Leukemia Research 31S3 (2007) S10–S15www.elsevier.com/locate/leukres

Guidelines on iron chelation therapy in patients withmyelodysplastic syndromes and transfusional iron overload

Norbert Gattermann*Klinik fur Hamatologie, Onkologie und klinische Immunologie, Heinrich-Heine-Universitat Dusseldorf, Dusseldorf, Germany

Abstract

Experts believe that iron overload is an important problem which could be avoided with suitable treatment. Guidelines on treatingmyelodysplastic syndromes (MDS) include sections on using iron chelation therapy to prevent or ameliorate transfusional iron overload.The proportion of MDS patients who may benefit from iron chelation therapy is 35−55%, depending on the length of survival necessaryfor iron to accumulate to a detrimental level. Candidates for iron chelation are mainly patients with dyserythropoietic and cytopenicsubtypes of disease, which fall into the International Prognostic Scoring System (IPSS) Low-risk or Intermediate-1-risk categories, withmedian survival of 3−6 years.© 2007 Elsevier Ltd. All rights reserved.

Keywords: Myelodysplastic syndrome; Transfusional iron overload; Treatment guidelines; Iron chelation therapy

1. Introduction

Iron overload in patients with myelodysplastic syndromes(MDS) has two different causes. The less important of theseis ineffective erythropoiesis which, as in b-thalassemia,leads to increased duodenal iron absorption. However, veryfew patients with MDS have a serum ferritin level above1000mg/l at diagnosis, as they usually present with levels of300–600mg/l. The main cause of iron overload in patientswith MDS is chronic transfusion therapy. Patients with ahigh transfusion requirement of 4 units/month will receiveabout 100 units in 2 years. Even patients with a moderatetransfusion requirement of 2 units/month will receive about100 units over 4 years. This amount of transfused blooddelivers at least 20 g of iron, which is 5−6 times the normalbodyiron content. Although the impact of iron overload inpatients with MDS undergoing transfusions has not beeninvestigated in prospective studies to date, the specificbenefits of iron chelation therapy have been identified.In a study by Brittenham et al. [1], iron chelation

was clearly shown to improve survival in patients withthalassemia major receiving transfusions, by reducing thebody-iron burden and helping to protect against diabetesmellitus and cardiac disease. Patients in this study wereaged 7−31 years, and were followed for 10 years or untildeath. However, it is not clear how these findings relate

*Klinik fur Hamatologie, Onkologie und klinische Immunologie,Heinrich-Heine-Universitat Dusseldorf, Moorenstr. 5, 40225 Dusseldorf,Germany. Tel.: +49 211 81 16500; fax: +49 211 81 18853.E-mail address: gattermann@med.uni-duesseldorf.de (N. Gattermann).

to patients with MDS as they may receive iron chelationtherapy over a much shorter time period. Set against this isthe fact that patients with MDS are generally elderly, with ahigh frequency of cardiac comorbidities, and may, therefore,be more vulnerable to the toxic effects of iron overload – inother words, iron chelation therapy may achieve a survivalbenefit in a shorter time. Unfortunately, there are no data toindicate whether the potential complications of iron over-load occur significantly more often in transfusion-dependentpatients with MDS than in age-matched control subjects.The situation has changed little since Rose et al. [2] in 2001concluded that there is no study in the literature specificallyand prospectively assessing the mortality attributable totransfusional iron overload in patients with MDS.The clinical dilemma for physicians is that they need to

know whether iron overload is an important problem forpatients with MDS and, therefore, whether iron chelationtherapy is needed. A number of guidelines have been pub-lished in Europe and the USA, and this article summarizesand compares their main recommendations.

2. Italian Society of Hematology guidelines

These guidelines were published in 2002, and acknowl-edged that at that time there were no published studieson MDS that evaluated the relationship between body-ironburden, and the clinical syndrome of iron overload and asso-ciated damage [3]. Despite this, the Expert Panel agreed thatiron chelation should be considered as a therapy for patients

0145-2126/ $ – see front matter © 2007 Elsevier Ltd. All rights reserved.

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with MDS, and made two main recommendations. Firstly,adult patients with MDS who have previously received morethan 50 units of red blood cells and with an expected lifes-pan of longer than 6 months should receive iron chelationtherapy (recommendation level B, supported by longitudinalstudies). This is quite a generous recommendation, as itusually takes much longer than 6 months for the clinicalmanifestations of iron overload to develop. Secondly, therecommended iron chelation regimen was deferoxamine ata dose of 2 g/day given as a 12-hour subcutaneous infusion,or 1 g/day given as a subcutaneous bolus for 5 days/week(recommendation level C, supported by case studies).

