reduction of body iron stores to normal range levels in thalassaemia by using a...

Reduction of body iron stores to normal range levels inthalassaemia by using a deferiprone ⁄deferoxaminecombination and their maintenance thereafter bydeferiprone monotherapyAnnita Kolnagou1,2, Marios Kleanthous1, George J. Kontoghiorghes1

1Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol; 2Thalassaemia Unit, Paphos General Hospital,

Paphos, Cyprus

Thalassaemia major is one of the most common inherited

disorders with a high morbidity and mortality rate

worldwide (1, 2). Its main form of treatment is chronic

red blood cell transfusions, which can lead to toxic iron

overload and damage to multiple organs (2). Cardiac

iron overload damage is the most frequent cause of

death (2–6). Removal of excess storage iron can be

accomplished using mainly subcutaneous or intravenous

deferoxamine, oral deferiprone, oral deferasirox and

deferiprone ⁄deferoxamine combinations (7–9). Daily

administration of chelating drugs is required for remov-

ing the accumulated excess storage iron. Most patients

Abstract

Background: Iron overload and toxicity is the major cause of morbidity and mortality in thalassaemia

patients. New chelating drug protocols are necessary to treat completely transfusional iron overload and

eliminate associated toxicity. Appropriate deferiprone ⁄ deferoxamine combinations could achieve this goal.

Methods: A single-centre, single-armed, proof-of-concept study of the combination of deferiprone (75–

100 mg ⁄ kg ⁄ d) and deferoxamine (40–60 mg ⁄ kg, at least 3 d per week) was carried out in eight patients

with thalassaemia major (four men and four women) for 21–68 months. The patients were previously trea-

ted with deferoxamine and had variable serum ferritin [geometric (G) mean ± SD = 1446 ± 1035 lg ⁄ L]

and magnetic resonance imaging relaxation times T2* cardiac (Gmean ± SD = 10.32 ± 6.72 ms) and liver

(G mean ± SD = 3.77 ± 4.69 ms). The use of deferiprone (80–100 mg ⁄ kg ⁄ d) continued for 7–26 months in

seven of the eight patients following the combination therapy. Organ function, blood and other biochemical

parameters were monitored for toxicity. Results: The deferiprone ⁄ deferoxamine combination caused an

absolute value increase in cardiac (G mean ± SD = 29.6 ± 6.6 ms, P < 0.00076) and liver (G mean ± SD =

25.9 ± 8.07 ms, P < 0.00075) T2* and reduction in serum ferritin (G mean ± SD = 114.7 ± 139.8 lg ⁄ L,

P < 0.0052) to within the normal body iron store range levels. In two cases, normalisation was achieved

within a year. Deferiprone monotherapy was sufficient thereafter in maintaining normal range cardiac

(G mean ± SD = 31.4 ± 5.25 ms, P < 0.79) and liver (G mean ± SD = 26.2 ± 12.4 ms, P < 0.58) T2* and

normal serum ferritin (G mean ± SD = 150.7 ± 159.1, lg ⁄ L, P < 0.17) in five of the seven patients. No

serious toxicity was observed. Conclusion: Transfusional iron overload in patients with thalassaemia could

be reduced to normal body iron range levels using effective deferiprone ⁄ deferoxamine combinations.

These levels could be maintained using deferiprone monotherapy.

Key words iron overload; chelation therapy; deferiprone; deferoxamine; combination therapy; deferiprone monotherapy; iron normali-

sation; optimal therapy; dose protocol, transfusion

Correspondence George J. Kontoghiorghes, Postgraduate Research Institute of Science, Technology, Environment and Medicine, 3

Ammochostou Street, Limassol 3021, Cyprus. Tel: +35726272076; Fax: +35726271434; e-mail: [email protected]

Accepted for publication 14 July 2010 doi:10.1111/j.1600-0609.2010.01499.x

ORIGINAL ARTICLE

European Journal of Haematology 85 (430–438)

430 ª 2010 John Wiley & Sons A/S

do not comply with the prescribed deferoxamine dose

protocol (20–60 mg ⁄kg ⁄d for at least 5 d per week),

resulting in iron overload and premature death (6, 10).

