Concepts and goals in the management of transfusional iron overload

John B. PorterDepartment of Haematology, University College London, London, UK

In this review, current concepts and goals of iron chelation therapy for thalassemias, sickle cell disease,and myelodysplastic syndromes are discussed. The primary goal of iron chelation therapy is to prevent theaccumulation of iron reaching harmful levels by matching iron intake from blood transfusion, with ironexcreted by iron chelation. Over 30 years of experience with deferoxamine has shown iron chelation to bean effective therapeutic modality. However, chelation efficiency is limited because most of the body’s ironstores are not directly chelatable, and only a small fraction of body iron is chelatable at any moment. Onceiron has been deposited in organs other than the liver, for example the heart, removal by chelation is slowand inefficient. Chelation efficiency can be improved by designing regimes where chelators are available 24hr a day to bind labile iron pools in cells and plasma. Deferoxamine has a short plasma half-life and theparenteral infusions required to achieve steady plasma levels are demanding, with consequent variable ad-herence to therapy. Once-daily oral administration of deferasirox achieves continuous chelation with troughconcentrations sufficient to decrease plasma labile iron species progressively, and achieves an efficiencyof chelation not obtainable with deferiprone or deferoxamine monotherapy. Am. J. Hematol. 82:1136–1139,2007. VVC 2007 Wiley-Liss, Inc.

IntroductionThe prognosis of patients with thalassemia major, has

dramatically improved in recent years because of continu-ing advances in blood transfusion and iron chelation ther-apy [1]. However, the impact of chelation therapy on prog-nosis in other conditions associated with iron overload,such as sickle cell disease or myelodysplastic anemias, isless well-documented. In thalassemia major, regular bloodtransfusions introduce between 0.3 and 0.5 mg/(kg day) ofiron in the majority of patients [2], although there is consid-erable variability in the accumulation rate between patients.Repeated transfusions initially overload macrophages withiron and lead to rapid saturation of transferrin and theappearance of plasma nontransferrin-bound iron (NTBI).NTBI is a collective term that refers to heterogeneousplasma iron species that are cleared from the circulation bydifferent uptake mechanisms, and with a different tissuedistribution from transferrin-mediated uptake [3]. Uptake ofiron from NTBI species into hepatocytes, endocrine tissues,and the myocardium is thus responsible for the abnormalpattern of iron distribution in transfusional iron overload.Accurate assessment and management of transfusionaliron overload in patients is crucial to preventing iron toxicity[4] as well as avoiding the deleterious effects associatedwith excess chelation.

Consequences of Transfusional Iron Loading

ThalassemiaTransfusion-dependent thalassemia major is a severe

anemia that typically becomes symptomatic in the first yearof life. A regular program of chronic transfusion is requiredto sustain growth and development during childhood. Themajority of transfusional iron is accumulated in the liver, butthe small amount of iron that is deposited in the heart isthe major cause of death in patients with thalassemia major[1]. In the prechelation era, thalassemia major patients gen-erally died in childhood or before the age of 20 years,mainly as a result of cardiac failure [1]. Postmortem dataobtained during the prechelation era revealed the lack ofiron accumulation in skeletal muscle, and although these

patients had very high iron concentrations in the liver, itwas the heart that was the cause of death [5]. Cardiac ironoverload is still reported to be the most frequent cause ofdeath in thalassemia major patients, even though thiscomplication is steadily falling in progressive birth cohorts(Table I) [1].Iron-chelation therapy benefits thalassemia major

patients both by reducing the iron-loading burden, andimproving established iron-induced dysfunction within theheart [6,7]. The accumulation of iron in the heart is not in-evitable provided that liver iron levels are controlled at alltimes, however once iron has accumulated in the heart, itis removed much more slowly by chelation therapy thanliver iron [7], which can lead to a lack of correlation of liverand heart iron in previously chelated patients. Despite che-lation treatment, several studies show that for some thalas-semia patients treated with deferoxamine (particularly thosewho start treatment late, or fail to comply with treatment),high levels of iron (above 15 mg iron per gram liver, dryweight) are still present—a level associated with a high riskof cardiac disease and early death over a long period oftime [8]. Failure to control serum ferritin over prolongedperiods is also associated with an increased risk of cardiacdisease and death [9]. Despite this, it is clear that compli-cations of iron overload have been steadily falling since theintroduction of deferoxamine [1]. In Table I, it can be seenthat for thalassemia major patients started on deferoxamineafter subcutaneous infusions became widely available inItaly after 1980, death from cardiac disease fell from 5% at20 years to 1%, and that hypogonadism, diabetes, andhypothyroidism also fell significantly.

