadeh A. T2( *) MRI changes in the heart and liver of ex-thalassemic patients after hematopoietic stem cell transplantation. Hematol Oncol Stem Cell Ther 2014; 7: 103–8.
36. 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: 832–7.
37. Angelucci E, Muretto P, Lucarelli G, Ripalti M, Baronciani D, Erer B, Galimberti M, Annibali M, Giardini C, Gaziev D, Rapa S, Polchi P. Treatment of iron overload in the “ex-thalassemic”. Report from the phlebotomy program. Ann N Y Acad Sci 1998; 850: 288–93.
38. 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: 916–21.
39. Vallejo C, Batlle M, Vazquez L, Solano C, Sampol A, Duarte R, Hernández D, López J, Rovira M, Jiménez S, Valcárcel D, Belloch V, Jiménez M, Jarque I. Phase IV open-label study of the efficacy and safety of deferasirox after allogeneic stem cell transplantation. Haematologica 2014; 99: 1632–7.
40. Yesilipek MA, Karasu G, Kaya Z, Kuskonmaz BB, Uygun V, Dag I, Ozudogru O, Ertem M. A Phase II, Multicenter, Single-Arm Study to Evaluate the Safety and Efficacy of Deferasirox after Hematopoietic Stem Cell Transplantation in Children with beta-Thalassemia Major. Biol Blood Marrow Transplant 2018; 24: 613–8.
41. Inati A, Kahale M, Sbeiti N, Cappellini MD, Taher AT, Koussa S, Nasr TA, Musallam KM, Abbas HA, Porter JB. One-year results from a prospective randomized trial comparing phlebotomy with deferasirox for the treatment of iron overload in pediatric patients with thalassemia major following curative stem cell transplantation. Pediatr Blood Cancer 2017; 64: 188–96.
42. Jaekel N, Lieder K, Albrecht S, Leismann O, Hubert K, Bug G, Kröger N, Platzbecker U, Stadler M, de Haas K, Altamura S, Muckenthaler MU, Niederwieser D, Al-Ali HK.. Efficacy and safety of deferasirox in non-thalassemic patients with elevated ferritin levels after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2016; 51: 89–95.
43. Moukalled N.M., Bou-Fakhredin R., Taher A.T. Deferasirox: over a decade of experience in thalassemia. Mediterr J Hematol Infect Dis 2018, 10(1): e2018066,