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Iron overload, cardiac iron loading and function in myelodysplastic syndrome
Leukemia Research 33 (2009) 743–744
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Editorial
Iron overload, cardiac iron loading and function in myelodysplastic syndrome
The issue of iron overload and iron cardiac loading in patients affected by myelodysplastic syndrome (MDS) has acquired increasing interest during the last few years. Until recently, allogeneic hemopoietic stem cell transplantation and supportive care were the only available treatment options for MDS. No systematic studies exist on either supportive care and/or on transfusion regimen and iron chelation therapies in this setting. In thalassemias, iron chelation therapy has achieved impressive clinical results in the last decades [1]. However, while thalassaemia major is a congenital disease of children, adolescent and (so far) young adults with long life expectancy, MDS is a malignant progressive disease with a wide range of life expectancy of adult-elderly people with various association of co-morbidities. Thus, clinical scenarios and challenges are quite different for the two diseases. A new oral chelator has been recently shown to be safe and effective in MDS patients [2,3]. These results have prompted new interest in investigating what should be part of a proper supportive care regimen in MDS, and if iron chelation should be included in this regimen. There is good evidence that iron overload develops in transfusion-dependent MDS at a rate similar to that of other transfusion-dependent haematological disease, and it is proportional to transfusion burden [2,4]. In under-treated patients, additional iron may accumulate because of the effects of anaemia on iron absorption and metabolism. However, less convincing evidence exists on the issue of whether iron overload independently decreases life expectancy in MDS, with conflicting results coming from retrospective studies [5,6]. The majority of retrospective studies suggest that iron overload can significantly impact survival in MDS, at least in patients belonging to the low and intermediate-1 IPSS risk classification [6]. However, retrospective clinical studies [7–9] have so far provided only an intermediate level of evidence. Nevertheless, several guidelines [10,11] now recommend chelation therapy for transfusion-dependent patients belonging to the lower IPSS and WPSS [6,12] groups. The much shorter life expectancy of high-risk group patients does not support a possible benefit for chelation because iron related tissue damage only develops after a significant iron burden. However the development of effective disease-modifying therapies [13–16] with significant improvements in survival, could lead to less-restrictive indications for chelation therapy even in high-risk patients. Cardiac disease has emerged as the leading causes of death due to iron overload in children and adult thalassaemia patients [17]. Recent development of magnetic resonance imaging (MRI) technologies has provided additional confirmation to the fact that the heart, although not the main site of iron deposition, is clinically the
0145-2126/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2008.12.018
main target of iron overload [18]. However, even in thalassemias, a strong level of evidence can only be achieved for the correlation between cardiac iron and ejection fraction [18]. Cardiac iron accumulation has been demonstrated to develop in unchelated MDS patients after a very large (approximately 80 pure red blood cells units) amount of transfusional iron intake [4,19,20] but this has not been shown to be consistently and significantly associated with an impairment of cardiac function. The determination of a possible relationship between cardiac iron loading and cardiac function is more complex in MDS than thalassemias, due to the coexistence of several risk factors for cardiac disease. Hemoglobin level fluctuation, preloading and after loading transfusion related modification, aging related phenomenon like hypertension – diabetes—atherosclerosis have all independent effects on cardiac function and may all contribute to cardiac-related death. In this complex context, cardiac iron could be an important co-factor for cardiac morbidity and/or mortality: however, large studies and multivariate analysis are required to tease-out these effects. The article by Kazuma Ohyashiki and colleagues published in this issue of Leukemia Research is a relevant contribution in this setting being the first attempt to study this complex network of effects and correlations in MDS patients. For the first time, these Authors reported a positive correlation between transfusional burden and cardiac ejection fraction. Larger clinical studies are still necessary to properly identify the so far missing link between iron overload and decrement of cardiac function in adult MDS patients. Only after this connection has been established, we should face the more relevant, question: could iron chelation improve survival in transfusion-dependent MDS patients? This is an issue that can only be confirmed by a prospective randomized trial using appropriate survival endpoint surrogates. Acknowledgements Both authors equally contributed to the paper. No information to disclose. References [1] Angelucci E, Barosi G, Camaschella C, Cappellini MD, Cazzola M, Galanello R, et al. Italian Society of Hematology practice guidelines for the management of iron overload in thalassemia major and related disorders. Haematologica 2008;93(May (5)):741–52. [2] Porter J, Galanello R, Saglio G, Neufeld EJ, Vichinsky E, Cappellini MD, et al. Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study. Eur J Haematol 2008;80(February (2)):168–76.
