Best Practice & Research Clinical Haematology 26 (2013) 431–444

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When is iron overload deleterious, and whenand how should iron chelation therapy beadministered in myelodysplastic syndromes?

David P. Steensma, MD, Associate Professor a,Norbert Gattermann, MD, Associate Professor b,*aDana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USAbKlinik für Hämatologie, Onkologie und Klinische Immunologie, Heinrich-Heine-Universität, Moorenstr. 5,40225 Düsseldorf, Germany

Keywords:ironred blood cell transfusion [complications]haemosiderosismyelodysplastic syndromeschelation therapydeferasiroxdeferoxaminedeferiprone

* Corresponding author. Tel.: þ49 211 8116500;E-mail address: gattermann@med.uni-duesseld

1521-6926/$ – see front matter � 2013 Elsevier Lthttp://dx.doi.org/10.1016/j.beha.2013.09.009

Iron overload in MDS starts even before patients become red-blood cell transfusion dependent, because disease-associatedineffective erythropoiesis suppresses hepcidin production in theliver and thus causes unrestrained iron absorption in the duo-denum. However, the main cause of iron overload is regulartransfusion therapy, which in MDS is associated with a risk ofunclear magnitude for iron-related complications. Iron depositionin tissues can now be detected with non-invasive techniques suchas T2* MRI. Iron toxicity in MDS may not only depend on the de-gree of tissue iron accumulation but also on the extent of chronicexposure to non-transferrin-bound iron (NTBI), including labileplasma iron (LPI) and intracellular labile iron pools, which increasethe level of oxidative stress. Iron chelation therapy (ICT) canrapidly lower NTBI and LPI and more slowly mobilizes tissue ironstores. Further studies, including the ongoing TELESTO controlledtrial, will more clearly define the role of ICT in MDS, including anyeffect on specific morbidities or mortality in the MDS setting.

� 2013 Elsevier Ltd. All rights reserved.

Fax: þ49 211 8118853.orf.de (N. Gattermann).

d. All rights reserved.

D.P. Steensma, N. Gattermann / Best Practice & Research Clinical Haematology 26 (2013) 431–444432

Introduction

“All things are poison, and nothing is without poison; only the dose permits something not to bepoisonous.” – “Paracelsus” (Philippus Aureolus Theophrastus Bombastus von Hohenheim), SeptumDefensiones, 1538.

This famous quote from Paracelsus, which earned the iconoclastic Renaissance German–Swissphysician and occultist the title, “Father of Toxicology”, describes elemental ironwell. On the one hand,iron is an essential component of numerous biological enzymes and metalloproteins, a scarce traceelement hoarded by the body and necessary for many critical physiological processes. On the otherhand, an excessive “dose” of iron can be toxic, because iron strongly catalyses biochemical reactionsthat generate reactive oxygen species and free radicals via Fenton chemistry. These volatile molecules,in turn, chemically attack macromolecules (DNA, proteins, lipids) and organelles, causing cellulardamage that ultimately leads to organ dysfunction.

The potentially life-threatening nature of iron overload, mainly through cardiac and hepatic com-plications, is well recognized in patients with inborn errors of iron metabolism including hereditaryhaemochromatosis [1], as well as the congenital anaemias such as b thalassaemia major that areassociated with transfusional iron overload. The specific contribution of iron overload tomorbidity andmortality in patients with acquired haematological neoplasms such as the myelodysplastic syndromes(MDS), where there are competing morbidity andmortality risks from cytopenias and clonal evolution,is less well defined [2–6]. In this article, we summarize the causes and potential consequences of ironoverload in MDS, and discuss risk-stratified treatment strategies to mitigate iron-relatedcomplications.

Causes of iron overload in MDS

Iron overload in MDS starts even before patients become red blood cell (RBC) transfusion-dependent, in part because disease-associated ineffective erythropoiesis suppresses hepcidin pro-duction in the liver [7]. Hepcidin suppression leads to unrestrained intestinal iron uptake, becausehepcidin normally limits iron uptake in the duodenum by binding to and inhibiting ferroportin, theiron channel on the basolateral surface of enterocytes [8]. In thalassaemia major, hepcidin is sup-pressed by dramatically elevated expression of Growth Differentiation Factor 15 (GDF15), a trans-forming growth factor-b superfamily member that is secreted by maturing erythroblasts is the bonemarrow [9]. In MDS, serum levels of GDF15 are much less elevated than in thalassaemia, and hepcidinlevels are more variable [7]. Other signals like Twisted Gastrulation Protein Homologue 1 (TWSG1),another erythroid-derived regulator of hepcidin, may be involved in MDS instead of GDF15 [10].

While increased intestinal iron absorption contributes to iron overload in MDS, it is not the maincause, as indicated by serum ferritin (SF) levels at diagnosis and prior to the start of transfusion therapy,which are usually around 400 ng/ml and rarely exceed 1000 ng/ml [7,11]. Instead, the most importantcause of iron overload in MDS is chronic RBC transfusion therapy.

