Practical management of iron overload

British Journal of Haematology, 2001, 115, 239±252

Review

PRACTICAL MANAGEMENT OF IRON OVERLOAD

The practical management of iron overload requires reliableestimation of body iron content and distribution as well asan understanding of how iron overload translates intoclinical consequences. In this article, it will be seen that ourability to estimate the distribution of excess tissue iron, topredict its consequences and therefore to tailor treatmentaccordingly is surprisingly imprecise. Our understandingof how iron chelators best prevent these consequences isalso limited. It will be seen that the safest and mosteffective ways of removing excess iron vary depending onthe degree and rate of iron loading as well as the underlyingcondition being treated. Evidence of benefit in survivalwith chelation treatment takes many years to emergeand currently only exists for thalassaemia major patientstreated with desferrioxamine. Long-term survival benefitshave not been demonstrated in other iron-overloadedconditions or with other chelation regimens. In suchcircumstances, practical treatment protocols are necessarilybased on inference rather than direct evidence.

ASSESSMENT OF IRON OVERLOAD

Estimation of the iron loading rateThe rate of iron loading will determine when chelationshould start as well as the chelation regimen to beadopted. Excess loading may occur secondary to increasediron absorption or from repeated blood transfusions.

Iron loading from blood transfusion. This can be estimatedfrom the total number of units of red cells given. A unitprocessed from 420 ml of donor blood contains approxi-mately 200 mg of iron (0´47 mg/ml of whole donorblood). A more precise estimation of iron loading canbe derived from the volume of blood transfused and themean haematocrit of processed blood obtained from thetransfusion centre. For the UK, assuming a mean haema-tocrit of 0´6 for SAG±M (saline adenine glucose±mannitol)blood, then the iron content is 0´7 mg per ml transfused.

Transfusion requirements vary with diagnosis. In thalas-saemia major, the rate of iron loading is reasonably welldefined provided a mean Hb value of 12 g/dl is achieved.The equivalent of 100±200 ml of pure red cells/kg/year(Modell, 1977) (i.e. 160±330 ml/kg of SAG±M blood/year)are transfused (equivalent to 116±232 mg of iron/kg bodyweight/year or 0´32±0´64 mg/kg/d) (Thalassaemia Inter-national Federation (TIF) Guidelines, 2000). The transfusionrequirements and hence iron loading in unsplenectomized

thalassaemia major patients are generally higher. However,hypertransfusion can also decrease splenic size (O'Brien et al,1972) and the early introduction of a hypertransfusionregimen (Modell, 1977) may therefore reduce bloodrequirement.

In other forms of anaemia, such as aplastic anaemia,myelofibrosis and pyruvate kinase (PK) deficiency, thetransfusion requirement is highly variable and a record oftransfusion requirement is necessary to calculate transfu-sional iron loading.

Iron loading from increased gastrointestinal (GI) absorption.In healthy individuals, iron absorption is 1±1´5 mg/d and isbalanced by iron loss from skin, gut, menstruation orpregnancy. Iron absorption is increased by anaemia,hypoxia, ineffective erythropoiesis and by the presence ofHFE variant genes. In thalassaemia syndromes, ironabsorption exceeds iron loss when erythron expansionexceeds five times that of healthy individuals (Cazzola et al,1997). Thus, iron absorption in thalassaemia intermediacan be up to 5±10 times normal, or 0. 1 mg/kg/d (Pippardet al, 1979; Gordeuk et al, 1987; Pootrakul et al, 1988).Splenectomy appears to increase the rate of GI hyper-absorption in thalassaemia intermedia (Fiorelli et al, 1990)and other conditions such as PK deficiency (Zanella et al,1993) through mechanisms which remain speculative, suchas hypoxia associated with micropulmonary emboli (Chuan-sumrit et al, 1993).

In thalassaemia major, hypertransfusion decreaseshypoxia and expansion of the erythron, thereby decreasingGI absorption to 1±4 mg/d (Pippard & Weatherall, 1984).In individuals who are poorly transfused, absorption rises to3±4 mg/d or more. This represents a supplementary 1±2 gof iron loading per year (equivalent to up to 3 monthschelation treatment).

In other forms of haemolytic anaemia, excess ironabsorption is highly variable. Thus, in sickle cell disease,despite chronic haemolytic anaemia, iron overload is notseen in untransfused patients (O'Brien, 1978; Porter &Huehns, 1987). In contrast, in PK deficiency, iron overloadis common in untransfused patients, particularly in thosewho are splenectomized (Zanella et al, 1993). The co-inheritance of HFE mutations (H63D, C282Y) with con-ditions predisposing to increased iron absorption such ascertain haemolytic anaemias could, in principle, increaseiron absorption (Arruda et al, 2000). However, in thalas-saemia major, the co-inheritance of HH genes has littleimpact on net iron loading (Longo et al, 1999).

Estimation of tissue ironSerum ferritin. The association between serum ferritin and

q 2001 Blackwell Science Ltd 239

Correspondence: Professor John B. Porter, University College

London, Consultant, Thalassaemia and Sickle Cell Unit UCLHospitals, 98 Chenies Mews, London WC1E 6HX, UK. E-mail:

[email protected]

levels of body iron is well established (Worwood, 1986) andthe test is easy to perform compared with other tests for ironoverload. However, the correlation between serum ferritinand body iron is not sufficiently precise to be of strongprognostic value. Serum ferritin will be disprortionatelyraised when inflammation or tissue damage is present.Conversely, serum ferritin will be falsely depressed whenpatients are scorbutic, a frequent occurrence in ironoverload owing to rapid oxidation of vitamin C (Chapmanet al, 1982). Serum ferritin is also influenced by chelationtreatment in a manner which is not a simple relationshipwith body iron. Thus, particularly for values above3000 mg/l, serum ferritin levels fall faster with chelationthan would be predicted from a diminution of body ironalone (Davis & Porter, 2000). A further problem is that therelationship between serum ferritin and body iron appearsto be different for different haematological conditions,tending to be depressed relative to body iron in conditionsin which iron overload is not predominantly secondary toblood transfusion. Thus, in thalassaemia intermedia, serumferritin tends to underestimate the degree of iron over-loading (unpublished observations).

With these caveats in mind, serum ferritin measured atregular intervals (at least 3 monthly with thalassaemiamajor) has some therapeutic and prognostic uses. A targetferritin of approximately 1000 mg/l is generally recom-mended standard practice in thalassaemia major (TIFGuidelines, 2000) and other forms of iron overload resultingfrom blood transfusion. However, the only study demon-strating a link between serum ferritin and prognosis showedthat patients with values below 2500 mg/l on two thirds ofoccasions had less risk of cardiac complications thanpatients who failed this achievement (Olivieri et al, 1994).

The rate of fall in serum ferritin with chelation treatmentis also a useful tool for giving information back to patientsabout their progress. Serum ferritin values below 3000 mg/lfall at a reasonably consistent rate with intravenousdesferrioxamine therapy (130 mg/kg/month on 50 mg/kg/d) and this can be used to encourage patients and cliniciansabout realistic target values which can be achieved withsuch a regimen (Davis & Porter, 2000).

