observational study comparing long-term safety and efficacy of deferasirox with desferrioxamine...

Observational study comparing long-term safety and efficacyof Deferasirox with Desferrioxamine therapy in chelation-naıve children with transfusional iron overloadYesim Aydinok1, Sule Unal2, Yesim Oymak3, Canan Vergin3, Zeynep D. Turker4, Dilek Yildiz1,Akif Yesilipek4

1Department of Pediatric Hematology, Ege University Faculty of Medicine, Izmir; 2Department of Pediatrics, Antakya State Hospital, Antakya;3Department of Pediatric Hematology, Behcet Uz Children’s Hospital, Izmir; 4Department of Pediatric Hematology, Akdeniz University Faculty of

Medicine, Antalya, Turkey

Transfusion-dependent children with congenital blood

disorders rapidly develop potentially damaging levels of

iron overload in the body during early childhood (1).

Excess iron from transfusions initially invades the liver

but later spreads to the heart and endocrine organs lead-

ing to organ failures if not controlled and eliminated by

chelation therapy (2). The implementation of iron chela-

tion therapy in the late 1970s has resulted in a significant

decline in early cardiac deaths and endocrine complica-

tions of iron overload in patients with thalassemia major

(TM) (3). Growth deceleration and pubertal failure are

the earliest consequences of iron toxicity resulting from

pituitary iron deposition and may be prevented by main-

taining body iron at safe levels at all times.

Principles of chelation practice in infancy and child-

hood have been determined based on experience with

Desferrioxamine (DFO), the first chelator available.

Intensive chelation therapy starting at or close to the

time when a transfusion program was initiated to prevent

iron toxicity resulted in chelator toxicity such as

impaired growth and skeletal changes (4). In conse-

quence of this observation, chelation therapy has been

Abstract

Objectives: An observational study was conducted to explore postmarketing safety and efficacy of Defer-

asirox (DFX) in comparison with conventional Desferrioxamine (DFO) in chelation-naıve children with trans-

fusional iron overload. Methods: Transfusion-dependent children (aged £5 yr) who had serum ferritin

above 1000 lg ⁄ L and had been prescribed either first-line DFX or DFO for at least 12 months to maintain

serum ferritin between 500 and 1000 lg ⁄ L were included. Initial DFX dose was 20 mg ⁄ kg ⁄ d for 7 d a

week, and DFO dose was 25–35 mg ⁄ kg ⁄ d subcutaneously, given for 5 d a week. Dose adjustments were

based on serum ferritin changes and safety markers. The primary efficacy endpoint was change in serum

ferritin from baseline. The effect of transfusional iron loading rate (ILR) and different doses of chelators on

serum ferritin was also assessed. Results: A total of 111 patients were observed for a median of 2.29 yr

on DFX (n = 71) and 2.75 yr on DFO (n = 40). Absolute change in serum ferritin from baseline to the last

available observation was not significant with DFX (91 lg ⁄ L, P = 0.5) but significantly higher with DFO

(385 lg ⁄ L, P < 0.005). ILR and DFX doses had a major impact on serum ferritin changes in DFX cohort.

The height- and weight-standard deviation scores did not differ significantly in both cohorts during the

study. Fluctuations in liver enzymes and non-progressive increase in serum creatinine were the most

common adverse events (DFX; 9.8%, 18.0% and DFO; 5.0%, 7.5%, respectively). Conclusion: DFX is well

tolerable and at least as effective as DFO to maintain safe serum ferritin levels and normal growth

progression in chelation-naıve children.

Key words thalassemia major; iron overload; iron chelation; Desferrioxamine; Deferasirox

Correspondence Yesim Aydinok, Department of Pediatric Hematology, Ege University Faculty of Medicine, 35100 Bornova, Izmir,

Turkey. Tel: +90 532 3962746; Fax: +90 232 3438090; e-mail: [email protected]

Accepted for publication 8 February 2012 doi:10.1111/j.1600-0609.2012.01769.x

ORIGINAL ARTICLE

European Journal of Haematology 88 (431–438)

ª 2012 John Wiley & Sons A/S 431

initiated after 10–20 red cell transfusions once serum fer-

ritin exceeds 1000 lg ⁄L, and this recommendation has

also been applied to the other chelators. Chelation ther-

apy is administered to maintain serum ferritin levels

between 500 and 1000 lg ⁄L (1).