Every unit of RBCs provides 200–250 mg of haem iron, while the daily loss of iron in sweat andexfoliated skin and mucosal cells only amounts to 1–2 mg, which is compensated by duodenal dailyiron uptake of 1–2 mg. One unit of blood is therefore equivalent to about 200 days of steady-statenutritional iron uptake. A patient receiving 4 units of RBC per month will receive approximately 100units over 2 years, supplying at least 20 g of iron, while the normal total body iron is less than 4 g. Inpatients with hereditary haemochromatosis, clinical manifestations usually begin to develop whentotal body iron exceeds 15–20 g.

Potential consequences of iron overload in MDS

Surplus iron from increased intestinal iron uptake is mainly deposited in the liver but is also takenup by cells in other organs, whereas surplus iron from blood transfusions initially is deposited in cells ofthe reticuloendothelial system. With continued RBC transfusions, however, iron accumulation inparenchymal organs also occurs, probably as a result of redistribution from reticuloendothelial cells.

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The clinical and pathological findings of transfusional haemosiderosis are then similar to thoseobserved in hereditary haemochromatosis [1].

Theremay be hepatosplenomegaly inMDS after transfusional haemosiderosis develops, but hepaticfunction is usually normal or only slightly impaired at the time of diagnosis [12]. Iron overload in theliver, sometimes accompanied by iron deposition in the islet cells of the pancreas or in the pituitary, canlead to impaired glucose tolerance, diabetes mellitus and other endocrine problems. Increased skinpigmentation rarely occurs in transfusional haemosiderosis. Cardiac arrhythmias and heart failure areimportant complications and a common cause of death in thalassaemia, but their frequency in MDSand the independent contribution of iron versus anaemia to these complications is debated, and mayvary by population.

Iron toxicity in MDS may not only depend on the degree of tissue iron accumulation but also on theextent of chronic exposure to non-transferrin-bound iron (NTBI), including labile plasma iron (LPI) andintracellular labile iron pools, which increase the level of oxidative stress. NTBI appears wheneverplasma iron exceeds transferrin’s iron binding capacity. LPI, a type of NTBI, is redox-active, readilychelatable and membrane-permeant [13]. LPI is readily taken up by certain parenchymal cells where itcan generate reactive oxygen species. The clinical relevance of NTBI is underscored by the experiencewith intensive iron chelation therapy (ICT) in patients with thalassaemia major and heart failure due tohaemosiderosis, in which clinical improvement occurs well before much iron has been removed fromthe tissues of the heart. In this setting, benefits of continuous deferoxamine (DFO) treatment on heartfunction accrue well before changes in storage iron are visible in T2*-weighted magnetic resonanceimaging (MRI) sequences, which is consistent with early removal of a toxic labile iron pool withinmyocytes [14]. These observations show that substantial clinical benefit can potentially be derivedfrom the detoxification of NTBI.

Clinical relevance of iron overload in MDS?

Both RBC transfusion dependence and elevated levels of SF, indicating possible iron overload, areclearly associated with a decreased likelihood of survival in patients with lower-risk MDS. Above a SFthreshold of 1000 ng/ml, there is a dose-dependent impact of iron overload on overall survival [15]. It isstill a matter of debate whether this finding can be taken as evidence of the clinical relevance of ironoverload and as an argument favouring the urgency of ICT in MDS, however. One has to be aware thatthe data could also be interpreted the other way round: higher SF levels reflect higher transfusionrequirements, which reflect more severe bone marrow disease, the latter being the real cause ofshortened survival. However, it has been shown that SF is an independent prognostic factor in MDS,even if transfusion dependency is taken into account in multivariate analysis by including the numberof transfusions per month as a covariate. Under these transfusion-adjusted conditions, Italian in-vestigators still observed a 30% greater risk of death for every 500 ng/ml increase in SF above the1000 ng/ml threshold [15]. Similar conclusions were drawn from a multicenter retrospective analysisin Spain [16].

Transfusion dependency in MDS is certainly associated with shorter survival than transfusion in-dependence because transfusion requirements reflect more severe bone marrow disease, with asso-ciated complications such as infections, bleeding, and adverse effects of chronic anaemia. In addition,however, transfusion dependency is a risk factor for iron overload, thereby creating a new medicalproblem that has its own negative impact on survival. The relative weight of these two risk factors –bone marrow failure and iron overload –may vary considerably from patient to patient. A patient withpure sideroblastic anaemia (MDS subtype refractory anaemia with ring sideroblasts, RARS), forinstance, has a long life expectancy and low risk of death from infection or bleeding. In such a patient,anaemia is the dominant cytopenia and with time, transfusional iron overload may become a majorproblem. On the other hand, a patient with higher risk forms of MDS such as refractory anaemia withexcess blasts (RAEB)-I or -II may not have the time to develop clinical complications of iron overload,because severe bonemarrow failure or leukaemic transformation limit the overall prognosis. However,arguing against this idea, one series of ICT in MDS showed greater benefit with non-RARS MDS di-agnoses [17], while a retrospective Mayo Clinic series of patients with RARS showed no correlationbetween SF and survival [18].