Finally, serum ferritin measurement can help to reducethe risk of desferrioxanine overdosing, particularly as thelevel of body iron falls with treatment. In thalassaemiamajor, if the mean daily desferrioxamine dose (mg/kg)divided by the serum ferritin (mg/l) exceeds 0´025 (this ratiois referred to as the Therapuetic Index) then the dose shouldbe decreased (Porter et al, 1989b, 1998). The relationshipbetween serum ferritin and body iron may differ in otherconditions and this ratio is not applicable. This isparticularly the case in sickle cell disorders in which theserum ferritin is disproportionately increased for weeksfollowing vaso-occlusion (Brownell et al, 1986; Porter &Huehns, 1987).

Liver iron. The liver is the major site of iron storage in ironoverload, containing 70% or more of body iron stores(Modell & Berdoukas, 1981; Angelucci et al, 2000). Liveriron correlates closely with total body iron in transfusionaliron overload and total body iron, and is approximately

equivalent to 10´6 times the hepatic iron concentration (inmg/g of liver, dry weight) (Angelucci et al, 2000). The liver isalso accessible for biopsy or for non-invasive measurementof iron content by Superconducting Quantum InterfaceDevice (SQUID) or magnetic resonance imaging (MRI) andhas therefore been the measurement most used formonitoring treatment and assessing prognosis.

Liver iron concentration appears to have prognostic valuein iron overload. The major study showing such a relation-ship was in 59 patients over 7 years of age, who had beentreated with desferrioxamine for variable periods of time. Itwas found that all patients who died with cardiaccomplications had liver iron concentrations . 15 mg/gdry weight (Brittenham et al, 1994). It was then argued(Olivieri & Brittenham, 1997) that patients with liver ironvalues in this range should be regarded as `high risk'.However, as heart failure was the cause of death in allpatients, it is likely that liver iron was not the primarydeterminant of cardiac-free survival but represented anassociation of risk. Furthermore, the duration of exposure toexcess iron must also be taken into account as a prognosticdeterminant. Another important prognostic variable isprobably the age and the levels of iron loading when thishappens. Thalassaemia major patients currently alive intheir late thirties and early forties began treatment in latechildhood or adolescence at a time when liver iron valueswere considerably in excess of 15 mg/g dry weight (Barryet al, 1974). This shows that, provided iron levels can besubsequently reduced, a poor outcome does not inevitablyresult.

It has been suggested that realistic target levels of liver ironin treated patients should be less than 7 mg/g dry weight asheterozygotes with HH can reach such levels withoutsignificant pathology resulting (Olivieri & Brittenham,1997). This analogy assumes that the distribution of ironbetween heart and liver is similar in heterozygotes with HHto patients with transfusional iron overload treated withchelators. This necessarily cannot take into account thatsuch levels take a lifetime to accumulate in heterozygoteswith HH but are reached in early childhood in transfusion-dependent patients. Furthermore, recent evidence suggeststhat levels of liver iron correlate poorly with cardiac iron inpatients on chelation. Despite these caveats, a liver ironvalue above 7 mg/g dry weight, particularly in a youngindividual, is probably the best indicator currently availablefor initiating chelation treatment.

Liver iron concentrations are usually measured bychemical determination on a liver biopsy sample. Biopsy isan invasive procedure, but in experienced hands has a verylow complication rate (Angelucci et al, 1995). Inadequatesample size (, l mg dry weight) or uneven distribution ofiron in the presence of cirrhosis (Villeneuve et al, 1996) maygive misleading results. The measurement of liver iron canbe performed on wet or dried samples and the conversionof one to the other varies according to the dryingand measuring techniques used in the laboratory. Anagreed international standardization of measurement andreporting would be helpful to practising clinicians. Liveriron can also be measured non-invasively by magnetic

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q 2001 Blackwell Science Ltd, British Journal of Haematology 115: 239±252

biosusceptiometry (SQUID) (Brittenham et al, 1994),although these are very expensive to purchase and maintainand there are no such machines in the UK. MRI using T2relaxation has hitherto not given sufficiently preciseestimation of liver iron because liver iron in overloadconditions lies above the linear range. Recent developmentsusing a modified form of acquisition called T2* gives asomewhat better approximation to liver iron as measured bybiopsy (Anderson et al, 2000a).

Heart iron and function. Although heart failure is the maincause of death in iron overload (Zurlo et al, 1989;Brittenham et al, 1994), little is known about the relation-ship of heart iron content to mortality. This is partly becauseendomyocardial biopsy is impractical in routine clinicalpractice and is not a useful indicator of heart iron as a wholeowing to very uneven iron distribution in the heart (Barosiet al, 1989). Post-mortem measurement of iron concen-tration in many organs (Modell & Berdoukas, 1981) showedthan, even in patients dying of heart failure, heart iron wasonly a fraction of that in the liver. Furthermore, a simplerelationship between heart iron concentration and heartfailure is not consistent with the marked improvement inclinical heart failure left ventricular ejection fraction andcardiac dysrhythmias observed soon after commencingintravenous desferrioxamine (Davis & Porter, 2000). Recentdevelopment of cardiac T2* MRI measurement has providedan opportunity to study the relationship between thisindirect parameter of heart iron and cardiac function as wellas liver iron (Anderson et al, 2000a, b). Preliminary resultssuggest that patients with right or left ventricular ejectionfraction below control values tend to have the lowest T2*values and, by implication, the highest myocardial iron.Interestingly, there was no correlation between liver iron asmeasured by biopsy or MRI and cardiac T2*. A cardiac MRIcan measure right and left ventricular ejection fractions atthe same time as T2* and, in principle, could be measured inany hospital with suitable MRI facilities. How this parametercan best be used in the monitoring and treatment of patientsrequires careful prospective study.

Urinary iron estimation. Different iron chelators inducedifferent proportions of urinary iron relative to faecalexcretion. Deferiprone excretes iron almost entirely in theurine (Collins et al, 1994), desferrioxamine excretes anapproximately equal amount in the faeces (Pippard et al,1982a), and the new oral chelator developed by Novartis,ICL670A (Sergejew et al, 2000), appears to excrete ironexclusively in the faeces in preclinical studies. Urine ironexcretion with desferrioxamine increases in proportion toiron loading with transfusions (Modell & Beck, 1974), doseof chelation used (Sephton-Smith, 1962; Pippard et al,1978a), ascorbate status (Pippard et al, 1982a) and point inthe transfusion cycle (Pippard et al, 1982a), being pro-portionally higher in the urine as the Hb level falls. Theproportion of urinary and faecal excretion iron excretionincreases with the dose of desferrioxamine given (Pippardet al, 1982a). There is very considerable day to day variationin urinary iron excretion with the same dose of chelation,even in fully controlled trial conditions. Because of thisday to day variability in urinary iron excretion and the

variable proportion of faecal excretion, 24 h urinary ironmeasurement with desferrioxamine must be interpretedwith caution.

INDICATIONS FOR TREATING IRON OVERLOAD

General principlesThe decision of when to treat iron overload depends onlinking a given level of iron overload to risk. As seen above,risk from iron overload is likely to depend not just on body orliver iron levels but also the duration of exposure to excessiron. Furthermore, not all tissues are equally susceptible todamage from a given level of excess iron; heart failureoccurs at significantly lower levels of tissue iron thancirrhosis (Modell & Berdoukas, 1981).