Although Deferasirox (DFX) was approved by FDA

for the treatment of patients with transfusional iron

overload who were older than 2 yr of age as first-line

therapy, it is important to assess postmarketing long-

term efficacy and safety of DFX in this group of small

children. This study aimed to explore whether DFX

therapy provides acceptable chelation and tolerability

compared with DFO in chelation-naıve children with

transfusional iron overload up to 5 yr.

Design and methods

This multicenter observational study was conducted in

four thalassemia centers in Turkey. Permission for retro-

spective review of medical records according to the

Declaration of Helsinki was approved by the IRB

Committee of Ege University Faculty of Medicine

(number: 11-11.1 ⁄ 62).

Inclusion and exclusion criteria

Transfusion-dependent (more than eight transfusions

annually) male and female children (aged £5 yr) who

were in need for chelation therapy based on serum ferri-

tin levels (‡1000 lg ⁄L) after 2003 and have been pre-

scribed either DFX or DFO as first-line therapy and

received either chelator for at least 12 months were

recruited into the study. Patients whose first-line chelator

has been switched to another chelating agent or stopped

for any reason (e.g., stem cell transplantation) were with-

drawn from the study.

Treatment and study design

This study is an observational study in which chelation-

naıve patients were initiated either DFX or DFO treat-

ment by their hematologists’ judgment based on family

interview and availability of either chelators. Initial DFX

dose was 20 mg ⁄kg ⁄d, once daily, 7 d ⁄wk in accordance

with the DFX-prescribing information. Dose titration of

DFX has been performed based on serum ferritin levels

and safety markers in steps of 5–10 mg ⁄kg ⁄d (in the

range of 0–40 mg ⁄kg ⁄d). DFO has been prescribed at

25–35 mg ⁄kg ⁄d as 8–12 h subcutaneous infusion, 5 d a

week in accordance with the guidelines for DFO dosing

in children (1). DFO doses were adjusted based on serum

ferritin levels and by considering safety markers up to

50 mg ⁄kg ⁄d.

The primary efficacy endpoint was the change in

serum ferritin from baseline. Serum ferritin levels were

evaluated monthly. Absolute change in serum ferritin

levels from baseline to final measurement for each sub-

ject was taken into consideration. The mean serum ferri-

tin levels at each completed chelation year were taken as

the average of available measurements during 1-yr per-

iod. Change in serum ferritin levels from baseline to each

chelation year for each subject was also evaluated. Safety

was evaluated by continuous monitoring for adverse

events as well as by laboratory assessments for hepatic

and renal toxicity and physical examination. Pediatric

growth was assessed by monitoring changes in height

and weight at 3-monthly intervals, expressed as height-

and weight-standard deviation scores (h-SDS and

w-SDS, respectively) at yearly intervals. h-SDS of

patients was calculated against the median height relative

to age for a non-thalassemia population, and median

change in h-SDS from baseline to each chelation year

was evaluated. The iron loading rate (ILR) as mg ⁄kg ⁄dwas calculated in each chelation year from transfusional

volumes of six consecutive transfusions and corrected for

hematocrit to obtain pure red blood cell (RBC) volume

that was multiplied by 1.08 (mg iron ⁄mL pure RBC) and

then divided by the days between the first and the last

transfusion and kg b.w. of patients. The corresponding

mean hemoglobin values (g ⁄dL) per chelation year were

also calculated.

Statistical analysis

Statistical analysis was performed using spss 13.0 for

Windows (SPSS Inc., Chicago, IL, USA). For continuous

variables, descriptive statistics were obtained, and com-

parisons were made using corresponding nonparametric

approaches (Mann–Whitney U-test, Wilcoxon signed

ranks test) or the two-sided independent and paired sam-

ples t-test when appropriate. The data obtained from

each chelation year with either chelator were compared

whenever the number of patients per chelation year was

sufficient for comparison. The last available observation

data of the patients were compared with their baseline

values regardless of the duration of chelation. A P value

of <0.05 was considered significant.

Results

Baseline characteristics of patients

A total of 123 children met the eligibility criteria and

received either DFX or DFO. Although most of the

chelation-naıve patients were prescribed DFX after the

registration of DFX in Turkey in 2007, few patients

who have already been initiated first-line DFX chelation

Deferasirox in chelation naive children Aydinok et al.

