The Relevance of Iron Overload and the Appropriateness of Iron Chelation Therapy for Patients with Myelodysplastic Syndromes: A Dialogue and Debate
First Online: 05 March 2011 DOI:
Cite this article as: Steensma, D.P. Curr Hematol Malig Rep (2011) 6: 136. doi:10.1007/s11899-011-0084-z Abstract
Accumulation of excessive amounts of iron in vulnerable organs and tissues, together with elevated plasma and intracellular concentrations of reactive iron molecules, are likely to be harmful to some patients with myelodysplastic syndromes (MDS) who have received numerous red blood cell transfusions. But what is the real magnitude of risks related to iron overload in MDS, and how strong is the evidence that reducing total body iron and labile plasma iron through treatment with chelating drugs is beneficial to patients? Available data can be interpreted in different ways, and as a result, these topics continue to be areas of heated debate among physicians who care for patients with MDS. Using the traditional but rarely employed format of a classical dialogue, I explore here the potential dangers of iron overload and the risks and benefits of iron chelation therapy for patients with MDS.
Keywords Myelodysplastic syndromes (MDS) Iron overload Transfusional hemosiderosis Deferasirox Deferoxamine Iron chelation therapy Clinical controversy Classical dialogue Labile plasma iron Ferritin Practice guidelines T2* magnetic resonance imaging References Recently published papers of interest have been highlighted as: • Of importance •• Of major importance
Steensma DP. Myelodysplasia paranoia: iron as the new radon. Leuk Res. 2009;33:1158–63.
Tefferi A, Stone RM. Iron chelation therapy in myelodysplastic syndrome—Cui bono? Leukemia. 2009;23:1373.
Leitch HA. Controversies surrounding iron chelation therapy for MDS. Blood Rev. 2011;25:17–31.
Steensma DP. The role of iron chelation therapy for patients with myelodysplastic syndromes. J Natl Compr Canc Netw. 2011;9:65–75.
Malcovati L. Impact of transfusion dependency and secondary iron overload on the survival of patients with myelodysplastic syndromes. Leuk Res. 2007;31 Suppl 3:S2–6.
Cazzola M, Malcovati L. Myelodysplastic syndromes–coping with ineffective hematopoiesis. N Engl J Med. 2005;352:536–8.
Lesnefsky EJ. Tissue iron overload and mechanisms of iron-catalyzed oxidative injury. Adv Exp Med Biol. 1994;366:129–46.
Steensma DP, Tefferi A. Anemia in the elderly: how should we define it, when does it matter, and what can be done? Mayo Clin Proc. 2007;82:958–66.
Cazzola M, Della Porta MG, Malcovati L. Clinical relevance of anemia and transfusion iron overload in myelodysplastic syndromes. Hematology Am Soc Hematol Educ Program. 2008:166–75.
Malcovati L, Porta MG, Pascutto C, et al. Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making. J Clin Oncol. 2005;23:7594–603.
Takatoku M, Uchiyama T, Okamoto S, et al. Retrospective nationwide survey of Japanese patients with transfusion-dependent MDS and aplastic anemia highlights the negative impact of iron overload on morbidity/mortality. Eur J Haematol. 2007;78:487–94.
Remacha AF, Arrizabalaga B, Del Canizo C, Sanz G, Villegas A. Iron overload and chelation therapy in patients with low-risk myelodysplastic syndromes with transfusion requirements. Ann Hematol. 2010;89:147–54.
Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–88.
DeLoughery TG. Iron: The fifth horseman of the apocalypse? Am J Hematol. 2009;84:263–4.
Chee CE, Steensma DP, Wu W, Hanson CA, Tefferi A. Neither serum ferritin nor the number of red blood cell transfusions affect overall survival in refractory anemia with ringed sideroblasts. Am J Hematol. 2008;83:611–3.
• Patnaik MM, Lasho TL, Finke CM, et al. WHO-defined ‘myelodysplastic syndrome with isolated del(5q)’ in 88 consecutive patients: survival data, leukemic transformation rates and prevalence of JAK2, MPL and IDH mutations. Leukemia. 2010;24:1283–9.
This paper, taken together with reference , suggests that the relationship between serum ferritin and risk of death in MDS is not simple.
Tefferi A, Mesa RA, Pardanani A, et al. Red blood cell transfusion need at diagnosis adversely affects survival in primary myelofibrosis-increased serum ferritin or transfusion load does not. Am J Hematol. 2009;84:265–7.
Cazzola M, Barosi G, Gobbi PG, Invernizzi R, Riccardi A, Ascari E. Natural history of idiopathic refractory sideroblastic anemia. Blood. 1988;71:305–12.
• Pullarkat V. Objectives of iron chelation therapy in myelodysplastic syndromes: more than meets the eye? Blood. 2009;114:5251–5.
This is a thoughtful discussion of the possibility that iron chelation may be important not because it removes large amounts of iron from the body, but because chelation reduces the serum and cellular levels of labile, redox-active iron species.
Sane A, Manzi S, Perfect J, Herzberg AJ, Moore JO. Deferoxamine treatment as a risk factor for zygomycete infection. J Infect Dis. 1989;159:151–2.
Armand P, Kim HT, Cutler CS, et al. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood. 2007;109:4586–8.
Mahindra A, Bolwell B, Sobecks R, et al. Prognostic impact of elevated pretransplant serum ferritin in allogeneic hematopoietic stem cell transplantation [abstract]. Blood (ASH Annual Meeting Extracts). 2007;110:1109.
Pullarkat V, Blanchard S, Tegtmeier B, et al. Iron overload adversely affects outcome of allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2008;42:799–805.
