thalassemia, biology

Light and shadows in the iron chelation treatment of haematological diseases

Aurelio Maggio

Haematology II with Thalassaemia and Regional Coordination Centre for the Network on Haemoglobinopathies, Hospital ‘V. Cervello’,

Palermo, Italy

Summary

This review outlines the main chelator groups studied to date,

and the evidence for their clinical effectiveness. For each

treatment, the strength of evidence was documented according

to the guidelines from the American College of Cardiology and

the American Heart Association. Three main haematological

diseases were considered as models: thalassaemia major, sickle-

cell disorders and myelodysplasia. Although the data in the

literature do not allow firmly evidence-based conclusions, the

findings suggest that in thalassaemia major: (i) deferoxamine

remains the drug of choice for chelation treatment; (ii) if there

is deferoxamine intolerance or a change of treatment is

suggested, the options are deferiprone or, if the liver iron

concentration is high, deferasirox treatment; and (iii) if the

ferritin level is >2500 lg/l and liver iron concentation is >7 mg/g/dry weight, continuous subcutaneous (s.c.) or intra-

venous (i.v.) deferoxamine, or combined treatment with

deferiprone and deferoxamine is advised. In case of heart

failure, there is currently more solid documentation to support

continuous s.c. or i.v. deferoxamine treatment than combined

treatment with deferiprone and deferoxamine. However, more

recent data in the literature suggest that the latter could be

a satisfactory alternative. Finally, if iron chelation is required

for sickle-cell disorders or myelodysplastic syndromes, the

current data support the use of deferoxamine treatment.

Keywords: thalassaemia, sickle-cell disease, myelodysplasia.

Iron chelators complex with iron to enable it to be removed

from the body in the urine or bile. Chelation treatment aims to

reduce the labile iron pool or labile intracellular iron within

cells, non-transferrin-bound iron outside cells, and iron

overload in the form of ferritin and haemosiderin deposits in

different organs.

This review, addresses the successes and the disappoint-

ments of iron chelation therapy, and describes the effectiveness

of the main chelator groups in transfusion-dependent anae-

mias, including thalassaemia major, sickle-cell anaemia (SCA)

and myelodysplastic syndromes (MDS).

The effectiveness of iron chelation therapy is assessed

according to the principles of evidence-based medicine, using

the levels of evidence-designated in American College of

Cardiology and the American Heart Association guidelines

(Table I) (Ritchie et al, 1995; Klocke et al, 2003). The litera-

ture was searched for all three of these diseases using the Pub

Med (http://www.pubmed.gov) and American Society of

Haematology (ASH) meeting websites. Considering ‘thalas-

saemia’ as an example, relevant trials were identified using the

terms: thalassaemia and desferrioxamine or deferoxamine

(DFO), thalassaemia and deferiprone (L1), thalassaemia and

deferasirox or ICL670. All electronic searches were updated as

of April 2007. All published, randomised, controlled trials were

included in the evaluation, but published cohort studies were

also considered. Abstracts reported at ASH meetings were

reported in the text, but were not considered in the evaluation.

Main chelator groups

Chelators can be divided into three main groups according to

the way they bind iron: bidentate, tridentate and hexadentate

compounds. These differences involve differences in molecular

weight (MW) (Table II), leading to differences in intestinal

absorption. Intestinal absorption is about 95% for bidentate

and tridentate chelators, but is very poor for hexadentate

chelators. The main clinically studied compounds are sum-

marised below. For the other chelators listed in Table II, the

reader may consult other papers (Jackson et al, 1983; Rakba

et al, 1998; Torti et al, 1998; Bergeron et al, 1999; Green et al,

2001; Lovejoy & Richardson, 2002; Kontoghiorghes et al, 2004;

Donovan et al, 2005; Schroeder & Hasinoff, 2005; Alvero et al,

2006).

Bidentate group – deferiprone

Deferiprone was the first orally-active iron chelating drug to be

developed (Kontoghiorghes, 1982, 1993). Three molecules of

Correspondence: Professor Aurelio Maggio, Hospital V. Cervello,

Haematology II with Thalassaemia, Via Trabucco no 180, 90146

Palermo, Italy. E-mail: [email protected] and

[email protected]

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ª 2007 The Author Journal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 138, 407–421 doi:10.1111/j.1365-2141.2007.06666.x

chelator bind one iron atom (3:1 complexes) (Kontoghiorghes,

1982). Absorption is rapid and the drug is mainly excreted in the

urine (>75% in 24 h) (Kontoghiorghes et al, 1990a; Al-Refaie

et al, 1995a). The remaining 20% was not eliminated in the urine

and may be excreted in the faeces (Olivieri et al, 1990). Studies in

rats have shown accumulation mainly in the liver (Hileti et al,

1995), but there may well be differences between rodents and

humans in metabolism of L1. It is suggested that once the drug

reaches the liver, it can follow two metabolic pathways, ending

either in the excretion of the L1-iron complex in the bile, or in

the elimination of an L1-glucuronic acid complex through the

vascular pool. As glucuronidated L1 cannot bind iron, the rate

and the degree of glucuronidation may influence the effective-

ness of L1 (Singh et al, 1992). The effectiveness of an L1 dose

ranged between 3Æ8 and 6Æ8% (Kontoghiorghes et al, 1990a; Al- Refaie et al, 1995a). L1 has received authorisation as a second

line indication by the European Agency for the Evaluation of the

Medicinal Products (EMEA).

Tridentate group – deferasirox

Deferasirox (ICL670) is a tridentate orally-administered iron

chelator (Table II). It is absorbed rapidly, and the plasma half-

life ranges from 11 to 19 h (Nick et al, 2003). In iron-overloaded

rats, treatment with deferasirox caused a continuous decrease in

liver iron over the entire test period. In vivo studies of biliary

excretion suggest a chelation efficiency of 18% (Nick et al, 2003).