The long-term efficacy of chelating drugs and of che-

lation protocols for iron removal can be monitored using

mainly serum ferritin and magnetic resonance imaging

relaxation times T2* (11–13). In general, normal range

cardiac and liver iron load is considered when T2*

> 20 ms and T2* > 6.3 ms, respectively, and serum

ferritin levels are between 40–340 lg ⁄L in men and

14–200 lg ⁄L in women (12–18). However, serum ferritin

could be misleading for cardiac iron overload (14, 15).

Similarly, there is no correlation between liver and car-

diac iron concentration (16). Patients with cardiac iron

overload of T2* < 10 ms are considered to be in danger

of cardiomyopathy, which can be prevented in most cases

by using effective chelation therapy protocols (12–18).

Chelating drugs have different physicochemical, phar-

macological, toxicological and iron removal properties,

and each protocol varies with regard to drug dose, toler-

ance, compliance and efficacy, which overall results in

different levels of iron overload and toxicity (8). Each

patient has a different drug absorption, distribution,

metabolism, elimination and toxicity profile, resulting in

a variable response to the drug or drug combinations.

Similarly, the rate of iron accumulation from transfu-

sions and its absorption from the gut, as well as dietary

and other factors could affect each patient’s overall iron

intake, tissue distribution and excretion (19). The high

cost of chelating drugs prevents the vast majority of

patients with thalassaemia major who live in the develop-

ing countries from receiving adequate chelation therapy

(1, 20).

The ability of deferiprone in effectively and rapidly

removing excess cardiac iron load and in preventing iron

accumulation appears to have caused a reduction in the

cardiomyopathy- related mortality in thalassaemia (10,

17, 21, 22). Similarly, the introduction of deferi-

prone ⁄deferoxamine combinations into many European

and other countries has resulted in improvements in iron

removal efficacy including an increase in the rate of

depletion of excess cardiac iron load (23–26). Several

deferiprone ⁄deferoxamine combinations including the

protocols suggested by the International Committee on

Chelation (ICOC) consisting of oral deferiprone at 80–

100 mg ⁄kg ⁄d and sc deferoxamine at 40–60 mg ⁄kg for at

least 3 d per week have been tested, leading to variable

levels of iron removal which generally reflected the over-

all chelating drug dose (25–28). Different synergistic and

other mechanisms of iron binding and removal were

applied to deferiprone and deferoxamine during the

administration of the combination, which depend on the

dose and timing of administration of each of the two

drugs (8, 29, 30). A second arm of the suggested ICOC

protocol is the application of deferiprone monotherapy

(80–100 mg ⁄kg ⁄d) for maintaining normal range body

iron levels (5, 8, 25).

A single-centre, single-armed, proof-of-concept study

was designed to evaluate the safety and efficacy of the

ICOC deferiprone ⁄deferoxamine combination protocol in

eight patients with thalassaemia major previously treated

with deferoxamine, with an end point set as the normali-

sation of the body iron stores. Subsequently, deferiprone

monotherapy was introduced for the maintenance of nor-

mal range body iron stores in seven of the eight patients.

Patients and methods

Deferiprone ⁄ deferoxamine combination treatment

The deferiprone ⁄deferoxamine combination was intro-

duced as a standard form of chelation therapy in Cypriot

hospitals in 2000, and the study took place between 2001

and 2008. Approval was obtained and instituted since

1999, by an expert appointed committee by the Cypriot

Ministry of Health, which thoroughly reviewed all the

related information. Eight patients with thalassaemia

major (four men and four women) from the Thalassae-

mia Unit in Paphos General Hospital volunteered and

gave their informed consent for the study (Table 1). All

eight patients were previously treated with deferoxamine

but were showing signs of decreasing compliance. Three

of the female patients (5, 6 and 8) were previously

reported with cardiomyopathy complications, while on

deferoxamine therapy (14).