Platzbecker U, Ehninger G, Bornhauser M. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem-cell transplantation. Blood. 2007;110:3083. author reply -4.
Metcalf D. The granulocyte-macrophage colony-stimulating factors. Science (New York, NY). 1985;229:16–22.
•• Cappellini MD, Porter J, El-Beshlawy A, et al. Tailoring iron chelation by iron intake and serum ferritin: the prospective EPIC study of deferasirox in 1744 patients with transfusion-dependent anemias. Haematologica. 2010;95:557–66.
This is the largest prospective study to date of deferasirox in transfusion-dependent anemias, including MDS.
List A, Baer M, Steensma D, et al. Deferasirox (ICL670; Exjade) reduces serum ferritin (SF) and labile plasma iron (LPI) in patients with myelodysplastic syndromes (MDS) [abstract]. Blood (ASH Annual Meeting Abstracts). 2007;110:1470.
Sanz G, Nomdedeu B, Such E, et al. Independent impact of iron overload and transfusion dependency on survival and leukemic evolution in patients with myelodysplastic syndrome [abstract]. Blood (ASH Annual Meeting Abstracts). 2008;112:640.
Nagata S, Tsuchiya M, Asano S, et al. Molecular cloning and expression of cDNA for human granulocyte colony-stimulating factor. Nature. 1986;319:415–8.
Chacko J, Pennell DJ, Tanner MA, et al. Myocardial iron loading by magnetic resonance imaging T2* in good prognostic myelodysplastic syndrome patients on long-term blood transfusions. Br J Haematol. 2007;138:587–93.
Konen E, Ghoti H, Goitein O, et al. No evidence for myocardial iron overload in multitransfused patients with myelodysplastic syndrome using cardiac magnetic resonance T2 technique. Am J Hematol. 2007;82:1013–6.
Di Tucci AA, Matta G, Deplano S, et al. Myocardial iron overload assessment by T2* magnetic resonance imaging in adult transfusion dependent patients with acquired anemias. Haematologica. 2008;93:1385–8.
Pascal L, Rauzy OB, Brechignac S, et al. Highly transfused MDS patients often have cardiac iron overload, as shown by MRI assessment [abstract]. Blood (ASH Annual Meeting Extracts). 2010;116:2906.
Brittenham GM, Griffith PM, Nienhuis AW, et al. Efficacy of deferoxamine in preventing complications of iron overload in patients with thalassemia major. N Engl J Med. 1994;331:567–73.
Olivieri NF, Nathan DG, MacMillan JH, et al. Survival in medically treated patients with homozygous beta-thalassemia. N Engl J Med. 1994;331:574–8.
Tanno T, Bhanu NV, Oneal PA, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med. 2007;13:1096–101.
Ghoti H, Amer J, Winder A, Rachmilewitz E, Fibach E. Oxidative stress in red blood cells, platelets and polymorphonuclear leukocytes from patients with myelodysplastic syndrome. Eur J Haematol. 2007;79:463–7.
Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108:419–25.
Gattermann N, Finelli C, Della Porta MG, et al. Hematologic responses in myelodysplastic syndromes (MDS) patients treated with deferasirox: an EPIC post-hoc analysis using International Working Group (IWG) 2006 Criteria [abstract]. Blood (ASH Annual Meeting Extracts). 2010;116:2912.
Leitch HA, Wong DHC, Leger CS, et al. Improved leukemia-free and overall survival in patients with myelodysplastic syndrome receiving iron chelation therapy: a subgroup analysis. Blood (ASH Annual Meeting Abstracts). 2007;110:1469.
Rose C, Brechignac S, Vassilief D, et al. Does iron chelation therapy improve survival in regularly transfused lower risk MDS patients? A multicenter study by the GFM (Groupe Francophone des Myelodysplasies). Leuk Res. 2010;34:864–70.
List AF, Baer MR, Steensma DP, et al. Two-year analysis of efficacy and safety of deferasirox (Exjade®) treatment in myelodysplastic syndrome patients enrolled in the US03 Study [abstract]. Blood (ASH Annual Meeting Extracts). 2009;116:3829.
Jensen PD, Heickendorff L, Pedersen B, et al. The effect of iron chelation on haemopoiesis in MDS patients with transfusional iron overload. Br J Haematol. 1996;94:288–99.
Kontoghiorghes GJ. Ethical issues and risk/benefit assessment of iron chelation therapy: advances with deferiprone/deferoxamine combinations and concerns about the safety, efficacy and costs of deferasirox. Hemoglobin. 2008;32:1–15.
Messa E, Carturan S, Maffe C, et al. Deferasirox is a powerful NF-kappaB inhibitor in myelodysplastic cells and in leukemia cell lines acting independently from cell iron deprivation by chelation and reactive oxygen species scavenging. Haematologica. 2010;95(8):1308–16.
Greenberg PL, Rigsby CK, Stone RM, et al. NCCN Task Force Report: Transfusion and iron overload in patients with myelodysplastic syndromes. J Natl Compr Canc Netw. 2009;7(Suppl 9).
Gattermann N. Overview of guidelines on iron chelation therapy in patients with myelodysplastic syndromes and transfusional iron overload. Int J Hematol. 2008;88:24–9.
Schmid M. Iron chelation therapy in MDS: what have we learnt recently? Blood Rev. 2009;23 Suppl 1:S21–5.
• Bennett JM, MDS Foundation’s Working Group on Transfusional Iron Overload. Consensus statement on iron overload in myelodysplastic syndromes. Am J Hematol. 2008;83:858–61.
This is one of several “expert-opinion” practical guidelines on the management of iron overload in patients with MDS, but it is limited by the lack of a solid evidence base on which to base recommendations.
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