Leukemia Research 38 (2014) 145–146
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Editorial
Iron chelation in MDS: Still a controversial issue
Keywords: MDS Iron chelation Survival
In this issue of Leukemia Research data from a prospective registry concerning the outcomes of lower-risk MDS patients receiving iron chelation therapy are presented. The authors analysed data from 600 lower-risk MDS patients (IPSS low and intermediate-1) with transfusional iron overload that were enrolled in a prospective 5-year registry. They compared the clinical outcome 24 months after inclusion into the registry of chelated and nonchelated patients and found a significantly longer survival especially in consequently chelated patients as well as a trend towards longer leukaemia-free survival and fewer cardiac events as compared to nonchelated patients. In patients with thalassaemia, robust data exist that iron chelation leads to a better survival and reduces comorbidities due to iron overload like chronic heart failure, diabetes mellitus or liver cirrhosis. In MDS, iron overload usually occurs as most of the MDS patients suffer from anaemia and develop transfusion dependency during the course of disease. As lower-risk MDS patients have a median survival of several years and each unit of red blood cells contains 200–250 mg iron, especially this patient cohort is at higher risk to develop an iron overload with iron accumulation in heart, liver or endocrine organs. Studies with T2* MRI showed iron accumulation especially in the liver of heavily transfused MDS patients and there is evidence that iron chelation can lead to an improvement of elevated liver enzymes. It has not been shown that iron chelation can reduce death due to liver failure. MDS is a disease of the elderly people and cardiac diseases are a relevant comorbidity in this patient cohort. In a study by Della Porta and colleagues, the authors presented a comorbidity index for MDS patients (MDS-CI). In their patient cohort, cardiac comorbidities were present in 25% of all patients. Due to the strong prognostic impact, the presence of cardiac comorbidities was counted twice in the score [1]. Iron chelation therapy is assumed to reduce cardiac iron overload and prevent progression of cardiac diseases. However, cardiac T2* MRI imaging could not deliver evidence that cardiac iron accumulation has a significant impact on cardiac comorbidities and outcome of MDS patients in contrast to thalassaemia patients suggesting that other factors like non-transferrin-bound iron (NTBI) or labile plasma iron (LPI) might be important mediators of cardiac dysfunction in lowrisk MDS patients. However, in the published study in this issue of
Leukemia Research as well as in previously published studies, there is a trend towards fewer cardiac events in chelated patients. Therefore, it will be interesting to see further information on the outcome of low-risk MDS patients in this registry presented after 5 years of follow up. Iron chelation found entrance in treatment guidelines for lowerrisk MDS patients since several studies showed an improvement of the median survival in patients receiving iron chelation therapy. In contrast, data regarding a reduced risk of leukemic progression or fewer infections in adequately chelated patients are not consistent. Several guidelines vary in defining iron overload and when to initiate iron chelation treatment, the recommended time point when to start iron chelation or how to monitor treatment response [2]. The recommendations for iron chelation in low-risk MDS are based on several studies that all have shortcomings: (a) most of them are retrospective analyses, (b) no studies exist comparing different treatment modalities like subcutaneous application of deferoxamine or oral application of deferasirox or deferiprone and (c) the decision to start treatment was based on the physicians choice potentially leading to a bias in patient selection. Another shortcoming concerns the duration of treatment. As deferoxamine has to be administered subcutaneously, compliance of the patients is pivotal for effective removal of iron. Major side effects of deferasirox concern nausea, diarrhoea and increase of serum creatinine. In two prospective trials, the EPIC as well as the US03 trial, dropout rates due to adverse events were high with 48.7% and 45%, respectively [3,4]. A prospective, randomised, placebo controlled study evaluating the effect of deferasirox in heavily transfused low-risk MDS patients is underway (NCT00940602). The results of this study may help to bring more light into this field. In patients with higher risk MDS, iron chelation can be considered if these patients are candidates for allogeneic stem cell transplantation, as several studies have shown a favourable outcome for patients with normal pretransplantation serum ferritin levels. The inferior survival of patients with iron overload was attributable to a significant increase in treatment-related mortality [reviewed in 5]. Although there are approved iron chelation therapies for MDS patients, future efforts should concentrate on findings better treatment options in order to avoid transfusion dependency and consecutive iron overload.
