Original Article

Efficacy of deferasirox in children with β-thalassemia: Single-center3 year experience

Ali Aycicek,1 Ahmet Koc2 and Mahmut Abuhandan3

1Pediatric Hematology/Oncology Clinic, Eskisehir State Hospital, Eskisehir, 2Pediatric Hematology/Oncology Department,Marmara University Medical Faculty, Research Hospital, Istanbul and 3Pediatrics Department, Harran University MedicalFaculty, Research Hospital, Sanliurfa, Turkey

Abstract Background: Iron chelation therapy is an important component in the management of patients with β-thalassemia.Methods The study included 87 children with transfusion-dependent β-thalassemia aged 2–17 years (mean, 8.2 ± 4.1years), 49 (56%) of whom were male. The patients received deferasirox 9–40 mg/kg per day as a single dose for36 months. They were clinically and laboratory monitored.Results: The treatment was generally well tolerated. Drug-related adverse events, including abdominal pain (14.9%) andnausea (5.8%), high alanine aminotransferase more than double the upper limit of normal (5.8%), and non-progressiverise in serum creatinine (2.3%), were generally mild to moderate, transient, and reduced in frequency over time. Twopatients discontinued treatment due to severe abdominal pain and nausea. Mean deferasirox dose was calculated as 21.2± 8.6, 23.7 ± 8.1, 30.7 ± 8.2 and 32.4 ± 7.6 mg/kg per day at 0, 12, 24 and 36 months, respectively. Mean (median) serumferritin level was found to increase progressively during the first 22 months of treatment, from 3.161 ± 1.683 ng/mL(2.760 ng/mL) to 3.679 ± 1.997 ng/mL (3.071 ng/mL; P < 0.001) and then decreased gradually to 2.907 ± 1.436 ng/mL(2.670 ng/mL; P = 0.023) at 36 months.Conclusion: Deferasirox is safe and well tolerated; doses 21–24 mg/kg per day were not able to maintain stable ironbalance, but ≥30 mg/kg per day was able to reduce iron in regularly transfused pediatric patients.

Key words β-thalassemia, deferasirox, iron-chelating agents, iron overload, treatment outcome.

In cases of ongoing transfusion therapy, with each red blood cell(RBC) unit containing approximately 200 mg of iron, cumulativeiron burden is an inevitable consequence leading to excess ironaccumulation in many organs, resulting in tissue damage andorgan dysfunction.1–3 Therefore, iron chelation is essential in themanagement of this otherwise fatal disease. In β-thalassemiapatients, the rate of transfusional and gastrointestinal (GI) tractiron accumulation is generally 0.3–0.6 mg/kg per day.1 To date,three major iron chelators have been described: hexadentate(deferoxamine, Desferal), in which one atom of iron is bound toone deferoxamine molecule; bidentate (deferiprone, Ferriprox),in which one atom of iron is bound to three deferipron molecules;and tridentate (deferasirox, Exjade), in which one atom of iron isbound to two deferasirox molecules.4,5 Deferoxamine has beenthe standard of care for transfusional iron overload for more than40 years, although s.c. infusion negatively affects patient com-pliance.6 The oral iron chelators deferiprone and deferasirox areeffective in reducing iron burden, while at the same time they

improve compliance and patient quality of life.7 Deferasirox is aonce-daily oral iron chelator that has proven effective in reducingliver iron concentration (LIC) and serum ferritin level >1 year inpatients with various transfusion-dependent anemias8,9

Few trials have been conducted on the efficacy of long-termdeferasirox chelation therapy in different geographic regions andethnic groups. The present study examined the safety, tolerabilityand efficacy of deferasirox for 3 years in children with transfu-sion dependent β-thalassemia at Sanliurfa province in the south-east region of Turkey.