3. United Kingdom MDS guidelines

The UK guidelines for the diagnosis and managementof adult MDS were published in 2003, and also containcomments on the topics of red blood cell transfusion andiron chelation therapy [4]. Again, it was acknowledgedthat the recommendations for iron chelation treatment inpatients with MDS were based on limited data (evidencegrade B, level III). The UK guidelines recommendedthat iron chelation therapy should be considered once apatient has received 5 g of iron, which is equivalent toapproximately 25 units of red blood cells. But they alsostate that therapy should only be given to patients for whomlong-term transfusional therapy is likely, such as thosewith pure sideroblastic anemia or 5q-syndrome. It was alsorecommended that deferoxamine should be given at a doseof 20−40mg/kg/day, as a 12-hour subcutaneous infusion on5−7 days/week, aiming for a ferritin concentration of below1000mg/l.The UK guidelines are somewhat less stringent than

the Italian guidelines as far as the patient’s transfusionhistory is concerned. The UK guidelines recommend thatiron chelation therapy should be started after 25 units oftransfused red blood cells, in contrast to 50 units in theItalian guidelines. However, the UK guidelines are a littlemore demanding as far as the prognosis of the patient isconcerned, as they specify that only patients requiring long-term transfusion therapy should be given iron chelationtherapy; this suggests those receiving transfusional therapyfor longer than 6 months, although this is not defined.

4. Consensus meeting – iron overload in MDS

In 2005, at the 8th International Symposium on MDS inNagasaki, Japan, a consensus meeting was convened todiscuss the problem of iron chelation therapy in patientswith MDS. The outcome of that meeting was presented asa series of questions with answers [5], some of which aresummarized in Table 1. The Consensus Group noted that thelack of data on the complications of iron overload in patientswith MDS necessitated extrapolation from data in patients

with thalassemia major, although patients with MDS areless heavily transfused and may not survive long enoughto develop the complications of iron overload.The Nagasaki guidelines were the first to recommend

that allograft transplantation candidates should receive ironchelation therapy. There is accumulating evidence thatiron overload might increase transplant-related mortalityin hematopoietic stem-cell transplantation, mainly as aresult of an increased rate of infectious complicationsand liver toxicity [6–10]. These guidelines advise ironchelation therapy for patients with serum ferritin levels>1000–2000mg/l or other evidence of significant tissue ironoverload. In addition, the Nagasaki guidelines also rec-ommended that irrespective of World Health Organization(WHO) or French–American–British (FAB) disease type,patients with MDS who have a documented stable courseof disease should not be excluded as candidates for ironchelation therapy.

5. National Comprehensive Cancer Networkguidelines

Among the more recent guidelines, the NCCN practiceguidelines for MDS consider iron overload as a concomitantproblem in some detail. They acknowledge that highlytransfused patients may develop iron overload and itsclinical consequences and that this should be reversed [11].They make a clear recommendation of initiating iron chela-tion therapy in relatively low-risk patients with excessiveiron accumulation resulting from red blood cell transfusionsand, in addition, for those with concurrent cardiac orhepatic dysfunction. Thus the NCCN guidelines recognizethat patients with MDS may have additional factors whichmay make them more vulnerable to the toxic effects ofiron overload.The NCCN guidelines also indicate that chelation therapy

is generally administered to patients who have previouslyreceived 20−30 units of red blood cells, and for whomongoing transfusions are anticipated, as well as thosewith serum ferritin levels above 2500mg/l. This representsa slight inconsistency, in that serum ferritin levels of1000mg/l are usually reached after an average of 21 unitsof red blood cells, so 2500mg/l would correspond to about50 units of red blood cells. The NCCNMDS panel membersstrongly recommended that chelation with subcutaneousdeferoxamine or oral deferasirox should be considered toreduce the iron burden.

6. Consensus meeting – iron overload

In May 2007, another iron-overload consensus meetingwas convened in Florence, Italy, under the auspices of theMDS Foundation. The aim of the meeting was to derivea set of consensus guidelines from a discussion of thedata developed in an international series of 20 roundtablemeetings. It is anticipated that the full guidelines will be

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Table 1Consensus statements on iron overload and its treatment in patients with MDS from the Iron Overload in MDS Consensus Meeting, Nagasaki,Japan,2005 [5]

Question Consensus

How would you define the role of chelation therapy in MDS? Highly likely to be clinically important in a subgroup of patients

What does chelation therapy need to achieve in MDS patients withiron overload?