The most important reason for initiating treatment is toprevent heart failure, which is the major cause of death intransfusional iron overload (Zurlo et al, 1989). However,considerable other morbidity results from iron overload,particularly if it occurs in childhood, and the prevention ofcomplications such as diabetes, hypogonadotrophic hypo-gonadism, poor growth, hypothyroidism and hypopara-thyroidism are achievable goals with optimal chelation (DeSanctis et al, 1989; Zurlo et al, 1989).

Thalassaemia majorThe point at which blood transfusions have depositedenough iron to cause irreversible tissue damage has notbeen assessed in prospective trials. Current practice is basedon balancing the known risks of excessive early treatmentwith the perceived risks of delayed treatment. Currentpractice is to start desferrioxamine when ferritin valuesreach 1000 mg/l or when 10±20 transfusions have beengiven. It is clear that the risk of overdosing is greatest inyoung children, particularly from effects on growth (Pigaet al, 1988; Olivieri et al, 1992a) and audiometricdisturbances (Olivieri et al, 1986). If treatment is com-menced before the age of 3 years then this should be givenwith great caution. Liver iron concentrations above 7 mg/ddry weight should be regarded as an indication fortreatment, although arguably lower levels of liver iron(e.g. above 3´5 mg/g dry weight) also require treatment(Olivieri & Brittenham, 1997).

Thalassaemia intermediaAs already discussed, the rate of iron loading is highlyvariable and the relationship between serum ferritin andbody iron can be different from thalassaemia major (Fiorelliet al, 1990). Treatment typically needs to begin later in lifethan thalassaemia major. An estimation of liver iron isadvisable before starting treatment to see whether this hasexceeded 7 mg/g dry weight, as serum ferritin tends tounderestimate parenchymal iron loading in this condition.In general, the rates of iron loading will be less than inthalassaemia major and the regime must be modifiedaccordingly. Many patients with thalassaemia intermediabegin on a hypertransfusion regimen similar to thalassaemiamajor at some point in their lives and a chelation regime


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similar to that given in thalassaemia major will need tocommence at this point.

Other anaemias associated with excess iron absorptionAs with thalassaemia intermedia, the rate of iron over-loading is highly variable and difficult to predict. Ineffectiveerythropoiesis and the co-inheritance of HFE mutationsmay increase the risk of iron loading (Cotter et al, 1999)as, unlike thalassaemia intermedia, conditions such aspyruvate kinase deficiency and inherited sideroblasticanaemia commonly affect Northern Europeans and co-inheritance of a HFE mutations will occur in about 1 in 10such patients. Liver biopsy for measurement of tissue ironlevels and for assessment of fibrosis is advisable beforestarting treatment. It is probable that the measurement ofcardiac iron is these conditions using MRI will be anadditionally useful variable. In congenital dyserythropoieticanaemia, iron overload is generally a function of ageand the degree of ineffective erythropoiesis, althoughthe rate of loading is variable (variability independent ofHFE) and some patients never require chelation therapy(Wickramasinghe et al, 1999).

Sickle cell disordersIron overload is not seen in sickle cell disease without bloodtransfusions. Although there are no large studies of theeffects of transfusional iron loading in HbSS, it is likely tocarry similar risks to other disorders. Typically, transfusionbegins later in life than in transfusion-dependent anaemiasand is often given sporadically, except in the prevention ofrecurrent stroke. Manual exchange transfusion decreasesthe risk of iron loading and can even reverse iron loading(Porter & Huehns, 1987) and should be encouraged.However, when exchange is not possible on a regular basisbecause of poor venous access or because sufficientnumbers of trained staff are not available, then top-uptransfusion is frequently given, inevitably leading to ironoverload. In steady state, there is a reasonable correlationbetween serum ferritin and the number of units ofblood transfused (Porter & Huehns, 1987) or liver iron(Brittenham et al, 1993). However, the measurement of ironoverload in sickle cell disease using serum ferritin isseriously flawed, as the serum ferritin remains dispropor-tionately raised for weeks after a vaso-occlusive episode(Brownell et al, 1986; Porter & Huehns, 1987). Liver iron(and ideally heart iron with MRI) should be measured beforetreatment and at regular intervals thereafter. Decisionsabout when to start treatment will depend on practical aswell as theoretical considerations. Regular use of desferri-oxamine infusion can be very difficult for sickle patients,particularly in adolescence and beyond, and Portacathshave a high thrombosis and infection rate in sickle celldisorders (personal observations).

Other forms of transfusional iron overloadThe age at which regular transfusion begins is critical to theiron removal strategy to be adopted. Inherited anaemiaswhich may be transfusion dependent and require chelationtreatment include Fanconi anaemia and Diamond±Blackfan

anaemias (Ambruso et al, 1982). The decision to startchelation in such conditions will be based on similarprinciples to thalassaemia major. In transfusion-dependentanaemias of adult onset, such as acquired aplastic anaemia,myelofibrosis, osteopetrosis or iron overload resulting fromtransfusion with repeated courses of high-dose chemo-therapy, the decision to remove accumulated iron must beweighed against the prognosis of the underlying conditionon a case by case basis.

Genetic haemochromatosisUntil the recent identification of the genes responsible forgenetic haemochromatosis, the most effective way ofidentifying this condition was using a transferrin saturationof . 50% on two samples, the second of which being afasting value (Worwood, 1999). Serum ferritin is usuallyelevated but has been shown to be less reliable as a screenthan fasting transferrin saturation. Historically, confir-mation of the diagnosis has been achieved by liver biopsyand measurement of liver iron with an `hepatic ironindex' . 2 (hepatic iron index � mmol iron per g dry wtdivided by the patients age). However, it is now possible tomake an early genetic diagnosis based on homozygosity forC262Y or compound heterozygotes for C282Y/H63D. Thisthen raises the question as to the role of liver biopsy indeciding when to commence phlebotomy, particularly inyounger patients. Detection of fibrosis is often given as areason for biopsy but it has been shown that, in absence ofhepatomegaly, a raised alanine transaminase (ALT) or aserum ferritin . 1000 mg/l, fibrosis is very unlikely andbiopsy may not be necessary (Guyader et al, 1998).Therefore, in younger patients, identified using geneticscreening and without the above risk factors, liver biopsymay not be mandatory. Treatment is generally indicated inmen with serum ferritin levels of . 300 mg/l and in womenwith serum ferritin levels of . 200 mg/l, regardless of thepresence or absence of symptoms. In cases in whichtransferrin saturation or serum ferritin are raised butgenetic screening for HFE mutations does not showhomozygous C282Y or C282Y/H63D, liver biopsy can beof value in determining the extent of iron loading or of otherliver pathology.

TREATMENT OF IRON OVERLOAD

PhlebotomyPhlebotomy is the most efficient and least toxic way toremove excess iron, as 1 pint of blood contains 200 mg ofiron and can be performed 1±2 times a week in patientswho do not have compromised erythropoiesis.

Genetic haemochromatosis. This should be treated byphlebotomy (Barton et al, 1998), as a unit of blood cangenerally be removed once or twice per week, resulting iniron removal of between 1 and 2 g of iron per month,considerably in excess of that achieved with iron chelationtherapy. Phlebotomy is continued until the serum ferritinand transferrin saturation indicate that iron stores havejust reached the iron deficient range (ferritin , 20 mg/land transferrin saturation , 16%). Thereafter 1 unit of

242 Review


blood is venesected every 3±4 months to prevent the re-accumulation of iron, generally maintaining serum ferritin, 50 mg/l.