Methods

In total, 102 consecutive children with transfusion-dependentβ-thalassemia were enrolled into the study. The patients were2–17 years old (mean, 8.4 years), and received 9–40 mg/kg perday deferasirox between 1 March 2009 and 20 December 2012 atthe Pediatric Hematology Clinic at Harran University andSanliurfa Children’s Hospital. Children with β-thalassemia andtransfusional iron overload aged ≥2 years and with serum ferritin>1000 ng/mL were eligible for inclusion in the study regardlessof prior intake of iron chelator types. Patients were excludedfrom this trial if they had one of the following conditions: alanineaminotransferase (ALT) >250 U/L during the year prior to enroll-ment, chronic hepatitis B infection, active hepatitis C infection,

Correspondence: Ali Aycicek, MD, Pediatric Hematology/OncologyClinic, Eskisehir State Hospital, Eskisehir 26010, Turkey. Email:ayciceka@hotmail.com

Received 31 May 2013; revised 12 October 2013; accepted 26December 2013.

bs_bs_banner

Pediatrics International (2014) ••, ••–•• doi: 10.1111/ped.12323

© 2014 Japan Pediatric Society

serum creatinine above the upper limit of normal (ULN),nephrotic syndrome, uncontrolled systemic hypertension, orsystemic infection within the 10 days prior to entry. Additionally,patients were excluded if they underwent bone marrow transplan-tation, had no regular follow-up visits, were non-compliant withprescribed therapy, had GI conditions preventing absorption of anoral medication, or concomitant conditions preventing therapywith deferasirox.

Deferasirox dose was assigned according to ferritin level,whereby patients with ferritin 500–1000, 1001–2000, or>2000 ng/mL were assigned deferasirox doses of 15, 20, or30 mg/kg per day, respectively. The dose was subsequentlyincreased or decreased by 5–10 mg/kg per day every 3–6 monthsaccording to trends in serum ferritin level and safety markers.8 TheMinistry of Health approved the dose of deferasirox 40 mg/kg perday in April 2011, after which, the maximum dose of deferasiroxwas increased up to 40 mg/kg/day in patients with ferritin >2000ng/mL.

Once-daily treatment with deferasirox at the assigned dose wasgiven as a suspension in water half an hour prior to breakfast 7 daysper week. Treatment with either therapy was continued for36 months, and was interrupted only at the discretion of theinvestigator for intercurrent illness or adverse events. Dose modi-fications were mainly permitted for safety reasons. Blood trans-fusion was done regularly during the study period according topatient requirement. Assessments for safety and efficacy, per-formed at monthly intervals at Harran University Research Hos-pital Biochemistry Laboratory, included complete blood count/differential, electrolytes, liver function tests, and serum creatinineand ferritin. The local scientific ethics committee approved thisstudy. Informed consent was obtained from the patients’ parents.

Statistical analysis

The data are expressed as number (%), mean ± SD and median.Paired samples t-test was used to compare mean serum ferritinlevels, assuming a 95% confidence interval. Differences wereconsidered statistically significant at P < 0.05. Statistical analysiswas done using SPSS for Windows Release 11.5 (SPSS Inc,Chicago, IL, USA)

Results

The mean patient age at the start of the study was 8.4 ± 4.3 years(range, 2–17 years; 57 boys and 45 girls), and was 11.2 ± 4.4years (range, 11–18 years; 49 boys and 38 girls) at the end of thestudy. The patient demographics at the start and end of study aregiven in Table 1.

Eighty-seven patients completed the study. Five patientsunderwent bone marrow transplantation, three moved away fromSanliurfa, and seven had no regular follow-up visits. Meandeferasirox dose was calculated as 21.2 ± 8.6 mg/kg per day(range, 10.1–35.6), 23.7 mg/kg per day (range, 9.4–40.4),30.7 mg/kg per day (range, 12.7–41.1) and 32.4 mg/kg per day(range, 15–40.6) at 0, 12, 24 and 36 months, respectively. Overthe course of the study, the proportion of patients receiving≤25 mg/kg per day markedly decreased; most patients receivedfinal doses of approximately 32 mg/kg per day (Table 1). Overall

blood intake was 15.6 ± 5.4 mL/kg per month, <7 mL/kg permonth in three patients (4%), 7–14 mL/kg per month in 42patients (48%), and >14 mL/kg per month in 42 patients (48%).Mean iron intake was 0.59 ± 0.3 mg/kg per day.