The dose protocol, duration of the combination ther-

apy and other clinical information are shown in Table 1.

Deferiprone was administered daily, and deferoxamine at

least 3 d per week at 40–60 mg ⁄kg. When initiating the

combination therapy, a low dose of deferiprone

(75 mg ⁄kg ⁄d) was used to assess the possibilities of

deferiprone or deferiprone ⁄deferoxamine combination

intolerance including allergic, gastrointestinal or other

adverse reactions (8). Deferiprone increased to 80–

100 mg ⁄kg ⁄d, according to the tolerance of the patients,

and the dose maintained at this range until the body iron

load was reduced to near normal body iron store range

levels (Table 1). At this stage the dose and frequency of

administration of deferoxamine was progressively

reduced, in some cases to 1 d per week, and then the def-

eroxamine administration terminated, leaving deferiprone

as the sole treatment (Table 1). Details on the rate of

transfusion, mean haemoglobin level and of splenectomy

in this cohort of patients are shown in Table 2. During

the study, patient 2 was started on a hyper-transfusion

regimen because of the reappearance of a leg ulcer he

had previously developed during deferoxamine treat-

ment.

Kolnagou et al. Normal body iron stores in thalassaemia

ª 2010 John Wiley & Sons A/S 431

Monitoring of toxicity and compliance

Personal interviews for assessing compliance and other

complications related to the deferiprone ⁄deferoxamine

combination including mandatory full blood counts were

obtained every week. On a few occasions, full blood count

monitoring was delayed and carried out within a maximum

of 12 d. Regular toxicity assessment involved biochemical

monitoring of liver and kidney function and echocardio-

graphy for cardiac function as previously described (14).

Iron load monitoring

Serum ferritin was estimated at about 2- to 5- month inter-

val in the biochemistry reference laboratory of Makarios

Hospital in Nicosia using the automatic immunofluores-

cence ferritin assay IMx technique of the microparticle

enzyme immunoassay (MEIA) (Abbott laboratories,

Abbott Park, IL, USA). Normal serum ferritin levels

were considered to be between 40–340 lg ⁄L in males and

14–200 lg ⁄L in females.

Cardiac and liver magnetic resonance imaging relaxa-

tion times T2* measurements were carried out about

once a year with an average frequency of 13.15 months

and range 4–23 months at Agios Therissos Medical

Diagnostic Centre in Nicosia using the breath hold

method at 11 different time echoes with a minimum time

echo 2.5 ms and maximum time echo 14 ms in a Philips

Magnetic Resonance Imaging scanner, 1.5 Tesla ACS

NT Intera Master (Philips Medical Systems, Eindhoven,

the Netherlands) as previously described (14). Normal

range cardiac T2* levels are considered as > 20 ms and

liver T2* levels > 6.3 ms (12).

Monitoring of the efficacy of deferiprone monotherapy

Deferiprone was administered for 7–26 months in seven

of the eight patients following the normalisation of

serum ferritin, cardiac and liver T2* levels, which was

the result of the deferiprone ⁄deferoxamine combination

treatment (Table 3). The methods of monitoring iron

load and toxicity during the deferiprone monotherapy

were the same as those used during the deferiprone ⁄defe-roxamine combination therapy.