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Indications for iron chelation in MDS

Whether and when treatment with an iron chelator is started in MDS depends on what the indi-vidual risk is of damage to health as a result of iron overload. This risk, in turn, not only depends on theextent but also on the duration of iron overload. According to a 1981 series by Schaefer et al., cardiacdamage, impaired glucose tolerance and focal portal liver fibrosis can develop within less than fouryears in adult patients with anaemia requiring regular transfusions [19]. Not all tissues are equallysusceptible; heart failure develops sooner than hepatic cirrhosis and is one of the main causes of deathfrom transfusion-induced siderosis [20,21]. Prevention of heart failure is thus an important therapeuticgoal, not just in children with thalassaemia major but also potentially in elderly patients with MDS,whose hearts may be even more susceptible to iron-related toxicity because of advanced age and thepresence of cardiac comorbidities.

As it is not exactly known to what extent transfusional iron overload contributes to morbidity andmortality in patients with MDS, recommendations concerning ICT in clinical practice are largely basedon expert opinions. A non-comprehensive, representative list of expert guidelines on this topic is givenin Table 1. These guidelines usually recommend ICT for MDS patients who have a transfusion history ofat least 20 or 25 units of RBCs and a SF exceeding a certain threshold, e.g. 1000 ng/ml. They focus onpatients with lower-risk MDS who have a reasonable life expectancy and are thus expected to receivelong-term transfusion therapy, which puts them at risk of developing clinical complications of ironoverload. The guidelines do not take into account the variable rate at which iron overload develops indifferent patients, however, nor do they consider individual risk factors such as cardiac comorbiditiesor HFE genotype. Some patients with MDS who also have an HFE C282Y or H63D polymorphism, forinstance, already have a heavy tissue iron burden at the time of MDS diagnosis, while other patients,especially thosewho have thrombocytopaenia and frequent bleeding events, may receivemore than 20transfusions without substantial elevation of SF.

Table 1Guidelines on iron chelation therapy in patients with MDS [22–32].

Countries Transfusion status Serum ferritin(ng/Ml)

Patient profile Target serumferritin level

Italian (Ref. [22]) �50 RBC units NR � Life expectancy > 6 months NRUK (Ref. [23]) w25 RBC units

(5 g iron)NR � Pure sideroblastic anaemia

� del 5q<1000

US (Ref. [24]) 20–30 RBC units(�5–10 g iron)

>2500 � IPSS low or Int-1� Potential transplant patients

For pts withSF > 2500, aimto decrease to<1000

International(Ref. [25])

Transfusion-dependent

>1000–2000 � RA, RARS, del 5q� IPSS low or Int-1

NR

Japanese(Ref. [26])

>40 Japaneseunits

>1000 � Life expectancy > 1 year 500–1000

Canadian(Ref. [27])

Transfusion-dependent

>1000 � RA, RARS, del 5q� IPSS low or Int-1� IPSS Int-2 or high

(if SF > 1000 and� SCT candidates/life

expectancy > 1 year)

NR; reduce dosewhen < 2000;discontinue chelatorwhen <1000

Spanish(Ref. [28])

Transfusion-dependent

>1000 � IPSS low or Int-1� WPSS very low, Low, or Int� Spanish prognostic index low risk

NR

Austrian(Ref. [29])

Transfusion-dependent

>2000 � Life expectancy > 2 years NR

Israeli (Ref. [30]) 20–25 RBC units >1000 � Low or Int-1 (IPSS)� Candidates for SCT

<500 – <1000

MDS Foundation(Ref. [31])

2 RBC units/monthfor �1 year

>1000 � Life expectancy > 1 year NR

Italian update(Ref. [32])

�20 RBC units(4 g iron)

NR � Low or Int-1 (IPSS)� Int-2, high when responding to

disease-modifying agent orcandidates for SCT

NR

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Potential benefits of iron chelation therapy (ICT) in MDS

Decreased organ damage

In a large USMedicare population, Goldberg and colleagues found that transfusedMDS patients hada higher prevalence of billing codes related to cardiac events, diabetes mellitus, dyspnea, and hepaticand infectious diseases than non-transfused MDS patients [33]. All these complications were signifi-cantly more frequent than in age-matched individuals without MDS. While anaemia is probably aconfounding factor for the development of cardiac events, it cannot easily explain the increasedincidence of diabetes, which may therefore be related to iron overload.

