A narrative review of the role of sirolimus in the treatment of congenital vascular malformations.

OBJECTIVE: Vascular malformations arise from defects in the morphologic development of the vascular system and can have an impact on quality of life and/or lead to severe complications. To date, vascular malformations are frequently managed by invasive techniques, after which recurrence is common. Sirolimus, a downstream inhibitor of the phosphatidylinositol 3 kinase/AKT pathway and best known for its immunosuppressive effect, has been used off-label for lesions for which approved therapies were associated with unsatisfactory results or recurrence. The aim of this study was to review the available data on the effect of sirolimus on the size and symptoms of different types of malformations and to summarize the main safety issues.

METHODS: A literature search in Pubmed, Embase, Web of Science, and SCOPUS was performed. Case reports, case series, and clinical trials evaluating the effect of sirolimus in vascular malformations were eligible for this review. Fully terminated studies published between January 2010 and May 2019 reporting an evaluable response on size and/or symptoms were included. Relevant data on lesion size, symptoms, side effects and duration of treatment were extracted as reported in the study. Additionally, we reported 10 unpublished cases who were treated in UZ Leuven.

RESULTS: The literature review included 68 articles, describing 324 patients. The median duration of therapy was 12 months (range, 1-60 months). After 6 months of treatment, the size of the malformation had at least decreased in 67% of patients with common venous malformations (VM), in 93% of patients with blue rubber bleb nevus syndrome and in all patients with verrucous VM. The size of lymphatic malformations improved in more than 80% of the patients, even in the case of extensive involvement such as in Gorham-Stout disease and generalized lymphatic anomaly. In addition, the majority of patients with syndromic vascular malformations experienced a decrease in size and reported symptoms improved in almost all patients, regardless of the type of malformation. Side effects were common (53%) but usually mild; mucositis and bone marrow suppression were the most common. Regrowth or recurrence of symptoms occurred in 49% of patients who discontinued treatment. Comparable effects were seen in our own patients.

CONCLUSIONS: This review shows that sirolimus is effective in decreasing the size and/or symptoms of particularly lymphatic malformations as well as VMs. Although common, side effects were usually mild. Nevertheless, clinical trials are needed to confirm the safety and effectivity of sirolimus and to identify the required serum levels and duration of treatment.