Pediatr Blood Cancer 2009;52:616–620

Oral Iron Chelation and the Treatment of Iron Overload in aPediatric Hematology Center

Jean L. Raphael, MD, MPH,1* M. Brooke Bernhardt, PharmD,2

Donald H. Mahoney, MD,1 and Brigitta U. Mueller, MD, MHCM1

INTRODUCTION

Hemoglobinopathies, such as thalassemia and sickle cell disease

(SCD), represent a significant category of pediatric transfusion-

dependent diseases. Transfusion therapy is mainly used in patients

with SCD to reduce the probability of stroke in high-risk populations

[1]. In thalassemia, chronic transfusions prevent life-threatening

anemia. Despite the benefits of transfusion therapy, it renders

patients vulnerable to iron overload. In the absence of treatment,

iron overload leads to progressive dysfunction of the heart, liver, and

endocrine glands and has significant impact on morbidity and

mortality [2–6]. Iron overload is particularly harmful in children

because it may cause growth failure and have adverse effects on

sexual maturation [5,7–9].

Iron chelation therapy forms an integral component in the

management of pediatric transfusion-dependent anemias [10–13].

For decades, deferoxamine has been employed as an effective iron

chelator and the standard of care [14,15]. Its poor oral bioavailability

and short half-life require that it be administered by subcutaneous or

intravenous infusion, usually over 8–12 hr on 5–7 days per week

[5]. Patient adherence to this regimen is frequently poor and

adversely affects efficacy [16–18].

In 2005, the U.S. Food and Drug Administration approved

deferasirox (Exjade1, ICL670) for the treatment of patients

ages 2 years and older with chronic iron overload secondary to

recurrent blood transfusions. Deferasirox is a once-daily oral

therapy, which has demonstrated good efficacy and safety in

children as well as adults with chronic anemias [19,20]. In well-

controlled clinical trials, including all types of anemia, daily

doses of 20 or 30 mg/kg/day of deferasirox over 1-year resulted in

overall maintenance or reduction of liver iron concentration (LIC).

Deferasirox has also demonstrated cost-effectiveness and improved

patient satisfaction compared to deferoxamine [21,22]. Availability

of an oral iron chelator has been anticipated to improve overall

compliance, leading to more effective iron overload control.

However, little is known about clinical outcomes with deferasirox

outside of clinical trials where efficacy, safety, and compliance are

closely controlled and monitored. Here we provide data on the use

of deferasirox as standard of care treatment in a large pediatric

hematology center.

METHODS

Study Design

We conducted a retrospective chart review to assess the use of

deferasirox at the Texas Children’s Hematology Center. The Baylor

College of Medicine institutional review board determined this

study to be exempt from the requirement for informed consent.

Patients

All iron overloaded patients primarily followed at the Texas

Children’s Hematology Center with any history of deferasirox use

comprise the subjects in this study. These include patients with

the following diagnoses: SCD, thalassemia, Blackfan-Diamond

syndrome, red cell aplasia, sideroblastic anemia, and pyruvate

kinase deficiency. Patients who previously participated in a

deferasirox clinical trial were included [19].

Study Setting

The Texas Children’s Hematology Center is part of a large

teaching hospital. Guidelines for initiation of chelation therapy

Background. Recent advances have led to the development oforal iron chelators, which have changed clinical practice. Theobjective of this study was to descriptively assess the use of onesuch agent, deferasirox, as standard of care treatment in a largepediatric hematology center. Procedure. We retrospectively studiedall patients at the Texas Children’s Hematology Center who werepreviously or currently treated with deferasirox. We gathered data ondemographics, clinical diagnoses, length of time on chronic trans-fusions, previous use of deferoxamine, adherence to therapy, andreasons for discontinuation. We also assessed changes in serumferritin, liver function tests, and creatinine for those on deferasirox fora minimum of 12 months. Results. Fifty-nine patients were studied.Eighty-one percent of patients treated with deferasirox had adiagnosis of sickle cell disease. The mean baseline ferritin level for

our study population was 2,117 ng/ml (range 754–7,211). Fifty-threepercent of patients had been previously treated with deferoxamine.Adherence to oral therapy was documented in 76% of patients. Forthose on deferasirox for a minimum of 12 months, serum ferritindecreased in 30% of patients (44% of compliant patients, 11% ofpoorly compliant patients). Changes in creatinine and liverfunction tests were mild and did not result in long-term discontinua-tion of deferasirox in any cases. Conclusions. Outside of controlledclinical trials, deferasirox can be utilized safely as an oral ironchelator in children although adherence to therapy and the complexinteraction of factors that contribute to iron overload still presentchallenges for clinicians. Pediatr Blood Cancer 2009;52:616–620.� 2009 Wiley-Liss, Inc.