The main route of excretion is in the faeces (Nick et al, 2003).

Nephrotoxicity occurred in preclinical trials in rats and

marmosets, but was commonest in animals that were not

heavily iron-loaded (Nick et al, 2003).

The drug has reached the clinical stage. Its use was approved in

the United States by the Food and Drug Administration (FDA)

in November 2005 and it was licensed by EMEA for use in

Table I. Levels of evidence for individual class assignments according

to the American College of Cardiology and the American Heart

Association (Ritchie et al, 1995; Klocke et al, 2003).

A Data derived from multiple

randomised clinical trials

B Data derived from a single randomised

trial, or from non-randomised studies

C Consensus opinion of expert

Table II. Comparison of chelator properties in preclinical studies and their clinical stage of development.

Groups Compounds

Route of

administration Studies Clinical stage Company

Bidentate (3:1)

MW ¼ 100–250 Da Deferiprone Oral Phase I/II/III Marketed in Europe

(1999) and India (1995)

Apotex (Toronto,

Canada) Cipla

(Mumbai, India)

Hydroxamates Oral Only in 40 Egyptian

patients with TM

Not marketed —-

Catechols Oral Only in eight patients

with TM

Not marketed —-

Tridentate (2:1)

MW � 370 Deferasirox Oral Phase I/II/III Marketed in USA (2005)

licensed in Europe (2006)

Novartis (Basel,

Switzerland)

Deferitrin (GT252–56) Oral Phase I Not marketed Genzyme

(Cambridge,

MA, USA)

Thioesemicarbazones

(Triapine)

Intravenous Phase I/II as

antitumor agent

Not marketed Vion Pharm

(New Haven,

CT, USA)

PIH and Aroylhydrazone

analougues

Oral Only in cell cultures

and rodents

Not marketed —-

Exadentate (1:1)

MW ¼ 400–1000 Da Deferioxamine Subcutaneous,

intravenous

Phase I/II/III Marketed in USA and

Europe (1968)

Novartis

Tachpyr ND Only in cell cultures

and in rodents

—- —-

Hydroxyquinoline Need ‘in vivo’ studies

for oral activity

Only in cell cultures —- —-

Aminocarboxylates

(dexrazoxane)

Intravenous Phase III as cardioprotector

vs. anthracycline

Marketed in USA and

Europe (2004)

Pfizer (New York,

NY, USA),

Chiron

(Emeryville,

CA, USA)

Da, Daltons; MW, molecular weight; ND, not yet determined; PIH, pyridoxal isonicotinoyl hydrazone; TM, thalassaemia major.

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ª 2007 The Author 408 Journal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 138, 407–421

Europe in 2006 (Table II). It is authorised as first-line therapy in

patients with thalassaemia major aged >6 years, and as second-

line therapy in other chronic iron-overload conditions, and in

patients aged 2–5 years.

Hexadentate group – deferoxamine

Deferoxamine is effective in clinical use (Table II), although

the gastro-intestinal absorption of DFO is poor because of its

high MW. It is infused subcutaneously (s.c.) 5–7 times a week

for 8–12 h, usually overnight. The advised daily dose is 20 mg/

kg/d in children and 40–60 mg/kg/d in adults (Hershko et al,

1998). Intensive intravenous (i.v.) DFO treatment has been

used at 40–60 mg/kg/d in severely iron overloaded patients

(Davis & Porter, 2000). However, it is noteworthy to consider

that these recommended dosages are an oversimplification,

because they are varied according to the degree of iron

overload. The iron chelate is mainly excreted in the urine as

ferrioxamine, but biliary excretion may predominate at high

doses (Propper et al, 1976; Pippard et al, 1982).

Effectiveness of chelation treatments

Thalassaemia major

Deferoxamine treatment

Control of body iron burden Eight trials were considered: one

compared DFO with placebo and included a report with a

follow-up on the same trial (Barry et al, 1974; Modell et al,

1982), five studies compared DFO with L1 (Olivieri et al, 1990;

Maggio et al, 2002; Mourad et al, 2003; Gomber et al, 2004;

Olivieri & Brittenham 1997) and two compared different

schedules of DFO (Graziano et al, 1978; Borgna-Pignatti &

Cohen, 1997). However, few trials measured the same

outcomes. When DFO was compared with L1 or a different

DFO schedule, no statistically significant differences in effects

on iron overload were observed.

Conclusion: the high effectiveness of DFO in controlling

body iron burden has been demonstrated in multiple rand-

omised clinical trials (Level of evidence: A).

Side-effects The main side-effects of DFO, local skin reaction,

hyper-sensitivity, oto- and ophthalmic-toxicity, skeletal

impairment and infection with Yersinia enterocolitica, have

been described extensively (Orton et al, 1985; Olivieri et al,

1986; Dickeroff, 1987; De Virgiliis et al, 1988; Giardina et al,

1993; Rodda et al, 1995). Anaphylaxis, pulmonary fibrosis and

renal impairment have been reported less frequently (Bousquet

et al, 1983; Freedman et al, 1990; Koren et al, 1991). These

side-effects are generally agreed to be dose related (Porter &

Davies, 2002). Episodes of neutropenia have also been

described in patients receiving only DFO (Origa & Galanello,

2004; U. Bertola, M. Collel and A. Piga, unpublished

observations).

Conclusion: several side effects of DFO, mainly dose related,

were reported in mainly non-randomised clinical trials (Level

of evidence: B).