432 ª 2012 John Wiley & Sons A/S

as subjects of a phase III study (CL670107) in 2003 or

as part of compassionate use program under the super-

vision of the Turkey Ministry of Health in 2004 were

also included. A total of 111 patients (n = 106 TM

and n = 5 sickle cell disease) whose medical records

were complete for data collection were included in this

observational study. Table 1 shows descriptive statistics

of the two groups. The median time from first transfu-

sion to first initiation of chelation was substantially

longer in the DFO group as compared to the DFX

group. In line with this observation, baseline median

serum ferritin, alanin aminotransferase (ALT), and

aspartate aminotransferase (AST) values were also

significantly higher in the DFO group. The median time

on both chelators was comparable with 2.75 yr (range

1.0–6.1 yr) for a total of 109.33 patient-years on DFO

and 2.29 yr (range 1.0–7.0) for a total of 183.25

patient-years on DFX. The number of patients per che-

lation period (‡1, 2, 3, 4, or 5 yr) was comparable

between the treatment groups for the first four

chelation years.

Transfusional iron loading rates, average meanhemoglobin, and exposure to treatment

The mean ILR averaged at ranges between 0.3 and

0.4 mg ⁄kg ⁄d and the mean hemoglobin values main-

tained at 8.7–8.8 g ⁄dL throughout the years in both

study groups and did also not vary significantly through-

out the years within each chelation group. However,

although the mean actual DFX dose was similar

throughout the years, a continuous and significant

increase in DFO doses was observed during the years

(P = 0.003) (Table 2).

Effect of chelators on serum ferritin

Absolute change in serum ferritin from baseline to the

last available observation was not significant with DFX

(91 lg ⁄L, P = 0.5) but was significantly higher with

DFO (385 lg ⁄L, P < 0.005). Although a significant

increase in median serum ferritin from baseline was

observed in patients receiving DFX during the first 2 yr,

normalization to baseline levels in serum ferritin was

achieved at the following years. Increase from baseline in

median serum ferritin was significant during the first 3 yr

in patients receiving DFO, and a substantial normaliza-

tion toward baseline levels was obtained at the 4th year

(Fig. 1). Absolute change in serum ferritin from baseline

at first year of chelation showed no significant correla-

tion with the age at chelation start in both cohorts.

The effect of transfusional iron loading rate on serumferritin

Under the conditions of this study, a decrease in median

serum ferritin from baseline was achieved in patients with

lower ILR (<0.3 mg ⁄kg ⁄d) following a substantial

increase in the first year with DFX chelation. In contrast,

an increase in median serum ferritin from baseline in sub-

jects with higher ILR (ILR ‡ 0.3–0.4 and ‡0.4 mg ⁄kg ⁄d)with DFX chelation was observed for the first 2 yr,

(Table 3). There was no consistent correlation between

transfusional ILR and median change in serum ferritin

Table 1 Baseline characteristics of the patients

Variable Deferoxamine Deferasirox P

No. patients 40 71 –

Sex, no (%)

Male 22 (55) 45 (62.5) 0.44

Female 18 (45) 27 (37.5)

Median age of chelation start, yr (range) 3.1 (1.3–5.9) 2.6 (1.2–5.9) 0.32

Median time from 1st

transfusion to chelation, yr (range)

2.2 (0.3–5.0) 1.6 (0.1–4.7) 0.07

Median chelation duration, yr (range) 2.75 (1.0–6.1) 2.29 (1.0–7.0) 0.48

Median height-standard

deviation scores at baseline (range)

)0.28 ()2.8 to 3.2) )0.6 ()2.5 to 3.0) 0.39

Median weight-standard

deviation scores at baseline (range)

)0.30 ()2.9 to 2.2) )0.36 ()2.2 to 2.2) 0.47

Median serum ferritin at

baseline, lg ⁄ L (range)

1848 (937–3945) 1513 (995–3241) 0.009

Median aspartate aminotransferase

at baseline, U ⁄ L (range)

37 (17–182) 35 (9)89) 0.017

Median alanin aminotransferase

at baseline, U ⁄ L (range)

37.5 (10–200) 21 (8–178) 0.006

Median serum creatinine at

baseline, mg ⁄ dL (range)

0.3 (0.17–0.5) 0.23 (0.1–0.83) 0.37

Aydinok et al. Deferasirox in chelation naive children


from baseline by years in patients receiving DFO chelation

(data not shown).