Key words: anemia; chelation; iron overload

� 2009 Wiley-Liss, Inc.DOI 10.1002/pbc.21929Published online 15 January 2009 in Wiley InterScience(www.interscience.wiley.com)

——————Abbreviations: LIC, liver iron concentration; SCD, sickle cell disease.

1Department of Pediatrics, Baylor College of Medicine, Texas

Children’s Sickle Cell Center, Houston, Texas; 2Department of

Pharmacy, Texas Children’s Hospital, Houston, Texas

*Correspondence to: Jean L. Raphael, Clinical Care Center, Suite

D.1540.00, Texas Children’s Hospital, 6621 Fannin Street, Houston,

TX 77030. E-mail: Raphael@bcm.edu

Received 5 September 2008; Accepted 9 December 2008

included the history of 100 ml/kg of packed red blood cells

(approximately 20 units) and/or a serum ferritin of 1,000 ng/ml or

greater, on more than one occasion. Iron overload was, in some

cases, confirmed by a LIC obtained through liver biopsy. Prior to

starting deferasirox, patients underwent baseline laboratory assess-

ment given that dose-dependent increases in creatinine (Cr) and

elevation of liver function tests (LFTs) may occur with the

administration of deferasirox [19,20,23]. Baseline measurements

included serum ferritin, LFTs, blood urea nitrogen (BUN), and

Cr. All patients received a starting dose of 20 mg/kg per the

deferasirox package insert [24]. After initiation of treatment,

laboratory parameters were assessed every 3–5 weeks, in

accordance with a patient’s transfusion schedule. Deferasirox

was titrated upward by 5 mg/kg/dose if ferritin increased over

2–3 months despite medication compliance. At each visit, patients

were screened for potential side effects. If a patient experienced

any of the following complications: vomiting, diarrhea, rash, or

abnormal laboratory values, deferasirox was held for 4 weeks and

then re-introduced at a dosage 5 mg/kg lower than their previous

dosage. Deferasirox was discontinued once a ferritin level of 500 or

lower was obtained.

Data Variables

General patient characteristics, including age, gender, and

insurance type, were determined for all subjects in addition to

clinical diagnoses. We tabulated the length of time on chronic red

blood transfusion therapy prior to deferasirox initiation and any

prior chelation therapy with deferoxamine. Baseline laboratory

values prior to deferasirox treatment were also collected.

The baseline ferritin was defined as the most recent ferritin level

assessed prior to initiation of chelation therapy. Other baseline

values included LFTs, BUN, Cr, and LIC when performed. At the

12-month assessment point, all studies were repeated.

Adherence to medication therapy was indirectly assessed using

patient self-report as documented in the medical record. Simple

patient self-report can effectively measure compliance although

there are few validated tools for such measurement [25,26]. Patients

who admit to poor compliance are generally candid [26]. In this

study, we defined poor compliance as patient report of missing 3 or

more doses/month separately in 2 or more months.

Data Analysis

Descriptive statistics were employed to evaluate patient

demographics and clinical data. Summary statistics calculated

included means, medians, standard deviations, and proportions

wherever appropriate.