Conflict of interest statement DOI of original article: http://dx.doi.org/10.1016/j.leukres.2013.11.004. 0145-2126/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.leukres.2013.12.004
The author declares to have no conflict of interest.
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Editorial / Leukemia Research 38 (2014) 145–146
References [1] Della Porta MG, Malcovati L, Strupp C, Ambaglio I, Kuendgen A, Zipperer E, et al. Risk stratification on both disease status and extra-hematologic comorbidities in patients with myelodysplastic syndrome. Haematologica 2011;96:441– 9. [2] 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. [3] Gattermann N, Finelli C, Porta MD, Fenaux P, Ganser A, GuerciBresler A, et al. EPIC study investigators deferasirox in iron overloaded with transfusion-dependent myelodysplastic syndromes: patients results from the large 1-year EPIC study. Leuk Res 2010;34:1143– 50. [4] List AF, Baer MR, Steensma DP, Raza A, Esposito J, Martinez-Lopez N, et al. Deferasirox reduces serum ferritin and labile plasma iron in RBC transfusion-dependent patients with myelodysplastic syndrome. J Clin Oncol 2012;30:2134–9. [5] Mitchell M, Gore SD, Zeidan AM. Iron chelation therapy in myelodysplastic syndromes: where do we stand? Expert Rev Hematol 2013;6:397– 410.
Judith Neukirchen ∗ Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Duesseldorf, Germany ∗ Correspondence
to: Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany. Tel.: +49 211 8117720; fax: +49 211 8118853. E-mail address: [email protected] 24 November 2013 1 December 2013 Available online 11 December 2013
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Editorial
Iron chelation in MDS: Still a controversial issue
Keywords: MDS Iron chelation Survival
In this issue of Leukemia Research data from a prospective registry concerning the outcomes of lower-risk MDS patients receiving iron chelation therapy are presented. The authors analysed data from 600 lower-risk MDS patients (IPSS low and intermediate-1) with transfusional iron overload that were enrolled in a prospective 5-year registry. They compared the clinical outcome 24 months after inclusion into the registry of chelated and nonchelated patients and found a significantly longer survival especially in consequently chelated patients as well as a trend towards longer leukaemia-free survival and fewer cardiac events as compared to nonchelated patients. In patients with thalassaemia, robust data exist that iron chelation leads to a better survival and reduces comorbidities due to iron overload like chronic heart failure, diabetes mellitus or liver cirrhosis. In MDS, iron overload usually occurs as most of the MDS patients suffer from anaemia and develop transfusion dependency during the course of disease. As lower-risk MDS patients have a median survival of several years and each unit of red blood cells contains 200–250 mg iron, especially this patient cohort is at higher risk to develop an iron overload with iron accumulation in heart, liver or endocrine organs. Studies with T2* MRI showed iron accumulation especially in the liver of heavily transfused MDS patients and there is evidence that iron chelation can lead to an improvement of elevated liver enzymes. It has not been shown that iron chelation can reduce death due to liver failure. MDS is a disease of the elderly people and cardiac diseases are a relevant comorbidity in this patient cohort. In a study by Della Porta and colleagues, the authors presented a comorbidity index for MDS patients (MDS-CI). In their patient cohort, cardiac comorbidities were present in 25% of all patients. Due to the strong prognostic impact, the presence of cardiac comorbidities was counted twice in the score [1]. Iron chelation therapy is assumed to reduce cardiac iron overload and prevent progression of cardiac diseases. However, cardiac T2* MRI imaging could not deliver evidence that cardiac iron accumulation has a significant impact on cardiac comorbidities and outcome of MDS patients in contrast to thalassaemia patients suggesting that other factors like non-transferrin-bound iron (NTBI) or labile plasma iron (LPI) might be important mediators of cardiac dysfunction in lowrisk MDS patients. However, in the published study in this issue of