Statistical evaluation of serum ferritin and T2* changes

The statistical evaluation was based on a comparison

of the starting and end point of each treatment with the

Table 2 Rate of red blood cell transfusions

and haemoglobin levels in patients with

thalassaemiaPatients

SplenectomyYes ⁄ No (size)

Study period(Number of years)

Red blood cellstransfusions (mL ⁄ kg ⁄ yr)

Haemoglobin(g ⁄ dL ⁄ yr)

Mean (range) Mean (range)

1 Yes 2001–2008 (7) 180 (157–199) 8.9 (8.6–9.6)

2 No (14.2 cm) 2002–2008 (6) 222 (188–260) 9.5 (8.9–10.1)

3 Yes 2005–2008 (3) 177 (172–188) 8.9 (8.8–9.0)

4 Yes 2003–2008 (5) 180 (168–196) 8.8 (8.6–9.0)

5 Yes 2005–2008 (3) 166 (149–183) 10.1 (9.6–11.1)

6 Yes 2004–2008 (4) 143 (133–156) 9.4 (9.1–9.8)

7 Yes 2003–2008 (5) 120 (112–132) 9.7 (9.4–10.2)

8 No (11.4 cm) 2004–2008 (4) 227 (211–254) 9.1 (9.0–9.4)

Table 1 Clinical data, dose and duration of the combination therapy of deferiprone and deferoxamine in patients with thalassaemia.

Patients Weight (kg) Age (yr) Deferiprone mg ⁄ kg ⁄ d (months) Deferoxamine mg ⁄ kg-d ⁄ wk* (months) Chelation (months)

Men

1 64 28 75 (43), 80 (9), 90 (16) 45-3 d ⁄ 24 h-I (43), 45-2 d ⁄ 24 h-I (25) 68

2 70 25 75 (14), 85 (28), 90 (4) 40-3 d ⁄ 12 h-P (46) 46

3 58 38 75 (16), 90 (7), 100 (9) 50-3 d ⁄ 12 h-P (16), 60-3 d ⁄ 12 h-P (4), 50-3 d ⁄ 12 h-P (12) 32

4 58 29 75 (1), 80 (5), 85 (3), 95 (29) 50-4 d ⁄ 12 h-P (9), 50-3 d ⁄ 12 h-P (15), 60-3 d ⁄ 12 h-P (6),

50-3 d ⁄ 12 h-P (8)

38

Women

5 51 41 75 (2), 80 (15), 95 (5) 60-5 d ⁄ 18 h-I (8), 45-4 d ⁄ 18 h-I (9), 55-2 d ⁄ 15 h-I (5) 22

6 63 36 75 (3), 85 (7), 90 (2), 85 (9) 40-6 d ⁄ 48 h-I (12), 40-2 d ⁄ 48 h-I (3), 50-1 d ⁄ 24 h-I (6) 21

7 69 38 80 (10), 90 (22), 100 (16) 40-3 d ⁄ 12 h-P (32), 40-1 d ⁄ 12 h-P (16) 48

8 51 31 75 (2), 85 (19) 60-3 d ⁄ 24 h-I (14), 49-2 d ⁄ 24 h-I (3)

30-2 d ⁄ 30 h-I (3), 60-2 d ⁄ 24 h-I (1)

21

*Dose of deferoxamine mg ⁄ kg, overall days (d) per week and duration of administration (in months) using an elastomeric pump (I) or electronic

pump (P). The overall duration of each infusion is shown in hours (h).

Normal body iron stores in thalassaemia Kolnagou et al.


target in the first part of the study being the achievement

of normal range serum ferritin and T2* levels using the

deferiprone ⁄deferoxamine combination. In the second

part of the study, the maintenance of normal range

serum ferritin and T2* levels was evaluated by compar-

ing serum ferritin and T2* levels before the introduction

of deferiprone monotherapy and at the end of the deferi-

prone monotherapy treatment.

The student t-test of paired samples of StatEL add-in

for Microsoft statistical Software Package was used for

the statistical evaluation of serum ferritin and T2*

changes by estimating the geometric (G) mean and stan-

dard deviation (SD). The P value was estimated, and

results were considered significant, if P < 0.5.