*Correspondence to: Prof. J. B Porter, Department of Haematology, Univer-sity College London, 98 Chenies Mews, London, WC1E 6HX, UK.E-mail: j.porter@ucl.ac.uk

Received for publication 1 October 2007; Accepted 1 October 2007

Am. J. Hematol. 82:1136–1139, 2007.

Published online 29 October 2007 in Wiley InterScience (www.interscience.wiley.com).DOI: 10.1002/ajh.21100

VVC 2007 Wiley-Liss, Inc.

American Journal of Hematology 1136 http://www3.interscience.wiley.com/cgi-bin/jhome/35105

Myelodysplastic syndromesPatients with myelodysplastic syndromes (MDS) may

develop a long-term dependence on blood transfusions andrequire iron-chelation therapy [10,11]. Postmortem studiesin the 1970s [12] and magnetic resonance imaging (MRI)data obtained more recently [13], show that after 75 ormore units of transfused blood, over half of patients willhave excess iron in the myocardium. In heavily transfusedpatients with MDS who were treated at University CollegeLondon, MRI T2* showed iron accumulation in nearly halfof those evaluated (Fig. 1) [14]. Survival and quality of lifeappear to be significantly worse in transfusion-dependentpatients with MDS, compared with untransfused MDSpatients, but without prospective studies is not clear towhat extent this results from the toxic effects of iron, orfrom worsening underlying disease that is associated witha need for transfusion [10,11].

Sickle cell diseaseSickle cell disease (SCD) is an inherited disorder of he-

moglobin synthesis characterized by life-long hemolyticanemia, but with relatively little ineffective erythropoiesiscompared with thalassemia syndromes. Consequently,there is no evidence of iron overload in sickle cell anemia,unless blood transfusions are given repeatedly [15,16].About 10–20% of patients with SCD receive repeatedtransfusions and serum ferritin values increase proportion-ately with units of blood transfused [17] and liver iron con-centrations [18]—provided ferritin samples are taken a suffi-cient interval after a vaso-occlusive crisis, when values canbe greatly elevated [17]. Patients with SCD and transfu-sion-dependent thalassemia, if transfused at the same rate,show a similar rate of liver iron loading as well as the samerisk of liver fibrosis at certain iron levels [19,20]. My ownexperience [14] (Fig. 1) as well as that of others [21] hasrevealed that patients with sickle cell anemia with transfu-sional overload are less likely to develop iron in the heartthan other patients with transfusion overload disorders. Apossible explanation is that patients with SCD have lowerNTBI levels than those with thalassemia, at matched levelsof liver iron loading [22]. Therefore, although the cardiacrisk from excess iron appears to be less in patients withSCD than in those with thalassemia, the risk of fibrosis andcirrhosis is reported to be similar. Because the transfusionrate is typically less in patients with SCD than in those withthalassemia major, particularly if exchange transfusions areused, somewhat lower doses of deferoxamine or deferasioxare often required to achieve iron balance than in thalasse-mia major [23].

Chelation Therapy

Goals and mechanisms of action of chelation therapyThe principal goal of chelation therapy involves prevent-

ing the accumulation of iron reaching harmful levels in thebody. The chances of achieving this goal can be maximizedby starting chelation treatment before iron accumulation isexcessive [8], as well as maintaining iron balance i.e.matching iron excretion with transfusional loading. Iron (III)has six coordination sites for iron chelation, and for com-plete coordination requires either one molecule possessingsix coordination sites (hexadentate chelation e.g. deferoxa-mine), two molecules each possessing three coordinationsites (tridentate chelation e.g. deferasirox), or three mole-cules each possessing two coordination sites (bidentatechelation e.g. deferiprone) [24].Storage iron present as ferritin or hemosiderin is not

available for direct chelation over a biologically useful time-scale [25,26] so chelators must act so as to bind rapidlychelatable iron pools that are typically rapid-turnover pools.The most important of these pools, quantitatively, are ironreleased from macrophages after the breakdown of old redblood cells [24,27], and iron released by the breakdown offerritin in lysosomes [27,28]. These chelated pools are pri-marily responsible for iron excreted by chelators in theurine or feces. With deferoxamine, urine iron accounting forabout half of excreted iron, is derived from red blood cellbreakdown, whereas fecal iron is derived from hepatocellu-lar chelation of lysosomally degraded ferritin [27,29]. Withdeferiprone, the chelated pools are the same, but both areexcreted in the urine with little fecal excretion [30]. Withdeferasirox, the chelated turnover pools are again thesame, but iron is excreted almost entirely in feces [31].Another important goal of chelation treatment involves