RESULTS

Patient Characteristics

Fifty-nine patients, treated with deferasirox between June 2004

and June 2008 were eligible for study. Of the total group, 19 of

59 previously participated in a clinical trial assessing deferasirox

efficacy [19]. Patient demographics are shown in Table I. The

majority of patients treated with deferasirox were ages 11 years and

older and publicly insured. Eighty-one percent of the patients

treated with deferasirox had a diagnosis of SCD. Of these patients,

88% (42/48) were started on chronic red blood cell transfusions for a

history and/or risk of stroke with an abnormal transcranial Doppler

screening result. The remainder of patients with SCD had chronic

transfusions initiated for disease severity. Subjects with all other

diagnoses were started on chronic red blood cell transfusions for

severe anemia. Fifty-three percent of subjects had been managed

with deferoxamine prior to deferasirox. The mean ferritin level for

entire patient population was 2,117 ng/ml (range 754–7,211).

Twenty-five of our patients had a liver biopsy to assess iron content

prior to starting deferasirox. The mean LIC for this group was

14.7 mg/g dw� 1.8 (range 2.6–43.9).

Patient Experience With Deferasirox

As shown in Table II, 42% of patients at our institution have been

on deferasirox for less than a year. The distribution in maintenance

dose shows significant numbers of patients at various dosages with

an overall mean dose of 24.7 mg/kg/day. Data on compliance are

also shown in Table II. Per patient report as documented in the

medical record, 76% of patients on deferasirox were compliant with

treatment. Multiple reasons were cited for poor compliance. Four

patients reported difficulty with their insurance company with

acquisition and delivery of deferasirox. Other patients reported

somatic complaints including vomiting and rash. In addition to

compliance, reasons for discontinuation were assessed. Twelve

patients (20%) discontinued management with deferasirox for

various reasons including normalized ferritin, discontinuation of

chronic blood transfusions, and bone marrow transplant. Two

patients had such significant difficulties with compliance that they

were switched to deferoxamine. No patients discontinued due to

adverse reactions.

Pediatr Blood Cancer DOI 10.1002/pbc

TABLE I. Patient Baseline Characteristics

Variable Number (%)

Gender

Male 27 (46)

Female 32 (54)

Age

0–5 5 (8)

6–10 17 (29)

11þ 37 (63)

Insurance type

Public 41 (70)

Private 18 (30)

Diagnosis

Sickle cell disease 48 (81)

Thalassemia 3 (5)

Sideroblastic anemia 1 (2)

Red cell aplasia 2 (3)

Blackfan-Diamond syndrome 3 (5)

Epidermolysis Bullosa 1 (2)

Pyruvate kinase deficiency 1 (2)

Previous use of deferoxamine 31 (53)

Ferritin (ng/ml)

Mean� SD 2,117� 1,307

Range 754–7,211

Liver iron concentration (mg/g dry wt)

Mean� SD 14.7� 1.8

Range 2.6–43.9

Months on transfusion therapy prior to deferasirox

Mean� SD 44� 37.5

Range 1–182

Oral Iron Chelation in Pediatrics 617

Changes in Serum Ferritin

Of the 59 patients to undergo treatment with deferasirox, 34 were

managed for a minimum of 12 months. For this subgroup, trends in

laboratory values were assessed. The ferritin at baseline and

12 months were calculated to be 2,394 ng/ml� 1,558 (range 784–

7,211) and 2,679 ng/ml� 1,742 (range 520–9,730), respectively.

Thirty percent of patients experienced reductions in ferritin while

70% of patients experienced increases. For compliant patients,

ferritin decreased in 44% (11/25) of cases. For poorly compliant

patients, ferritin decreased in only 1 of 9 cases. As dose may impact

responses to deferasirox, we assessed dose response and were

unable to document such a relationship in our patients. As iron

burden may also play a role in the variation of ferritin trends, we

assessed the relationship between iron burden (mg/kg/year of

packed red blood cells for the 12-month period) and ferritin trends.

No statistically significant relationship was established between

these two variables.

A subgroup analysis was conducted with 20 patients who had

been on deferoxamine for 12 months or greater prior to taking

deferasirox for a minimum of 1-year. Ferritin increased separately

on both deferoxamine and deferasirox in three patients. It increased

on deferoxamine and subsequently decreased on deferasirox in eight

patients. Ferritin separately decreased on both deferoxamine and

deferasirox in four patients. It decreased on deferoxamine and

subsequently increased on deferasirox in five patients.