Mean serum ferritin level was found to increase progressivelyduring the first 22 months of treatment, from 3.161 ±1.683 ng/mL (median, 2.760 ng/mL) to 3.679 ± 1.997 ng/mL(median, 3.071 ng/mL; P < 0.001) and then decreased gradually

Table 1 Subject characteristics

Characteristic Start of study(n = 102)

End of study(n = 87)

Age (years)Median (range) 8 (2–17) 11 (5–18)Mean ± SD 8.4 ± 4.3 11.2 ± 4.2

Sex (%)Male 57 49Female 45 38

Serum ferritin (ng/mL)Median (range) 2.761 (1.007–7.924) 2.694 (470–7.173)Mean ± SD 3.161 ± 1.683 3.010 ± 1.562*

Serum ferritin category, n (%)<1000 ng/mL 0 4 (4.6)1000–2500 ng/mL 42 (41.2) 31 (35.6)2501–4000 ng/mL 32 (31.4) 37 (42.5)>4000 ng/mL 28 (27.5) 15 (17.3)

Deferasirox dosing, n (%)<15 mg/kg per day 13 (12.8) 1 (1.2)15–25 mg/kg per day 38 (37.3) 12 (13.8)25.1–35 mg/kg per day 46 (45.1) 57 (65.5)>35 mg/kg per day 5 (4.9) 17(19.5)

*Paired sample t-test (P = 0.599).

Months

M35

M33

M31

M29

M27

M25

M23

M21

M19

M17

M15

M13

M11

M9

M7

M5

M3

M1

Mea

n se

rum

ferr

itin

(ng/

mL)

5000

4000

3000

2000

Fig. 1 Effect of deferasirox on serum ferritin level in children withβ-thalassemia (95% confidence intervals).

2 A Aycicek et al.

© 2014 Japan Pediatric Society

to 2.907 ± 1.436 ng/mL (median 2670 ng/mL; P = 0.023) at36 months of the study (Fig. 1). Mean serum ferritin level slightlydecreased between 12 and 14 months, decrease becoming pro-gressively decreased when the average actual dose of deferasiroxincreased to >30 mg/kg per day after 22 months. At the start ofthe study, 42, 32, and 28 patients had a serum ferritin level1000–2500, 2501–4000, and >4000 ng/mL, respectively (Fig. 1).A total of 37 patients (36.3%) reached a serum ferritin level≤2500 ng/mL after 1 year of deferasirox treatment. Moreover,four of the patients achieved a serum ferritin level ≤1000 ng/mLat 36 months, considered a target of iron chelation therapy after 1year’s exposure; 31, 37, and 15 had serum ferritin level 1000–2500, 2501–4000, and >4000 ng/mL, respectively, at the end ofthe study (Fig. 1).

Abdominal pain and nausea were observed in 13 (14.9%) andfive patients (5.9%), respectively. These symptoms were gener-ally of mild to moderate severity and resolved when the drug wascontinued except in two who had extensive abdominal pain. Fivepatients (5.9%) developed elevated ALT greater than twice theULN, and two (2.3%) had elevated ALT fivefold the ULN. In givepatients (5.9%) elevated ALT greater than twice the ULN con-tinued while receiving deferasirox. Two patients (2.3%) devel-oped at least two consecutive increases in serum creatinine abovethe upper limit of age-appropriate normal. ALT and creatininespontaneously normalized within 4–6 months. In neither casewas alkaline phosphatase or bilirubin elevated significantly abovethe baseline. No drug-related agranulocytosis was observedduring this trial.

Discussion

Iron overload is a leading cause of morbidity and mortality intransfusion-dependent patients with thalassemia major; relatedcomplications include liver cirrhosis and cardiac disease.8,10,11

The introduction of iron chelation therapy has led to a significantimprovement in the survival of patients with thalassemia major,but long-term management of iron overload is suboptimal inmany patients, in part because of compliance issues associatedwith the parenteral regimen of iron chelation therapy with defero-xamine.5,8,12 The oral iron chelator deferasirox became availablein the USA in 2005, in Europe in 2006, and in Turkey in 2007,and is an orally ingested, highly bioavailable chelator that isabsorbed in the GI tract for use in transfusional overloadpatients.12 Because of its dose-dependent half-life of 12–18 h, itcan be taken once a day. It is reported that daily use of a singleoral dose of 20–30 mg/kg per day results in dose-dependentdecreases in LIC with similar trends in serum ferritin comparablewith those achieved by s.c. 8 h treatment of 40–60 mg/kg per daydeferoxamine.7,13,14 It is also reported, however, that the literatureshows risks of bias, and additional larger and longer trials areneeded.14