A study from Italy showed that cardiac failure and infections were the most common causes ofdeath in patients with lower-risk MDS. Cardiac failure was significantly more frequent in transfusedpatients, which may be confounded by their more severe anaemia [34]. Japanese researchers reportedthat MDS patients dying from cardiac or hepatic failure had received more than twice the number ofRBC units than MDS patients dying from other causes [35].

In elderly MDS patients with comorbid ailments, iron overload may not have a dramatic, eye-catching effect on a single particular organ system. Instead, the simultaneous aggravation of severalcommon ailments may add up to a strong cumulative effect. However, such an effect of iron overload,even if substantial, could easily hide behind the usual morbidities and causes of death in the elderly.Even the finding of iron in tissues at post-mortem examination is neither necessary nor sufficient toindicate a clinically relevant contribution of excess iron to the patient’s death. Therefore, it has provendifficult to clearly define themagnitude and contribution of iron overload tomorbidity andmortality inMDS patients.

The TELESTO trial, a prospective, multicentre placebo-controlled study with the oral iron chelatordeferasirox (discussed further below) in 630 MDS patients, will hopefully provide further insight intothe clinical benefit of chelation therapy in patients with lower-risk MDS, including effects on organfunction. The primary end-point of the TELESTO study is event-free survival, with a protocol-specificcombined event definition with special emphasis on cardiac and hepatic events (ClinicalTrials.govIdentifier: NCT00940602).

Diminished risk of infections

The increased prevalence of infectious complications in transfused MDS patients noted in theGoldberg study is consistent with another recent report from the M.D. Anderson Cancer Center [36]showing that infections were second only to cardiac events as the most frequent cause of death inpatients with lower-risk MDS. While these infections are likely largely attributable to disease-associated neutropenia or granulocyte dysfunction, increased availability of iron in iron-overloadedstates provides a nutrient for growth of siderophoric microorganisms, increasing the risk of bacterialand fungal infections [37].

Improved haematopoietic function

When considering the possible deleterious effects of iron overload, the bone marrow itself is rarelymentioned among the organs that may suffer. However, the increased oxidative stress that has beenobserved in haematopoietic cells in patients with MDS [38–41] may at least partly be attributable toiron overload and NTBI. It has been documented in several case reports and small patient series that ICTis associated with improved haematopoiesis in a proportion of MDS patients [42–53]. Responsesincluded increased haemoglobin, diminished transfusion requirements or even transfusion indepen-dence. One must be cautious of the Hawthorne effect in interpreting such results in unblinded studieswhere patients were known to be receiving ICT, since clinicians whose patients were enrolled in thesestudies might have been more restrictive about transfusion practisespractises in individuals for whomthere was enough concern about iron overload to enrol them in a study. However, occasional majorneutrophil responses and platelet responses have also been observed and are less subject to con-founding by transfusion practises.

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The largest study of haematopoietic changes during ICT to date is the post-hoc analysis of the cohortof 341 MDS patients included in the 1-year EPIC study of 1744 patients with a variety of transfusion-dependent chronic anaemias who were treated with deferasirox (DFX) [54]. Among patients includedin the analysis, 22.6% were reported to show evidence of an erythroid response. An increase in hae-moglobin by at least 1.5 g/dl was seen in about half these responders, and a diminished transfusionrequirement in the other half. Improved platelet counts according to International Working Group(IWG) criteria were seen in 14%, and improved neutrophils counts in 19.6% of patients in the EPICanalysis group. The median time to erythroid response was about 3–4months, while it took somewhatlonger to achieve a platelet or a neutrophil response. The results regarding haematological responses inthe EPIC trial have recently been corroborated by the US03 trial of ICT with DFX in patients with MDS,where 15% of patients achieved an erythroid response, 22% achieved a platelet response, and 15%achieved a neutrophil response [55].

More than 15 years ago, Jensen et al. already reported on the effect of ICT with DFO on haemato-poiesis in MDS patients with transfusional iron overload [56]. They followed 11 MDS patients for up to60 months during and after treatment with DFO and observed at least a 50% reduction in tranfusionrequirement in 7 of 11 patients; 5 patients became transfusion independent. All patients in whom ICTwas highly effective showed improvement of erythropoietic output. The most obvious reasons for lackof response to treatment were a high blood transfusion requirement eventually combined withhypersplenism, or insufficient ICT. The fact that these results were obtained with DFO suggests that thebeneficial effect of ICT on haemopoiesis in MDS patients is not specific to a particular iron chelator. Theexact mechanism of haematologic improvement remains to be elucidated, but diminished oxidativestress and reduction in intramedullary apoptosis appears to be the most plausible explanation [57].

Decreased rate of disease progression

ICT may not only benefit patients with lower-risk MDS, but may also become an option for patientswith higher-risk disease. This view is based on the hypothesis that iron overload may cause a degree ofoxidative stress that is sufficient to aggravate the genomic instability of the preleukaemic clone,thereby promoting the clonal evolution of leukaemia, particularly in patients with higher-risk MDS.There are data from animal experiments supporting this idea [58] but further evaluation in animalmodels and human clinical trials is necessary to elucidate the clinical implications of these observa-tions, especially regarding the deployment of ICT. In studies reported to date, AML-free survival has notdiffered between chelated and unchelated patient groups.