Safety

The most common adverse events with an apparent relationship

to deferasirox were transient gastrointestinal events in two patients

that included abdominal pain, nausea, vomiting, diarrhea, and

constipation. Skin rash was documented in one patient. All

symptoms lasted less than a week and did not require permanent

discontinuation of deferasirox.

Kidney and liver toxicity were respectively assessed by

measuring serum creatinine and LFTs for patients treated with

deferasirox for a minimum of 1-year. Any increases in serum

creatinine were mild and never exceeded the normal range.

Mild, dose-independent increases in serum AST were observed in

52% (18/34) of patients receiving deferasirox for a minimum of

12 months. These increases were generally in the normal range and

only one exceeded two times the upper limit of normal. Mild, dose-

independent increases in serum ALT were observed in 65% (22/34)

of patients receiving deferasirox for a minimum of 12 months. These

increases were also generally in the normal range and only two

increases exceeded two times the upper limit of normal.

DISCUSSION

As once-daily oral therapy, the utilization of deferasirox signifies

a notable change in the clinical management of iron chelation for

transfusion-dependent anemias. This study provides novel data on

the use of deferasirox as standard of care in a pediatric hematology

center. It also builds on previous clinical trials in demonstrating the

practical experience of clinicians and ongoing challenges with iron

chelation (regardless of ease of administration) outside of controlled

settings. Of all children, those with SCD comprised the largest

percentage of patients on deferasirox. As more institutions adopt

recommendations to implement chronic transfusions for stroke risk,

the need for iron chelation will most likely increase in children

with SCD. Older children had the highest frequency of deferasirox

use. This is consistent with increasing exposure to blood trans-

fusions over time leading to iron overload. Most of the patients on

deferasirox were publicly insured, indicating that access was not

restricted based on socioeconomic status.

In clinical trials assessing the efficacy of deferasirox, LIC and

ferritin, as a surrogate, have been utilized as outcome measures

[19,20,23,27]. In our patient population, liver biopsies were not

routinely performed after 24 months of treatment. Therefore,

changes in LIC at 12 months could not be assessed for our study. For

patients on deferasirox for a minimum of 12 months, reduction in

serum ferritin was observed for only 30% of subjects. The mean

ferritin increased from 2,394 to 2,679 ng/ml for the entire group,

which received an average deferasirox dose of 24.7 mg/kg/day. In

accordance with the package insert for deferasirox [24], our

institution utilized a starting dose of 20 mg/kg/day irrespective of

the degree of iron overload at baseline. In a phase II trial of

deferasirox in pediatric patients by Galanello et al. serum

ferritin concentration similarly increased over a period of 42 weeks

in tandem with LIC. The mean deferasirox in that study was

11.3 mg/kg/day [27]. These results support our data that lower

starting doses of deferasirox may not correlate with a reduction in

ferritin.

Several factors may explain the variation in ferritin outcomes

seen in our patients. The effect of deferasirox on serum ferritin has

been demonstrated to be dose-dependent [19]. In a phase 3 study by

Cappellini et al. deferasirox doses of 5–10 mg/kg led to increasing

serum ferritin, 20 mg/kg led to stable ferritin, and 30 mg/kg led to

reduced ferritin values. When we stratified patients according

to intent to treat doses of deferasirox, no dose dependence was

Pediatr Blood Cancer DOI 10.1002/pbc

TABLE II. Patient Experience With Deferasirox

Measure Number (%)

Maintenance dose

10 1 (2)

20 23 (39)

25 16 (27)

30 16 (27)

35 3 (5)

Months on deferasirox

0–11 25 (42)

12–23 18 (31)

24–35 13 (22)

35þ 3 (5)

Poor compliance 14 (24)

Difficulty with insurance coverage 4

Taste 1

Forgetfullness 1

Somatic complaints 2

Feels not needed 1

Unsure of dose 2

Nonspecific 3

Discontinuation of deferasirox 12 (20)

Low feritin 4

Noncompliance 2

Loss to follow up 2

Insurance coverage 1

Pregnancy 1

Off chronic transfusions 1

Bone marrow transplant 1

618 Raphael et al.

observed. A larger sample size may have yielded the dose-

dependent relationship between deferasirox and serum ferritin

observed in the study by Cappellini et al. Overall, conservative

dosing regimens combined with dose increases occurring relatively

late may not be able to counterbalance iron burden secondary to

persistent blood transfusions. This most likely accounts for gradual

increases in ferritin observed [27].