In frequently transfused patients, defined as individualsreceiving 2–4 units/month (or 7–14 mL/kg per month) packedRBC, the rate of transfusional and GI tract iron accumulation isgenerally 0.3–0.6 mg/kg per day and oral deferasirox at a once-daily dose of 20 mg/kg seems to be an effective orally active iron

chelator.12 Cappellini et al. reported that a dose of 20 mg/kg waspredicted to be able to maintain stable iron balance in regularlytransfused patients.7 In the present study, mean blood volumereceived was 15.6 ± 5.4 mL/kg per month, mean iron intake was0.59 ± 0.3 mg/kg per day, and mean deferasirox dose was 23.7 ±7.2 mg/kg per day, a high dose, which did not stabilize the meanserum ferritin level close to 3000 ng/mL, and did not achieve ironbalance during the first year of study, but deferasirox ≥30 mg/kgper day achieved net negative iron balance during the course ofthe last year. The present results are not consistent with a previ-ously published study examining the ability of deferasirox toremove iron from the body.7,8,13 Also, Taher et al. reported thatdeferasirox ≥30 mg/kg per day was generally required because ofhigh transfusional iron intake and high baseline serum ferritinlevel, highlighting the importance of using an adequate dose toachieve net negative iron balance.15 Even at a dose of 40 mg/kgper day, however, not all patients achieve net negative ironbalance.16,17 The present results are consistent with these reports.Further analysis evaluating the most appropriate deferasiroxdosing strategy in pediatric patients would be of value, includingchelation-naïve patients and those switching from other chelationtherapies. The efficacy of deferasirox was dependent ontransfusional intake and optimal dose, highlighting the impor-tance of timely dose adjustment in order to achieve clinicalgoals.18

Furthermore, this study adds to information on the nursingcare for thalassemic children, due to the close monitoring of ironburden with timely dose adjustments and description of potentialside-effects, and will facilitate optimal adherence to oralchelation agent.

The most common symptoms reported with a suspected rela-tionship to repeated use of deferasirox were abdominalpain, nausea, vomiting, diarrhea, constipation, and skin rash.These symptoms were generally of mild to moderate severityand often resolved even when the drug was continued.7,8 In thepresent study, elevations in liver function tests to more thantwice the ULN, which were thought to be related to deferasirox,occurred in 5.8% of patients. It is reported that mild, non-progressive increases in serum creatinine, generally within thenormal range, were the most common laboratory abnormalitiesthat have occurred in patients receiving deferasirox andwere more frequent in patients receiving 20 or 30 mg/kg.7

In the present study, at least two consecutive increases inserum creatinine above the upper limit of age-appropriatenormal were detected in only two (2.3%) of the 87 patients.Both adverse effects occurred at rates lower than previousobservation in children with β-thalassemia.15,19 Moreover, inter-ruption or discontinuation of deferasirox was not requiredin cases of unexplained progressive increase in transaminase,progressive increase in serum creatinine, or progressive GIsymptomatology.

The major limitations of this study include a lack of liverbiopsy, cardiac iron overload, and comparison of other ironchelators.1,11 Although this most likely led to underdosing ofpatients assessed using this methodology, it did not alter theprimary outcome of the study.

Deferasirox efficacy in children 3

© 2014 Japan Pediatric Society

Conclusion

Deferasirox is safe and well-tolerated; doses 21–24 mg/kg perday were not able to maintain stable iron balance, but ≥30 mg/kgper day was able to reduce iron in regularly transfused pediatricpatients.

Acknowledgments

We wish to disclose no competing interests. Our academic insti-tution or employment has no financial interest in or financialconflict with the subject matter or materials discussed in thismanuscript.