Prevention of complicationsTreatment of complicationsImproved survival

What are the clinical consequences of no iron chelation? Potential cardiac, hepatic, and endocrine complications

In patients with MDS, when would you assess body iron stores? At diagnosisAt regular intervals (depending on individual transfusion rates)

How frequently would you monitor iron overload? At least every 3 months in patients receiving transfusion

Which tools would you use to diagnose and monitor iron overload? Serum ferritinTransferrin saturationLiver magnetic resonance imaging (problems of cost and availability)

− What would you use most frequently? Serum ferritin

When would you start chelation therapy? Serum ferritin level >1000–2000mg/l (depending on individual transfusionrates)

For how long would you continue chelation therapy? As long as transfusion therapy continues (as long as iron overload is clinicallyrelevant)

What is the profile of the patient who might benefit from thetreatment of iron overload?

Transfusion-dependent patientsLow-risk MDS (IPSS Low or Int-1)WHO-type RA, RA with ringed sideroblasts, and 5q-syndromeCandidates for allograftingMDS patients with documented stable diseaseSerum ferritin levels >1000–2000 mg/l or other evidence of significanttissue-iron overload

Absence of comorbidities severely limiting prognosis

IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndromes; RA, refractory anemia; WHO, World Health Organization.

published in 2008; however, the main conclusions from themeeting are briefly summarized here.Patients with MDS often become transfusion-dependent,

and the Consensus Group concluded that patient survival isadversely affected by increased transfusions, to an extentthat is dependent on the degree of iron overload [12].The goal of chelation therapy is primarily prevention ofiron overload in order to preserve organ function, with thepossible additional benefit of improving patient survival.It was agreed that the indications for iron chelation

therapy should include a ferritin level of 1000 ng/ml, and/ortransfusion of 2 units/month for at least 1 year. Patientsshould be identified as candidates for iron chelation therapyif they had no erythroid response to primary therapy, orwere ineligible for primary therapy. It was also noted,however, that ferritin level is not the only factor toconsider because some patients present with an elevatedferritin level due to ineffective erythropoiesis, or becauseof inflammatory conditions. In addition, patients in whomtransplantation is imminent should be considered for ironchelation therapy. In general, iron chelation therapy shouldnot be offered to patients with an anticipated survival of

less than 1 year, although earlier chelation therapy shouldbe considered in patients with compromised organ functionwho experience an increased transfusion burden.The Consensus Group thought that the choice of the

chelating agent should be at the discretion of the treatingphysician, but noted that three products (deferasirox,deferiprone, and deferoxamine) are available worldwide.They recommended that iron chelation therapy with one ofthese agents should continue for life, though not necessarilycontinuously. Interruptions may be possible if the serumferritin level decreases adequately, or may be necessary ifthe patient cannot tolerate the therapy for long periods.The Consensus Group recommended periodic follow-up,

with serum ferritin levels measured every 3 months toassess the trend in values. The goal of regular assessmentis to ensure either a decrease in the serum ferritin level,a slowdown in the rise of the serum ferritin level, orstabilization of the serum ferritin level. In those patientsin whom the serum ferritin level is not thought to besufficiently accurate, an assessment of organ functionshould also be performed, as determined by the treatingphysician.

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Table 2WHO classification of MDS subtypes a

MDS subtype Blood findings Bone marrow findings

5q-syndrome AnemiaBlasts <5%Platelets normal to increased

Megakaryocytes normal to increasedBlasts <5%No Auer rodsIsolated del(5q)

RA AnemiaBlasts �1%

Dyserythropoiesis onlyBlasts <5%Ringed sideroblasts <15%

RARS AnemiaBlasts �1%

Dyserythropoiesis onlyBlasts <5%Ringed sideroblasts <15%

RCMD Cytopenia of �2 lineagesBlasts �1%Monocytes <1000/ml

>10% of cells per lineage dysplasticNo Auer rodsBlasts <5%Ringed sideroblasts <15%

RCMD-RS Cytopenia of �2 lineagesBlasts �1%Monocytes <1000/ml

>10% of cells per lineage dysplasticNo Auer rodsBlasts <5%Ringed sideroblasts �15%

RAEB-1 Cytopenia of �2 lineagesPB blasts �5%Monocytes <1000/ml

Unilinear or multilinear dysplasiaNo Auer rodsBlasts 5−9%

RAEB-2 Cytopenia of �2 lineagesPB blasts �19%± Auer rods

Unilinear or multilinear dysplasia± Auer rodsBlasts 10−19%

a Modified with permission from [13].MDS, myelodysplastic syndromes; PB, peripheral blood; RA, refractory anemia; RAEB, RA with excessblasts; RARS, RA with ringed sideroblasts; RCMD, refractory cytopenia with multilineage dysplasis;RCMD-RS, RCMD with ringed sideroblasts; WHO, World Health Organization.

7. Guidelines in preparation

Finally, it should be noted that more guidelines are inpreparation which are tailored to different countries’ needs,for example guidelines from Canada and Japan. Anotherguideline is being developed under the auspices of theEuropean Leukemia Net and this will be evidence- andconsensus-based for the therapy of primary MDS, includingrecommendations on iron chelation therapy.