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Editorial / Leukemia Research 33 (2009) 743–744
[3] Yang LP, Keam SJ, Keating GM. Deferasirox: a review of its use in the management of transfusional chronic iron overload. Drugs 2007;67(15):2211–30. [4] Buja LM, Roberts WC. Iron in the heart. Etiology and clinical significance. Am J Med 1971;51(August (2)):209–21. [5] 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(August (8)): 611–3. [6] Malcovati L, Germing U, Kuendgen A, Della Porta MG, Pascutto C, Invernizzi R, et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 2007;25(August (23)):3503–10. [7] Sanz G, Nomdedeu B, Such E, Bernal T, Belkaid M, Ardanaz MT, et al. Indipendent impact of iron overload and transfusion dependency on survival and leukemic evolution in patients with myelodysplastic syndrome. Blood 2008;112(Abstracts Book):A640. [8] Kao JM, McMillan A, Greenberg PL. International MDS risk analysis workshop (IMRAW)/IPSS reanalyzed: impact of cytopenias on clinical outcomes in myelodysplastic syndromes. Am J Hematol 2008;83(October (10)):765–70. [9] Tasaka T, Tohyama K, Kishimoto M, Ohyashiki K, Mitani K, Hotta T, et al. Myelodysplastic syndrome with chromosome 5 abnormalities: a nationwide survey in Japan. Leukemia 2008;22(October (10)):1874–81. [10] Alessandrino EP, Amadori S, Barosi G, Cazzola M, Grossi A, Liberato LN, et al. Evidence- and consensus-based practice guidelines for the therapy of primary myelodysplastic syndromes. A statement from the Italian Society of Hematology. Haematologica 2002;87(December (12)):1286–306. [11] Gattermann N. Overview of guidelines on iron chelation therapy in patients with myelodysplastic syndromes and transfusional iron overload. Int J Hematol 2008;88(July (1)):24–9. [12] Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89(March (6)):2079–88. [13] List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005;352(February (6)):549–57. [14] Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, OdchimarReissig R, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 2002;20(May (10)):2429–40.
[15] Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H. Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer 2008;112(June (11)):2341–51. [16] 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(May (10)):4586–8. [17] 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(July (8653)):27–30. [18] Anderson LJ, Holden S, Davis B, Prescott E, Charrier CC, Bunce NH, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J 2001;22(December (23)):2171–9. [19] Di Tucci AA, Matta G, Deplano S, Gabbas A, Depau C, Derudas D, et al. Myocardial iron overload assessment by T2* magnetic resonance imaging in adult transfusion dependent patients with acquired anemias. Haematologica 2008;93(September (9)):1385–8. [20] Konen E, Ghoti H, Goitein O, Winder A, Kushnir T, Eshet Y, 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(November (11)):1013–6.