Additionally, one of the major findings of this study was that,

according to medical records, 76% of patients were adherent to

treatment with deferasirox. Given that our assessment of poor

compliance solely relied on chart review, it is possible that our

determination underestimates actual poor compliance. Therefore,

poor compliance may have contributed even more significantly that

what we were able to document. These findings are not surprising in

the context of general studies on medication adherence [28].

Adherence rates among patients with chronic conditions drops

dramatically after the first 6 months of therapy [29–31]. A previous

clinical trial demonstrated an 89% rate of adherence in patients

taking deferasirox according to pill count [19]. However, the

average rate of adherence in clinical trials can be remarkably high,

attributable to the selection of subjects and the attention study

subjects receive [28]. By comparison, adherence to deferoxamine,

as measured by various techniques, has been estimated to be

64–77% [15,32].

This study was not designed to evaluate drug efficacy as those

assessments have been previously performed. It was undertaken to

convey the practical experience of implementing oral chelation

therapy in a large hematology center and therefore has several

limitations. First of all, it has all the limitations inherent in a

retrospective chart review. Given the small sample size, results

should be cautiously interpreted. Our results may not be general-

izable to other pediatric populations outside our institution. We only

assessed serum measurements for 12 months based on prior studies

of deferasirox. However, this may have limited our assessment

of benefits and adverse events consistent with long-term use of

deferasirox. Our determination of medication compliance was

based on documentation of patient report in the medical record. In

prospective studies, more rigorous methods of measuring compli-

ance, such as patient survey and tablet counting, are typically

employed [19,28].

CONCLUSION

Deferasirox represents a novel once-daily oral approach to the

management of iron overload in transfusion-dependent childhood

anemias. As our study demonstrates the availability of an oral iron

chelator only provides a partial solution to reducing iron overload,

which is impacted by the complex interaction of numerous factors

including compliance, variable responses to medications at fixed

doses, iron burden, inflammation, and nutritional intake. Systematic

LIC measures need to be considered for more accurate assessment

of iron management and adequate starting doses. Future research

should prospectively determine the demographic and clinical

variables most likely to be associated with effective reductions in

iron overload as well as strategies (e.g., electronic devices, drug

dispensers, patient logs) to improve adherence to therapy.

REFERENCES

1. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by

transfusions in children with sickle cell anemia and abnormal

results on transcranial Doppler ultrasonography. N Engl J Med

1998;339:5–11.

2. Ballas SK. Iron overload is a determinant of morbidity and

mortality in adult patients with sickle cell disease. Semin Hematol

2001;38:30–36.

3. Manci EA, Culberson DE, Yang YM, et al. Causes of death in sickle

cell disease: An autopsy study. Br J Haematol 2003;123:359–365.

4. McLaren CE, Barton JC, Adams PC, et al. Hemochromatosis and

iron overload screening (HEIRS) study design for an evaluation of

100,000 primary care-based adults. Am J Med Sci 2003;325:53–

62.

5. Porter JB. Practical management of iron overload. Br J Haematol

2001;115:239–252.

6. Nick H, Acklin P, Lattmann R, et al. Development of tridentate iron

chelators: From desferrithiocin to ICL670. Curr Med Chem

2003;10:1065–1076.

7. De Sanctis V, Roos M, Gasser T, et al. Impact of long-term iron

chelation therapy on growth and endocrine functions in thalassae-

mia. J Pediatr Endocrinol Metab 2006;19:471–480.

8. Olivieri NF. The beta-thalassemias. N Engl J Med 1999;341:99–

109.

9. Britton RS, Leicester KL, Bacon BR. Iron toxicity and chelation

therapy. Int J Hematol 2002;76:219–228.

10. NHLBI., The management of sickle cell disease, In.: Washington,

DC: National Institutes of Health; 2002.

11. Olivieri NF, Brittenham GM. Iron-chelating therapy and the

treatment of thalassemia. Blood 1997;89:739–761.

12. Cohen AR, Martin MB. Iron chelation therapy in sickle cell

disease. Semin Hematol 2001;38:69–72.