8. Identifying MDS patients who will benefit fromiron chelation therapy

Although the details vary somewhat, the published guide-lines, and those in preparation, are in broad agreementwith each other on how and when patients with MDS whohave transfusional iron overload should be treated with ironchelation therapy. However, it is still not clear what propor-tion of patients with MDS may benefit from such therapy.The WHO classifies MDS into a number of subgroups,

based on the cytomorphologic abnormalities found in

the bone marrow (Table 2) [13]. Those with refractoryanemia with excess blasts (RAEB)-1 and RAEB-2 arenot optimal candidates for iron chelation therapy, becausetheir survival is very poor; they represent about one-third of the MDS population. In contrast, most patientswhose MDS mainly affects their erythropoiesis havea much better prognosis, and in the Dusseldorf MDSRegistry these patients represent about 20% of the MDSpopulation [14]. In this registry, about half of the MDSpopulation belongs to subtypes classified as refractorycytopenia with multilineage dysplasia (RCMD) and RCMDwith ringed sideroblasts (RCMD-RS). These patients arealso anemic and require blood transfusions; however, theirprognosis is very heterogeneous, with about one-third ofthe RCMD population (with or without RCMD-RS) fallinginto the International Prognostic Scoring System (IPSS)Low-risk category, with a median survival of about 6 years(similar to that of patients with dyserythropoietic MDS). Afurther 50% fall into the IPSS Intermediate-1-risk category,with a median survival of about 3 years [14].

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8.1. MDS candidates for iron chelation therapy (crudeestimate)

In total therefore, about 35−55% of patients with MDSmay potentially benefit from iron chelation therapy. Theseinclude: (a) patients with MDS with dyserythropoiesisonly (up to 20% of the entire MDS patient population);(b) patients with MDS with IPSS Low-risk RCMD (withor without RCMD-RS) (around 15%); and (c) perhaps alsopatients with MDS with Intermediate-1 risk RCMD (withor without RCMD-RS) (about 20%).A major goal of iron chelation therapy in MDS is to avoid

myocardial iron accumulation, because cardiac diseaseis a major co-morbid condition among elderly patientswith MDS [15]. Glanville et al. [16] performed magneticresonance imaging (MRI) with cardiac T2* analysis in7 patients with MDS, demonstrating that cardiac ironoverload occurred between 2 and 4 years of consistenttransfusion, but may not occur even after 12 years. Notthe total blood volume, but transfusion intensity, i.e. thetotal blood volume per year, was higher in those patientswho developed cardiac iron overload. Recently, two othersmall MRI studies [17,18], investigating 11 and 10 patients,respectively, reported lack of cardiac iron overload in MDSpatients. More data are needed in order to draw definitiveconclusions.There may be a long latency period between the first

accumulation of iron in the liver and the demonstrationof iron in the myocardium. This was already suggested bya study from the pre-chelation era. Buja and Roberts [19]looked for cardiac iron deposits in autopsy material from131 patients with various types of leukemias and otheranemias, excluding thalassemias and sickle-cell disease.They found that more than 75 units of blood were requiredto render the majority of patients positive for cardiac ironoverload. However, it must not be forgotten that non-transferrin bound iron (NTBI) in the plasma is a majordeterminant of iron toxicity. Labile plasma iron (LPI), afraction of NTBI, is readily taken up by tissues, includingthe heart, where it catalyzes the production of reactiveoxygen species. NTBI has been found to be elevated inpatients with MDS [20]. Therefore, iron chelation therapyin MDS patients may be beneficial even in the absence ofgross myocardial iron deposition.

9. Conclusions

The relative importance of transfusional iron overload inpatients with MDS is hard to assess, because these patientssuffer many clinical problems in addition to transfusionaliron overload, such as complications of chronic anemia,bone marrow failure, leukemic transformation, problemsof normal aging, and concomitant diseases. The extent ofthe mortality and morbidity attributable to transfusionaliron overload needs further investigation. Much of ourcurrent knowledge about iron-related clinical problems is

derived from studies in patients with thalassemia major.Extrapolating that knowledge to patients with MDS hashelped formulate a number of guidelines which are largelybased on expert opinion and common sense rather thana firm database. Accordingly, the recommendations differslightly, for example, regarding the extent of iron overload/length of transfusion history that should trigger the startof chelation therapy. However, all guidelines currentlyavailable have one thing in common, which is that expertsin the field are convinced that iron overload is a significantissue that could be avoided with effective iron chelationtherapy.

Acknowledgment

Dr Gattermann has received speaker’s honoraria fromNovartis.

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