Results

Efficacy

Normalisation of cardiac and liver T2* following the

deferiprone ⁄deferoxamine combination: The patients had

variable levels of excess iron in the liver, heart and total

body iron load before the introduction of the combina-

tion therapy, as shown by the serum ferritin and T2*

levels (Fig. 1A–C). The deferiprone ⁄deferoxamine combi-

nation treatment resulted in a progressive increase in the

T2* relaxation times of the heart and liver, reaching the

normal range levels at different time intervals in each

patient (Fig. 1A, B). The cardiac T2* levels before the

study were showing mostly moderate to severe iron

deposition (G mean ± SD = 10.32 ± 6.72, range

4.5–24.2 ms), which exceeded the normal range levels

(T2* > 20 ms) in all cases following the combination

treatment with an absolute value increase in cardiac

(G mean ± SD = 29.6 ± 6.6, range 22–41 ms, P <

0.00076) (Fig. 1A). Similarly, the T2* levels of the liver

indicated moderate to severe iron deposition levels in

most patients (G mean ± SD = 3.77 ± 4.69, range 1.4–

14 ms) before the combination treatment, which

exceeded the normal range levels (T2* > 6.3 ms) in all

the cases (G mean ± SD = 25.9 ± 8.07, range 9.1–

35 ms, P < 0.00075) following the combination treat-

ment (Fig. 1B). In three cases, (patients 4, 5 and 8) iron

load reached normal range levels in cardiac and liver

T2* within 1 yr of the introduction of the combination

therapy (Fig. 1A–C). In cases of severe iron loading, the

rate of normalisation was slower, and normal range car-

diac and liver T2* and serum ferritin levels were achieved

following longer- term treatments, for example up to

3 yr in patient 7 (Figs 1A–C and 2).

In the case of the male patient 1, the T2* method was

not available at the time and 1 month prior to the intro-

duction of the combination therapy, T2 measurements

indicated moderate iron load in both the heart (38.7 ms)

and liver (32.1 ms) (Fig. 1A, B).

Normalisation of serum ferritin levels following the deferi-

prone ⁄ deferoxamine combination: Serum ferritin levels

indicated excess but variable body iron load (G

mean ± SD = 1446 ± 1035, range 539–3845 lg ⁄L)before the combination treatment, which progressively

decreased and reached normal range levels in almost all

the patients (G mean ± SD = 114.7 ± 139.8, range 40–

421 lg ⁄L, P < 0.0052) (Fig. 1C). Generally, the normali-

sation rate of serum ferritin levels was achieved at about

the same time as the normalisation of cardiac and liver

Table 3 Results of cardiac and liver MRI T2* and serum ferritin, during deferiprone monotherapy.

Patients Weight (kg) Age (yr)Deferiprone dosemg ⁄ kg ⁄ d (months) Serum ferritin lg ⁄ L (months in monotherapy)

MRI T2* ⁄ ms (monthsin monotherapy)

Heart Liver

Men

1 63 34 90 (11) 279 (3), 273 (5), 268 (7) 31 (3) 35

359 (11) 23 (11) 20

2 70 29 95 (6), 100 (9) 640 (3), 433 (6), 397 (8), 406 (12), 479 (15) 38 (11) 9.8

3 59 40 100 (7) 66 (2), 149 (6) 29 (7) 22

4 60 32 95 (5), 100 (12) 189 (2), 124 (5), 118 (7), 129 (11), 140 (13), 138 (17) 32 (7) 34

Women

5 53 43 95 (7) 425 (2), 125 (5), 86 (7) 37 (7) 43

6 3 38 90 (19), 80 (7) 41 (2), 23 (7), 85 (10), 27 (3) 27

32 (13), 24 (18), 25 (21) 35 (14) 36

48 (25) 33 (26) 43

7 73 42 90 (7), 80 (3) 125 (4), 149 (6), 127 (7), 121 (10) 28 (11) 31

81 51 33 None 212 (2), 366 (4), 513 (9) 24 (5) 12

423 (11), 381 (15), 276 (17), 505 (21), 385 (25), 438 (28) 38 (20) 5.6

1Patient 8 received deferoxamine monotherapy (60–70 mg ⁄ kg, 3 d per week, 12 h per day using an elastomeric pump) instead of deferiprone

monotherapy.