Emanuele Angelucci ∗ Anna Angela Di Tucci Struttura Complessa Disciplina di Ematologia e Centro Trapianti Cellule Staminai Emopoietiche, Ospedale Oncologico di Riferimento Regionale “Armando Businco”, Cagliari, Italy ∗ Corresponding
author at: Hematology Unit, “Armando Businco” Cancer Centre, Via Edward Jennar, 09121 Cagliari, Italy. Fax: +39 070 6095171. E-mail address: [email protected] (E. Angelucci) 25 December 2008 Available online 4 February 2009
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Editorial
Iron overload, cardiac iron loading and function in myelodysplastic syndrome
The issue of iron overload and iron cardiac loading in patients affected by myelodysplastic syndrome (MDS) has acquired increasing interest during the last few years. Until recently, allogeneic hemopoietic stem cell transplantation and supportive care were the only available treatment options for MDS. No systematic studies exist on either supportive care and/or on transfusion regimen and iron chelation therapies in this setting. In thalassemias, iron chelation therapy has achieved impressive clinical results in the last decades [1]. However, while thalassaemia major is a congenital disease of children, adolescent and (so far) young adults with long life expectancy, MDS is a malignant progressive disease with a wide range of life expectancy of adult-elderly people with various association of co-morbidities. Thus, clinical scenarios and challenges are quite different for the two diseases. A new oral chelator has been recently shown to be safe and effective in MDS patients [2,3]. These results have prompted new interest in investigating what should be part of a proper supportive care regimen in MDS, and if iron chelation should be included in this regimen. There is good evidence that iron overload develops in transfusion-dependent MDS at a rate similar to that of other transfusion-dependent haematological disease, and it is proportional to transfusion burden [2,4]. In under-treated patients, additional iron may accumulate because of the effects of anaemia on iron absorption and metabolism. However, less convincing evidence exists on the issue of whether iron overload independently decreases life expectancy in MDS, with conflicting results coming from retrospective studies [5,6]. The majority of retrospective studies suggest that iron overload can significantly impact survival in MDS, at least in patients belonging to the low and intermediate-1 IPSS risk classification [6]. However, retrospective clinical studies [7–9] have so far provided only an intermediate level of evidence. Nevertheless, several guidelines [10,11] now recommend chelation therapy for transfusion-dependent patients belonging to the lower IPSS and WPSS [6,12] groups. The much shorter life expectancy of high-risk group patients does not support a possible benefit for chelation because iron related tissue damage only develops after a significant iron burden. However the development of effective disease-modifying therapies [13–16] with significant improvements in survival, could lead to less-restrictive indications for chelation therapy even in high-risk patients. Cardiac disease has emerged as the leading causes of death due to iron overload in children and adult thalassaemia patients [17]. Recent development of magnetic resonance imaging (MRI) technologies has provided additional confirmation to the fact that the heart, although not the main site of iron deposition, is clinically the
0145-2126/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2008.12.018
main target of iron overload [18]. However, even in thalassemias, a strong level of evidence can only be achieved for the correlation between cardiac iron and ejection fraction [18]. Cardiac iron accumulation has been demonstrated to develop in unchelated MDS patients after a very large (approximately 80 pure red blood cells units) amount of transfusional iron intake [4,19,20] but this has not been shown to be consistently and significantly associated with an impairment of cardiac function. The determination of a possible relationship between cardiac iron loading and cardiac function is more complex in MDS than thalassemias, due to the coexistence of several risk factors for cardiac disease. Hemoglobin level fluctuation, preloading and after loading transfusion related modification, aging related phenomenon like hypertension – diabetes—atherosclerosis have all independent effects on cardiac function and may all contribute to cardiac-related death. In this complex context, cardiac iron could be an important co-factor for cardiac morbidity and/or mortality: however, large studies and multivariate analysis are required to tease-out these effects. The article by Kazuma Ohyashiki and colleagues published in this issue of Leukemia Research is a relevant contribution in this setting being the first attempt to study this complex network of effects and correlations in MDS patients. For the first time, these Authors reported a positive correlation between transfusional burden and cardiac ejection fraction. Larger clinical studies are still necessary to properly identify the so far missing link between iron overload and decrement of cardiac function in adult MDS patients. Only after this connection has been established, we should face the more relevant, question: could iron chelation improve survival in transfusion-dependent MDS patients? This is an issue that can only be confirmed by a prospective randomized trial using appropriate survival endpoint surrogates. Acknowledgements Both authors equally contributed to the paper. No information to disclose. References [1] Angelucci E, Barosi G, Camaschella C, Cappellini MD, Cazzola M, Galanello R, et al. Italian Society of Hematology practice guidelines for the management of iron overload in thalassemia major and related disorders. Haematologica 2008;93(May (5)):741–52. [2] Porter J, Galanello R, Saglio G, Neufeld EJ, Vichinsky E, Cappellini MD, et al. Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study. Eur J Haematol 2008;80(February (2)):168–76.