preventing tissue damage from labile iron pools that maybe present in plasma as NTBI species [32], or as labile ironwithin cells [33] (Fig. 2). As these pools are constantlybeing turned over, continuous exposure to chelation is the-oretically desirable, both in terms of maximizing the effi-ciency of chelation therapy, as well as minimizing the expo-sure to harmful free-radicals generated by labile iron spe-cies (see below). Other considerations include efforts tominimize toxicity from excess chelation, and rescue therapyif iron has already accumulated in tissues. The overall goalis to find a balance between the effects of too much ironand too much chelator (Fig. 2). Different chelators mayhave distinct modes of access to labile iron pools in certaincell types not usually critical to iron turnover but where

TABLE I. Decline in Complications with Deferoxamine

Birth 1970–1974a Birth 1980–1984b

Death at 20 years (%) 5 1

Hypogonadism (%) 64.5 14.3

Diabetes (%) 15.5 0.8

Hypothyroidism (%) 16.7 4.9

Patients with Thalassaemia major born after 1960 (n 5 977) [1]. Data

from Borgna-Pignatti C, et al. Haematologica 2004;89:1187–1193.aDeferoxamine intramuscularly 1975.bDeferoxamine subcutaneously 1980. In 1995, 121 patients switched to

deferiprone (censored at this time).

Figure 1. The percentage of multitransfused patients atUniversity College London Hospital with T2* < 20 mses isshown by diagnosis [14]. Data from Glanville J, et al.Blood (ASH Annual Meeting Abstracts) 2006;108:Abstract1553. PK, pyruvate kinase. The number of patients in eachgroup is shown by the respective bar.

American Journal of Hematology DOI 10.1002/ajh 1137

iron-mediated toxicity may occur [33]. This may result invariable rates of removal between such tissues, as well asdifferent patterns of potential toxicity from over-chelation.

Impact of compliance on effectiveness ofchelation therapyAlthough overall survival and complication-free survival

has increased with the use of deferoxamine (Table I), oneof the main problems with deferoxamine has been poorcompliance with therapy, which impacts on outcome [8].Compliance with chelation therapy is treatment-center spe-cific, with better long-term survival in centers with experi-ence in chelation management, than in centers where smallnumbers of patients are treated [34]. Recent evidence fromcontrolled trials shows that the convenience of therapy issignificantly improved with once-daily administration of anorally absorbed chelator, compared with deferioxamine thathas to be administered parenterally as either a subcutane-ous or an intravenous infusion because it has a short half-life and poor oral bioavailability [35].

Advantages of 24-hr chelation coverageChelators may also act by preventing the uptake of iron

into cells. Since the abnormal pattern of iron distribution intransfusional iron overload is secondary to NTBI uptakeinto parenchymal cells [3], this is an important target forchelation therapy (Fig. 2). NTBI is constantly being turnedover, reappears rapidly after chelators are cleared from thecirculation [32], and is incompletely removed by standard

chelation regimes with subcutaneous deferoxamine [36]. Achelation regime that provides 24-hr cover from NTBIuptake is desirable.Although the conventional NTBI assay is applicable to

measuring NTBI in the presence of deferoxamine, becausethe iron complex of deferoxamine is stable under conditionsof the assay, this is not the case with deferiprone or defera-sirox. A modified assay has therefore been developed [37]that detects a subfraction of NTBI that is redox active, termedlabile plasma iron (LPI). Although it is not yet known whetherthe remaining NTBI species (that are not redox active) aretaken up as rapidly into cells as the species detected as LPI,the assay has the advantage of being usable in the presenceof chelators such as deferiprone and deferasirox. Using thisassay, this fraction is effectively removed by standard 8–10hr deferoxamine subcutaneously at night, but LPI is presentduring the day [37]. Conversely, with deferiprone LPI is par-tially removed during the day, rebounding between doseswith high levels of LPI at night. By giving deferoxamine atnight and deferiprone during the day, LPI is efficientlyremoved over a 24-hr period [37]. This is a demanding re-gime however, and 24-hr cover can be more simply achievedusing once-daily deferasirox. With repeated once-daily dos-ing of deferasirox at 20 mg/kg, mean trough levels of defera-sirox are 20 lM [38]. A progressive removal of LPI with timeusing this regime has been reported [39].

