Pediatric Hematology and Oncology

ISSN: (Print) (Online) Journal homepage: and efficacy of deferasirox in patients with transfusion-dependent thalassemia: A 4-year single-center experienceGizem Zengin Ersoy, Ali Ayçiçek, Işık Odaman Al, Cengiz Bayram, Esra Arslantaş, Gül Nihal Özdemir, Ezgi Paslı Uysalol, Zafer Şalcıoğlu, Ferhan Akıcı & Gönül AydoğanTo cite this article: Gizem Zengin Ersoy, Ali Ayçiçek, Işık Odaman Al, Cengiz Bayram, Esra Arslantaş, Gül Nihal Özdemir, Ezgi Paslı Uysalol, Zafer Şalcıoğlu, Ferhan Akıcı & Gönül Aydoğan (2021): Safety and efficacy of deferasirox in patients with transfusion-dependent thalassemia: A 4-year single-center experience, Pediatric Hematology and Oncology

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Safety and efficacy of deferasirox in patients with transfusion-dependent thalassemia: A 4-year single-center experience

Gizem Zengin Ersoy, Ali Ayc¸ic¸ek, Is¸ık Odaman Al, Cengiz Bayram, Esra Arslantas¸, Gu€l Nihal O€ zdemir, Ezgi Paslı Uysalol, Zafer S¸alcıog˘lu, Ferhan Akıcı, and
Go€nu€l Aydog˘an
Pediatric Hematology Oncology, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey


Received 14 December 2020
Revised 23 February 2021
Accepted 27 February 2021

Beta-thalassemia; chelation therapy; deferasirox; refugees


Iron overload is a condition that occurs when iron is deposited in multiple organs and the serum ferritin (SF) value is greater than 1000 ng/mL.1 Many congenital anemias characterized by a decrease in red blood cell (RBC) production or increase in cell destruction such as beta thalassemia or sickle cell anemia are treated with regular RBC transfusions, leading to chronic iron overload. Thus, these rare anemias often require

CONTACT Gizem Zengin Ersoy [email protected] Kanuni Sultan Suleyman Training and Research Hospital, Pediatric Hematology Oncology Istanbul, 34303 Turkey.
© 2021 Taylor & Francis Group, LLC

iron chelation therapy.2 When body iron exceeds the iron-binding capacity of transfer- rin, this causes the formation of non-transferrin–bound iron, which has a subfraction called labile plasma iron that catalyzes the generation of reactive oxygen species (ROS) resulting in damage of organelles and DNA, and eventually of organs.3 Three iron-che- lating medications are currently available for the treatment of iron overload: deferox- amine, deferasirox, and deferiprone.4 Chelation therapy with deferoxamine (DFO) was the gold standard over several decades. However, the subcutaneous route of administra- tion of DFO is associated with low compliance which lowers the sufficiency of iron che- lation. Deferasirox (DFX) has proven to have better compliance and higher treatment adherence as compared with DFO because it has an oral and once daily form. Moreover, it has been shown that DFX can lower serum ferritin, total body iron, and organ iron deposits.5–7
Nevertheless, high drug termination rates with DFX were reported in clinical trials
such as the EPIC or the US03, which were mainly due to gastrointestinal and renal adverse events.6,8 The aim of this study was to determine the efficacy of DFX in reduc- ing the SF of patients with transfusion-dependent thalassemia (TDT) in an outpatient setting, and also to identify the adverse reactions related to DFX use.

Material and methods
This is a retrospective, descriptive study including 101 patients with transfusion-depend- ent thalassemia major (20 Syrian patients and 81 Turkish patients) who were followed regularly in the outpatient clinic of pediatric hematology in a tertiary care center in Istanbul for 48 months. Polyclinic records and the hospital database were used to collect
data. DFX started to all patients after 2 years old, as permitted by The Health Ministry, and if yhe SF level is >1000 ng/dl at two consecuative measurements. SF concentrations, which were analyzed monthly before transfusion, the drug used for chelation, adverse
reactions, and any change in treatment due to adverse reactions were noted. A total of 29 patients (17 Turkish and 12 Syrian) were excluded; 11 patients used an alternative chelator either alone or combined with DFX, two were not compliant with the treat- ment, five patients changed the drug due to adverse reactions, one patient had multiple transfusions because of immunization, and 10 patients did not complete the 4 years of DFX use.

