Single-center experience with sirolimus therapy for vascular malformations

Abstract

Vascular malformations (VMs) are described as congenital malformations of the vasculature derived from capillaries, veins, lymphatic vessels, arteries, or a combination of these vessels. They can cause significant morbidity resulting from soft tissue hypertrophy-related disfiguration, bony abnormalities, and even organ compromise. They are usually treated with various interventional procedures to achieve local control; however, the chance of success decreases as the anatomical distribution of the malformation widens. Unfortunately, medical treatment options have been quite limited in these patients. Sirolimus is an antiangiogenetic and antiproliferative pharmacologic agent that has been used for the management of VM in the last decade. We report 6 pediatric patients (4 with capillary lymphaticovenous malformations, 1 with lymphaticovenous malformation, and 1 with venous malformation) seen at our clinic within the last 2 years with lesions covering wide anatomical areas. After the patients had unsuccessfully undergone various treatments at various centers, they were treated at our facility with peroral sirolimus. The mean duration of treatment was 13 months, but in 3 patients, tapered dosing continues. Five patients achieved partial responses. The response to sirolimus treatment increased as the lymphatic component of the VM increased. All patients tolerated sirolimus well; side effects were acceptable. Sirolimus is a safe and effective medical treatment for widely distributed VMs with significant lymphatic components and no further local treatment option.

Sirolimus therapy for kaposiform hemangioendothelioma with long‐term follow‐up

“…mTOR acts as a master switch of the majority of cellular processes, including angiogenesis, cell growth and apoptosis, cellular catabolism and anabolism . Sirolimus is a specific mTOR inhibitor with potent antitumor action on various vascular malformations . Sirolimus was administered orally at a dose of 0.8 mg/m 2 twice daily, with subsequent dosing adjustments to the target drug level between 10 and 15 ng/mL.…”

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

“…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 .…”

Fibroadipose vascular anomaly treated with sirolimus: Successful outcome in two patients

“…Although the cause of FAVA has not been delineated, the PIK3CA ‐related overgrowth spectrum includes a group of disorders with fibroadipose overgrowth and infiltration into muscle and vascular malformations . Sirolimus, an inhibitor of the mammalian target of rapamycin, has been shown to improve a range of vascular anomalies . With the hypothesis that FAVA may be the result of a somatic activating mutation in PIK3CA, we thought a trial of sirolimus would be worthwhile.…”