Deferasirox (Exjade®, ICL670) Demonstrates Iron Chelating Efficacy Related to Transfusional Iron Intake in Pediatric Patients.

Abstract

Chelation therapy is the conventional treatment for transfusional iron overload, which leads to complications in the heart, liver and endocrine glands. A 1-year, open-label, multicenter, Phase III study compared the investigational, once-daily, oral iron chelator deferasirox (DSX) with deferoxamine (DFO) in adult and pediatric β-thalassemia patients aged ≥ 2 years. Patients with liver iron concentration (LIC) of 2–3, >3–7, >7–14 and >14 mg Fe/g dw were randomized to receive daily DSX 5, 10, 20 and 30 mg/kg or DFO 20–30, 25–35, 35–50 and ≥ 50 mg/kg, respectively. In total, 586 patients received treatment; 299 (51%) were aged <16 years, of whom 154 were treated with DSX. Baseline demographics and changes in LIC and serum ferritin after 1 year of treatment are shown in the table; data are presented as mean ± SD (standard deviation). DSX produced a fall in LIC in all age groups. A more moderate reduction in LIC occurred in patients aged <6 years despite the administration of an average dose of 21.9 mg/kg in this subgroup; these patients had the highest mean transfusional iron intake. The results strongly suggest that transfusional iron intake is the major factor in determining response and should be considered carefully when dosing iron chelators in children. In those with high transfusion requirements, a dose of 30 mg/kg may be considered.DSXDFOAge at baseline, years<6 (n=30)6–11 (n=67)12–15 (n=57)<6 (n=28)6–11 (n=68)12–15 (n=49)Female: male, n12:1835:3235:229:1933:3530:19Average daily dose, mg/kg21.9 ± 7.6121.1 ± 8.4918.0 ± 9.0043.6 ± 9.1742.5 ± 9.1143.5 ± 9.62Baseline LICa, mg Fe/g dw13.2 ± 7.415.2 ± 10.612.4 ± 10.512.6 ± 6.013.2 ± 9.413.3 ± 10.4EOS LICa, mg Fe/g dw12.1 ± 4.411.1 ± 7.79.6 ± 7.08.8 ± 3.810.6 ± 7.49.8 ± 6.6Baseline SF, ng/mL2479 ± 8433058 ± 18342813 ± 15672260 ± 8742745 ± 16332847 ± 1507EOS SF, ng/mL2791 ± 10662710 ± 15262787 ± 14941774 ± 7692439 ± 13562495 ± 1529Transfusional iron intakea, mg/kg/day0.48 ± 0.110.43 ± 0.090.37 ± 0.100.47 ± 0.120.44 ± 0.120.40 ± 0.10EOS = end of study; SF = serum ferritin; aAll patients with a baseline and EOS LIC assessmentDSX was well tolerated in children as young as 2 years of age at all dose levels, with a safety profile similar to that observed in adults. The most common adverse events (AEs) with a suspected relationship to DSX were abdominal pain, nausea, vomiting, diarrhea and skin rash. Of 154 pediatric patients who received DSX, 5 (3.2%) discontinued due to suspected drug-related AEs. There was no treatment-related neutropenia, agranulocytosis or arthralgia. Sexual development proceeded normally with no differences between the treatment groups. DSX has a safety profile that is compatible with long-term use in children as young as 2 years and is generally well tolerated at doses as high as 30 mg/kg in these heavily transfused patients.