Hematology ISSN: (Print) 1607-8454 (Online) Journal homepage: https://www.tandfonline.com/loi/yhem20 International sentinel site surveillance of patients with transfusional hemosiderosis treated with deferasirox in actual practice setting Amal El-Beshlawy, Baba Inusa, David Beneitez Pastor, Blanca Xicoy, Maria Soledada Duran Nieto, Andreas Bruederle, Amin Azmon, Geralyn Gilotti & Mohsen Elalfy To cite this article: Amal El-Beshlawy, Baba Inusa, David Beneitez Pastor, Blanca Xicoy, Maria Soledada Duran Nieto, Andreas Bruederle, Amin Azmon, Geralyn Gilotti & Mohsen Elalfy (2019) International sentinel site surveillance of patients with transfusional hemosiderosis treated with deferasirox in actual practice setting, Hematology, 24:1, 238-246, DOI: 10.1080/16078454.2018.1558758 To link to this article: https://doi.org/10.1080/16078454.2018.1558758 © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group Published online: 17 Dec 2018. Submit your article to this journal Article views: 316 View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=yhem20 HEMATOLOGY 2019, VOL. 24, NO. 1, 238–246 https://doi.org/10.1080/16078454.2018.1558758 International sentinel site surveillance of patients with transfusional hemosiderosis treated with deferasirox in actual practice setting Amal El-Beshlawya, Baba Inusab, David Beneitez Pastor c, Blanca Xicoyd, Maria Soledada Duran Nietoe, Andreas Bruederlef, Amin Azmonf, Geralyn Gilottig and Mohsen Elalfyh a Cairo University, Cairo, Egypt; bEvelina Children’s Hospital, Guy’s and St Thomas’ Hospital NHS Trust, London, UK; cHematology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain; dICO-Badalona-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute, Barcelona, Spain; eDepartamento de Hematologíca, Hospital Materno Infantil de Jaen, Jaén, Spain; fNovartis Pharma AG, Basel, Switzerland; gNovartis Pharmaceuticals Corporation, East Hanover, NJ, USA; hAin Shams University, Cairo, Egypt ABSTRACT KEYWORDS Objective: The study evaluates the long-term deferasirox treatment of adult and pediatric Deferasirox; iron overload; patients with chronic transfusional iron overload in clinical practice. iron chelation therapy; safety Methods: In this non-interventional study, patients were observed for up to 3 years from initiation of deferasirox treatment both prospectively and retrospectively for up to 1 year prior to enrollment. The primary end points were the proportion of patients with ≥1 notable increase in serum creatinine (SCr), and ≥1 notable increase in alanine aminotransferase (ALT). Results: Overall, 120 patients were enrolled and 51 completed the study, with a limited 3-year dropout rate of 12.5% due to adverse events (AEs). Increase in SCr > 33% above baseline and the age-adjusted ULN (upper limit of normal) was observed in 14 patients (95%CI, 7.1–19.2). The ALT levels >5 × ULN was observed in 1 patient. Most frequent AEs reported during treatment with deferasirox include gastrointestinal disturbances. Conclusions: The long-term treatment with deferasirox was manageable in most transfusion- dependent patients with no unexpected safety findings. Regular monitoring and an adjusted deferasirox dosing strategy per local labels allowed continued iron chelation treatment and control of transfusional iron in the majority of patients on study. 1. Introduction transfusional iron overload in the actual practice setting. Patients with thalassemia, sickle-cell disease (SCD), myelodysplastic syndromes (MDS), and other transfu- sion-dependent anemias require long-term red blood 2. Materials and methods cell transfusions. Long-term iron chelation therapy is 2.1. Study design required in regularly transfused patients to manage chronic iron overload and associated risks [1–3]. Cur- This was a global, non-interventional study (July 2011– rently, three main iron chelators are available for October 2015) conducted on 14 sites in four countries clinical use: deferoxamine, deferiprone, and defera- (Egypt, Jordan, Spain and UK). The data were collected sirox. The once-daily oral deferasirox dispersible for 3 years from the initiation of treatment with defer- tablet formulation, available since 2005, offered an asirox (Exjade®). The registry did not impose a therapy