744
Editorial / Leukemia Research 33 (2009) 743–744
[3] Yang LP, Keam SJ, Keating GM. Deferasirox: a review of its use in the management of transfusional chronic iron overload. Drugs 2007;67(15):2211–30. [4] Buja LM, Roberts WC. Iron in the heart. Etiology and clinical significance. Am J Med 1971;51(August (2)):209–21. [5] 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(August (8)): 611–3. [6] Malcovati L, Germing U, Kuendgen A, Della Porta MG, Pascutto C, Invernizzi R, et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 2007;25(August (23)):3503–10. [7] Sanz G, Nomdedeu B, Such E, Bernal T, Belkaid M, Ardanaz MT, et al. Indipendent impact of iron overload and transfusion dependency on survival and leukemic evolution in patients with myelodysplastic syndrome. Blood 2008;112(Abstracts Book):A640. [8] Kao JM, McMillan A, Greenberg PL. International MDS risk analysis workshop (IMRAW)/IPSS reanalyzed: impact of cytopenias on clinical outcomes in myelodysplastic syndromes. Am J Hematol 2008;83(October (10)):765–70. [9] Tasaka T, Tohyama K, Kishimoto M, Ohyashiki K, Mitani K, Hotta T, et al. Myelodysplastic syndrome with chromosome 5 abnormalities: a nationwide survey in Japan. Leukemia 2008;22(October (10)):1874–81. [10] Alessandrino EP, Amadori S, Barosi G, Cazzola M, Grossi A, Liberato LN, et al. Evidence- and consensus-based practice guidelines for the therapy of primary myelodysplastic syndromes. A statement from the Italian Society of Hematology. Haematologica 2002;87(December (12)):1286–306. [11] Gattermann N. Overview of guidelines on iron chelation therapy in patients with myelodysplastic syndromes and transfusional iron overload. Int J Hematol 2008;88(July (1)):24–9. [12] Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89(March (6)):2079–88. [13] List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005;352(February (6)):549–57. [14] Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, OdchimarReissig R, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 2002;20(May (10)):2429–40.
[15] Jabbour E, Issa JP, Garcia-Manero G, Kantarjian H. Evolution of decitabine development: accomplishments, ongoing investigations, and future strategies. Cancer 2008;112(June (11)):2341–51. [16] 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(May (10)):4586–8. [17] 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(July (8653)):27–30. [18] Anderson LJ, Holden S, Davis B, Prescott E, Charrier CC, Bunce NH, et al. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. Eur Heart J 2001;22(December (23)):2171–9. [19] Di Tucci AA, Matta G, Deplano S, Gabbas A, Depau C, Derudas D, et al. Myocardial iron overload assessment by T2* magnetic resonance imaging in adult transfusion dependent patients with acquired anemias. Haematologica 2008;93(September (9)):1385–8. [20] Konen E, Ghoti H, Goitein O, Winder A, Kushnir T, Eshet Y, 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(November (11)):1013–6.
Emanuele Angelucci ∗ Anna Angela Di Tucci Struttura Complessa Disciplina di Ematologia e Centro Trapianti Cellule Staminai Emopoietiche, Ospedale Oncologico di Riferimento Regionale “Armando Businco”, Cagliari, Italy ∗ Corresponding
author at: Hematology Unit, “Armando Businco” Cancer Centre, Via Edward Jennar, 09121 Cagliari, Italy. Fax: +39 070 6095171. E-mail address: [email protected] (E. Angelucci) 25 December 2008 Available online 4 February 2009