Statistical analysis
The data were analyzed using the IBM SPSS V23 package program. Compliance with normal distribution was examined using the Shapiro-Wilk test. Temporal variation of the normally distributed data was analyzed using repeated variance analysis. The Friedman test was used to compare normally distributed data. The Kruskal-Wallis and Mann-Whitney U test were used for comparisons between the groups. The Wilcoxon test was used for the analysis of values at the start and end of the study. Analysis results are presented as arithmetic mean, standard deviation, median, minimum and maximum.
The significance level was accepted as p < 0.05.

1. Exclusion criteria of study patients.
A total of 72 patients completed the study. The age distribution of the patients was as follows: 6-12 years (n 23, 32%); 13-18 years (n 20, 28%); 19 years (n 29, 40%). Serum ferritin concentrations were decreased across four years of DFX therapy from a median of 1254 ng/mL (mean 1930, range: 276-14,500 ng/mL) to a median of 1124 ng/mL (mean 1297, range: 365-5598 ng/mL) (p 0.117). SF decreases were
noted for the 6-12 and >18 years groups, from a median of 1532 ng/mL to 1190 ng/mL,
and from 1386 ng/mL to 1165 ng/mL, respectively (p 0.460; p 0.465). However, in
the 13-18 years age group, the SF concentrations increased from a median of 774 ng/mL at baseline to 1017 ng/mL at the end of the study (p 0.831). Also, there was a consid-
erable decrease in the proportion of patients with SF values >2000 ng/mL (29% at base- line, which decreased to 15% at the end of the study) during the 48 months
In the study cohort, the mean DFX dose was 28.5 ± 8.9 mg/kg at baseline and 29 ± 9.1 mg/kg at the end. There was no statistically significant difference (p 0.341). Of note, there was no statistically difference between the mean DFX dose of either the sex or age groups (p 0.452; p 0.527, respectively). The mean dosages in the respective age groups were as follows: 29 ± 8.3 mg/kg/day for the 6-12 years group (n 23); 29 ± 9.9 mg/kg/day for the 13-18 years group (n 20); and 30 ± 9.4 mg/kg/day for those aged 19 years (n 29). Overall, during the study period, patients were transfused 3 or 4 weeks at most with 15 mL/kg of packed RBCs, which means 180-255 mL/kg per year
Higher mean dosages were used in patients with higher SF values: the median SF concentrations of patients who used <25 mg/kg/day DFX was 739 ng/mL, whereas it was 1555 ng/mL for patients who used >25 mg/kg DFX (p 0.035). When patients were stratified according to dosage groups of <30 mg/kg/day (n 38) and >30 mg/kg/day (n 34), the median SF of those who used lower doses increased from 767 to 1006,
whereas the higher dose group’s SF values decreased from a median of 1575 ng/mL to 1209 ng/mL, respectively (p ¼ 0.029).

2. Changes in DFX dose vs. time.

3. Change in SF values during the 48 months.

Among the 72 patients, 14 patients (19.4%) had gastric irritation symptoms; mostly abdominal pain (9.7%), nausea, and diarrhea, respectively. Three (4.1%) were serious, leading to discontinuation of DFX. A small increase in hepatic enzymes was seen in a group of patients with different episodes, but only 3 (4.1%) were serious (2 times greater than the upper normal limit), but were relieved shortly after interrupting treat- ment with the drug. A patient who was seropositive for hepatitis C had severe elevation of transaminases during DFX treatment, thus it was switched to another chelation agent. One patient who experienced severe gastric irritation symptoms with elevation of transaminases also had treatment change. One patient had acute renal failure during DFX use; the drug was discontinued despite there being no clear relationship with DFX. Another patient had a severe urticarial reaction that relapsed with DFX continuation, thus the treatment was changed. Mild proteinuria was found in a girl during routine urine examination, and was treated with enalapril. The total DFX discontinuation ratio was calculated as 9.7% (7 out of 72 patients).