improved option with greater compliance over par- protocol, diagnostic/therapeutic interventions, or a enteral deferoxamine [3–6]. The efficacy and safety strict visit schedule. Patients were treated with defera- of deferasirox dispersible tablet have been well sirox in clinical practice settings, at the discretion of the defined through an extensive clinical trial program investigator, and as per local country prescribing infor- in adult and pediatric patients with a variety of mation. Retrospective data were collected in patients transfusion-dependent anemias in adult and pedi- who had treatment with deferasirox for up to 1 year atric patients aged ≥2 years [7–11]. The present prior to enrollment. study reports the results of a post-marketing active surveillance program for deferasirox. The aim of 2.2. Key inclusion/exclusion criteria the study was to evaluate the long-term safety and clinical management of deferasirox in adult Male or female patients aged ≥2 years and treated with and pediatric patients aged ≥2 years with chronic deferasirox for transfusional hemosiderosis in accord- CONTACT Amal El-Beshlawy amalelbeshlawy@yahoo.com © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. HEMATOLOGY 239 Table 1. Demographics and baseline data by age group. <18 years ≥18 years All patients Characteristics (n = 69) (n = 51) (n = 120) Mean age, years 7.5 57.9 28.9 SD 4.2 22.1 29.0 Female: Male, n 35:34 21:30 56:64 Race, n (%) Caucasian 37 (53.6) 44 (86.3) 81 (67.5) Black 21 (30.4) 6 (11.8) 27 (22.5) Asian 7 (10.1) 0 (0.0) 7 (5.8) Native American 0 (0.0) 1 (2.0) 1 (0.8) Other 4 (5.8) 0 (0.0) 4 (3.3) Disease, n (%) β thalassemia major 34 (49.3) 7 (13.7) 41 (34.2) β thalassemia intermedia 7 (10.1) 1 (2.0) 8 (6.7) Refractory anemia 0 (0.0) 2 (3.9) 2 (1.7) Sideroblastic anemia 0 (0.0) 3 (5.9) 3 (2.5) Myelodysplastic syndrome 0 (0.0) 21 (41.2) 21 (17.5) Diamond–Blackfan anemia 2 (2.9) 0 (0.0) 2 (1.7) Hemolytic anemia 0 (0.0) 1 (2.0) 1 (0.8) Sickle cell disease (SS or Sbeta zero or both) 24 (34.8) 7 (13.7) 31 (25.8) Other 2 (2.9) 9 (17.6) 11 (9.2) History of blood transfusions Mean ± SD, time since start of blood transfusions* (years) 4.3 ± 4.0 8.7 ± 12.9 6.1 ± 9.1 Total number of blood transfusions received (median) 33.0 29.0 30.0 Patients with prior chelation therapy, n(%) Deferoxamine 17 (24.6) 12 (23.5) 29 (24.2) Deferiprone 23 (33.3) 3 (5.9) 26 (21.7) Deferoxamine + deferiprone 0 1 (2.0) 1 (0.8) Deferasirox 1 (1.4) 13 (25.5) 14 (11.7) Duration of exposure to deferasirox Median 36.0 10.0 29.9 Mean 30.6 15.1 23.9 *Time since start of blood transfusions = (first study drug dose date – start of blood transfusion date + 1)/365.25. ance with the local prescription information, patients secondary objective was to evaluate the long-term who were either starting treatment with deferasirox efficacy of deferasirox as measured by serum ferritin at the time of enrollment or currently under treatment (SF) levels over a period of 3 years. Secondary objec- with deferasirox up to 12 months prior to enrollment tives also included the evaluation of safety as measured were observed in this study. In order to assess the by adverse events (AEs), laboratory parameters, renal primary end point, only patients with available baseline histology, cardiac magnetic resonance (CMR), electro- values for serum creatinine (SCr) and alanine amino- cardiograms (ECGs), echocardiography, vital signs, transferase (ALT) measured up to a maximum period audiometry, and ophthalmology assessments. of 45 days prior to the first dose of deferasirox were included. Exclusion criteria included the following: 2.4. Statistical evaluations patients with non-transfusional hemosiderosis and patients treated with deferasirox in an interventional The full analysis set (FAS) consisted of all patients who clinical trial. Patients (or parents/guardians) provided received at least one dose of deferasirox during the written informed consent prior to any screening pro- study. The FAS was used for the statistical analysis of cedures. The study was conducted according to the SF levels. The safety set consisted of all patients who ethical principles of the Declaration of Helsinki. received at least one dose of deferasirox during the study