T2* levels (Figs 1A–C and 2). The higher the overall dose

of the chelating drug combination the faster the normali-

sation of serum ferritin and T2* as shown in patients 5

and 6 (Fig. 1A–C). In contrast, the lower the overall dose

and the higher the intake of iron from transfusions, the

slower the rate of iron removal and the normalisation rate

of serum ferritin, as shown in patient 2 (Fig. 1A–C).

Maintenance of normal cardiac and liver T2* and of serum

ferritin levels using deferiprone monotherapy: Seven

patients continued with deferiprone monotherapy for 7–

26 months but patient 8 used deferoxamine monotherapy

because of complaints of gastric discomfort caused by

deferiprone during the combination therapy. Cardiac and

liver T2* levels remained within the normal range,

and there were no significant changes in cardiac (G

mean ± SD = 31.4 ± 5.25, range 23–38 ms, P < 0.79)

and liver (G mean ± SD = 26.2 ± 12.4, range 9.8–

43 ms, P < 0.58) T2* levels in comparison with the T2*

and serum ferritin levels achieved at the end of the def-

eriprone ⁄deferoxamine combination period (Fig. 1A–C

and Table 3). Serum ferritin levels remained within nor-

mal range in five of the seven patients (48–149 lg ⁄L)and increased slightly above normal range in two

patients (359 and 479 lg ⁄L) (G mean ± SD =

150.7 ± 159.1, range 48–479 lg ⁄L, P < 0.17) (Table 3).

In contrast, an increase in serum ferritin and a decrease

in liver T2* was gradually observed in patient 8, who

used deferoxamine monotherapy after the deferi-

prone ⁄deferoxamine combination period (Table 3).

Decisions to change the dose of deferiprone usually

reflected changes in serum ferritin. For example, in

patients reaching iron deficiency levels, the dose was

reduced to 80 mg ⁄kg ⁄d, whereas in patients with increas-

ing trend of serum ferritin to above normal range levels,

the dose increased to up to 100 mg ⁄kg ⁄d (Table 3).

45

35

40

30

20

25

T2*

(m

s)

15

5

10

0–5 0 5 10 15 20 25 30 35 40 45 50 55 60 65

Time (months)

40

35

25

30

20

T2*

(m

s)

10

15

5

0–5 0 5 10 15 20 25 30 35 40 45 50 55 60 65

Time (months)

4000

3000

3500

2000

2500

1000

1500

Ser

um

fer

riti

n (

µg

/L)

500

0–12 –8 –4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72

Time (months)

C

A B

Figure 1 Normalisation of serum ferritin, cardiac and liver T2* during the deferiprone ⁄ deferoxamine combination therapy. (A) Cardiac magnetic

resonance imaging relaxation time T2* changes before and after the introduction of the deferiprone ⁄ deferoxamine combination therapy (time

zero). (B) Liver magnetic resonance imaging relaxation time T2* changes. (C) Serum ferritin changes. The symbols for the four male (in black) and

the four female (in white) patients with thalassaemia major are as follows: Patient (P) 1: black square; P2: black circle; P3: black diamond; P4:

black triangle; P5: white circle; P6: white diamond; P7: white triangle; P8: white square.



Tolerance of the deferiprone ⁄ deferoxamine combination

and deferiprone monotherapy protocols: No serious

toxic side effects have been observed during the deferi-

prone ⁄deferoxamine combination or deferiprone mono-

therapy period, which lasted in total 24.7 and 7.7 patient

years, respectively. Both treatments were generally well

tolerated. Although there have been variations in the

enzymatic and other biochemical parameter assessment

of the liver and kidney function tests, the overall trend in

the changes was not substantially different to suggest

any damaging effects to these organs before or after the

treatments or by comparison with other groups of

patients receiving other forms of deferiprone and defe-

roxamine treatments in the same clinic (data not shown).

