Safety of Sirolimus in the Treatment of Vascular Anomalies in Asian Children

Objective(s): Sirolimus, a mammalian target of rapamycin inhibitor, has shown promising results in the treatment of vascular anomalies (VA). Variations in drug metabolism due to ethnic differences can lead to differences in the incidence and severity of adverse effects. Our study aims to describe the safety profile of sirolimus in treating a cohort of Asian pediatric patients with VA. Methods: We retrospectively reviewed the medical records of all patients with VA, seen in the multidisciplinary VA clinic and treated with sirolimus between April 2017 and July 2022. Sirolimus was initiated at 0.8 mg/m 2 /dose twice daily, and the dose was adjusted according to trough levels. Target sirolimus trough levels were initially set at 5–15 ng/mL, then subsequently narrowed to 10–15 ng/mL in line with updated practice guidelines. Patients were evaluated every 1–3 months. Adverse events (AE) were evaluated using clinical and laboratory parameters. Results: Twenty-one patients between 7 months and 18 years of age were included. There were more males (66.7%). Twenty (95.2%) patients had vascular malformations, and only 1 (5.8%) patient had a vascular tumor. The median duration of treatment was 20.5 months (range 4–67 months). The median maximum dose was 2.22 mg/m 2 /day (range 0.85–5.00 mg/m 2 /day, absolute dose range 0.1 mg per day to 4 mg per day). All patients experienced at least 1 AE, although the majority of AEs were mild. Only 2 patients required discontinuation of sirolimus due to oral mucositis and persistent proteinuria, respectively. Ten different AE were identified, namely proteinuria (61.9%), oral mucositis (57.1%), hypercholesterolemia/hypertriglyceridemia (38.1%), lymphopenia (38.1%), neutropenia (38.1%), hepatotoxicity (23.8%), nausea and vomiting (19.0%), infections (9.5%), diarrhea (4.8%), and giddiness (4.8%). Only 3 patients had grade 3 or 4 AE. There were no serious AEs resulting in death or serious infections. Conclusion: Sirolimus is generally well-tolerated in the pediatric population and is a safe therapeutic option for VA. AEs are mostly mild and reversible. Further studies are required to evaluate for more long-term renal AE and to determine optimal drug dosing in Asian children.