and had at least one post-baseline safety assess- ment. The primary end point was performed based on 2.3. Assessments the safety set. Data are presented in mean ± SD or The primary objective was to evaluate the long-term median (range). safety of deferasirox treatment in adult and pediatric patients aged ≥2 years with chronic transfusional iron 3. Results overload in actual practice setting. The two co- 3.1. Patient demographics and clinical primary end points were the proportion of patients characteristics (within a maximum of 3 years of observation) with the following: (1) at least one increase in SCr, defined The majority of the patients included in the study were as >33% above baseline and the age-adjusted upper diagnosed with β thalassemia (n = 49), SCD (n = 31), limit of normal (ULN) on at least two consecutive MDS (n = 21), and other transfusion-dependent measurements (≥7 days apart); and (2) at least one anemias (n = 19). The mean (±SD) age was 28.9 ± 29.0 increase in ALT, defined as >5 × ULN on at least two in the study population, 7.5 ± 4.2 years in patients consecutive measurements (≥7 days apart). A <18 years (n = 69) and 57.9 ± 22.1 years in patients 240 A. EL-BESHLAWY ET AL. Table 2. Overall patient disposition by age group. <18 years ≥18 years All patients (n = 69) (n = 51) (n = 120) Disposition reason n (%) n (%) n (%) Patients treated Completed study 45 (65.2) 6 (11.8) 51 (42.5) Discontinued study, n (%) 24 (34.8) 45 (88.2) 69 (57.5) Subject’s condition no longer requires study drug 7 (10.1) 16 (31.4) 23 (19.2) Adverse event(s) 2 (2.9) 13 (25.5) 15 (12.5)a Consent withdrawal 9 (13.0) 4 (7.8) 13 (10.8) Lost to follow-up 6 (8.7) 2 (3.9) 8 (6.7) b Death 0 7 (13.7) 7 (5.8) Protocol deviation 0 2 (3.9) 2 (1.7)c Disease progression 0 1 (2.0) 1 (0.8) a Disposition for an additional seven patients who discontinued due to both an adverse event and death is accounted for under the most severe outcome (death). b Only on-treatment deaths from day 1 to the day of last study drug +30 days are provided; 1 additional death occurred during the study; this patient discontinued due to a protocol deviation and died within 30 days of stopping treatment. c One patient who discontinued due to a protocol deviation died within 30 days after stopping treatment (on-treatment death). ≥18 years (n = 51). The median number of blood trans- dose reduction or interruption were AEs (27.4%) and fusions before entering into the study was 30.0 (<18 others (20.5%) (including, but were not limited to, years, 33.0; ≥18 years, 29.0), with the majority of dose adjustment for weight, improvement/decrease patients requiring bi-weekly (16.7%) or monthly in SF, drug unavailability, investigator decision, and (62.5%) blood transfusions (Table 1). patients discontinued taking drug therapy due to an error). 3.2. Patient disposition The first patient first visit was July 2011, and the last 3.5. Prior iron chelation therapy patient last visit was October 2015. A total of 120 Overall, 54.2% of patients (n = 65) were chelation-naïve patients with transfusional hemosiderosis were and 45.8% (n = 55) received prior iron chelation enrolled (<18 years, n = 69 and ≥18 years, n = 51). therapy. Evaluable chelation-naïve patients received a The FAS included all 120 patients, and the safety analy- lower average actual dose (mg/kg/day, mean ± SD) of sis set included 117 patients. Sixty-nine patients deferasirox compared to patients receiving prior iron (57.5%) discontinued the study. Fifteen (12.5%) of chelation therapy (<18 years, 23.8 ± 5.2 vs. 27.6 ± 7.4; these discontinuations were related to AEs and more ≥18 years, 15.4 ± 7.7 vs. 20.3 ± 9.7). commonly observed in adult patients (25.5%) com- pared to pediatric patients (2.9%). The reasons for study discontinuation are presented in Table 2. 