Improved outcome of haematopoietic stem cell transplantation

In patients undergoing haematopoietic stem cell transplantation (HSCT), there is a drastic increasein transferrin saturation immediately after the conditioning regimen [59,60], accompanied by theappearance NTBI and LPI. There are several explanations for this phenomenon. First, patients under-going HSCT have increased iron stores because they usually received many transfusions prior to HSCTand also absorbedmore iron from the gut as a consequence of ineffective erythropoiesis. Second, muchintracellular iron is released during the conditioning regimen from dying parenchymal cells, mainlyliver cells, and from dying haematopoietic cells in the marrow. Third and perhaps most importantly,there is decreased iron utilization during chemotherapy-induced bone marrow aplasia. Erythroblastsin the bone marrow, which are the main consumers of iron, are temporarily eliminated by the con-ditioning regimen, thus leaving all the iron destined for haem synthesis with “nowhere to go”.

Iron overload, or at least elevated SF as a surrogate, is increasingly being recognized as a risk factorfor treatment-related morbidity and mortality in the context of HSCT [61]. Post-transplant complica-tions including mucositis, bacteraemia, fever, and graft-versus-host disease have been observed to beinfluenced by elevated pre-transplantation levels of SF [62]. A large retrospective study found a strongcorrelation between elevated pre-transplant SF levels and shortened survival, particularly in patientswith MDS and AML [63]. Although evidence is accumulating that iron overload causes increasedtransplant-related complications, it remains to shown by prospective studies that interventions aimedat diminishing iron overload or the related oxidative stress can indeed improve the outcome of HSCT. In

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most patients undergoing HSCT, the time period between identification of transplant need and thebeginning of conditioning is too short for mobilization of substantial tissue iron stores with ICT, thoughNTBI and LPI can be dramatically reduced within just a few weeks by ICT.

Improved survival?

Since clinical benefit from ICT in MDS patients is expected through diminished incidence of cardiacevents, diabetes, and hepatic impairment, fewer infectious complications, improved haematopoieticfunction, lower risk of leukaemic transformation, and improved outcome after allogeneic stem celltransplantation, the question arises whether those benefits might translate into improved overallsurvival. A link between ICT and improved survival was first suggested by a small retrospective studyfrom Canada, where patients with lower-risk MDSwho had received ICT had a much better cumulativesurvival [64]. The finding was corroborated by a larger, partly prospective and partly retrospectivestudy from France, which again showed that transfusion-dependent patients with InternationalPrognostic Scoring System (IPSS) Low- or Intermiediate-1-risk MDS who were treated with ICT had asignificantly better prognosis than unchelated patients [65]. A matched-pair analysis from the Düs-seldorf MDS Registry also showed a significant correlation between ICT and improved overall survivalbut not on leukaemia-free survival [66].

However, in all these retrospective analyses there is still a possibility of bias, because one cannotrule out that patients with a better performance status or other favourable features correlated withimproved survival were perhaps more likely to be started on ICT. Such a bias can only be avoided with aprospective, randomized, placebo-controlled trial like the TELESTO trial mentioned above.

Diagnosis of iron overload in patients with MDS

As SF levels can be increased not just by iron overload but also by inflammation, alternativemethods to measure the iron content of liver or heart that are not sensitive to other conditions can behelpful to support the suspected diagnosis of transfusional iron overload. Liver biopsy is rarely used forthat purpose in MDS patients, mainly because of concerns regarding increased bleeding complicationsdue to thrombocytopaenia or platelet dysfunction, and increased infection risk due to neutropenia andgranulocyte dysfunction.

After intensive development workwith T2* and R2* sequencing techniques, MRI is now able to fulfilthe task as a non-invasive, reliable and well-tolerated method to diagnose iron overload. This tech-nique is widely available, in contrast to magnetic susceptometry with a superconducting quantuminterference device (SQUID), which is available in only four centres worldwide. While some MRIstudies in transfusion-requiring MDS patients have shown a high incidence of cardiac iron deposition,others have shown a correlation between hepatic iron deposition and transfusions received but nocorrelation with cardiac iron [67].

Treatment with iron chelating agents

The most effective method for removing iron from the body and the one with fewest side effects isphlebotomy. In MDS patients, however, phlebotomy is generally not possible because of the anaemiathat is nearly always present. An exception is the situation after successful allogeneic HSCT; if fullengraftment occurs and there is no longer a need for transfusion, phlebotomymaybe undertaken for thetreatment of persistent iron overload. The same applies to those patientswhose anaemia has beenmoreor less eliminated by immunosuppressive or other disease-modifying treatment. In most patients withMDS, however, anaemia persists and the treatment of iron overload requires the use of chelating agents.