Post bone marrow transplant (BMT). Patients who havereceived successful BMT for b-thalassaemia major must bevenesected repeatedly until normal (or low normal) levels ofiron stores are obtained (Angelucci et al, 1998). This canbe achieved with phlebotomy, the frequency of which willbe determined empirically by what can be tolerated withoutclinically relevant falls in Hb values. Baseline Hb valuesare affected by the genotype of the donor (i.e. whetherthalassaemia trait) and it is unrealistic to expect to achievethe same Hb levels as those seen with patients venesectedfor genetic haemochromatosis.

In other groups of patients, such as those who are insustained remission following BMT or chemotherapy forhaematological malignancy but have received multipleblood transfusions, phlebotomy may be advisable to normal-ize iron loading. Assessment of iron overload using serumferritin alone can be unreliable, so that independentconfirmation of excess iron loading should be sought. Thismay simply be a reliable documentation of the transfusion ofmany units of blood. It is not unusual for a patientundergoing induction, consolidation and BMT to havereceived in excess of 60±100 units of blood (Bradley et al,1997). Transferrin saturation in excess of 50% supports asuspicion of iron overload. Non-invasive estimation of liveriron stores using SQUID or MRI can be helpful if available.

Sideroblastic anaemia. Iron overload often complicatessideroblastic anaemia. Co-inheritance of an HFE variantsuch as C282Y of H63D may increase the risk of ironloading. Phlebotomy should be considered as a therapeuticoption as some patients have surprisingly shown animprovement in Hb levels following normalization of tissueiron with phlebotomy (Cotter et al, 1999). The rate ofphlebotomy that can be tolerated is highly variable andneeds to be determined empirically.

Porphyria cutanea tarda. This disorder, characterized bya photosensitive dermatosis and hepatic siderosis, isassociated with a number of risk factors including co-inheritance of an HFE mutation, high alcohol ingestion,hepatitis C infection (Bulaj et al, 2000) and thalassaemiatrait (Adjarov et al, 1984). Treatment is effective withphlebotomy or desferrioxamine (Rocchi et al, 1991).Provided there is adequate erythropoietic reserve, phle-botomy is generally simpler to perform.

Principles and objectives of chelation therapyThe goals of chelation can be summarized firstly as theachievement of safe tissue iron concentrations by promotingnegative iron balance and secondly as the detoxification ofiron until this goal has been achieved. Only a smallproportion of body iron is available for chelation at anypoint in time and some of this iron is required for a variety ofessential metabolic functions. Chelatable iron is that whichbecomes available from the continuous catabolism of redcell haemoglobin amounting to 20±30 mg/d, as well as ironthat is made available within cells from the continuousbreakdown of ferritin within lysosomes. It follows that large

intermittent doses of chelator will be less efficient andpotentially more toxic than lower doses given morecontinuously. Because iron is needed for essential metabolicfunctions, the dose schedule used for any chelator involves abalance between the risks of excess iron and those of excesschelator (Porter, 1997). The efficiency of currently usedchelator regimens is remarkably low; 90% of administeredsubcutaneous desferrioxamine is excreted without bindingiron (Porter et al, 2000) with 96% of deferiprone having thesame fate (Al-Refaie et al, 1995b). As discussed, a `safe' levelof tissue iron varies with age diagnosis and rate of ironloading and probably also on iron distribution within thebody. An assessment of organ function in addition to tissueiron levels will influence chelation management (TIFGuidelines, 2000).

Detoxification of iron requires stable binding of the sixco-ordination sites of iron by a chelator, with theprevention of redox cycling and oxidative damage. Ingeneral, hexadentate chelators, having six binding sites,have a more stable co-ordination chemistry than bidentatechelators, which have only two active co-ordination sitesand therefore require three chelator molecules for each ironatom. This is particularly important at low concentrationsof chelators when bidentate compounds tend to dissociate.Rapid improvement in cardiac function with continuousintravenous desferrioxamine is probably a result of chelationof relatively small toxic iron pools within the plasmacompartment, such as plasma non-transferrin-bound iron(Porter et al, 1996), or within the heart, such as thechelatable labile intercellular pool (Zanninelli et al, 1997).The reader is referred to other publications (Porter, 1996)for a detailed discussion of the principles of chelationtherapy.

Subcutaneous desferrioxamine infusionMechanism of action and pharmacology. Desferrioxamine is

a siderophore (a naturally occurring iron-carrier) and isproduced and purified from the microbe Streptomyces pilosus.One molecule of chelator binds one atom of iron forming thehighly stable hexadentate iron complex ferrioxamine atphysiological pH values. Owing to its size, desferrioxamine ispoorly absorbed from the gut. Desferrioxamine is metabo-lized in the liver into iron-binding metabolites which aremore plentiful when the therapeutic index is high andthere is greater excess of iron-free chelator (Porter et al,1998). Urine iron is derived from that released after thebreakdown of red cells in macrophages, whereas faecal ironis derived from iron chelated within the liver (Hershko &Rachmilewitz, 1979; Pippard et al, 1982b). Desferrioxaminehas a short plasma half-life (initial half-life, 0´3 h) (Lee et al,1993), being eliminated rapidly in urine and bile. Once aninfusion of desferrioxamine stops, iron chelation will ceasesoon thereafter. Because at any moment only a smallproportion of body iron is available for chelation, the longerthe duration of infusion, the more efficient the chelationprocess. This may be particularly important in patients withsevere iron overload (Davis & Porter, 2000).

Evidence of efficacy. There is now overwhelming evidencefor the efficacy of desferrioxamine on long-term survival


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and in preventing complications of iron overload and,hence, it is recommended as first-line therapy for trans-fusions. However, this evidence has taken over 30 years toaccumulate. Desferrioxamine was initially evaluated intra-muscularly and early studies showed that liver iron andfibrosis could be stabilized over a period of 8 years inchildren (Barry et al, 1974). It was then found that 24 h i.v.desferrioxamine infusions induced more urinary iron thanthe same dose given as an intramuscular bolus (Propperet al, 1976). Later it was shown that 24 h subcutaneouswas nearly as effective as intravenous desferrioxamine atinducing urinary iron excretion (Hussain et al, 1976;Propper et al, 1977). Iron balance could be achieved intransfusionally-dependent thalassaemia with only a 12-hinfusion at a dose of 30 mg/kg, measuring urinary iron only(Pippard et al, 1978, 1982a). In principle, iron balance canbe achieved at even lower desferrioxamine doses when givendaily, if faecal excretion and increased excretion withascorbate (Pippard et al, 1982a) are taken into account.

Evidence of the efficacy in preventing (Wolfe et al, 1985;Zurlo et al, 1989; Brittenham et al, 1994; Olivieri et al,1994) and reversing (Marcus et al, 1984; Davis & Porter,2000) the long-term cardiac complications is persuasive.Evidence for improvement in survival with desferrioxamineis now incontrovertible (Zurlo et al, 1989; Brittenham et al,1994; Olivieri et al, 1994; Gabutti & Piga, 1996).Compliance with treatment is the key to survival. Patientswho comply have 100% survival at the age of 25 years,whereas survival is only 32% in those who comply poorly(Brittenham et al, 1994). Patients who administer sub-cutaneous desferrioxamine infusions more than 250 times ayear (about five times a week) have 95% survival at30 years of age, whereas survival at 30 years of age is only12% in those who fail to achieve this target (Gabutti & Piga,1996). Recently reported relatively poor results from the UKdatabase with only 50% survival at 35 years probablyreflect poor compliance in patients not attending thalas-saemia centres (Modell et al, 2000). The results contrastwith those of a single UK centre (University College LondonHospital, UCLH) in which actuarial survival in 103 patientsat 40 years was 80% (Davis et al, 2001).

