Long-Term Efficacy and Safety with Deferasirox (Exjade®, ICL670), a Once-Daily Oral Iron Chelator, in Pediatric Patients.
Authors: Piga Antonio , Vichinsky Elliott , Forni Gian Luca , Kilinc Yurdanur , Maseruka Henry , Kattamis Antonios 
Published: October 2019

Abstract
Background: Children with transfusion-dependent anemias will usually require lifelong iron chelation therapy. Establishing the long-term efficacy and safety profile of deferasirox is critically important in children. Presented here are cumulative long-term efficacy and safety data from a cohort of children treated with deferasirox in ongoing clinical trials.
Methods: Pediatric patients (<16 years old) with β-thalassemia, sickle cell disease or other transfusion-dependent anemias were enrolled in 4 clinical trials and treated for 1 year with deferasirox (studies 106/108) or randomized to either deferasirox or deferoxamine (DFO; 107/109). Study treatment was extended for 4 years (extension phases); patients either continued deferasirox (deferasirox cohort) or crossed over from DFO to deferasirox (crossover cohort). Doses in the extensions were adjusted based on efficacy and safety parameters. Efficacy was monitored via serum ferritin (SF); safety was assessed by the incidence and type of AEs. Growth and sexual development were evaluated every 6 months.
Results: 434 patients aged 2–<16 years (n=289 deferasirox cohort; n=145 crossover cohort) entered the extensions. In the deferasirox and crossover cohorts, respectively, 50 and 20 pediatric patients were ≥2–<6 years old, 123 and 69 were 6–<12 years old, and 116 and 56 were ≥12–<16 years old. Patients in the deferasirox cohort have received treatment for a median 3.5 years. Mean (SD) doses were 9.5 (1.6), 19.5 (2.6) and 29.6 (2.5) mg/kg/d in the 5/10, 20 and 30 mg/kg/d groups at month 1, respectively, and 22.9 (7.7), 24.6 (7.6) and 26.3 (9.5) mg/kg/d at month 42. Until month 12, median SF levels were maintained in the 20 mg/kg/d cohort, decreased in the 30 mg/kg/d cohort and increased in the 5/10 mg/kg/d cohort. After dose escalations at month 12, median SF levels fell below baseline at month 42 in all cohorts (Table).
390 (90%) children continue to receive deferasirox. Of 43 discontinuations, 22 were due to AEs. Two deaths, both considered unrelated to treatment, occurred in the deferasirox cohort. The most common drug-related AEs, including vomiting (n=26), nausea (n=25), abdominal pain (n=21), diarrhea (n=19) and mild/moderate skin rash (n=35), occurred mainly in the core phases. There were no significant changes in markers of liver function in the extension phases and no cases of progressive increases in serum creatinine. Physical and sexual development proceeded normally in all children.
Conclusions: Over a median period of 3.5 years, treatment with deferasirox provided dose dependent overall reduction in iron burden in transfusion-dependent children, as measured by SF levels. Deferasirox had a manageable safety profile in children, which was similar to that observed in the 1-year core trials. There was no negative impact on growth and sexual development.
Median SF values (ng/mL) in children (deferasirox cohort) Initial dose, mg/kg/d Month 5/10 20 30 All n=129 n=89 n=74 n=292 *Dose adjustments Baseline 2126 2504 3491 2420 1 2041 2488 2976 2451 6 2394 2724 2678 2460 12* 2653 2602 2608 2618 18 3037 2480 2271 2771 24 2929 2651 2106 2522 30 2747 2404 2007 2440 36 1967 1916 2008 1970 42 1830 1812 1889 1831