The Tolerability, Safety and Efficacy of a New Oral Solution of Deferiprone in Children with Transfusional Iron Overload

Abstract Although there are 20 yr of clinical experience with deferiprone in treating transfusional iron overload, limited data exist on the safety and efficacy of deferiprone in very young children. Difficulties in swallowing the tablet formulation of deferiprone (Ferriprox®, ApoPharma, Canada), is a limiting factor in the administration of deferiprone in young children. The current study evaluated the tolerability, safety and efficacy of a new liquid formulation of deferiprone (Ferriprox® Oral Solution) in iron-overloaded pediatric patients with transfusion-dependent anemias (≥ 8 transfusions/year). The study also assessed the daily neutrophil count in patients who continued deferiprone therapy during episodes of mild neutropenia. The study was approved by the relevant regulatory authorities and ethics review boards. Informed consent was obtained from the patients’ legal representatives. One-hundred children [91Thal major, 8 HbE, 1 Sickle Cell disease; 46 female and 54 male; 76 Caucasian (Egyptian), 24 Asian (9 Chinese, 13 Indonesian, 2 Malay)] ranging from 1 to 10 yr of age (median 5.0 yr) were enrolled. At enrollment, 51 children were being treated with deferoxamine (mean duration 1.82 ± 1.95 years; range 0.1–7.3 yr), 20 with deferiprone (mean duration 0.5 ± 0.6 yr; range 0. 04–2 yr), 8 patients with deferasirox (mean duration 0.4 ± 0.5 yr; range 0.1–1.6 yr) and 21 patients were naïve to chelation therapy. Deferiprone therapy was initiated at 50 mg/kg/day, divided in 3 doses, for the first 2 weeks, and then increased to 75 mg/kg/day. The dose was further increased to 100 mg/kg/day for those patients with ferritin > 2500 μg/L at baseline. Ninety-five children completed 6 months of therapy. One patient was lost to follow-up, 2 patients voluntarily withdrew consent (1 patient disliked the taste, 1 patient did not comply with weekly visits), and 2 were withdrawn due to adverse events. Therapy with the oral solution of deferiprone was not associated with unexpected adverse reactions. The incidence of gastrointestinal adverse reactions was lower than observed for the tablet formulation in older patients (Table). Oral solution in children ≤ 10 yr old Tablet formulation in children > 6 yr old and adults Adverse Reaction (AR) % Patients with AR % Patients with AR Nausea 1% 16% Abdominal Pain 6% 14% Vomiting 6% 12% Arthralgia 4% 11% Neutropenia (0.5 × 109/L ≤ ANC < 1.5 × 109/L) 6% 6% Agranulocytosis (0.5 < ANC) 2% 1% Five patients experienced single episodes of mild neutropenia [absolute neutrophil count (ANC) 1.5 × 109/L but not less than 1.0 × 109/L], which resolved and did not recur, despite continuous deferiprone use. Another patient experienced 2 transient episodes of mild neutropenia and a third episode that progressed to agranulocytosis (ANC < 0.5 × 109/L). Deferiprone was discontinued and the patient was treated with G-CSF. The event resolved (ANC > 1.5 × 109/L) within 9 days upon discontinuation of deferiprone. Another patient experienced a single episode of agranulocytosis, which resolved within 9 days upon discontinuation of deferiprone and therapy with G-CSF. During the 6-month therapy, there was a significant decrease in serum ferritin from a mean baseline value of 2532 ± 1463 to 2176 ± 1144 μg/L (p< 0.0005). The new oral solution of deferiprone was well tolerated and effective in lowering serum ferritin in young children with transfusion dependent anemias and exhibited a safety profile similar or better to that reported for the tablet formulation in older patients. The results also suggest that not all episodes of mild neutropenia progress to agranulocytosis with continued deferiprone therapy, and that further studies are warranted to differentiate those patients from those at risk of developing deferiprone-induced agranulocytosis following neutropenia. This study includes the first report of patients using deferiprone as their first iron chelator.

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