A variety of endocrine complications of transfusional ironoverload are also becoming less common in optimallytreated cohorts of patients (De Sanctis et al, 1989).Subcutaneous desferrioxamine infusions, beginning beforethe age of 10 years, significantly reduce gonadal dysfunc-tion, with improvement in pubertal status and growth(Bronspeigel-Weintrob et al, 1990). There is continuingimprovement in fertility, although secondary amenorrhoeais still common (Chatterjee et al, 1993). The onset of glucoseintolerance is delayed and glucose intolerance may beimproved by the timely use of desferrioxamine (Fosburg &Nathan, 1990).

Recommended dose and frequency. Accumulated experiencehas shown that, on a regime of 40 mg/kg (range 30±50 mg/kg) given as 8±10 h infusions on a minimum of fivenights a week, iron balance is achieved in hypertransfusedpatients with thalassaemia major and, by inference, otherpatients who are completely transfusion dependent. This

will maintain iron levels below those regarded as toxic(Olivieri & Brittenham, 1997). However, the dose ofdesferrioxamine should be adjusted according to body ironload, age and diagnosis. A dose of 40 mg/kg is usuallyadequate in transfusion-dependent patients who complywith treatment five nights a week, although a mean dailydose of up to 50 mg/kg may be necessary and morefrequently if unacceptable levels of iron loading have alreadyaccumulated. Doses above 40 mg/kg are not recommendeduntil growth is complete because of the risk of growthretardation with doses above this (Piga et al, 1988). Inpatients under 5 years of age, doses in excess of 35 mg/kg/dmay be inadvisable. In severe iron overload, although dosesabove 50±60 mg/kg have been given, these are notrecommended by the manufacturers and increase the riskof unwanted effects. Recently, it has been shown thaturinary iron excretion similar to that achieved with 10 hinfusions can be achieved by twice daily `bolus' s.c.injections of desferrioxamine infusion (Jensen et al, 1996;Borgna-Pignatti & Cohen, 1997; Franchini et al, 2000).However, the effects on faecal excretion and long-term ironbalance are not known. These `boluses' generally have to begiven over about 10 min to minimize the discomfort ofadministration. In patients already established on s.c.infusions, this approach has not been a popular alternativein our clinic. However, this may offer an alternative to theuse of infusion pumps when these are not available or inolder patients (e.g. with myelofibrosis) in whom training inthe use of infusion pumps proves impractical.

Downward adjustment of the dose can be made as ferritinfalls by reference to the therapeutic index in thalassaemiamajor (Porter et al, 1989a). If liver iron quantification isavailable, a scheme for dose adjustment has been suggested(Olivieri & Brittenham, 1997). However, liver iron determi-nations are unlikely to be available more frequently thanyearly, even in centres performing these measurementsroutinely, and ferritin measurements are therefore stillhelpful in dose adjustment. These schemes will reduce therisk of toxicity from excess chelator, but it is not a substitutefor careful clinical monitoring.

In patients with less than total transfusion requirement,clearly required dosing and frequency may be less. An effortshould be made in such cases to estimate the rate of ironloading and iron excretion. Subcutaneous infusions ofstandard doses of desferrioxamine two to three times weeklywill generally achieve negative iron balance in thalassaemiaintermedia and other haemolytic conditions requiringintermittent transfusions, but this should be worked outon an individual basis. In sickle cell disease, chelation is notnecessary unless patients receive frequent `top up' ratherthan exchange transfusions. Iron balance with desferri-oxamine and the proportions of faecal and urinary ironexcretion appear similar to those seen in thalassaemiasyndromes (Collins et al, 1994). Ferritin should not be usedas a criterion for starting treatment and estimation of liveriron is recommended for initiation and monitoring oftreatment.

Vitamin C increases desferrioxamine-induced urinaryiron excretion by increasing the availability of chelatable

244 Review


iron, but if given in excessive doses may increase the toxicityof iron (Nienhuis, 1981). It is recommended not to givemore than 2±3 mg/kg/d as supplements; these should betaken at the time of the desferrioxamine infusion so thatliberated iron is rapidly chelated. It is advisable not to startvitamin C supplementation until desferrioxamine treatmenthas been ongoing for several weeks.

The manufacturers do not recommend desferrioxaminefor use in pregnancy. However, there have been over 100pregnancies reported in iron-overloaded patients takingdesferrioxamine without apparent harm to the fetus. Abalanced judgement has to be made about possible risks tothe fetus from desferrioxamine and the risks to the motherof 9 months without chelation treatment. It is the author'spractice to give low-dose desferrioxamine (20±30 mg/kg) inthe final trimester to mothers who have a perceived highcardiac risk.

Achieving acceptable compliance. Practical measures may beused to maximize compliance. Local mild reactions are quitecommon with skin itching, erythema, induration and mildto moderate discomfort at the site of subcutaneousinfusions. Persistent local reactions may be reduced byvarying the site of injection, lowering the strength (thisshould never be above 10%) or by adding 5±10 mg ofhydrocortisone to the infusion mixture in severe cases. Thechoice of needles is important to success and various optionsmay need to be explored with the patients or parents to finda preference. Butterfly needles (25 gauge) suit manypatients; they must be inserted at an angle of about 458 tothe skin surface and care should be taken to teach patientsto avoid intradermal injection, which can lead to skinulceration. The needle tip should be inserted well into thesubcutaneous tissues and the tip should move freely whenthe needle is waggled. Other patients prefer needles whichare inserted vertically (such as `Thallaset' needles). Thesehave a very narrow gauge and preattached tape for easyadhesion to the skin. The siting of the needle insertion isalso important; the optimal position is generally in theabdomen, although the deltoid and thigh can be used ifpatients are shown how to avoid important vessels, nervesor organs. EMLA (Astra-Zaneca) cream applied at least30 min before insertion of the needle is helpful to somepatients, especially children.

Historically, the most widely used battery-operatedsyringe drivers (e.g. Graseby) deliver 10±30 ml. These aresuited to subcutaneous infusions for 8±12 h daily. However,they are intermittently noisy and larger than ideal fordaytime use. Recently, small silent infusors (Cronoject) havebecome available, which are more popular with patients,especially for daytime use. Pre-filled balloon pumps (e.g.Baxter) which are silent and light are now available thougha variety of distributors (Clinovia, Fresenius) (Araujo et al,1996). Although expensive, the cost can usually be agreedby the health authority and compliance is generallyimproved significantly. CADD (Sims±Graseby) devices havebeen also used as delivery systems, both intravenously andsubcutaneously; the more advanced of these have devicesrecord the time and frequency of use, thus helping inmonitoring compliance.