The effect of DFX doses on serum ferritin

All DFX doses resulted in a substantial increase in serum

ferritin from baseline at the first year. This effect was

highest at DFX doses higher than 30 mg ⁄kg ⁄d. It shouldbe noted that this group had the highest mean ILR com-

pared with those receiving lower DFX doses. In the fol-

lowing years, a small number of patients remained on

DFX doses of 20 mg ⁄kg ⁄d or below capable to maintain

iron balance. The mean ILR was the lowest in this group

compared with those receiving higher DFX doses. How-

ever, the patients receiving mean actual doses of DFX

above 30 mg ⁄kg ⁄d achieved higher reduction in serum

ferritin compared with the patients receiving DFX

between 20 and 30 mg ⁄kg ⁄d at the following years, and

mean ILR was comparable between the groups. Further,

6 of 71 patients (8.4%) on DFX showed an absolute

increase in serum ferritin above 1000 lg ⁄L from baseline

to the last available observation that ranged between 2.5

and 5 yr on DFX chelation. It has been observed that the

mean actual DFX doses had been increased from initiated

dose of 20–30 mg ⁄kg ⁄d in steps of 5–10 mg ⁄kg ⁄d by

investigator judgment in these patients with baseline

serum ferritin levels between 1096 and 1885 lg ⁄L (mean

1590 lg ⁄L). Although, 22 of 71 patients (30%) in DFX

cohort had received the mean DFX doses above

30 mg ⁄kg ⁄d at least one of the chelation years, it should

be noted that the highest DFX dose of 40 mg ⁄kg ⁄d was

administered to only four patients during the study years.

The effect of Deferasirox and Desferrioxamine ongrowth

Baseline median h-SDS of patients in DFX and DFO

arms were )0.28 ± 1.3 and )0.6 ± 1.1, respectively, and

not statistically significantly different between the groups

(P = 0.39). Absolute changes for h-SDS from start of

DFX and DFO treatments by years of chelation were

not significantly different. However, h-SDS tended to

improve slightly from baseline by years in patients with

DFX treatment, whereas h-SDS was diminishing slightly

by years in patients receiving DFO (Fig. 2).

Baseline median w-SDS of patients in DFX and DFO

arms were )0.36 ± 0.9 and )0.3 ± 1.2, respectively, that

is, were not significantly different between the groups

(P = 0.47). Median w-SDS were stable during DFX and

DFO treatments; the median change from baseline at 1st,

2nd, 3rd, and 4th years of treatment, respectively, was

)0.03 ± 0.7, )0.06 ± 0.6, )0.14 ± 0.7, and )0.05 ± 0.8

in DFX and )0.06 ± 0.6, )0.14 ± 0.8, )0.15 ± 0.8 and

)0.11 ± 0.7 in DFO treatment.

Adverse events

The ALT levels were slightly higher [£1.5· upper limit of

normal (ULN)] in seven (9.7%) and moderately higher

Table 2 Mean actual dose of the chelators, mean iron loading rate (ILR) and hemoglobin levels during chelation years

Chelation year of Deferasirox Year 1 (n = 71) Year 2 (n = 60) Year 3 (n = 40) Year 4 (n = 26) P

Mean actual dose

(mg ⁄ kg ⁄ d) ± SD, (range)

26.2 ± 5.1 (13–36) 28.5 ± 4.9 (18–40) 28.1 ± 6.1 (10–40) 29.4 ± 5.7 (21–40) 0.34

Mean ILR (mg ⁄ kg ⁄ d) ± SD 0.35 ± 0.15 0.35 ± 0.15 0.39 ± 0.18 0.36 ± 0.19 0.80

Mean Hb (g ⁄ dL) ± SD 8.7 ± 0.7 8.8 ± 0.6 8.8 ± 0.9 8.8 ± 0.5 0.72

Chelation year of Desferrioxamine Year 1 (n = 40) Year 2 (n = 38) Year 3 (n = 27) Year 4 (n = 13) P

Mean average actual dose

(mg ⁄ kg ⁄ d) ± SD, (range)

25.7 ± 6.6 (15–43) 31.2 ± 9.3 (20–50) 32.8 ± 8.7 (23–50) 38.8 ± 9.8 (23–50) 0.003

Mean ILR (mg ⁄ kg ⁄ d) ± SD 0.30 ± 0.08 0.34 ± 0.10 0.37 ± 0.10 0.41 ± 0.14 0.08

Mean Hb (g ⁄ dL) ± SD 8.8 ± 0.5 8.7 ± 0.5 8.7 ± 0.5 8.7 ± 0.4 0.65

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

0 1 2 3 4 Years

Med

ian

seru

m fe

rriti

n (µ

g/L)

DFODFX

P versus baseline (DFX)P versus baseline (DFO)

<0.0002 <0.005 0.124 0.717<0.04 <0.004 <0.013 0.327

Figure 1 Median serum ferritin ± 25th and 75th percentiles (lg ⁄ L)

during the chelation years in patients treated with Desferrioxamine

(DFO) and Deferasirox (DFX). P values demonstrate the significance

of median change from baseline in serum ferritin at the corresponding

year.