13. National Comprehensive Cancer Network. NCCN Clinical Prac-

tice Guidelines in Oncology- v.1.2007: Myelodysplastic Syn-

dromes. 2007. (Accessed at http://www.nccn.org/professionas/

physician_gls/pdf/mds.pdf).

14. Neufeld EJ. Oral chelators deferasirox and deferiprone for

transfusional iron overload in thalassemia major: New data, new

questions. Blood 2006;107:3436–3441.

15. Gabutti V, Piga A. Results of long-term iron-chelating therapy.

Acta Haematol 1996;95:26–36.

16. Treadwell MJ, Law AW, Sung J, et al. Barriers to adherence of

deferoxamine usage in sickle cell disease. Pediatr Blood Cancer

2005;44:500–507.

17. Nisbet-Brown E, Olivieri NF, Giardina PJ, et al. Effectiveness and

safety of ICL670 in iron-loaded patients with thalassaemia: A

randomised, double-blind, placebo-controlled, dose-escalation

trial. Lancet 2003;361:1597–1602.

18. Hershko CM, Link GM, Konijn AM, et al. Iron chelation therapy.

Curr Hematol Rep 2005;4:110–116.

19. Vichinsky E, Onyekwere O, Porter J, et al. A randomised

comparison of deferasirox versus deferoxamine for the treatment

of transfusional iron overload in sickle cell disease. Br J Haematol

2007;136:501–508.

20. Cappellini MD, Cohen A, Piga A, et al. A phase 3 study of

deferasirox (ICL670), a once-daily oral iron chelator, in patients

with beta-thalassemia. Blood 2006;107:3455–3462.

21. Cappellini MD, Bejaoui M, Agaoglu L, et al. Prospective

evaluation of patient-reported outcomes during treatment with

deferasirox or deferoxamine for iron overload in patients with beta-

thalassemia. Clin Ther 2007;29:909–917.

22. Delea TE, Sofrygin O, Thomas SK, et al. Cost effectiveness

of once-daily oral chelation therapy with deferasirox versus

infusional deferoxamine in transfusion-dependent thalassaemia

patients: US healthcare system perspective. Pharmacoeconomics

2007;25:329–342.

23. Piga A, Galanello R, Forni GL, et al. Randomized phase II trial of

deferasirox (Exjade, ICL670), a once-daily, orally-administered

Pediatr Blood Cancer DOI 10.1002/pbc

Oral Iron Chelation in Pediatrics 619

iron chelator, in comparison to deferoxamine in thalassemia

patients with transfusional iron overload. Haematologica 2006;

91:873–880.

24. Exjade (Accessed at http://www.pharma.us.novartis.com/product/

pi/pdf/exjade.pdf.).

25. Walsh JC, Mandalia S, Gazzard BG. Responses to a 1-month self-

report on adherence to antiretroviral therapy are consistent with

electronic data and virological treatment outcome. AIDS 2002;16:

269–277.

26. Haynes RB, Taylor DW, Sackett DL, et al. Can simple clinical

measurements detect patient noncompliance? Hypertension 1980;

2:757–764.

27. Galanello R, Piga A, Forni GL, et al. Phase II clinical evaluation of

deferasirox, a once-daily oral chelating agent, in pediatric patients

with beta-thalassemia major. Haematologica 2006;91:1343–1351.

28. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med

2005;353:487–497.

29. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy

in elderly patients with and without acute coronary syndromes.

JAMA 2002;288:462–467.

30. Cramer J, Rosenheck R, Kirk G, et al. Medication compliance

feedback and monitoring in a clinical trial: Predictors and

outcomes. Value Health 2003;6:566–573.

31. Haynes RB, McDonald HP, Garg AX. Helping patients follow

prescribed treatment: Clinical applications. JAMA 2002;288:

2880–2883.

32. Arboretti R, Tognoni G, Alberti D. Pharmacosurveillance

and quality of care of thalassaemic patients. A large scale

epidemiological survey. Eur J Clin Pharmacol 2001;56:915–

922.

Pediatr Blood Cancer DOI 10.1002/pbc

620 Raphael et al.