References

1 Rachmilewitz EA, Giardina PJ. How I treat thalassemia. Blood2011; 118: 3479–88.

2 Gardenghi S, Marongiu MF, Ramos P et al. Ineffectiveerythropoiesis in beta thalassemia is characterized by increasediron absorption mediated by down regulation of hepcidin and upregulation of ferroportin. Blood 2007; 109: 5027–35.

3 Duman O, Arayici S, Fettahoglu C et al. Neurocognitive functionin patients with β-thalassemia major. Pediatr. Int. 2011; 53: 519–23.

4 Giardina PJ, Grady RW. Chelation therapy in beta-thalassemia: Anoptimistic update. Semin. Hematol. 2001; 38: 360–66.

5 Neufeld EJ. Oral chelators deferasirox and deferiprone fortransfusional iron overload in thalassemia major: New data, newquestions. Blood 2006; 107: 3436–41.

6 Delea TE, Edelsberg J, Sofrygin O et al. Consequences and costsof noncompliance with iron chelation therapy in patients withtransfusion-dependent thalassemia: A literature review. Transfu-sion 2007; 47: 1919–29.

7 Cappellini MD, Cohen A, Piga A et al. A phase 3 study ofdeferasirox (ICL670), a once-daily oral iron chelator, in patientswith beta-thalassemia. Blood 2006; 107: 3455–62.

8 Cappellini MD, Bejaoui M, Agaoglu L et al. Iron chelation withdeferasirox in adult and pediatric patients with thalassemia major:Efficacy and safety during 5 years’ follow-up. Blood 2011; 118:884–93.

9 Cappellini MD, Porter JB, El-Beshlawy A et al. Tailoring ironchelation by iron intake and serum ferritin trends: The prospectivemulticenter EPIC study of deferasirox in 1744 patients withvarious transfusion-dependent anemias. Haematologica 2010; 95:557–66.

10 Borgna-Pignatti C, Rugolotto S, De Stefano P et al. Survival anddisease complications in thalassemia major. Ann. N. Y. Acad. Sci.1998; 850: 227–31.

11 Pennell DJ, Porter JB, Cappellini MD et al. Efficacy of deferasiroxin reducing and preventing cardiac iron overload in beta-thalassemia. Blood 2010; 115: 2364–71.

12 Nisbet-Brown E, Olivieri NF, Giardina PJ et al. Effectiveness andsafety of ICL670 in iron-loaded patients with thalassaemia: Arandomised, double-blind, placebo-controlled, dose-escalationtrial. Lancet 2003; 361: 1597–602.

13 Cohen AR, Glimm E, Porter JB. Effect of transfusional iron intakeon response to chelation therapy in beta-thalassemia major. Blood2008; 111: 583–7.

14 Maggio A, Filosa A, Vitrano A et al. Iron chelation therapy inthalassemia major: A systematic review with meta-analyses of1520 patients included on randomized clinical trials. Blood CellsMol. Dis. 2011; 47: 166–75.

15 Taher A, Elalfy MS, Al Zir K et al. Achieving treatment goals ofreducing or maintaining body iron burden with deferasirox inpatients with β-thalassaemia: Results from the ESCALATORstudy. Eur. J. Haematol. 2011; 87: 349–54.

16 Chirnomas D, Smith AL, Braunstein J et al. Deferasiroxpharmacokinetics in patients with adequate versus inadequateresponse. Blood 2009; 114: 4009–13.

17 Grady RW, Galanello R, Randolph RE, Kleinert DA, Dessi C,Giardina PJ. Toward optimizing the use of deferasirox: Potentialbenefits of combined use with deferoxamine. Haematologica2013; 98: 129–35.

18 Taher A, El-Beshlawy A, Elalfy MS et al. Efficacy and safety ofdeferasirox, an oral iron chelator, in heavily iron-overloadedpatients with beta-thalassaemia: The ESCALATOR study. Eur.J. Haematol. 2009; 82: 458–65.

19 Pennell DJ, Porter JB, Cappellini MD et al. Deferasirox for up to 3years leads to continued improvement of myocardial T2* inpatients with β-thalassemia major. Haematologica 2012; 97:842–8.

4 A Aycicek et al.

© 2014 Japan Pediatric Society