Monitoring and encouraging compliance. Compliance isaffected by many factors, both practical and psychological.It is becoming clear that results from dedicated thalassaemiacentres are better than for isolated clinicians. Compliancerequires a sustained and secure relationship between thedoctor, patient or parents with regular discussion andsupport. In an appropriately funded centre, the input ofhaemoglobinopathy specialist nurses and psychologists isinvaluable to maximize compliance at different stages in apatient's life. Continuity of care is critical to success,particularly in adolescence and early adult life. Input froman experienced psychologist, counsellor or trained nursecan help to identify when `life events' have contributed to aperiod of poor compliance.

There is no perfect way to measure compliance,particularly if the patient wishes to mislead cliniciansabout chelation use. One approach is to give patients acalendar in which each infusion of desferrioxamine is noteddown during the treatment. Poor compliance should besuspected when the serum ferritin rises in the absence ofinflammatory disease or when liver iron increases. Thereturn of used vials, the use of prescriptions and the loggingof infusion times with CADD pumps have all been used tomonitor compliance.

Prevention and management of chelation-related compli-cations. Toxic effects resulting from desferrioxamine over-dosing are now rare provided recommended dosingschedules are not exceeded and doses are reduced at lowlevels of iron loading. Toxicities resulting from excess dosinginclude: high frequency sensory neural loss with tinnitusand deafness in severe cases (Olivieri et al, 1986; Porter et al,1989a); retinal toxicity with night blindness, impairedcolour vision, visual fields and visual acuity (Davies et al,1983; Olivieri et al, 1986); growth retardation (Piga et al,1988) and skeletal changes (De Sanctis et al, 1996). At veryhigh doses of 10 mg/kg/h or more, occasional cases ofrenal impairment (Koren et al, 1991) and interstitial pneu-monitis have been reported (Freedman et al, 1990).

High frequency sensorineural loss and retinal damage aregenerally reversible provided they are identified early(Olivieri et al, 1986; Porter et al, 1989a). Therefore, regularscreening is advised particularly if intensive chelationtreatment is being contemplated. In patients developing com-plications, desferrioxamine should be temporarily stoppedand reintroduced at lower doses when investigations showresolution. There may also be an increased risk of retinaltoxicity in patients with diabetes (Arden et al, 1984).

Interpretation of poor growth requires considerable skilland experience because both iron overload and excessivetreatment can retard growth. Risk factors include a youngage of starting treatment (, 3 years) and doses in excess of40 mg/kg/d (De Virgillis et al, 1988; Piga et al, 1988).Growth velocity resumes rapidly when the dose is reduced to, 40 mg/kg/d and does not respond to hormonal treat-ment. Skeletal changes include rickets-like bony lesions andgenu valgum in association with metaphyseal changes,particularly in the vertebrae, giving a disproportionatelyshort trunk (De Virgillis et al, 1988; Olivieri et al, 1992a;Gabutti & Piga, 1996). Radiographic features include


Review 245

vertebral demineralization and flatness of vertebral bodies.Growing patients should have annual radiological assess-ment of the thoracolumbar±sacral spine as well as theforearm and knees, and the dose of desferrioxamine shouldbe reduced if significant changes are noted, as they areirreversible (De Sanctis et al, 1996). The risk factors are thesame as for growth retardation.

Care should be taken to prevent sudden intravenousboluses of desferrioxamine as this may lead to nausea,vomiting, hypotension with acute collapse or even transientaphasia (Dickerhoff, 1987). Care should also be taken withdesferrioxamine in combination with psychotrophic drugs,as desferrioxamine potentiated the action of phenothiazinederivatives leading to reversible coma in two non-iron-overloaded patients (Blake et al, 1985).

Severe allergy to desferrioxamine is a rare event andindependent of dose. This can present with true anaphylaxisor, occasionally, with less obvious features such as fevers,muscle aches or arthralgia during infusions. It can beeffectively treated by careful desensitization, carried outunder close medical supervision (Miller et al, 1981; Bosquetet al, 1983). Desensitization is usually successful, butmay need to be repeated more than once. If it is unsuc-cessful, an alternative chelator such as deferiprone shouldbe considered. Occasionally, severe local reactions with localerythema at the site of the subcutaneous infusion canrespond to desensitization.

There is an increased risk of Yersinia infection in ironoverload and this increases further with desferrioxamine usebecause ferrioxamine can be used by Yersinia as a source ofiron for growth (Robins-Browne & Prpic, 1985; Gallant et al,1986). Any patient taking desferrioxamine who presentswith diarrhoea, abdominal pain or fever should stop treat-ment until Yersinia infection can be reasonably excluded.Yersinia can be diagnosed using special culture media fromblood or stool or by serological tests, but the pick-up rate islow and treatment should be initiated on clinical suspicion.Ciprofloxacin is the current treatment of choice. Desferri-oxamine can generally be restarted after about 2 weeks oftreatment. Rarely, is infection recurrent. Other infectionssuch as Klebsiella may also be exacerbated by continueddesferrioxamine. It is sensible to stop desferrioxamine inanyone with an unexplained fever until the cause has beenidentified.

Intravenous desferrioxamine for high-risk casesIn patients with consistently high levels of iron overload orthose who develop cardiac or other serious complications,24 h continuous chelation therapy should be considered.Historically, high doses of i.v. desferrioxamine were given inhigh-risk cases, with resulting toxicity (Davies et al, 1983;Marcus et al, 1984), and often as intermittent infusions(Cohen et al, 1987). In principle, continuous infusion willprovide better protection from non-transferrin plasma iron(Porter et al, 1996) and recent findings provide evidence ofthe long-term benefit of continuous desferrioxamine atrelatively modest doses (Davis & Porter, 2000). An actuarialsurvival of 61% at 13 years was found in high-risk patients(n � 25) with life-threatening cardiac dysrhythmias

(n � 6), left ventricular dysfunction (n � 6), gross ironoverload (n � 10) and poor tolerability of subcutaneousdesferrioxamine (n � 3). Using continuous infusion ofdesferrioxamine through the Portacath, cardiac dysrhyth-mias were reversed in 6/6 patients; resting left ventricularejection fraction improved in 7/9 patients from 36 ^ 6% to49 ^ 8% (P � 0´002), with reversal of biventricular heartfailure in 4/4 patients. The principal catheter-relatedcomplications were infection (1´15/1000 catheter days)and thromboembolism (0´48/1000 patient days), similar toother patient groups. Desferrioxamine toxicity was observedin only one patient, in whom the recommended therapeuticindex was transiently exceeded. Portacaths stayed in situ amedian of 21 months, which was generally long enough toobserve a significant fall in serum ferritin and improvementin cardiac performance. The rate of fall in ferritin wasinitially rapid (approximately 1000 g/l/month) for valuesabove 4000 mg/l and slower at 130 mg/l/month below thisvalue. Preliminary results in a further prospective study alsoshow significant improvement in cardiac T2* within6 months of commencing this regimen (Anderson et al,2000a).

Doses in excess of 50±60 mg/kg appear not to benecessary to achieve reversal of heart failure or dysrhyth-mias and continuous chelation appears to be the key to thissuccess. Attention to detail of Portacath management isimportant to successful outcome. Patients had Portacathsaccessed with repositioning of the needle once weekly bytrained staff on daycare. The regular repositioning of theneedle appeared to be helpful in reducing local infection atthe exit site of the port. Owing to the finding of thrombosisand the prothrombotic tendency of thalassaemia patients,concomitant use of warfarin with a view to running anInternational Normalized Ratio (INR) value between 2 and3 is now standard practice in our unit.