Leukemia Research as well as in previously published studies, there is a trend towards fewer cardiac events in chelated patients. Therefore, it will be interesting to see further information on the outcome of low-risk MDS patients in this registry presented after 5 years of follow up. Iron chelation found entrance in treatment guidelines for lowerrisk MDS patients since several studies showed an improvement of the median survival in patients receiving iron chelation therapy. In contrast, data regarding a reduced risk of leukemic progression or fewer infections in adequately chelated patients are not consistent. Several guidelines vary in defining iron overload and when to initiate iron chelation treatment, the recommended time point when to start iron chelation or how to monitor treatment response [2]. The recommendations for iron chelation in low-risk MDS are based on several studies that all have shortcomings: (a) most of them are retrospective analyses, (b) no studies exist comparing different treatment modalities like subcutaneous application of deferoxamine or oral application of deferasirox or deferiprone and (c) the decision to start treatment was based on the physicians choice potentially leading to a bias in patient selection. Another shortcoming concerns the duration of treatment. As deferoxamine has to be administered subcutaneously, compliance of the patients is pivotal for effective removal of iron. Major side effects of deferasirox concern nausea, diarrhoea and increase of serum creatinine. In two prospective trials, the EPIC as well as the US03 trial, dropout rates due to adverse events were high with 48.7% and 45%, respectively [3,4]. A prospective, randomised, placebo controlled study evaluating the effect of deferasirox in heavily transfused low-risk MDS patients is underway (NCT00940602). The results of this study may help to bring more light into this field. In patients with higher risk MDS, iron chelation can be considered if these patients are candidates for allogeneic stem cell transplantation, as several studies have shown a favourable outcome for patients with normal pretransplantation serum ferritin levels. The inferior survival of patients with iron overload was attributable to a significant increase in treatment-related mortality [reviewed in 5]. Although there are approved iron chelation therapies for MDS patients, future efforts should concentrate on findings better treatment options in order to avoid transfusion dependency and consecutive iron overload.
Conflict of interest statement DOI of original article: http://dx.doi.org/10.1016/j.leukres.2013.11.004. 0145-2126/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.leukres.2013.12.004
The author declares to have no conflict of interest.
146
Editorial / Leukemia Research 38 (2014) 145–146
References [1] Della Porta MG, Malcovati L, Strupp C, Ambaglio I, Kuendgen A, Zipperer E, et al. Risk stratification on both disease status and extra-hematologic comorbidities in patients with myelodysplastic syndrome. Haematologica 2011;96:441– 9. [2] 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. [3] Gattermann N, Finelli C, Porta MD, Fenaux P, Ganser A, GuerciBresler A, et al. EPIC study investigators deferasirox in iron overloaded with transfusion-dependent myelodysplastic syndromes: patients results from the large 1-year EPIC study. Leuk Res 2010;34:1143– 50. [4] List AF, Baer MR, Steensma DP, Raza A, Esposito J, Martinez-Lopez N, et al. Deferasirox reduces serum ferritin and labile plasma iron in RBC transfusion-dependent patients with myelodysplastic syndrome. J Clin Oncol 2012;30:2134–9. [5] Mitchell M, Gore SD, Zeidan AM. Iron chelation therapy in myelodysplastic syndromes: where do we stand? Expert Rev Hematol 2013;6:397– 410.
Judith Neukirchen ∗ Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Duesseldorf, Germany ∗ Correspondence
to: Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany. Tel.: +49 211 8117720; fax: +49 211 8118853. E-mail address: [email protected] 24 November 2013 1 December 2013 Available online 11 December 2013