Deferoxamine (desferrioxamine, DFO; Desferal�)

DFO has been a standard drug for the treatment of iron overload associated with congenitalanaemias and RBC transfusions formore than three decades. It must be administered parenterally sinceit is poorly absorbed from the gut. The plasma half-life of DFO is very short (0.3 h) as the drug is rapidly

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eliminated in the urine. Thus effective ICT ends almost immediately after the end of a DFO infusion.Since there is always just a small amount of body iron available for chelation, the efficacy of treatmentcorrelates mainly with the duration of the infusion.

DFO is usually administered subcutaneously. A negative iron balance can usually be achieved with adaily dosage of 40mg per kg bodyweight (30–50mg/kg) administered as a subcutaneous infusion over8–10 h, 5–7 nights a week, in thalassaemia major and probably also in other iron loading anaemias,despite an ongoing transfusion need. In extreme iron overload, DFO can also be given at a higher dosageof 50–60 mg/kg/day, 5 times aweek. Still higher dosages are associated with an unacceptably high rateof side effects. In patients who are only occasionally transfused, a subcutaneous infusion 2–3 times aweek or a subcutaneous bolus injection at the standard dosage may be sufficient to maintain negativeiron balance. In principle, the intensity of the treatment should be determined on an individual basis byassessment of the iron overload, preferably by determining the liver iron content via MRI.

Subcutaneous bolus injectionSeveral authors have shown that twice-daily subcutaneous bolus injections of DFO can achieve

similar iron elimination in the urine as a 10-h infusion [68–70]. The subcutaneous boluses should beadministered as slowly as possible (over several minutes). Bolus injection may be advantageousparticularly in elderly patients who find it difficult to get used to handling the infusion pumps.

Adverse effectsDuring DFO therapy, local irritation at the site of infusion or injection is frequent, with pruritus,

erythema, induration and slight pain. Severe DFO-associated adverse effects include tinnitus andimpaired hearing, retinal disorders with night blindness, impaired colour vision and visual field de-fects. Growth retardation in children has also been described. If extremely high doses are used, rarecases of renal failure and interstitial pneumonia have occurred. Most side effects are reversible if theyare diagnosed early. Accordingly, DFO treatment should be stopped promptly once adverse events aredocumented but can often be resumed later at a lower dose once the problems have been resolved. Theintravenous administration of DFO can result in nausea, vomiting, hypertension, collapse and neuro-logical disturbances such as transient aphasia. Allergic reactions to DFO are very rare, regardless of thedose, but anaphylactic reactions have been described. Fever, muscle pain and arthralgia are morefrequent during infusion.

Intravenous deferoxamine therapy in extreme iron overloadIf there is massive iron overload, e.g. with SF levels >2500 ng/ml or an extremely high liver iron

content, or if there has already been cardiac damage with arrhythmias or ventricular dysfunction, 24-hcontinuous chelation therapy of DFO should be considered. Intravenous administration via a Port-a-cath system is suitable for this. Various studies have shown an improvement in left ventricular func-tion or the disappearance of cardiac arrhythmias [71,72]. Catheter-associated complications such asthromboembolism or infections are rare. Using a Port-a-cath system, DFO doses of 50–60 mg/kg/daymay be given long term with high treatment adherence rate, since local side effects are prevented.

Adherence problemsPatient adherence to the prescribed regimen is the limiting factor in DFO treatment. However,

adherence is important in success of DFO ICT, at least in congenital anaemias. Brittenham et al. [73]showed that thalassaemia patients who did not have a 12-h DFO infusion at least 250 times a yearhad a much worse survival (only 12% lived through the age of 30) than patients who tolerated ICT on aconsistent basis (95% got to the age of 30).

Deferiprone (L1, DFP; Ferriprox�)

Because of its small size and better lipid solubility compared with DFO, deferiprone (DFP) isabsorbed in the gastrointestinal tract and reaches intracellular iron stores. However, this oral ironchelator has to be taken by mouth three times daily. After a DFP dose of 50 mg/kg body weight, thesubstance appears in the plasmawithin 5–10 min and there reaches a high concentration. The half-life

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is short (approximately 1.5 h). A DFP dose of 75 mg/kg/day is necessary to achieve a negative ironbalance [74–77]. While overall DFP is a less potent chelator than DFO, a few clinical studies have shownthat DFP is better able than DFO to prevent or reduce cardiac iron overload [78]. In a randomized,controlled trial, DFP monotherapy was significantly more effective than DFO over 1 year in improvingasymptomatic myocardial siderosis in patients with b thalassaemia major [79].