Endocrine complications Large retrospective and prospective

studies suggest that DFO treatment has some effect in

preventing endocrinopathy (Kruger et al, 1986; Brittenham

et al, 1994; Italian Working Group on Endocrine

Complications in Non-endocrine Diseases, 1995; Gamberini

et al, 1998, 2004; Borgna-Pignatti et al, 2004; Cunningham

et al, 2004), and the prevalence of insulin dependent diabetes,

hypogonadism and hypothyroidism has been lower in the last

decade, in comparison with earlier reports (Brittenham et al,

1994; Italian Working Group on Endocrine Complications in

Non-endocrine Diseases, 1995; Gamberini et al, 1998, 2004;

Borgna-Pignatti et al, 2004; Cunningham et al, 2004). There

are no sufficiently large prospective clinical trials in the

literature to show whether, DFO treatment alone is able to

reverse-established endocrinopathy.

Conclusion: some effectiveness of DFO in preventing

endocrinological complications has been reported in non-

randomised clinical trials (Level of evidence: B).

Cardiac complications It has been shown in retrospective and

prospective clinical studies (Table III), that intensified DFO

treatment by either s.c. or i.v. route can reverse cardiac

dysfunction because of iron overload, and increase survival in

thalassaemia-major patients with early or overt cardio-

myopathy (Davis & Porter, 2000; Miskin et al, 2003; Davis

et al, 2004). In these patients, improvement of the left

ventricular ejection fraction (LVEF) was associated with a

progressive increase in myocardial T2* (star) signal (Anderson

et al, 2004). Finally, a serum ferritin level consistently, above

2500 lg/l is associated with a high prevalence (75%) of cardiac disease (Olivieri et al, 1994), and lower ferritin levels

(£1000 lg/l) are associated with lower probability of heart failure (Borgna-Pignatti et al, 2004).

Conclusion: non-randomised clinical trials (Level of evi-

dence: B) suggested effectiveness of DFO in: (i) reversing heart

failure and cardiomyopathy progression; (ii) reducing heart

iron; and (iii) improving LVEF.

Effect on survival Two retrospective studies of patients with

thalassaemia-major treated by DFO reported an increased

survival for the most recent cohorts (Zurlo et al, 1989;

Borgna-Pignatti et al, 2004). The major variables associated

with prolonged survival were female sex (P < 0Æ01) and lower ferritin levels (£1000 lg/l). Recently, after a 15-year prospective study, in patients chelated with DFO, Efthimidias et al (2006)

suggested that left ventricular restrictive filling pattern measured

by echo-Doppler is an important predictor of cardiac mortality.

Data from the UK thalassaemia register, which covers the whole

country, showed poorer survival than that reported from

specialist centres (Modell et al, 2000). This was attributed to

non-adherence to the burdensome iron chelation regimen with

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ª 2007 The Author Journal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 138, 407–421 409

DFO, particularly, where the patients were cared for at general

hospitals with less of experience of the disease.

A study from Hong Kong showed an 87Æ6% probability of survival beyond the age of 20 years (Li et al, 2002). A number

of factors may coincide to produce disappointing results, such

as late start of DFO chelation treatment (the median age of

starting in the three cohorts studied was 5 years), the small

number of patients, poor treatment compliance, and the

inclusion of deaths from bone marrow transplantation.

Conclusion: non-randomised clinical trials (Level of evi-

dence: B) suggest the effectiveness of DFO in improving survival.

Deferiprone treatment

Control of body iron burden A meta-analysis (Addis et al, 1999)

showed that 51Æ8% of the patients receiving 75 mg/kg/d or more of L1 achieved negative iron balance. In three

randomised clinical trials (Olivieri et al, 1990; Olivieri &

Brittenham, 1997; Maggio et al, 2002) that compared

treatment with DFO and L1 for measures of iron overload,

there was no difference observed after 12 months of treatment

in ferritin levels, urinary iron excretion (UIE) or liver iron

concentration (LIC). Compliance was addressed in two of these

trials, and was found to be better in the L1 group than the DFO

group (P < 0Æ005) in one (Olivieri & Brittenham, 1997). In 1997, 532 thalassaemia patients from 86 different centres

were enrolled in a 3-year programme of the Italian Ministry of

Health for the controlled distribution of L1 (Ceci et al, 2002).

This study showed that 75 mg/kg/d of L1 was effective in

controlling body iron load, as determined by serum ferritin

levels.

Conclusion: these findings, derived from multiple random-

ised clinical trials (Level of evidence: A), suggest that, after

short-term treatment, L1 is as efficacious as DFO in controlling

iron load.

Main side effects There is a variable incidence of gastro-

intestinal symptoms and transient hypertransaminasaemia (Al-

Refaie et al, 1995b; Taher et al, 1997; Hoffbrand et al, 1998;

Cohen et al, 2000; Maggio et al, 2002). Arthropathy and/or

arthralgia are common, with an incidence of 3–38Æ5% (Agarwal et al, 1995; Cohen et al, 2000; Ceci et al, 2002;

Maggio et al, 2002). An increased incidence was observed in

patients with high ferritin levels and in those taking high doses

of L1 (Agarwal et al, 1995). Arthropathy, usually resolves

following a reduction in dose or temporary cessation of the

drug. There are occasional reports of zinc deficiency (Al-Refaie

et al, 1994; Hoffbrand et al, 1998) particularly in patients with

diabetes (Al-Refaie et al, 1994): this requires oral

administration of zinc. The most important side-effects are

neutropenia and agranulocytosis, and constant monitoring of

the white cell count is required during L1 treatment. The

reported incidence of neutropenia was from 2Æ1 to 5Æ4/100 patient-years, and the incidence of agranulocytosis ranges from

0Æ4 to 0Æ6/100 patient-years (Cohen et al, 2000; Ceci et al, 2002). The cause of agranulocytosis and neutropenia is

unknown. Rechallenge with L1 is associated with higher risk

of agranulocytosis or neutropenia (Ceci et al, 2002). A

reported increase in liver fibrosis (Olivieri et al, 1998) was

not confirmed in subsequent reports (Callea, 1998; Töndury

et al, 1998; R. Galanello, S. De Virgiliis and A. Agus,

unpublished observations; Stella et al, 1998; Maggio et al,

2002; Wanless et al, 2002).