(>1.5–£5· ULN) in other seven (9.7%) patients at base-

line in the DFX group. The ALT levels were slightly

higher in two (5%), moderately higher in eight (20%)

patients, whereas one patient (2.5%) had an elevated

ALT >5· ULN at baseline in DFO group. Elevations in

serum ALT levels were observed in both chelation

groups. However, increments >5· ULN were observed

more frequently in the DFX group compared with the

DFO group. One patient receiving DFX had ALT

increased >10· ULN (Table 4). The ALT levels >5·ULN were observed at early stages of chelation (up to

6th months) in the DFO group, whereas ALT >5·ULN was observed at the 3rd month in four of seven

patients in DFX group and at the 12th, 24th, and 30th

months of DFX in the other three DFX patients.

Increments in AST were observed along with the increase

in ALT.

Table 3 Median (range) changes from baseline in serum ferritin by ILR (mg ⁄ kg ⁄ d) in patients receiving Deferasirox (DFX)

Chelation yearsof DFX

Year 1(n = 71)

Year 2(n = 60)

Year 3(40)

Year 4(26)

ILR <0.3 mg ⁄ kg ⁄ d, (%) 34.4 28.6 19.2 33.3

Mean actual dose, mg ⁄ kg ⁄ d± SD, (range)

24.3 ± 4.9 (13–35) 27.0 ± 4.7 (20–40) 28.0 ± 9.1 (18–40) 24.0 ± 2.6 (21–26)

Median serum ferritin

lg ⁄ L, (range)

1927 (795–2999) 2204 (815–4742) 1567 (767–2996) 989 (692–2206)

Median change from

baseline in ferritin lg ⁄ L, (range)

178 ()717 to 857) 33 ()681 to 2627) 91 ()726 to 598) )496 ()778 to 491)

ILR ‡0.3–0.4 mg ⁄ kg ⁄ d, (%) 37.5 51.0 42.3 50.0


26.6 ± 4.9 (15.6–35) 29.0 ± 4.4 (18–35) 29.0 ± 2.9 (25–35) 28.4 ± 3.3 (23–32.5)


lg ⁄ L, (range)

1790 (1082–2912) 1951 (639–3945) 1840 (583–3836 1335 (720–3060)

Median change from

baseline in ferritin lg ⁄ L, (range)

373 ()355 to 1474) 493 ()1155 to 1955) 17 ()1317 to 1983) )352 ()783 to 291)

ILR ‡0.4 mg ⁄ kg ⁄ d, (%) 28.1 20.4 38.5


28.2 ± 4.7 (20–35) 30.2 ± 5.6 (23–40) 26.7 ± 8.1 (10–35) n.a.


lg ⁄ L, (range)

1609 (1020–3527) 1717 (584–3421) 1747 (741–3978)

Median change from baseline in

ferritin lg ⁄ L, (range)

171 ()641 to 909) 410 ()997 to 975) 196 ()819 to 2008)

ILR; iron loading rate; %, indicates % of patients with low, moderate and high ILR in each chelation year; SD, indicates standard deviation;

n.a., not applicable.

–1.2–1.0–0.8–0.6–0.4–0.2

0.00.20.40.60.81.01.2

YearsMed

ian

chan

ge in

h-S

DS

from

bas

elin

e

DFODFX

1 >1–2 >2–3

Patients (n) 70 40 58 35 32 24 20 11

>3–4

Figure 2 Change in height-standard deviation scores (h-SDS) from

start of Deferasirox (DFX) and Desferrioxamine (DFO) treatments by

years of chelation. Whiskers indicate ± 25th and 75th percentiles of

change in h-SDS from baseline. n shows the number of patients

whose h-SDS were eligible at each years. Absolute changes for

h-SDS from start of DFX and DFO chelations by years were not signif-

icantly different.