Compliance is generally much improved using thisregimen often continuing after the Portacath was removed.Continuous desferrioxamine infusion should thus be con-sidered in patients at high risk, namely those with ferritinvalues persistently . 2500 mg/l (Olivieri et al, 1994); liveriron . 15 mg/g dry weight (Brittenham et al, 1994);significant cardiac disease such as significant cardiacdysrhythmias (Davis & Porter, 2000) or evidence of failingventricular function (Davis & Porter, 2000). This regimenshould also be considered for those with the inability to usesubcutaneous desferrioxamine regularly, or with persistentpoor compliance, female patients who plan pregnancy,patients planning a bone marrow transplant and those withactive hepatitis C. Before inserting a Portacath, or after thisis removed, continuous subcutaneous desferrioxamineusing disposable infusors should also be considered, asexcellent results can be obtained. Experience of Portacathuse in sickle cell patients has been less good, with a higherincidence of thrombosis and infections, and we do notgenerally recommend this approach.

Oral chelation therapy with deferiproneMechanism of action and pharmacology. Three deferiprone

(L1) molecules are required to bind one iron atom (bidentate

246 Review


chelation). Each molecule is neutrally charged, has abouta third of the molecular weight of desferrioxamine and ismore lipid soluble. These properties allow rapid GI absorp-tion and access to intracellular iron pools (Porter, 1996).The drug appears in the plasma 5±10 min after oralingestion with high plasma concentrations in excess of300 mmol/l at a dose of 50 mg/kg (Kontoghiorghes et al,1990; Al-Refaie et al, 1995b). The plasma half-life isshort (1´52 h) (Al-Refaie et al, 1995b) and there is rapidinactivation by glucuronidation in the liver. The major formin the urine is the iron-free glucuronide (Kontoghiorgheset al, 1990). Unlike desferrioxamine, there is no effectiveiron excretion in the faeces. The iron±chelate complex ofbidentate chelators are less stable than hexadentatechelators such as desferrioxamine and there is in vitro andanimal data to support this concern. There has been littleclinical investigation which addresses this question,although it is possible that the arthritis associated withdeferiprone, particularly in heavily iron-loaded patients,results from instability of the iron±chelate complex. Theeffect of ascorbate on iron excretion with deferiprone is notclear but is potentially harmful and is not recommended.

Evidence of efficacy. Evidence of efficacy is based on theeffects on iron excretion, serum ferritin and liver ironconcentration. There are as yet insufficient data to drawconclusions about the long-term effects on morbidity andmortality. Daily doses between 90 and 200 mg/kg wereinitially reported to induce sufficient urinary iron excretionfor negative iron balance in heavily overloaded patients(Kontoghiorghes et al, 1987). Later it was found that75 mg/kg/d but not 50 mg/kg/d promoted negative urinaryiron balance in poorly chelated patients and that urinaryiron correlated with serum ferritin (Olivieri et al, 1990).Balance studies showed the effect on faecal excretion is notclinically significant (Olivieri et al, 1990; Collins et al, 1994)and that total iron excretion at 75 mg/kg/d in three divideddoses is about 60% of that seen with a 12-h infusion ofdesferrioxamine at 50 mg/kg (Collins et al, 1994).

Falls in serum ferritin have been most apparent inuntreated or inadequately treated patients beginning withvalues above 5000 mg/l (Al-Refaie et al, 1992). In India,where many patients have no chelation treatment, theserum ferritin fell from initially very high levels by anaverage of more than 3500 mg/l over a 20-month period(Agarwal et al, 1992). There was also a significant but lessdramatic fall in serum ferritin in poorly chelated patientsfrom Canada over 3 years from 3975 to 2546 mg/l at adose of 75 mg/kg/d (Olivieri et al, 1995). In patientswith pretreatment values below 2500 mg/l there was nosignificant change, a finding confirmed in other studies(Hoffbrand et al, 1998; Cohen et al, 2000). An analysis ofchanges in serum ferritin for patients with pretreatmentvalues of approximately 1000 mg/l or less would be helpful.

The effects of deferiprone on liver iron were not reporteduntil 1995 when a 3-year follow-up was reported in 21patients (Olivieri et al, 1995). The findings tend to parallelthose with serum ferritin in that decrements occur mainlyin patients with high pretreatment values. In a more recentfollow up in the same patients over a mean of 4´6 years,

hepatic iron was above 15 mg/g dry weight in 7 out of 18patients (39%) (Olivieri et al, 1998), with a trend toreduction only in patients with the highest pretreatmentvalues. In other studies in which only single biopsies wereperformed (Hoffbrand et al, 1998), hepatic iron was greaterthan 15 mg/g dry weight in 10 out of 17 patients (58%)after a 2±4 year follow up and below 7 mg/g dry weight inonly two patients. In a 7±8 year follow up of seven patients,there was an `unexplained resurgence' of serum ferritinafter 4±5 years, associated with a concomitant increasein liver iron in three cases (Tondury et al, 1998). Thereis considerable variability between different studies con-cerning the effectiveness at reducing liver iron to acceptablelevels (Longo et al, 1998; Del Vecchio et al, 2000), whichcould reflect variable rates of metabolism such as glu-curonidation of deferiprone in different populations. It seemsclear, however, that liver iron does not equilibrate atacceptable levels in a sizeable proportion of patientsreceiving 75 mg/kg/d, the only dose at which prospectivetoxicity data are available.

In conditions in which the rate of iron loading is slowerthan in thalassaemia major, it would be anticipated thatliver iron should equilibrate at more acceptable levels atdoses of 75 mg/kg or less. Indeed, in a case report of apatient with thalassaemia intermedia, liver iron wasreduced from 14´6 to 1´9 mg/g dry weight after 9 monthsof deferiprone (Olivieri et al, 1992b). Controlled prospectivestudies on these and other iron-loaded patients, such astransfused patients, sickle cell disease would be helpful indeciding the balance of risk and benefit in such patients.

The effect on cardiac function, cardiac dysrhythmias andcardiac iron are uncertain, although anecdotal evidenceusing T2-weighted spin echo magnetic resonance imaging(Olivieri et al, 1992b) suggests that cardiac iron can bereduced. In a large study, 5 out of 51 patients treated withdeferiprone died after a mean of 18 months treatment, fourwith congestive heart failure (Hoffbrand et al, 1998).Because of the absence of a control group and theheterogeneity of the patients, it is not possible to interpretthe significance of these deaths with confidence.

Indications, dose and frequency. There is still uncertaintyabout the long-term efficacy of this drug (Pippard &Weatherall, 2000a). Thus, while some are wary ofrecommending deferiprone, even as second line-therapy(Pippard & Weatherall, 2000b), others are enthusiasticabout extending its use (Wonke et al, 1998; Kontoghiorgheset al 2000). This uncertainty is also reflected by the recentlicensing of the drug by the European Medicines EvaluationAgency (EMEA) in Europe but not by the Federal DrugAdministration (FDA) in the USA. In 1993 the FDArecommended that two prospective randomized studies beperformed before licensing could be considered. The first ofthese, the safety study, has been completed and publishedfor 187 patients (Cohen et al, 2000) and has been discussed.Unfortunately, the second, a randomized trial comparingthe efficacy of desfertioxamine and deferiprone, wasnever completed because of disagreements between someof the investigators and the participating pharmaceuticalcompany, Apotex. Because of remaining uncertainties, it


Review 247

seems advisable that all reasonable avenues for givingdesferrioxamine should be exhaustively explored beforeconsidering deferiprone.