Conclusion: non-randomised clinical trials (Level of evi-

dence: B) reported a variable incidence of side effects, mostly

transitory. The most severe side effect is agranulocytosis,

requiring careful monitoring.

Endocrinological complications: There is one published

prospective non-randomised clinical study comparing L1

with DFO in the prevention of major endocrinopathies in 47

beta-thalassaemia-major patients (Wang et al, 2006), all

previously treated with DFO. These patients were divided

into two groups, one of which received L1 and the other

continued DFO treatment. They were evaluated for the

incidence of new endocrinopathies, defined as growth

hormone insufficiency, diabetes mellitus, or gonadal

dysfunction over a period of 41Æ9 ± 17Æ7 months. The results suggest that there were no statistically-significant

differences in the incidence of endocrinopathies between the

groups. The limitations of this study were: small number of

patients, the possible risk of endocrinological damage during

prior chelation treatment and the relatively short-period of

study.

Table III. Comparison of effectiveness in car-

diac iron loading between deferoxamine (DFO)

versus DFO + L1 treatment.

DFO DFO + L1

No. of studies Evidence No. of studies Evidence

Reversal of heart failure 3 B 4* C

Heart iron 1 B 1 B

Progression of cardiomyopathy 2 B NT –

Improvement in LVEF (%)� or SF (%) 3 B 2 B

*An abstract on the reversal of heart failure with combined treatment was presented at ASH 2006

(Lai et al, 2006).

�Improvement was considered only where baseline values of LVEF were <55%. LVEF, left ventricular ejection fraction; NT, no trials; SF, shortening fraction.

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ª 2007 The Author 410 Journal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 138, 407–421

Conclusion: the effectiveness of L1 treatment in preventing

endocrinological complications has been reported in only one

non-randomised clinical trial (Level of evidence: B), and for

this reason, it has to be considered less documented in

comparison with DFO.

Cardiac complications Two retrospective clinical trials

(Anderson et al, 2002; Pepe et al, 2006) and one propective

randomised trial (Pennell et al, 2006) suggest that the ability of

L1 to remove iron is organ-specific, with greatest efficacy for the

heart as determined by variation in the cardiac T2* signal.

Moreover, in both the retrospective and the prospective

randomised trials the value of the cardiac T2* signal was

higher in the L1 than in the DFO-treated group (Anderson et al,

2002; Pennell et al, 2006; Pepe et al, 2006). After 1 year of

treatment in the randomised trial the L1-treated patients had a

greater increase in EF (3Æ1 ± 3Æ6%) than the DFO-treated patients (0Æ32 ± 3Æ4) (Pennell et al, 2006). However, these studies had some limitations. The L1 dosage (92 mg/kg) in the

randomised prospective clinical trial (Pennell et al, 2006) was

higher than that suggested by the manufacturer (75 mg/kg).

Secondly, the 3Æ1 ± 3Æ6% improvement in the EF (Pennell et al, 2006) was shown in subjects with normal baseline values and

may be without any clinical and cardiological significance.

Moreover, no change in EF was found in a very similar study

(Pepe et al, 2006). Thirdly, the clinical significance in terms of

heart iron removal, as indicated by the 1Æ5 ms increase in the myocardial signal (Pennell et al, 2006), is doubtful when

interpreted in the light of the cardiac iron concentration curve

in a gerbil model (Wood et al, 2005). Finally, the correlation

between the myocardial T2* signal and cardiac function for

wider T2* signal range is controversial (Anderson et al, 2002;

Pepe et al, 2006). An indirect suggestion about L1 heart-

specificity comes from two retrospective clinical studies (Piga

et al, 2003; Borgna-Pignatti et al, 2006), which found a higher

prevalence of cardiomyopathy progression in the DFO-group.

The limits of these studies may be: (i) different definitions of

progressive cardiomyopathy (an increase in New York Heart

Association (NYHA) class for Piga et al, 2003 and heart failure or

arrhythmia requiring treatment for Borgna-Pignatti et al, 2006);

(ii) a large number of patients in NYHA class I were considered

to have progression of cardiomyopathy (13/15) (Piga et al,

2003), a class not considered pathological (Dolgin, 1994); and

(iii) the lack of reference to major cardiac events (death or

hospitalisation for cardiovascular causes). Moreover, in the

studies of Ceci et al (2002) and Hoffbrand et al (1998), nine and

three patients respectively, died from heart failure during L1

treatment. Finally, to date, there are no papers in the literature

showing the ability of L1 administration alone to reverse heart

failure.

Conclusion: with a Level of evidence B, clinical trials with L1

suggest: (i) some effect on delaying progression of cardio-

myopathy; (ii) ability to reduce heart iron; (iii) mild improve-

ment of LVEF in subjects with normal values at baseline;

(iv) absence of data on the ability to reverse heart failure.

Effect on survival Because L1 was only recently marketed in

India (1995) and in Europe (1999), survival data for patients

treated from the outset with L1 alone are not available. So far,

all L1-treated patients who have been evaluated for the effect

on survival received prior therapy with DFO.

The main publications include two retrospective and two

prospective non-randomised clinical trials describing mortality

because of cardiac damage in patients treated with DFO and L1

(Hoffbrand et al, 1998; Ceci et al, 2002; Piga et al, 2003;

Borgna-Pignatti et al, 2006). The results of these studies are

summarised in Table IV.