3.6. Safety parameters 3.6.1. Adverse events 3.3. Exposure to deferasirox treatment Overall, 40 patients (34.2%) had AEs suspected to be related to study drug. The most common AEs (>3% The median average of actual dose of deferasirox was in the overall patient population) are presented in 23.3 mg/kg/day (range, 2.3–41.3). The median duration Figure 1. Deferasirox-related AEs gradually decreased of deferasirox exposure was 29.9 months (range, 0.8– over time (Figure 2(A)) for patients continuing on 39.2). The median dose of deferasirox with relation to study. blood intake in patients ≥18 years was 12.5 and Serious adverse events, suspected to be related to 23.7 mg/kg/day with low (<7 mL/kg/day) and inter- study drug, were reported in five patients (4.3%); the mediate (7–14 mL/kg/day) transfusional burden, most frequently reported being gastrointestinal respectively. Based on serum ferritin level, deferasirox hemorrhage (n = 2). A total of 99 patients (84.6%) had was adjusted or interrupted according to the local at least 1 AE regardless of relationship to the study label. drug. Overall incidence of AEs regardless of relation- ship with deferasirox also decreased over time (Figure 2(B)) for patients continuing on study. The 3.4. Dose reductions or interruptions most common AEs were gastrointestinal disorders, In the overall population, 55 patients (47.0%) had dose (43.6%; n = 51) and infections and infestations (43.6%; reductions or interruptions. The mean number of dose n = 51). Adverse events occurring in >10% of patients reductions or interruptions was 1.7 in all patients. The were vomiting (16.2%), pyrexia (15.4%), diarrhea most common reasons for patients with at least one (13.7%), cough (12.8%), abdominal pain (12.0%), head HEMATOLOGY 241 Figure 1. Adverse events (>3% in the overall patient population) suspected to be related to the study drug. Note: SCr, serum creatinine. Figure 2. Number of patients with adverse events over time (n = 117). (A) Patients with adverse events suspected to be related to deferasirox over time (by underlying disease). (B) Patients with adverse events regardless of relationship to deferasirox over time (by underlying disease). 242 A. EL-BESHLAWY ET AL. Table 3. Patients with increase in serum creatinine or alanine aminotransferase. <18 ≥18 All years years patients Criteria n = 66 n = 51 n = 117 95% CI Patients with at least 1 episode of SCr increase from baseline >33% and >age-adjusted ULN at 2 8 (12.1) 6 (11.8) 14 (12.0) 7.1, consecutive visits (≥7 days apart) 19.2 Patients with at least 1 episode of ALT > 5 × ULN at 2 consecutive visits (≥7 days apart) 1 (1.5) 0 1 (0.9) 0.0, 5.2 Notes: ALT, alanine aminotransferase; CI, confidence interval; SCr, serum creatinine; ULN, upper limit of normal. ache (10.3%), and upper respiratory tract infection Eight on-treatment deaths (6.8%) were reported, all (10.3%). Most patients had normal auditory and in patients ≥18 years, mainly due to neoplasms (acute ocular results during the study. For audiometric test leukemia, n = 1; acute lymphocytic leukemia, n = 1) and results, a 7-year-old male patient had three clinically gastrointestinal complications (gastrointestinal hemor- significant abnormalities (moderately severe sensori- rhage, n = 1; intestinal ischemia, n = 1). None of these neural affection at high frequencies, bilaterally lost deaths were suspected to be related to the study drug. acoustic reflexes, and mild bilateral sensorineural hearing loss at high frequencies) and an AE of neuro- 3.6.1.1. Adverse events leading to discontinuation of sensory deafness, which was suspected to be related study drug. Adverse events leading to discontinuation to study drug, was reported for the same patient. The of the study drug occurred in 22 patients (18.8%). Of patient withdrew consent and did not complete the these patients, 11 (9.4% [17.6% vs. 3.0% for ≥18 years study. Two patients had clinically significant abnormal- vs. <18 years]) had AEs suspected to be related to the ities for ocular examinations. One 7-year-old female study drug. The most common AEs (>2%) leading to patient had the most extreme post-baseline results of discontinuation regardless of relationship with study two possible inferior visual field defects, and the drug were increased SCr (3.4%) and diarrhea (2.6%), second 48-year-old female patient had a baseline both of which occurred only in patients aged ≥18 result of sickle-cell retinopathy and vitreous hemor- years. rhage in the right eye. The two patients did not com- plete the study, as their condition no longer required the study drug. 3.6.2. Laboratory parameters 3.6.2.1. Serum creatinine. Increase in SCr > 33% above