The dose of deferiprone for which prospective obser-vations about side-effects are available is 75 mg/kg/d inthree divided doses (Cohen et al, 2000). It is not knownwhether higher doses increase the risk of unwanted effects.It is advisable that treatment is monitored with weekly bloodcounts so that treatment can be stopped rapidly if the whitecount begins to fall significantly. A liver biopsy to assess liveriron and liver fibrosis is also advisable before startingtreatment and at intervals thereafter. Because of fluctua-tions in liver function, liver function tests should also bemonitored regularly.

Some clinicians have investigated the combined use ofdesferrioxamine with deferiprone, either concomitantly(Wonke et al, 1998) or sequentially (Aydinok et al, 1999),the former study being associated with a fall in serumferritin and the latter with a small fall in liver iron in 6/7patients over a 6-month period. Combined treatment hasthe potential advantage of decreasing exposure to bothdrugs and increasing the iron excretion obtained withdeferiprone alone. Reported patient numbers are too small tocomment on the possible toxic effects of combined chelation.However, mixed ligand therapy could, in principle, increaseboth the efficacy and the toxicity of chelation therapybecause the low-molecular-weight deferiprone could`shuttle' iron or other metals onto a desferrioxamine`sink'. Until these issues have been investigated further, itis difficult to make general recommendations except to saythat sequential treatment (i.e. desferrioxamine followed bydeferiprone) has theoretically less risk of unforeseen effectsof metal shuttling than concomitant treatment (i.e. bothdrugs at the same time).

Prevention and management of chelation-related compli-cations. The most serious adverse effect is agranulocytosis[absolute neutrophil count (ANC) , 0´5 � 109/l]. Thiswas initially reported in 3±4% of patients treated withdeferiprone, with mild neutropenia in an additional 4% (Al-Refaie et al, 1992, 1995a). The mechanism is unclearbecause, although agranulocytosis appears unpredictablein humans given at 75 mg/kg/d, the effect in laboratoryanimals was dose and time dependent (Porter et al, 1989b,1991; Hoyes et al, 1993). In a more recent prospectivemulticentre study, agranulocytosis occurred in 0´6% per100 patient years at a dose of 75 mg/kg (rounded down tothe nearest half tablet of 250 mg) in three divided doses inwhich patients had weekly blood counts and deferiprone wasdiscontinued if the ANC was , 1´5 � 109/l (Cohen et al,2000). Milder forms of neutropenia (ANC 0´5 21´5 � 109/l) were observed in 5´4/100 patient years more frequentlyin non-splenectomized patients. It is therefore recommendedthat the ANC be monitored every week or more frequently ifthere are signs of infection. Treatment should be stopped atthe first signs of falling neutrophil counts. Neutropenia andagranulocytosis generally resolve within 4±124 d of dis-continuation of treatment (Hoffbrand et al, 1989; Hoff-brand, 1994; Cohen et al, 2000). Growth factors have beenused in severe or protracted neutropenia, although their

value is uncertain. In patients with agranulocytosis,reintroduction of deferiprone leads to a rapid fall in theneutrophil count in some patients, and is therefore contra-indicated. In patients with milder forms of neutropenia, re-introduction should only be considered under conditions ofvery careful monitoring. It may be wise to avoid deferipronein patients in whom stem cell or progenitor function iscompromised, such as those with Diamond±Blackfananaemia.

Painful swelling of the joints, particularly the knees, hasbeen seen in 6±39% of patients treated with deferiprone(Agarwal et al, 1992; Al-Refaie et al, 1992). This compli-cation is more common in patients with higher ferritinvalues (Agarwal et al, 1992; Cohen et al, 2000) and usually,but not always, resolves after stopping therapy. Otherunwanted effects are nausea (8%), mild zinc deficiency(14%) and fluctuation in liver function tests (44%) (Al-Refaie et al, 1995a). In the prospective study (Cohen et al,2000), the ALT value was significantly higher than thebaseline value at 3 months and 6 months, but thosewith values twice baseline levels did not increase signifi-cantly either in the hepatitis C-positive or -negativegroup. Unwanted effects caused treatment to be stopped in13±30% of patients in various studies (Al-Refaie et al, 1992,1995a; Hoffbrand et al, 1998). Isolated initial reports withdeferiprone, such as a fatal systemic lupus erythematosus(Mehta et al, 1991), increased antinuclear antibodies andrheumatoid factors (Mehta et al, 1993), and a fatal varicellainfection, have not been confirmed in more recent studies.Progression of audiometric disturbances has been describedin five out of nine patients who were switched fromdesferrioxamine to deferiprone (Chiodo et al, 1997). In thesame study, however, seven patients without audiometricdisturbance who were switched to deferiprone developed nonew abnormalities. Deferiprone is teratogenic in animalsand should not be given to patients attempting to conceive.Until more is known, contraception must be used bypotentially fertile sexually active women and men takingdeferiprone.

One study has described progression of hepatic fibrosisduring treatment with deferiprone (Olivieri et al, 1998). Inanother study, hepatic fibrosis was found in 7 out of 11patients on long-term deferiprone, and the fibrosis wasgreater in the hepatitis C-positive group than the hepatitisC-negative group (Tondury et al, 1998). Other reports havefailed to find progression of fibrosis which could not beexplained by concomitant hepatitis C infection (Hoffbrandet al, 1998; Piga et al, 1998; Wanlass et al, 2000).Assessment of fibrosis does not lend itself to ease ofquantification and is also subject to sampling effects.Furthermore, the presence of hepatitis C confounds theinterpretation of results. Although there is no proof ofprogression of fibrosis on deferiprone treatment, it seemsadvisable to recommend serial liver biopsies for patients onlong-term treatment.

CONCLUSIONS AND FUTURE PERSPECTIVES

From the above, it can be seen that the management of iron

248 Review


overload has to be tailored to the disease and individual inquestion, but the treatments and diagnostic tools currentlyavailable have a number of limitations. Because ironchelators were historically viewed as `orphan drugs',much of the information gleaned about both desferri-oxamine and deferiprone was necessarily obtained fromrelatively small, clinician-led, observational studies. Thepaucity of large controlled prospective studies, which areinevitably prohibitively expensive if not financed by a largepharmaceutical company or a major governmental researchbody, allowed the emergence of a diverse range of viewsabout the safety and efficacy of available treatments. In thisarticle an attempt has been made to base recommendationsabout practical management on evidence, recognizing thatthis is not always possible.

Despite these limitations, life expectancy in iron-over-loaded patients continues to improve. Encouragingly thereare a number of new oral chelators in preclinical andclinical trials which are being supported by pharmaceuticalcompanies. It is hoped and anticipated that, with theemergence of new techniques for monitoring iron overload,the accumulated experience of clinicians and the futurebacking of the pharmaceutical industry, the practicalmanagement of iron overload will continue to improve.

University College London, Thalassaemiaand Sickle Unit UCL Hospitals, London,UK

John B. Porter

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252 Review


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Practical management of iron overload