4. Change in serum ferritin concentration from baseline to the end of the study according to the deferasirox dose group in patients with transfusion-dependent thalassemia.

Table 1. Demographic characteristics of patients.
Baseline (n ¼ 101)
Age (years) End of study (n ¼ 72) P
Median (range) Mean ± SD
Sex(%) Male 14 (2-31)14 ± 847 (46%) 20 (6-31)17 ± 734 (47%)0.157

Serum Ferritin (ng/mL) Median (range) 54 (54%)1254 (276-14500) 38 (53%)1124 (365-5598)0.117Turkish 1136 (335-7535) 1081 (365-5598) 0.629Syrian Mean ± SDSerum ferritin category, n (%)<2000 ng/mL (all) 2752 (689-14500)1930 ± 108171 (70%) 1752 (637-3212)1423 ± 100161 (85%) 0.043<0.001

<2000 ng/mL (Syrian) 7 (35%) 3 (37%)
>2000 ng/mL (all) 30 (30%) 11 (15%) 0.004
>2000 ng/mL (Syrian) 13 (65%) 5 (63%)

In a total of 42 patients, measurement of either liver iron concentration (LIC) or T2ω results of liver and heart was performed using magnetic resonance imaging (MRI). Of those, 34 and 42 had baseline values of LIC and T2 results, respectively. For the patients who had measurements available both at baseline and at the end of the study, the mean
LIC values decreased from 7.05 mg/kg to 6.19 mg/kg. Similarly, an improvement was detected in T2ω values. Cardiac T2ω values were increased from a mean of 30.12 ms to 31.03 ms, and liver T2ω values were increased from 9.96 ms to 13.94 ms (Table 1).

In this study, we aimed to describe the results of 4 years of DFX chelation therapy to analyze its safety and the dose-related efficacy of DFX for managing iron overload in patients with TDT.The oral iron chelator DFX became available in the United States of America in 2005, in Europe in 2006, and in Turkey in 2007.9 In the study cohort, we had patients from many age groups, and some patients had used DFX since 2007. For our institute, it is the first choice for chelation therapy, mostly due to availability of the drug at early ages and due to the relatively easier mode of administration.

The mean dosage of DFX was between 25-30 mg/kg/day, we saw this dosage maintain stable iron balances despite ongoing transfusion. Cappellini et al. reported that a dosage of 20 mg/kg/day was predicted to be able to maintain stable iron balance in patients who were regularly transfused.10 Although no statistically significant decrease in mean and median SF concentrations could be achieved with dosages between 25-30 mg/kg/ day, this might be due to the cohort being well-controlled, whose SF concentrations were already stable. However, another remarkable result of the present study was the
increase in median SF values of the <30 mg/kg/day dosage group, where the median SF
concentrations decreased in the opposite group. Also, Taher et al. reported that DFX
≥30 mg/kg per day was generally required because of high transfusional iron intake and high baseline serum ferritin level, highlighting the importance of using an adequate dose to achieve a net negative iron balance.11
Differential analysis of median ferritin values were performed both for Turkish and Syrian patients with thalassemia. Unlike Turkish patients, the decline of median SF val- ues for Syrian patients was statistically significant (p ¼ 0.043) . On the con- trary, a large national cohort study about Syrian patients with thalassemia indicated an increase in median SF values due to regular transfusions.12 All treatment expenses of refugee patients have been under the assurance of the government since the acceptance of refugees to Turkey as a host country. This situation has provided easy access to treat- ment centers and chelation drugs for Syrian patients with thalassemia. The improve- ment in treatment adherence owing to health ministry policies resulted in significant decrease in the median SF values of this group. Nevertheless, the median SF concentra- tions of Turkish patients remained stable during the study period. As mentioned previ- ously, these patients mostly had well-controlled iron balances already. The present result emphasizes the need for strict follow-up of SF concentrations and regulation of DFX doses. However, another study outlined the fact that even at a dosage of 40 mg/kg per day, not all patients achieved a net negative iron balance, probably due to differen- ces in DFX pharmokinetics.13
In this study, a decrease of the mean DFX dosage of the patients was remarkable at
the 36th month . Despite the fact that no obvious reasons for this decrease could be detected, one reason might be the underestimation of increasing body weights of our pediatric cohort, thus decreasing the dose of DFX per kilogram. This decrement, which was about 2 mg/kg/day, seems not to affect mean SF vlaues in corresponding months
The efficacy of DFX was influenced by the balance between transfusional load and optimal dose, highlighting the importance of timely dose adjustment in order to achieve clinical goals.14 In our cohort, it was seen that the patients with higher SF concetrations received higher doses of DFX. Thus, to a degree, it might be stated that dose adjustment was performed for the patients followed up in our clinic. Nevertheless, it is also obvious that despite the decreasing median SF values, no statistically significant decline could be

