Deferasirox Treatment for up to 3 Years in Iron-Overloaded Pediatric Patients Reduces Serum Ferritin with a Manageable Safety Profile

To prevent complications associated with iron overload in patients with transfusion-dependent anemias, iron chelation therapy is required throughout life starting from early childhood. Long-term studies of iron chelation therapy are therefore required, particularly in pediatric patients. The 1-year open-label, single-arm, multicenter EPIC (Evaluation of Patients' Iron Chelation with Exjade^®) trial evaluating the efficacy and safety of deferasirox in patients with transfusion-dependent iron overload enrolled 577 pediatric patients across 23 countries. In an extension period of up to 18 months, or until deferasirox was available locally, patients completing the core study could continue to receive deferasirox, thus providing long-term efficacy and safety data of deferasirox in iron-overloaded pediatric patients.

At enrolment, transfusion-dependent pediatric patients (defined as ≥2–<16 years at enrollment) had serum ferritin ≥1000 ng/mL OR <1000 ng/mL with a history of multiple transfusions (>20 transfusions or >100 mL/kg red blood cells transfused) and liver iron concentration >2 mg Fe/g dw confirmed by R2 magnetic resonance imaging. Deferasirox starting dose was 10–30 mg/kg/day depending on frequency of blood transfusions, with protocol-specified adjustments of 5–10 mg/kg/day (range 0–40 mg/kg/day) based on 3-monthly serum ferritin trends and safety. Biochemistry analysis including serum ferritin was performed on a monthly basis, and growth was monitored every 12 weeks, with continuous assessment of safety parameters. Creatinine clearance was calculated using the Schwarz formula for pediatric patients. Changes from the start of deferasirox treatment (core baseline) are presented.

267 pediatric patients aged 2–<6 (n=68), 6–<12 (n=114) and 12–<16 (n=85) years entered the extension period (n=141 [52.8%] male; n=248 [92.9%] with underlying thalassemia; n=33 [12.4%] with a history of hepatitis B and/or C). Median duration of deferasirox exposure was 101.3 weeks (range 55.6–159.9) with mean ± SD deferasirox dose 25.7 ± 5.8 mg/kg/day (13.4–40.0). Median serum ferritin decreased from a baseline of 3222 ng/mL (951–16,944) to 2431 ng/mL (238–29,681) at the end of the extension (absolute change from baseline –528 ng/mL [–6354 to 25,127]; P<0.0001; last observation carried forward).

Overall, 257/267 (96.3%) patients completed the extension; main reasons (more than two patients) for discontinuation were unsatisfactory therapeutic effect (n=4, 1.5%) and consent withdrawal (n=3; 1.1%). The most common (>5%) investigator-assessed drug-related AEs were increased alanine aminotransferase (ALT; n=47, 17.6%), increased aspartate aminotransferase (AST; n=44, 16.5%), increased blood creatinine (n=24, 9.0%) and rash (n=23, 8.6%). ALT and AST increases were mostly mild in severity, transient, non-progressive and managed with dose adjustments. There were no reported drug-related serious AEs and no deaths occurred.

45/267 (16.9%) patients had two consecutive ALT values >5 × upper limit of normal (ULN). Of these 45 patients, 40 had high ALT levels at baseline and 30 had ALT or AST >2.5 × ULN at baseline; 13/45 had a history of hepatitis B and/or C. 6/267 (2.2%) patients had two consecutive serum creatinine values >33% above baseline and >ULN; all had normal values at baseline. The relative change in creatinine clearance from baseline to end of the extension was between –10 and –20% for the majority of patients (n=52, 19.5%), although changes in both directions were variable.

Stature, growth and weight assessments indicated positive growth velocity. For all patients combined, mean ± SD growth velocity at end of extension was 5.9 ± 43.3 cm/year (median 2.6 cm/year).

Deferasirox therapy for up to 3 years in pediatric patients significantly decreased serum ferritin, similar to previous reports. The majority of patients with elevated liver enzymes during the study also had elevated levels at baseline; renal safety was consistent with previous reports. While patient age and gender will influence individual growth rates, positive growth velocity was nonetheless maintained during treatment.

Lin:Novartis: Honoraria. Aydinok:Novartis: Honoraria, Research Funding, Speakers Bureau; Ferrokin: Research Funding. Galanello:Novartis: Research Funding, Speakers Bureau; Apopharma: Research Funding, Speakers Bureau; Ferrokin: Research Funding. El-Ali:Novartis: Employment. Martin:Novartis: Employment. Cappellini:Novartis: Speakers Bureau.