However, these studies have some limitations (Table IV): (i)

the period of observation was quite different between studies;

(ii) within the same clinical study, there was a significant

difference in observation time between the L1 and DFO-

treated groups (Borgna-Pignatti et al, 2006); (iii) the age at

initial chelation treatment was not reported in one study

(Borgna-Pignatti et al, 2006) and in the other age was higher in

DFO- than in L1-treated patients (Piga et al, 2003); and (iv)

there are some discrepancies concerning the number of deaths

from heart failure and the onset of cardiomyopathy between

the studies of Ceci et al (2002) and Borgna-Pignatti et al

(2006) (Table IV). Recently, Ceci et al (2006) showed, in a

multicentre case-control study, that good compliance and L1

are protective against mortality.

Conclusion: these findings suggest (Level of evidence B) that

L1 probably has some effect on survival but, because of its

recent marketing and the limits of the reported studies, its

effect is less well documented than that of DFO.

Alternating or sequential deferoxamine and deferiprone treatment

Control of body iron burden An early report of the use of this

kind of treatment was reported by Aydinok et al (1999) who

performed a small non-controlled clinical study on seven

thalassaemic children. The results suggested a significant

reduction (P ¼ 0Æ03) in LIC at the 6th month of sequential therapy. In a prospective, randomised, controlled trial on the

safety and efficacy of alternating DFO (2 d/week) and L1 (5 d/

week) vs. DFO (5–7 d/week), Galanello et al (2006) did not find

any statistically significant difference between the two treatment

arms. However, in this trial the authors did not document

power calculations to define the number of patients that should

have been enrolled to find a possible statistically significant

difference between the two arms. A multicentre, randomised

sequential or alternating clinical trial comparing L1 vs. L1 (4 d/

week) and DFO (3 d/week) is ongoing (Maggio et al, 2004).

Conclusion: the single randomised controlled trial (Level of

evidence: B) suggests that alternating or sequential treatment is

not more efficacious than DFO alone in controlling body iron

burden.

Main side effects Adverse drug reactions were more common

in alternating treatment (24%) vs. DFO alone (7%), although

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ª 2007 The Author Journal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 138, 407–421 411

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Review

ª 2007 The Author 412 Journal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 138, 407–421

the majority of these were mild/moderate and occurred

within the first weeks of therapy (Aydinok et al, 1999;

Galanello et al, 2006). Two episodes of neutropenia were

described in the randomised trial during DFO treatment

(Galanello et al, 2006), while no episodes of agranulocytosis

were reported.

Conclusion: the main difference between sequential treat-

ment and L1 treatment alone was the absence of reported

agranulocytosis (Level of evidence: B). However, other large

clinical trials are necessary to confirm this finding. No

clinical studies have yet been published on the control of

complications, organ specificity and effect on survival

control.

Combined deferoxamine and deferiprone treatment

Control of body iron burden The first study showing success

with combined or associated treatment in five patients with

thalassaemia major was reported by Wonke et al (1998).

Subsequently three large prospective and two small, single

centre, randomised clinical trials addressed this issue in detail.

However, because of several limitations (number of patients,

missing data, short-period of treatment, etc.), the data from

the two randomised clinical trials must be interpreted with

caution and they were not included in the final evaluation

(Mourad et al, 2003; Gomber et al, 2004). In three prospective

clinical trials (Origa et al, 2005; Daar & Pathare, 2006;

Kattamis et al, 2006), in which, patients were treated for at

least 12 months, the serum ferritin levels fell dramatically. In

one prospective study, UIE was double that with DFO or L1

alone (P £ 0Æ01) (Origa et al, 2005). Similar results were reported by Athanassiou-Metaxa et al (2004). Two prospective

clinical trials (Daar & Pathare, 2006; Kattamis et al, 2006)

suggested that about 70% of subjects were compliant with

DFO.

Conclusion: non-randomised clinical trials (Level of evi-

dence: B) suggest good control of body iron burden using

combined DFO and L1 treatment.

Main side effects Four studies addressed major side effects in

patients with thalassaemia major receiving combined

treatment (Mourad et al, 2003; Origa et al, 2005; Daar &

Pathare, 2006; Kattamis et al, 2006). The incidence of

neutropenia, reported only in one publication (Origa et al,

2005) was 8Æ8%, while, the incidence of agranulocytosis (Mourad et al, 2003; Origa et al, 2005; Daar & Pathare,

2006; Kattamis et al, 2006) was from 2Æ2 to 4Æ2%, higher than that reported for L1 alone (Cohen et al, 2000; Ceci et al, 2002).

Another side effect was zinc deficiency (Origa et al, 2005),

normalised by zinc sulphate supplementation (Galanello et al,

2006).

Conclusion: non-randomised clinical trials (Level of evi-

dence: B) clearly suggest that, in combined DFO and L1

treatment, the incidence of agranulocytosis was higher in

comparison to that reported using L1 alone.

Control of complications and organ specificity

Endocrinological complications Platis et al (2004) reported the

effect of combined treatment in a small population of

thalassaemia-major patients with glucose metabolism

disturbances (GMD), diabetes mellitus, or impaired glucose

tolerance. There was an improvement of GMD in 1/3 cases

after 24–36 months of treatment. Recently, Farmaki et al

(2006) confirmed that combination treatment results in an

overall improvement in glucose metabolism.

Conclusion: some effect in reversing GMD has been reported

in combined DFO and L1 treatment (Level of evidence: B).