A comparison of groups of patients taking different che-

lation treatments in the same clinic has been previously

reported (28). Both methods of administration of defe-

roxamine in this study, i.e. by prolonged 24–48 h infu-

sion using elastomeric pump or 8–12 h infusion using

electronic pump, appear to be effective when used in the

combination therapy. In most cases, the patients using

the elastomeric pump found this method to be more

tolerable than the infusion of deferoxamine using an

electronic pump. The cardiac abnormalities previously

reported during the deferoxamine treatment in patients 5

(congestive cardiac failure), 6 (restrictive type of cardio-

myopathy and arrhythmias) and 8 (tachycardia and

supraventricular extrasystols) have been reversed

following the introduction of the deferiprone ⁄deferox-amine combination (14). Similarly, echocardiographic

findings have shown no cardiac abnormalities during the

remaining deferiprone ⁄deferoxamine combination or

the deferiprone monotherapy treatment periods in the

remaining five patients.

Discussion

The iron chelation protocols used in this study appear to

be sufficiently effective and safe for depleting excess iron

load and maintaining normal range body iron store lev-

els in this group of patients with thalassaemia major.

Iron overload toxicity as a result of low compliance with

subcutaneous or intravenous deferoxamine, causes

increasing morbidity and mortality (2–6, 10). Despite

improved compliance with both oral deferiprone and def-

erasirox, there is no convincing evidence that deferasirox

can cause negative iron balance to the level of achieving

and maintaining normal body iron store range levels and

in particular in clearing rapidly excess iron from the

heart (9, 20, 31). Deferiprone can effectively remove

excess iron load from the heart, but in many patients the

clearance rate of excess iron load from the liver is usually

BA

CFigure 2 MRI changes during the deferi-

prone ⁄ deferoxamine combination therapy. Short

axis view of liver and heart of patient 7 at

5 months before the deferiprone ⁄ deferoxamine

combination (A: Cardiac T2* was 14.5 ms and

liver T2*3.7 ms. Serum ferritin was 1626 lg ⁄ L,

1 month after the MRI scan), 9 months after

the combination (B: Cardiac T2* was 17 ms and

liver T2* 8.4 ms. Serum ferritin was 686 lg ⁄ L,

1.5 months after the MRI scan) and twenty and

a half months after the combination (C: Cardiac

T2* was 20.7 ms and liver T2* 18 ms. Serum

ferritin was 186 lg ⁄ L, 2.5 months after the

MRI scan). (T2*gradient echo short axis view in

the heart and the liver of TE 16.5 ms).



slower because of the much higher storage capacity of

iron in the liver (8, 32). In contrast, in patients with mild

to moderate iron overload, the use of deferiprone (75–

100 mg ⁄kg ⁄d) would appear to be sufficiently effective in

achieving and maintaining normal cardiac and liver iron

store levels (Table 3) (5, 33). Deferiprone can enter cells

readily at high concentration, and its iron complex can

be rapidly diffused out of cells and excreted. It can also

mobilise iron from transferrin and non- transferrin

bound iron and inhibit iron deposition in tissues (8, 17,

30, 34). These unique properties of deferiprone appear to

be particularly important in minimising the prospects of

iron overload cardiomyopathy and overall morbidity in

patients with thalassaemia major (5, 10, 20–22, 35).

Previous studies using combinations of deferi-

prone ⁄deferoxamine for shorter periods have shown in

general the effective clearance of excess iron from the

heart but slower rate of excess iron removal from the

liver (25, 26, 28, 36). Despite uneven distribution of iron

load between the liver and the heart being observed

before the combination therapy, clearance of excess iron

from both organs was achieved in all the patients includ-

ing patients 2, 3 and 6, who had moderate to severe liver

iron loading as shown by the T2* relaxation time mea-

surements (Fig. 1A, B).