Table 4 Alanin aminotransferase (ALT) levels during the study

Deferasirox(n = 71)

Deferoxamine(n = 40)

Baseline median ALT

(U ⁄ L) (range)

21 (8–178) 37.5 (10–203)

Final median ALT

(U ⁄ L) (range)

23 (8–151) 33 (7–94)

ALT at normal

ranges n (%)

38 (53.6) 24 (60)

ALT >1.5–£5·ULN n (%)

32 (45) 16 (40)

ALT >5· ULN n (%) 6 (8.4)1 2 (5)1

ALT >10· ULN n (%) 1 (1.4) –

Dose decrement 2 (2.8) None

ULN, upper limit of normal.1All showed fluctuations >1.5–£5· ULN throughout the study.



All patients had serum creatinine levels £ULN at the

start of DFO and DFX treatments. Although, median

serum creatinine levels tended to increase slightly but

nonsignificantly in DFX cohort, remained in the normal

ranges during the study in both cohorts. Two consecutive

serum creatinine level increases >50% above the base-

line value were reported in two (5%) patients in the

DFO group, and 10 (14%) patients in the DFX cohort.

Serum creatinine greater than the ULN was observed in

one (2.5%) and three (4%) patients in DFO and DFX

treatments, respectively. Increments in serum creatinine

were transient and returned to baseline without any dose

modification in all patients (Fig. 3A,B).

Gastrointestinal disorders or systemic allergic reactions

were not reported in any of the subjects. Transient rash

was observed in two (2.8%) patients of the DFX group

that resolved without any intervention.

Discussion

Although clinical symptoms resulting from iron toxicity

do not manifest until late adolescence and early adult-

hood, it has been revealed that iron deposition in liver

and endocrine tissues occurs at very early ages of child-

hood (5–7). The first objective of iron chelation therapy

is to maintain currently acceptable levels of body iron

burden by a balance with the patients’ iron intake (2).

This observational study showed that the median time

from 1st transfusion to chelation start and baseline

serum ferritin was significantly longer in patients on

DFO chelation compared with patients on DFX chela-

tion and hence longer in both cohorts than the recom-

mended optimum threshold time. The delay in initiation

of DFO treatment can partly be explained by the slow

provisional process in providing pumps for DFO infu-

sion, prolonged parents’ education or postponing cum-

bersome treatment by parents. When DFX therapy

became available, it has been prescribed as first-line

treatment to those patients who were unable to start

DFO treatment despite iron chelation requirement. This

may explain why some patients in the DFX cohort have

higher serum ferritin levels than the recommended

threshold for chelation initiation. Significantly higher

baseline liver enzymes measured in the patients at initia-

tion of DFO compared with those at initiation of DFX

chelation could also be explained by the higher baseline

iron burden in patients of DFO cohort.

Both DFX and DFO chelation have a clear effect on

serum ferritin levels over time reflecting the changes in

liver iron concentration on which transfusional ILR and

chelator doses have major impact (8, 9). In this study, the

average transfusional iron intake was similar at a range of

0.3–0.4 mg ⁄kg ⁄d in both cohorts and did not differ signifi-

cantly by years. While daily mean DFX doses were not

different throughout the study years, continuous increase

in mean daily DFO doses was observed. In this study,

serum ferritin levels showed increase from baseline during

the first 2 yr of DFX treatment with a stabilization and

normalization to baseline levels at the following years

(Fig. 1). This effect was observed at all subsets of mean

ILR (Table 3). Pharmacokinetic characteristics of DFX

were found similar in children (aged 2–12 yr) and adoles-

cents (aged 12–17 yr) who support a once-daily DFX dos-

ing for children based on body weight (10). However, it

has been reported that the absolute bioavailability of oral

DFX ranges between 62% and 80% (11), which may

cause variable response to given oral dose. The consistent

improvement in response to DFX by years in the study

group cannot be correlated with increments of bioavail-

ability by age as there was no correlation between the age

at chelation start and change in serum ferritin. It has been

speculated that ingestion of dispersed tablets by small chil-

dren may not be complete, and adaptation of patients to

administration of DFX may improve throughout the

years. In line with the previous studies (9, 12, 13), ILR

had an impact on the change in serum ferritin from base-

line in the DFX cohort (Table 3), and higher DFX doses

were more effective in reducing iron burden and hence

serum ferritin in patients with similar ILR. The clinical

A

0.00.10.20.30.40.50.60.70.80.91.01.1

DFO months

Med

ian

seru

m c

reat

inin

(mg/

dL) (

min

–max

)