Efficiency of chelation and iron balanceChelation efficiency refers to the proportion of the admin-

istered drug that ends up being excreted in the iron-boundform. As most of the intracellular iron sink is stored in astable form within ferritin or hemosiderin, this iron is notefficiently chelated. The efficiency of deferoxamine is about13%, deferiprone is about 4%, and deferasirox is about27% [40,41]. The high efficiency of chelation with defera-sirox is the result of several factors including, the continu-ous chelation achieved with once-daily oral treatments [38],the high-affinity constant for iron, and the favorable biodis-tribution properties [42,43]. The efficiency of chelation ther-apy can be calculated from the change in liver iron concen-tration over time (and hence the change in total body iron)[44], from the transfusional iron loading rate, and from theiron binding equivalents of the chelator that were givenover the time period studied. A subanalysis of the pivotalphase III studies [45] on deferasirox, and analysis of theefficiency of chelation over the dose-ranges studied [5–30mg/(kg day)] was undertaken [40]. It was found that the ef-ficiency of chelation was more or less constant over thisrange of doses and over the range of liver iron concentra-tion (LIC) values that were studied. This allows an estima-tion of the iron that will be excreted at any given dose. Itshould be remembered that because of individual patientsvariability with respect to transfusional iron intake rate that,as well as variability in pharmacokinetics and compliancebetween patients, it will not always be possible to predicton an individual patient basis the outcome of chelationtreatment from consideration of molar chelation efficiencyalone. However, if the rate of transfusional iron loading isknown, the dose required to achieve balance can in princi-ple be tailored to the transfusional requirements of thepatient, independent of actual LIC values at any given time-point. In general, rates of transfusional iron loading withSCD [23] are lower than in thalassemia major [2] or MDS[46] and, in principle, lower doses will be necessary toachieve neutral iron balance. While the mean change LICand thus the net iron balance show that most patients willbe in negative iron balance at 30 mg/(kg day); a significantfraction of patients using deferasirox still fail to achieveeven- or net negative- iron balance at these doses. In such

Figure 2. The pathways of iron uptake and distribution inparenchymal cells that load nontransferrin bound iron(NTBI) (e.g. hepatocytes or cardiac myocytes) under con-ditions of iron overload are shown in red, together withpotential targets for chelation therapy. In the absence ofiron overload, iron is taken into cells by transferrin. Underconditions of iron overload, plasma NTBI species aretaken into cells that express voltage-dependent calciumchannels (VDCC). Iron from either uptake mechanismenters a labile pool that, if too large, can generate free-radicals and damage organelles. Chelation therapy is notefficient at chelating iron directly from ferritin or hemosi-derein. Chelation should also not interfere with iron thatis needed for essential iron containing proteins or chela-tion-mediated toxicity will ensue. Effective mechanismsfor the action of chelation therapy in parenchymal cellsare: (1) by inhibiting NTBI uptake; (2) by directly chelatinglabile intracellular iron; (3) by preventing the incorporationof this iron into new ferritin synthesis; and (4) by inter-cepting iron derived from lysosomal degradation of ferri-tin. The net effect decreases labile plasma iron and there-fore ongoing cellular damage. [Color figure can be viewedin the online issue, which is available at www.interscience.wiley.com.]

1138 American Journal of Hematology DOI 10.1002/ajh

patients, who typically have a high transfusional iron burden>0.5 mg/(kg day)] (2), ongoing studies at higher doses arein progress to determine whether doses above 30 mg/(kgday) are effective and well tolerated.

ConclusionOver 30 years of experience with deferoxamine has

shown iron chelation to be an effective therapeutic modality.However, chelation efficiency is limited because most of thebody’s iron stores are not directly chelatable, and only asmall fraction of body iron is available for chelation at anymoment. Chelation efficiency can be improved by designingregimes where chelators are available 24 hr a day to bindlabile iron pools in cells and in plasma. Deferoxamine has ashort plasma half-life, and the parenteral infusions requiredto achieve steady plasma levels are demanding with conse-quent variable adherence to therapy. Once-daily oraladministration of deferasirox achieves trough concentra-tions sufficient to progressively decrease plasma labile ironspecies, and achieves an efficiency of chelation not obtain-able with deferiprone or deferoxamine monotherapy.

AcknowledgmentsIn preparation of this manuscript, the author received edi-

torial/writing support that was funded by Novartis Oncology.The author, however, was fully responsible for contents andeditorial decisions for this manuscript.

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