5. Change in SF values by time in Syrian and Turkish patients.

achieved, which means the dose adjustments were inadequate and needed to be higher. In DFX studies, the greatest median absolute change in serum ferritin values were observed in patients assigned a starting dose of 30 mg/kg/day,15 as confirmed by the present study. In a recent large cohort study from Turkey,16 the need for higher drug dosages (doses >30 mg/kg/day) was emphasized to achieve greater reductions in SF con- centrations. In our single center cohort, the similar results are obvious. The patients with higher SF concentrations are at greater risk of mortality and morbidity. Thus, adjusting DFX dosages higher than 30 mg/kg/day are essential for these patients in order to ensure a negative iron balance.
Dose escalation during therapy is essential to achieve treatment goals. Generally trials for DFX efficacy show that dosages >30 mg/kg/day are needed especially in patients with heavy iron overload, without additional risk of a rise in adverse effects.14,17 The mean and median DFX dosages were lower than 30 mg/kg/day in our study. The rea- sons for such a conservative approach could be the topic of another study. However, it
might be due to concerns about adverse effects and acceptance that high SF levels might be tolerable in chronically transfused patients.
Adverse events suspected to be related to DFX were detected in 19.4% of patients. Most of which were gastric irritation symptoms. Creatinine concentrations at the begin- ning and end of the study were not analyzed. However, only two patients experienced renal adverse effects, one as acute renal failure and the other as proteinuria. In both sit- uations, patients preferred to continue DFX after the symptoms were relieved. Approximately 10% of the cohort ceased treatment because of adverse effects. Many clinical trials have confirmed the safety of DFX for up to 5 years of therapy, including patients aged as young as two years, with no adverse effects noted on parameters of
growth or sexual development15 and also using dosages >30 mg/kg/day for up to three years, and again including patients as young as 2 years of age, have been found as
Although adherence to therapy was questioned at every polyclinic visit, it is not pos- sible to assess the exact adherence. For instance, the increase in median SF vaues in adolescents (1218 years age group) might be the result of inappropriate adherence to therapy in this age group. In a systematic review of 18 published studies, it was

established that patient survival and iron removal were strictly correlated with adher- ence to chelation therapy.20 Also, as this was a retrospective analysis, there might be some information loss about mild adverse reactions because of missing records or underestimation of the physician. Thus, the exact ratio of adverse reactions might have been influenced. Moreover, for cardiac and hepatic iron level measurements, not all
patients could be checked at baseline and at the end of the study. For the patients whose measurements were available, it is established the LIC and T2ω values improve.
The appropriate assessment of tissue iron levels for all patients was not possible, instead we used the SF concentrations, which may be easily influenced by other conditions, e.g. infections. However, as stated by Capellini et al., serial SF measurements are still valu- able and recommended for monitoring the efficacy of iron chelation therapy in patients with hemoglobinopathies.21 Thus, adjustment of treatment dosage not according to a single SF level but according to the analyses of increment or decrement trend from con- secutive SF measurements can be more effective.

Despite the limitations, the safety and efficacy of DFX for managing iron burden in patients with TDT was confirmed in our cohort. Dosages between 25-30 mg/kg/day are adequate to stabilize SF levels despite heavy transfusion in patients with TDT, but higher dosages are needed to achieve a statistically significant decrease in SF concentra- tions. Also, close follow- up of patients is essential to assess the changing body weight in the pediatric population and to adjust dosing according to the transfusional rate.

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