The most important adverse event associated with DFP is agranulocytosis, which is particularlyworrisome in patients with MDS who may already run a low neutrophil count. Absolute neutrophilcounts<500/ml are rare, but mild neutropenia is more common. Thus, close (i.e., weekly) monitoring ofthe blood count is necessary during treatment with DFP so that treatment can be withheld if there is adecrease in the granulocyte count. Neutropenia and agranulocytosis are, in principle, reversible, but ifthere is agranulocytosis, it is not recommended to use the drug again since in some cases there hasbeen recurrence of the agranulocytosis. In a four-year clinical study, the incidence of agranulocytosiswas 0.5% (or 0.2 cases per 100 treatment years), and the incidence of mild neutropenia was 8.5% (or 2.8cases per 100 treatment years) [80]. Since neutropenia on DFP treatment occurred significantly lessoften in patients who underwent splenectomy, it was suggested that the milder forms of neutropeniamight be more likely due to hypersplenism than to DFP treatment.

Painful joint swelling, especially of the knee, occurs on DFP treatment in approximately 15% ofpatients, but does not generally require cessation of treatment. Since joint and muscle pain was alsopresent during DFO treatment in 13% of thalassaemia patients, these problems could be due to thetreatment with any iron chelator. Early reports of increasing liver fibrosis as a result of DFP in patientswith thalassaemia were not confirmed in a larger study [81]. Since DFP had a teratogenic effect inanimal studies, it should not be taken without effective contraception. DFP has been authorised inEurope and India for many years, and in October 2011 was approved by the US Food and DrugAdministration (FDA), but only for use in thalassaemia under a restricted distribution programme, notMDS. In patients with MDS, DFP has shown to be effective at least in patients with SF levels <2000 ng/ml [82], and the risk of agranulocytosis does not seem to be much greater than in patients with othertransfusion-dependent anaemias [82,83].

Combination of deferoxamine (DFO) and deferiprone (DFP)

Several studies have investigatedwhether the combination of DFO and DFP has favourable effects inpatients with thalassaemia major [84–91]. Synergy is apparently present, thus opening the opportu-nity of combination treatment for patients in whom a negative iron balance cannot not be achievedwith DFO or DFP monotherapy. In particular, patients with inadequate removal of cardiac iron on DFOtreatment might benefit from combination therapy.

Deferasirox (ICL670, DFX; Exjade�)

DFX is an oral iron chelator which was approved in the US FDA at the end of 2004 and approved inEurope in 2006. DFX is licenced for use not only in thalassaemia, but also to treat chronic, transfusion-related iron overload in patients with other types of anaemia, when DFO therapy is contraindicated orinappropriate. Continuous iron chelaton is ensured as a result of the long half-life (t½ 8–16 h). UnlikeDFP, DFX is administered only once daily in the form of tablets dissolved in water or juice.

A randomised phase II multicentre study in 71 adult patients with b thalassaemia [92] showed thatDFX achieves a similar decrease in the liver iron content as DFO. Cappellini et al. [93] reported a phaseIII study with DFX versus DFO in 591 thalassaemia patients with transfusion-related iron overload. Itwas found that DFX doses of 5 or 10 mg/kg were too low to guarantee a negative iron balance, whiledoses of 20 or 30 mg/kg resulted in stable of decreasing SF and liver iron content. An internationalmulticentre study investigated the effect of DFX in 184 patients with transfusion-related iron overloadin various forms of anaemia (85 cases of b thalassaemia, 47 cases of MDS, 30 cases of Diamond-Blackfansyndrome, 22 cases of other types of anaemia) [94]. A dose-dependent effect of DFXwas observed on SFand liver iron content both in the thalassaemias and the other iron loading anaemias. Whereas 5–10 mg/kg/day proved to be too low of a dose, negative iron balance was achieved with 20–30 mg/kg/day. A DFX dose of 20 mg/kg is roughly equivalent to a DFO dose of 40 mg/kg.

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Adverse effectsThe common adverse effects of DFX are abdominal symptoms (especially diarrhoea and cramping),

rashes, and elevation of the serum creatinine level. Gastrointestinal (GI) disturbances, particularlydiarrhoea, have been recognized as the main cause for discontinuation of DFX treatment in differenttrials and reports. During an expert meeting held in July, 2010, in Lisbon, Portugal, data on GI distur-bances under DFX treatment in MDS patients were reviewed and discussed and consensus-basedrecommendations were made [95] (Fig. 1). Informing patients concerning GI side effects prior toinitiation of DFX treatment is pivotal. Patients should be told that GI disturbances are frequentlytransient in nature and can be managed with supportive care measures. If possible, DFX dosing shouldbe initiated and then maintained at an efficient level, which means that dose reduction or treatmentinterruption should only be considered if disturbances are severe or not manageable otherwise.Shifting the DFX administration from a breakfast dosing to a dinnertime dosingmight be beneficial andcircumvent the need of dose reduction or interruption.

Mild skin rashes usually subside without interrupting DFX treatment. If skin changes are moresevere, treatment with DFX should be stopped and, after symptoms have subsided, reinstituted in aslowly rising dose, possibly accompanied by short-term protection with corticosteroids.