Cardiac complications A significant improvement of the LVEF

and the shortening fraction (SF) in comparison with the low

values at baseline were reported in two papers (Origa et al,

2005; Kattamis et al, 2006). Recently, an abstract and later, a

paper on a randomised placebo-controlled, double blind trial,

suggested that combined treatment is superior to DFO and

placebo in removing myocardial iron in thalassaemia-major

patients (Tanner et al, 2005, 2007). However, there are no

large retrospective or prospective clinical studies suggesting an

effect on the reversal of heart failure in patients with initial or

overt cardiomyopathy, except a single abstract presented at the

2006 ASH meeting (Lai et al, 2006). At the time of submitting

this review, there were five case reports suggesting the efficacy

of combined treatment in reversing heart failure because of

iron overload in patients with thalassaemia major (Wu et al,

2004; Tsironi et al, 2005a,b; Porcu et al, 2006; Tavecchia et al,

2006). In addition, reversal of heart failure was observed in a

patient with a severe type of juvenile hemochromatosis

(Daraio et al, 2005; Fabio et al, 2007).

Conclusion: trials using combination treatment suggest: (i)

the possibility of reversing heart failure (Level of evidence: C);

(ii) the possibility of removing myocardial iron (Level of

evidence: B); (iii) the ability to improve LVEF (Level of

evidence: B). Preliminary, but not evaluable data also suggest

some efficacy of the treatment in controlling progression of

cardiomyopathy.

Effect on survival As with treatment with L1 alone, no survival

curves are available for patients treated from the outset with

combined treatment. A group of 125/539 patients with

thalassaemia major, born in Cyprus after 1960 and starting

combination treatment in 1999 have been evaluated (Telfer

et al, 2006) using both a univariate (OR 0Æ39, 95% CI ¼ 0Æ19– 0Æ81, P ¼ <0Æ01) and multivariate analysis (OR 0Æ44, 95% CI ¼ 0Æ20–0Æ99; P £ 0Æ05). A protective effect was found for follow-up after the year 2000 (Telfer et al, 2006). Moreover,

there were no cardiac deaths in the patients who switched to

combination chelation treatment (Telfer et al, 2006).

Conclusion: there is only one published study, reporting

some effect of combination treatment on survival (Level of

evidence: B). For this reason, this effect must be considered less

documented in comparison with DFO alone.

Review

ª 2007 The Author Journal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 138, 407–421 413

Deferasirox treatment

Control of body iron burden Recently, two randomised

multicentre clinical trials addressed the effect of deferasirox

on body iron burden (Cappellini et al, 2006; Piga et al, 2006).

The first trial, which evaluated drug effectiveness (Cappellini

et al, 2006) involved 586 thalassaemia-major patients, 296

receiving deferasirox and 290 receiving DFO, aged 2 years or

older. The primary response criterion was defined as the

maintenance or reduction of LIC measured by liver biopsy or

superconducting quantum interference device (SQUID).

However, because a validation sub-study suggested that LIC

determined by SQUID was not fully reliable, only LIC

measured by liver biopsy was considered for final evaluation

of the study (Cappellini et al, 2006).

The authors concluded that the primary endpoint was not

obtained in the overall population (Cappellini et al, 2006), and

that this could be because proportionally lower doses of

deferasirox relative to DFO were administered to patients with

LIC levels <7 mg Fe/g dry weight. However, subjects with LIC

values of 7 mg Fe/g dry weight or higher had significant and

similar dose-dependent reductions in LIC and serum ferritin

(Cappellini et al, 2006). Another recent randomised phase II

trial reported similar results for patients with a LIC >7 mg/Fe/

g dry weight (Piga et al, 2006). However, this study also

measured LIC by SQUID. Both trials suggest that deferasirox is

as effective as DFO in patients with LIC values of 7 mg Fe/g/

dry weight or higher and at dosage of 20 mg/kg/d. No data on

compliance was reported in these studies.

In conclusion, further studies are necessary to show whether,

higher doses of deferasirox (>10 mg/kg) can control iron

overloading in patients with low or medium LIC (£7 mg Fe/g/ dry weight) with acceptable side effects. These are in progress.

Conclusion: the effectiveness of Deferasirox in controlling

body iron burden was good only for patients with LIC >7 mg/

g/dry weight, and it was shown (Level of evidence A).

Main side effects Dose adjustments, dose interruptions and

discontinuations were similar in the deferasirox and DFO

treatment groups (Cappellini et al, 2006) and gastro-intestinal

events and skin rash appeared in 15Æ2% and 10Æ8% of patients respectively. Mild, dose-dependent and sometimes transitory

increases of creatinine were observed in 38% of cases and dose

reduction was necessary in 13% (Cappellini et al, 2006). Two

patients developed alanine transaminase levels that were

greater than twice the normal range, and sensorineural

deafness and hypoacusis were more common in the DFO

(n ¼ 5) than in the deferasirox (n ¼ 1) group. Cataracts or lenticular opacities were considered related to the study drug

in one patient on deferasirox and four patient on DFO. Drug-

related agranulocytosis was not observed during this trial, and

no changes in zinc and copper levels were found at the end of

the study (Cappellini et al, 2006). Recently, Piga et al, (2006)

reported, in a phase II trial, that no patient discontinued

deferasirox because of drug-related adverse events, although

the frequency of mild to moderate gastro-intestinal

disturbances was higher in the deferasirox group than with

DFO (Piga et al, 2006). A recent postmarketing update by

Novartis reported cases of acute renal failure with a fatal

outcome particularly in patients with preexisting renal

conditions (http://www.drugs.com/pro/exjade.html). More-

over, postmarketing reports of neutropenia, agranulocytosis

and thrombocytopenia, prevalently in patients with

haematological disorders, were described.

Conclusion: a variable incidence of side-effects was shown

by these studies (Level of evidence: A) with postmarketing

reports of cases of acute renal failure and cytopenias.

Control of complications and organ specificity Except for an

abstract (Porter et al, 2005), there are so far no published

studies on this issue and for this reason, it is too early to know

the effect of deferasirox on the heart (Neufeld, 2006).