B

0.00.10.20.30.40.50.60.70.80.91.01.1

0 1 2 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

0 1 2 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

DFX months

Med

ian

seru

m c

reat

inin

(mg/

dL) (

min

–max

)

Figure 3 Median serum creatinine (minimum and maximum) values

during study months. (A) Desferrioxamine (DFO) cohort and (B) Defer-

asirox (DFX) cohort. Dotted line indicates the upper limit of normal in

serum creatinine.



studies confirmed the importance of timely dose adjust-

ments based on serum ferritin trends for achieving thera-

peutic target of maintenance or reduction in iron burden

in patients with transfusional iron overload (12–14). In

the current study, 8.4% of patients had an absolute

increase in serum ferritin values of more than 1000 lg ⁄Lcompared with baseline with an increasing trend despite

DFX dose adjustments up to 30 mg ⁄kg ⁄d, which was the

highest approved dose as a label indication at those times.

Clinical studies have indicated that some patients require

DFX doses of more than 30 mg ⁄kg ⁄d to achieve their

therapeutic goals (9, 15). It has been suggested that

patients who require dose escalation above 30 mg ⁄kg ⁄dwere heavily iron loaded, which was reflected by high

serum ferritin (>2500 lg ⁄L) at baseline (15). The current

study indicated that some patients may need higher DFX

doses, while they have relatively lower iron burden. DFO

infusions resulted in a significant increase in serum ferritin

from baseline for the first 3 yr with a substantial decrease

and stabilization at the 4th year. No consistency between

the ILR, the actual mean DFO doses and the change in

serum ferritin from baseline could be observed in this

cohort. One explanation for this evident lack of correla-

tion could lie in the variable compliance to DFO, which is

cumbersome to use.

Both chelation regimens were generally well tolerated,

and none of the patients in each cohort had to discontinue

chelation therapy because of adverse events. Although

gastrointestinal disturbances and skin rash were predomi-

nant side effects of DFX chelation in clinical studies (8,

13, 16), no patient has complained about clinically signifi-

cant gastrointestinal disturbances and only two patients

(2.8%) had temporary skin rash that spontaneously

resolved. Although gastrointestinal disorders with a sus-

pected relationship to DFX treatment were observed less

frequently in patients aged <16 yr (15.8%) than ‡16 yr

(29.1%) (17), the gastrointestinal tolerance in chelation-

naıve patients aged £5 yr has not been specifically

addressed in other clinical studies as it was confirmed in

this observation study. Although fluctuations in serum

ALT and AST levels were observed in both DFX and

DFO cohorts, only one patient with severe liver enzyme

elevations (ALT >10· ULN) was recorded in the DFX

group. None of the patients in both cohorts had progres-

sive increases in serum creatinine. In line with the previous

studies (15, 18), DFX doses above 30 mg ⁄kg ⁄d were not

associated with increase in the incidence and severity of

adverse events in chelation-naıve patients.

Pediatric patients aged £5 yr continued growth in both

cohorts. Further, it has been shown that linear growth

improved by years in patients receiving DFX. In con-

trast, the only study assessing long-term growth in pedi-

atric patients with TM revealed slightly reduced growth

in patients compared with a normal population at the

age <12 yr (13). In that study, the mean age and median

serum ferritin of patients at study start was higher com-

pared with our chelation-naıve patients.

Our study had some limitations. This study is not a

randomized study of DFO and DFX with the records of

all dispensed and returned study medications to deter-

mine the chelation compliance that may support a higher

compliance to the study drug than real-life administra-

tions. In that point of view, a randomized study is obvi-

ously needed to provide more robust efficacy comparison

of these chelation regimens in chelation-naıve patients.

However, an advantage of such a study may be that the

patients included are more likely to represent the general

compliance characteristics of disease population to chela-

tion therapy.

In conclusion, this is the first study to demonstrate

comparable tolerability and efficacy of DFX versus DFO

in chelation-naıve pediatric patients aged £5 yr with

transfusional iron overload. This observational postmar-

keting study confirmed that DFX is an effective first-line

regimen to maintain iron balance and normal growth

progression with an excellent tolerance at doses above

30 mg ⁄kg ⁄d in children aged £5 yr.

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observational study comparing long-term safety and efficacy of deferasirox with desferrioxamine...

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