In the EPIC clinical trial, a rise in the serum creatinine level was found in 36% of patients taking DFX;in 33%, it exceeded the upper limit of normal in two consecutive visits [93]. However, these creatinineelevations did not progress in 2.5 years of further follow-up. In the US03 study of 173 MDS patients[55], which allowed enrolment of patients with elevated serum creatinine (up to twice the upper limitof the normal range), the rates of renal adverse events (AE) were higher in patients with abnormalbaseline serum creatinine (41.7%) than in patients with normal baseline serum creatinine (31.5%).Additionally, the number of renal severe AEs and renal AEs that led to study drug discontinuation washigher in patients who had abnormal baseline serum creatinine values compared with patients withnormal values (8.3% vs. 6% renal SAEs, respectively; 4.7% vs. 0.7% renal AEs that led to study drugdiscontinuation, respectively).

Since DFX was approved, acute renal failure (defined as elevation of the serum creatinine level over3 mg/dL) has been observed in a few patients. There have also been a few cases with a fatal outcome,but the cause of death was multifactorial in all cases; according to the manufacturer’s assessment,

Fig. 1. Algorithm for diarrhoea management in MDS patients receiving deferasirox (DFX) treatment. Reproduced with permissionfrom Ref. [95].

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death was mainly due to complications of the underlying disease, rather than the treatment (source:Novartis Safety Database). In some cases of reversible renal failure, DFX could not be ruled out as acontributory cause. It is, therefore, recommended that patients with renal risk factors should have theirserum creatinine levels checked weekly in the first month of treatment, and monthly thereafter. A riseof more than one-third in the serum creatinine level should be followed by a reduction of the DFX doseby (initially) at least 10 mg/kg/day.

More than 37,000 patients had been treated with DFX all over the world by October 2007. The DFXprescribing information was updated with new warnings in July 2008, including rare cases of liverdysfunction and liver failure (occasionally fatal), rare cases of renal tubulopathy, and rare cases ofoesophagitis, ulceration, and haemorrhage in the upper gastrointestinal tract. Liver failure in DFX-treated patients has been limited to patients with pre-existing severe liver disease, including hepat-ic cirrhosis and multi-organ failure. Liver failure has not been described in patients whose initial liverfunction tests are normal and who suffer from no other life-threatening complications of the under-lying disease. The revised DFX prescribing information for physicians also recommends periodicmonitoring serum levels of transaminases, bilirubin, and alkaline phosphatase.

Pancytopenia has been observed as well during DFX therapy, but only in patients whose bonemarrow disease provided a possible explanation. Agranulocytosis does not seem to be induced by DFX,unlike DFP.

As mentioned above, the EPIC study, the largest clinical trial to date with DFX [96], enrolled 1744patients with different types of anaemia and iron overload, including 341 MDS patients. Although DFXwas again found to be effective inMDS patients in reducing SF in the EPIC study, the number of patientswho stopped treatment with DFX for various reasons was significantly higher in the MDS population(48.7% in the first 12 months of therapy) than in patients with other, usually congenital forms ofanaemia [12]. A similar w50% 12 month dropout rate was observed in the US03 trial of DFX in MDSpatients [55]. This high dropout rate is likely attributable to themuch older age of theMDS patients andaccompanying comorbidities, concurrent medications, and diminished resilience to AEs, all causingdifficulty in staying the course of a clinical trial (which may require travelling etc.). Progression of theunderlying bone marrow disorder also contributes to the dropout rate in MDS.

DFX is nevertheless well suited to the treatment of transfusion-related iron overload in MDS pa-tients in daily clinical practice [97–99] and is a welcome alternative to the laborious parenteraltreatment with DFO.

Other chelators

Given the shortcomings of current chelators, there is room for development of newagents. FBS 0701(desferrithiocin) is a novel oral chelator with anti-malarial activity that has shown activity in earlyphase studies with patients with thalassaemia [100]. Additionally, a study of fresh wheat grass juice in20 transfusion dependent patients with MDS showed a reduction in mean SF from 2250 ng/ml to950 ng/ml after 6 months, though the active chelating agent in wheat grass is unclear and it seemsimportant for the grass to be fresh [101]. The combined use of oral chelators may further improvemorbidity and mortality in patients with MDS and congenital anaemias with transfusional ironoverload [102].

Conclusion

Patients with MDS who receive regular RBC transfusions have a risk of unclear magnitude for iron-related complications, and iron deposition in tissues can now be detected with non-invasive tech-niques such as T2*MRI. ICTcan rapidly lower NTBI and LPI andmore slowlymobilizes tissue iron stores.Further studies, including the ongoing TELESTO controlled trial, will more clearly define the role of ICTin MDS, including any effect on specific morbidities or mortality in the MDS setting.

Conflict of interest statement

The authors have no relevant disclosures.

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