Effect on survival There are no published data on survival

using treatment with deferasirox.

Sickle-cell disease

Deferoxiamine treatment

Control of body iron burden Studies using DFO in patients with

SCD suggested a degree of iron excretion similar to that in

thalassaemia major patients. In two small studies (Cohen &

Schwartz, 1978, 1979), UIE after DFO administration was

28Æ7 mg/24 h and 24Æ3 mg/24 h respectively. The only randomised, double-blind study was aimed at the dose-

response relationship (Silliman et al, 1993). The most

limiting factor in DFO treatment is compliance, especially in

patients who start chelation treatment later in life, as is usually

case with SCD. Recently, the neurocognitive status of children

with SCD was considered a high risk factor for non-adherence

with home DFO administration (Treadwell et al, 2005). All

these data, weakly suggest that DFO could control iron burden

in SCD-transfused patients.

Conclusion: some effectiveness of DFO in controlling body

iron burden in SCD is documented, although it is based on a

lower grade of evidence than in thalassaemia major (Level of

evidence: B).

Main side effects No specific trials addressing this issue are

available. The main side effects of DFO in patients with SCD

are likely to be the same as those reported in thalassaemia

major. However, attention should be given to the risk of some

side effects peculiar to SCD e.g. (i) ocular toxicity (SCD can

damage endothelium and cause vasculopathy); (ii) high

frequency of sensorineural hearing loss (SCD patients can

have ischaemic events); (iii) pulmonary toxicity (SCD patients

can have acute chest syndrome); and (iv) zinc deficiency (SCD

patients can have zinc deficiency).

Review

ª 2007 The Author 414 Journal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 138, 407–421

Control of complications and organ specificity Gonadal

dysfunction and liver damage seems to be less severe in

patients with SCD (P. Harmatz, E. Butensky, E. Fung, L. Louie,

E. Theil and L. Ferrell, unpublished observations). Moreover,

Wood et al (2004), reported neither cardiac dysfunction nor

very low T2* myocardial signal in SCD patients. However, this

study had two limitations: (i) the small number of SCD

patients receiving transfusions for 13 years or longer; and (ii) a

long-time interval between the liver biopsy and T2*

myocardial determination (Wood et al, 2004). In contrast, a

preliminary report on 205 subjects with SCD showed cardiac

dysfunction, defined as a shortening function (SF) <28% or

LVEF <55%, was at the same frequency as that found in a

group of 146 patients with thalassaemia major (Fung et al,

2004). Recently, Fung et al (2007) found that transfused SCD

patients who died began transfusion and chelation therapy

later compared with those who survived.

Conclusion: there is a lack of data on the control of

complications and organ specificity of DFO in SCD.

Deferiprone treatment

Control of body iron burden and main side effects Three small

clinical trials addressed this issue. The first report, by Collins

et al (1994), suggested that the mean total daily iron excretion

during L1 treatment was sufficient to maintain net negative

iron balance in transfused patients with SCD. Hoffbrand et al

(1998), reported no differences in efficacy and side-effects

between SCD and thalassaemia-major patients. Voskaridou

et al (2005) reported 15 patients with serum ferritin levels

from 754 to 7620 lg/l, evaluated at baseline and after 12 months of treatment. Ferritin levels decreased significantly

by the end of the trial in 10/12 patients who completed the

study (P ¼ 0Æ0056). The drug was well tolerated and agranulocytosis was not reported. Although these data must

be considered as preliminary, they suggest that L1 could safely

control iron burden in SCD patients.

Conclusion: some effectiveness of L1 in controlling body

iron burden in SCD patients was shown with a Level of

evidence: B in small clinical trials. No agranulocytosis was

described.

Deferasirox treatment

Control of body iron burden and main side effects A recent

abstract and paper on the treatment of iron overload with

deferasirox in SCD patients (Vichinsky et al, 2005; Vichinsky

et al, 2007) reported a phase II study over a 1-year period.

The primary objective of this study was to evaluate the

safety and tolerability of deferasirox in comparison with

DFO (Vichinsky et al, 2005; Vichinsky et al, 2007). The

commonest adverse events associated with deferasirox were

generally mild. Mild non-progressive increases in serum

creatinine >33% of baseline and above the upper limit of

normal were observed in three patients receiving deferasirox.

Discontinuation rates from deferasirox (11Æ4%) and DFO (11Æ1%) were similar. Concerning effectiveness, a dose-effect relationship was observed and most patients assigned to

receive deferasirox doses of 30 mg/kg and DFO ‡50 mg/kg had an absolute change in serum ferritin. However,

clinical phase III trials, aimed at determining the real

effectiveness of this drug in SCD patients with iron overload

are necessary.

Conclusion: deferasirox at doses of 30 mg/kg seems to have

similar efficacy to DFO in controlling body iron burden in

SCD but this is so far documented only in a single phase II

study (Level of evidence: B).

Hydroxycarbamide and chelation treatments Ad interim

analysis of a multicentre, randomised, clinical trial

comparing L1 (75 mg/kg) vs. DFO (50 mg/kg) in SCD

patients (Maggio et al, 2005) reported that final ferritin

levels during chelation (DFO or L1) and HC (also known as

hydroxyurea) treatment (13–14 mg/kg) was significantly lower

in patients treated with HC compared with non-HC treated

patients (P £ 0Æ05). In addition, a significant reduction of final ferritin levels occurred in patients treated with L1 and HC

(Maggio et al, 2005). No cases of agranulocytosis or

neutropenia were observed in subjects simultaneously treated

with HC. The lower ferritin levels in HC-treated patients could

be related to reduction of erythron mass and consequently less

gastro-intestinal iron absorption (Maggio et al, 2005). No

studies on the use of deferasirox and hydroxyurea are currently

reported.