A major advantage of the ICOC deferiprone ⁄deferox-amine protocol is that it is flexible and can be adapted

according to the needs of most patients. It is also very

effective because the combination of deferiprone and

deferoxamine has a high therapeutic index and the

native drugs, their metabolites and iron complexes can

be rapidly cleared thus allowing the use of overall

highly effective dose regiments (8, 34). Increased defe-

roxamine in the combination protocol for more days

per week and at the highest range of doses could result

in even more effective and rapid depletion of excess

storage iron. The same applies when the maximum dose

of deferiprone (100 mg ⁄kg ⁄d) in the combination ther-

apy is used. It is anticipated that the higher the overall

dose the higher the rate of removal of excess iron

load and normalisation of the body iron stores. It is

envisaged that some of the deferiprone ⁄deferoxamine

combination protocols can be routinely used for long-

term therapies, whereas other protocols of higher over-

all doses can be selected for more intensive chelation

therapies.

Patients on the deferiprone ⁄deferoxamine combina-

tions should be closely monitored for toxicity and iron

load levels. Adverse cardiac effects have already been

reported in a patient with thalassaemia major treated for

6 months with a combination of deferiprone (80

mg ⁄kg ⁄d) and a high dose of deferoxamine (80 mg ⁄kg ⁄d,3 d per week) with serum ferritin of 47 lg ⁄L and normal

range cardiac and liver T2* (37). The cardiac symptoms

were reversed on reducing the dose of deferoxamine to

30 mg ⁄kg, for 2 d per week. Dose reduction should be

introduced, if iron deficiency is caused by the deferi-

prone ⁄deferoxamine combination or deferiprone mono-

therapy protocols. In the latter, deferiprone could be

administered on alternating days or even temporarily

stopped for a few days per week, or stopped completely

until serum ferritin returns to normal range levels.

The maintenance of normal body iron store range lev-

els using deferiprone is not only an effective but also a

better tolerated method of treatment than the deferi-

prone ⁄deferoxamine combination therapy. There are also

economic advantages as deferiprone is a generic drug,

which can easily be synthesised and provided at low cost,

especially in developing countries (20, 38, 39).

The deferiprone ⁄deferoxamine combination and deferi-

prone monotherapy treatments may also have applica-

tions in other transfusional iron loading conditions, as

well as in many other non- iron loading conditions, such

as nephropathy conditions and Friedreich Ataxia, where

catalytic iron causing oxidative stress has been implicated

in tissue injury (8, 40–43). It remains to be seen whether

deferoxamine, deferasirox or their combination could

also be used effectively for maintaining normal body iron

store range levels in patients with thalassaemia major

and other transfused patients. However, at physiological

or low iron levels, the use of deferoxamine or deferasirox

is not recommended by the manufacturers because of

possible toxicity implications (44). Similarly, no synergis-

tic or additive effects were observed between deferox-

amine and deferasirox in a gerbil model of iron overload

(45).

Conclusion

Transfusional iron overload can be reversed and body

iron stores maintained within the normal body range lev-

els using appropriate protocols of deferiprone ⁄deferox-amine combinations and deferiprone monotherapy. Such

protocols should be adjusted according to the needs and

tolerability of patients. These forms of treatment are

potentially inexpensive and can benefit the vast majority

of patients with thalassaemia major and other transfused

patients living in developing countries. Randomised clini-

cal trials are needed to confirm these findings, which

could set the deferiprone ⁄deferoxamine combinations

and deferiprone monotherapy as a firstline chelation

treatment for the complete removal of excess iron in

thalassaemia and other transfused patients.

Conflict of interest disclosure

The authors declare no competing financial interests or

support by pharmaceutical companies.



Acknowledgements

We thank Dr Charalambos Economides and other mem-

bers of staff at the Agios Therissos Medical Diagnostic

Centre for the MRI measurements, the biochemistry lab-

oratory at the Makarios Hospital for the ferritin mea-

surements, Alexia Ioannou for helping with the statistical

evaluation and Christina Kontoghiorghe for English lan-

guage corrections. Internal funds of the Postgraduate

Research Institute of Science, Technology, Environment

and Medicine were used for the study.

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