baseline and the age-adjusted ULN in at least two Figure 3. Distribution of (A) serum creatinine and (B) alanine aminotransferase over time. Notes: Boxes indicate median ± 25th/75th centile. The means are presented as dots, and medians of time points are connected over time. ALT, alanine aminotransferase. HEMATOLOGY 243 consecutive measurements (≥7 days apart) was had decreased SF compared to baseline with a mean observed in 14 patients (12%; 95% confidence interval change of −223 μg/L. In patients aged <18 years, [CI], 7.1–19.2) with MDS (n = 3), SCD (n = 7), and other mean SF levels decreased from 2445 (range, 298– anemias (n = 4) (Table 3). Of these a higher proportion 8317) to 2170 (range, 151–9954), whereas in patients of patients aged <18 years (78.8%) had SCr values >18 years of age, mean SF levels decreased from ≤ULN during treatment as compared to patients with 2246 (range, 490–7500) to 2004 (range, 317–8250). A ≥18 years (37.3%). In the overall study population, higher proportion of the overall patient population the total SCr by quarters showed non-progressive, had SF values ≤1000 µg/L at the end of the observation stable SCr values over the 3 years (Figure 3(A)). Due period (27.5%) than at the start of deferasirox treat- to increased SCr, five patients had dose adjustments ment (13.3%) (Figure 4). or interruptions, and four patients discontinued, which were suspected to be related to drug. During the study, in the overall population, 55 patients had a 4. Discussion confirmed creatinine clearance (CrCl) ≥ 90 mL/min, and 9 patients had confirmed CrCl of 60 – <90 mL/ The observational study reported the long-term safety min on 2 consecutive measurements (≥7 days apart). of deferasirox in adult and pediatric patients aged ≥2 years with chronic transfusional iron overload at enroll- 3.6.2.2. Alanine aminotransferase ment. In this study, 52.7% of patients discontinued Of the eight patients, <18 years of age who presented treatment. The overall duration of deferasirox treat- with single events of elevated ALT >5 × ULN and >2 × ment in the present 3-year study was 29.9 months. baseline during the study period, four had an under- The total time on study drug was 26.9 months when lying diagnosis of β thalassemia and four had SCD. accounting for reported dose interruptions. Thus, None of the patients discontinued study drug due to patients received a daily dose of deferasirox in 90% elevated liver function tests (LFTs); reasons for the of days on chelation treatment indicating an accepta- increased LFTs were not apparent. Six of the eight ble overall safety profile. patients (75%) completed the study, despite transient In this study, there was a low discontinuation rate events of increased ALT, and two of the eight patients due to AEs, particularly in patients aged <18 years indi- ended the study because the investigator judged cating deferasirox was manageable in pediatric deferasirox as no longer necessary. All pediatric patients as well as in overall patient population. patients except one were chelation naïve while starting Although no direct comparison can be made across deferasirox. clinical trials, it seems that the rate of completion of Of the two patients (1.7%) aged ≥18 years who patients treated with deferasirox in this observational exhibited single events of elevated ALT (>5 × ULN trial is in line with the results obtained in the 4-year and >2 × baseline), one had an underlying diagnosis extension of a phase 2 study involving pediatric and of MDS and ended the study due to increased SCr. adult patients with transfusional hemosiderosis. The other patient received a stem cell transplant with The highest percentage of pediatric patients in the curative intent for the underlying chronic lymphocytic present study was in the β thalassemia major and the leukemia and this patient ended the study because second highest in SCD, which is expected for the deferasirox was deemed by the investigator as no most common red blood cell disorders diagnosed in longer needed. infancy. In this study, the majority of the patients Increase in ALT >5 × ULN in at least two consecutive were Caucasians (67.5%), followed by Blacks (22.5%), measurements (≥7 days apart) was observed in one