Efficacy and Safety of Mammalian Target of Rapamycin Inhibitors in Vascular Anomalies: A Systematic Review

Abstract

Mammalian target of rapamycin (mTOR) inhibitors are a promising new treatment in vascular anomalies, but no published randomized controlled trials are available. The aim of this systematic review of all reported cases was to assess the efficacy and safety of mTOR inhibitors in all vascular anomalies, except cancers, in children and adults. In November 2014 MEDLINE, CENTRAL, LILACS and EMBASE were searched for studies of mTOR inhibitors in any vascular condition, except for malignant lesions, in humans. Fourteen publications and 9 posters, with data on 25 and 59 patients, respectively, all < 18 years old were included. Of these patients, 35.7% (n = 30) had vascular tumours, and 64.3% (n = 54) had malformations. Sirolimus was the most frequent mTOR inhibitor used (98.8%, n = 83). It was efficient in all cases, at a median time of 2 weeks (95% confidence interval 1-10 weeks). Sirolimus was well tolerated, the main side-effect being mouth sores, which led to treatment withdrawal in one case. The dosage of sirolimus was heterogeneous, the most common being 1.6 mg/m2/day.

Sirolimus for the treatment of progressive kaposiform hemangioendothelioma: A multicenter retrospective study

“…A few recent studies have demonstrated that sirolimus had a positive effect on reducing KHE progression in patients with or without KMP . However, these findings were based on relatively small sample sizes . To confirm the effects of sirolimus in the treatment of KHE, more extensive clinical studies are required.…”

Developmental pharmacokinetics of sirolimus: Implications for precision dosing in neonates and infants with complicated vascular anomalies

“…The target concentration window of sirolimus for treatment of complicated vascular anomalies has been recently reviewed . Drug concentration targets depend on patient's clinical condition such as the type of vascular anomaly, status of disease, and patient's adverse events profile.…”

“…In the recent prospective Phase 2 study for complicated vascular anomalies, sirolimus dosed to achieve predose trough concentrations of 10–15 ng/ml was shown to be effective and safe . In other vascular anomalies treatment studies, a broader sirolimus target range of 5–15 ng/ml was reported . To accommodate both the higher and lower target concentrations, two target therapeutic windows, 10–15 and 5–10 ng/ml, were used to design the dosing regimens in this study.…”

“…Efforts were aimed at detecting age cutoffs and dosing levels that would maximize the percentage of patients achieving the target concentration of sirolimus, at steady state, after repeated administration. In the simulations, two target concentration ranges based on the clinical studies were used to determine the starting doses: 10–15 ng/ml as evaluated and defined in the previous prospective Phase 2 study and 5–10 ng/ml as the lower target used in the extension study . Based on previous experience and for practical purposes, eight age cohorts were defined to cover the 0–24 months age range as follows : 0–1, 1–2, 2–3, 3–4, 4–6, 6–9, 9–12, and 12–24 months.…”

“…Sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), has been evaluated as a new medication targeting the cellular signaling pathway involved in the occurrence and progression of vascular anomalies . A recent prospective Phase 2 clinical trial demonstrated that sirolimus is efficacious and well tolerated for the treatment of complicated vascular anomalies .…”