Myelodysplastic syndromes

Deferioxamine treatment

Control of body iron burden Evidence on the efficacy of iron

chelation therapy on iron overload in MDS patients was

reported in six-uncontrolled studies (Muntean et al, 1989;

Kontoghiorghes et al, 1990b; Jensen et al, 1992; Kobayashi

et al, 1996; Del Rio Garma et al, 1997; Borgna-Pignatti et al,

1998). Serum ferritin concentration decreased in 10/14

(71Æ4%) DFO-treated patients but increased in 2 and remained stable in 1. Iron chelation was found to decrease

blood transfusion requirements in 7/11 (64%) cases (Jensen

et al, 1992; Hemsen et al, 1996). However, this finding

should be confirmed in a phase III clinical trial.

The Italian Society of Haematology (ISH) recently published

consensus-based practice guidelines for the treatment of

primary MDS (Alessandrino et al, 2002): iron chelation

treatment is advised for in patients with a life span longer

than 6 months who have received more than 50 units of red

blood cells. The consensus statement on iron overload in MDS

(Gattermann et al, 2005) recommended that chelation treat-

ment should start when ferritin levels reach 1000–3000 lg/l and should be continued as long as iron overload remains

clinically relevant. UK-based medical experts in the clinical

Review

ª 2007 The Author Journal Compilation ª 2007 Blackwell Publishing Ltd, British Journal of Haematology, 138, 407–421 415

management of MDS and a representative from a District

General Hospital performed guidelines for the diagnosis and

therapy of adult MDS reviewed by the Sounding Board and by

the Committee of the British Committee for Standards in

Haematology (Bowen et al, 2003). The UK recommendations

for iron chelation in MDS are very similar to those from the

ISH, except that they suggested that treatment should be

started after approximately 25 units of red cells (Bowen et al,

2003). Moreover, according to the UK guidelines, the use of

twice daily subcutaneous bolus injections of DFO may be

considered where infusions are not tolerated, while the

addition of a single dose of DFO at each transfusion episode

was not considered to have any scientific basis (Bowen et al,

2003).

Conclusion: some effectiveness of DFO in controlling body

iron burden in MDS is documented (Level of evidence: B).

Deferiprone treatment

Control of body iron burden Kontoghiorghes et al (1990b)

reported no overall change of serum ferritin over a period of

up to 15 months in 2/6 patients with MDS. Kersten et al (1996),

in a 10 month prospective trial, found negative iron balance in

20/38 (56%) non-thalassaemic patients with transfusional iron

overload. L1 was clearly not effective in three patients (two with

myelofibrosis and one with myelodysplasia). One patient with

myelodysplasia developed agranulocytosis after 12 months of

treatment, which was rapidly reversed after stopping L1.

Conclusion: the effectiveness of L1 in controlling body iron

burden in MDS has been documented in a small number of

patients (Level of evidence: B). Agranulocytosis has been

reported.

Deferasirox treatment

Control of body iron burden In a prospective multicentre study

on 47 MDS patients, Gattermann (2005) reported a decrease of

LIC when deferasirox was used at doses of 10–30 mg/kg/d over

1 year. The effect of deferasirox on serum ferritin was the same as

for the LIC. Mild, moderate and transient adverse events were

reported. Four patients died because of disease-related causes

and two patients discontinued treatment because of drug-related

side-effects (vomiting and mild increase in creatinine values).

Mild increases in creatinine (>33% of baseline) were observed in

eight patients but only one discontinued therapy for this reason.

No neutropenia or arthralgia were described.

Conclusion: some effectiveness of Deferasirox in controlling

body iron burden in MDS is documented in only one study

(Level of evidence: B).

Practical considerations

Thalassaemia major From the reported documentation, it is

clear that DFO remains the drug of choice for chelation

treatment. If, during DFO treatment, ferritin levels are

<2500 lg/l and LIC <7 mg/g/dry weight continuation of this treatment is advised. Moreover, if, during the same treatment,

an increase of ferritin levels >2500 lg/l and of LIC >7 mg/g/ dry weight are demonstrated the following options are

available: an increase of DFO dosage, if this is possible, or L1

treatment, or, if a high value of LIC is demonstrated,

deferasirox therapy. If, after one of these treatments, ferritin

levels are <2500 lg/l and LIC <7 mg/g/dry weight, re- initiation of baseline treatment is advised. Alternatively, if

despite the change of treatment, ferritin levels remain

>2500 lg/l and LIC remains >7 mg/g/dry weight, continuous s.c. or i.v. DFO, or L1 associated with DFO therapy are

advised. In the presence of heart failure, continuous s.c. or i.v.

DFO treatment has more clear-cut documentation of efficacy

than combined treatment (DFO and L1) (Table III), although

more recent data in the literature seem to suggest that the latter

could be a satisfactory alternative. If DFO intolerance is

present, the following two options are possible: L1 or, if LIC is

>7 mg/g/dry weight, deferasirox. Monitoring of specific side

effects during chelation treatments is mandatory.

Sickle-cell disease and myelodysplastic syndromes There are few

relevant clinical trials to define the real impact of these

treatments in SCD and MDS or whether a particular form of

chelation therapy could be more effective than another.

However, at present there is more documentation to support

the use of DFO treatment in these diseases.

The author declares that he does not have potential conflicts

of interest with the pharmaceutical companies involved in

these studies.

Acknowledgements

The author thanks Dr Samir Ballas, Dr D. Rund, Dr B. Modell

and Dr L. Mancuso for reviewing the manuscript. Much of the

author’s knowledge of this subject was due to a research grants

from the Health Regional Service. Additional support for my

research was provided by Associazione per la Ricerca ‘Piera

Cutino’, Fondazione ‘Leonardo Giambrone’, Associazione del

Bambino Emopatico.

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