Asians (5.8%), and others (3.3%). This distribution is in patient (0.9%; 95% CI, 0.0–5.2) with β thalassemia line with the general association of diagnosis of thalas- (baseline ALT missing) (Table 3). In the overall popu- semia and MDS being more prevalent among Cauca- lation, the total ALT showed no apparent trend, with sians and SCD being more prevalent in Black patients. some fluctuations over time during the 3 years The most frequent AEs reported during the treat- (Figure 3(B)). Increased ALT lead to dose adjustments ment with deferasirox in adult and pediatric patients or interruptions in two patients (1.7%; β thalassemia were related to GI disturbances in about 26% of [n = 2]) aged <18 years. None of the patients discontin- patients (mainly nausea, vomiting, diarrhea, or abdomi- ued because of increased ALT. nal pain). Notable increases in SCr and liver function tests were observed in some patients, and those increases were consistent with the known safety 3.7. Long-term efficacy of deferasirox profile of deferasirox. In deferasirox registration In the overall patient population, mean SF levels studies [9–11], which included patients with transfu- decreased from 2373 μg/L (range, 298–8317) to sional siderosis, elevations in SCr of >33% on ≥2 con- 2110 μg/L (range, 151–9954) from baseline to end of secutive visits, sometimes > ULN, occurred in about study. In the overall population, >50% of the patients 36% of patients. In the present study, the proportion 244 A. EL-BESHLAWY ET AL. Figure 4. Median absolute change in serum ferritin (µg/L) values from baseline over time by the underlying disease. Notes: †Absol- ute change refers to change of serum ferritin values at each time point from baseline. *End of study refers to the last available post- baseline serum ferritin value. of patients with SCr > ULN at two consecutive visits at with a mild reversible hemodynamic effect on renal least 7 days apart was 12% during the 3-year obser- function in patients receiving short-term and long- vation period. Furthermore, the total SCr in all patients term treatments [16]. Renal parameters remained showed only a slight increase in SCr levels, remaining stable indicating no further decline in renal function stable over time during the 3-year observation over time. The findings observed from the current period. An evaluation of the change of renal function study were consistent with the 5-year renal data from in the adult population in the present study is limited the pivotal registration study, indicated no progressive by the relatively high number of missing values (n = worsening of the renal function over time on the basis 40, 78.4%). It is of note that renal safety in the study of SCr and CrCl monitoring [17]. population may be attributable to various factors and In a 5-year analysis within the deferasirox not limited to iron chelation treatment. Renal abnorm- program, elevations of transaminases >10 × ULN alities in patients with transfusion-dependent siderosis were uncommon (0.3%). Furthermore, there was an were previously reported in the literature and suggest initial increase in ALT levels during the first 2 years that iron overload and anemia are likely to contribute of deferasirox treatment following a downward to renal dysfunction [12,13]. A recent study evaluating trend for the remainder of the study [17]. The long-term renal safety in Italian patients who partici- increase in ALT could potentially be attributed to pated in deferasirox registration studies, indicated no iron overload, which is known to increase liver progressive or late change in renal function for patients enzyme levels, particularly in patients with high exposed to deferasirox and other chelation treatment liver iron concentration due to continued transfusion for up to 13 years [14]. dependence [18]. There was no apparent relationship The renal safety was also supported by a slight initial between deferasirox dose and liver transaminase decrease in CrCl, which remained stable in most increases [17]. In this observational study, ALT levels patients throughout the study and is consistent with >5 × ULN in at least two consecutive post-baseline the data from previous studies that have shown an measurements at least 7 days apart was observed early initial drop in CrCl, followed by stabilization [15]. in one patient and no patients in the study popu- Deferasirox has also been shown to be associated lation discontinued due to increases in ALT. HEMATOLOGY 245 A lower deferasirox median dose in relation to blood chelation and control of transfusional iron in the intake was observed mainly in adult patients with low majority of patients in clinical practice. transfusional burden compared to adult patients with intermediate burden. This observation suggests that dose adjustments are either multifactorial taking into Acknowledgments account other clinical parameters or that patient may We thank Haritha Nekkanti (Novartis Healthcare Pvt Ltd) for not be adequately dose adjusted as the transfusional providing medical editorial assistance. iron burden increases over time. Most of the patients had normal auditory and ocular results during the study, with few patients having clini- Disclosure statement cally significant auditory or ocular abnormalities. Of the B. Xicoy reports honoraria from Novartis Pharmaceuticals Cor- 120 observed patients in this study, one pediatric poration and Celgene. A. Bruederle, A. Amin, and G. Gilotti patient discontinued the study with neurosensory are full-time employees of Novartis Pharmaceuticals Corpor- ation. B. Inusa, D. Beneitez, M. Duran Neito, and M. Elalfy have affection of hearing. Most other observed impairments nothing to disclose. A El-Beshlawy reports research funding of hearing in the pediatric population were conductive, from Novartis Pharmaceuticals Corporation and ApoPharma transitory, and assessed not to be related to the study Inc. treatment. A 4-year extension study of the phase 2 study in an SCD patient population demonstrated a median absol- Funding ute change in SF from the start of treatment with defer- This study was funded by Novartis Pharma AG. asirox to the end of study and its 95% CI of −246 μg/L (−530; 402) in patients receiving deferasirox through- out the study [15]. The analysis of SF levels in the 5- ORCID year observational study, in a mixed population of David Beneitez Pastor http://orcid.org/0000-0002-6541- pediatric patients with iron overload including SCD, 6600 also demonstrated a better reduction in SF of −576 μg/L [19]. During this study, a proportion of patients with SCD (>50%) had an initial increase in SF References at 6 months before they start to have a negative [1] Karami H, Kosaryan M, Amree AH, et al. Combination balance. Overall, the SF was moderately reduced from iron chelation therapy with deferiprone and deferasirox baseline to the end of the study for the majority of in iron-overloaded patients with transfusion-dependent β-thalassemia major. Clin Pract. 2017;7:912. patients. [2] Cerchione C, Cerciello G, Avilia S, et al. Management of Approximately, 43% of patients completed the iron overload in myelodysplastic syndromes: combined global 3-year post-authorization safety study, with a deferasirox and deferoxamine in a patient with liver 3-year dropout rate of 12.5% due to AEs in all patients disease. Blood Transfus. 2016;24:1–4. and 2.9% in patients aged <18 years. None of the five [3] Cappellini MD. Exjade(R) (deferasirox, ICL670) in the deaths occurring during the study were observed in treatment of chronic iron overload associated with blood transfusion. Ther Clin Risk Manag. 2007;3:291– pediatric patients or suspected to be related to study 299. treatment. Thus, the data further add evidence that [4] Osborne RH, De Abreu Lourenço R, Dalton A, et al. chronic iron chelation therapy with deferasirox is man- Quality of life related to oral versus subcutaneous iron ageable in a pediatric patient population, as well as in chelation: a time trade-off study. Value Health. the overall patient population. Notable increases in SCr 2007;10:451–456. [5] Delea TE, Edelsberg J, Sofrygin O, et al. Consequences and liver function tests were observed in some and costs of noncompliance with iron chelation patients, and those increases were consistent with therapy in patients with transfusion-dependent thalas- the known safety profile of deferasirox. semia: a literature review. 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