Patients with Congenital Low-Flow Vascular Malformation Treated with Low Dose Sirolimus

Abstract

Introduction Patients with congenital vascular malformations often suffer from an impaired quality of life (QoL) because of pain and functional disabilities. Previous studies have shown that the mTOR inhibitor sirolimus can reduce complaints and improve QoL in some patients. High target levels of sirolimus of 10–15 ng/ml were well tolerated; however, in a relative high percentage of patients sirolimus caused serious adverse events (AEs). Methods A case series of 12 patients with therapy-resistant low-flow vascular malformations was treated with sirolimus, using low target levels of 4–10 ng/ml. Efficacy of sirolimus was evaluated in regard to pain symptoms using the visual analogue scale/numeric rating scale and patients reported QoL. To rule out a placebo effect of sirolimus, sirolimus was stopped after a certain time point and reintroduced as soon as complaints returned. Adverse events were closely monitored and graded using the Common Terminology Criteria for Adverse Events (CTCAE) grading. Results An improvement in symptoms was seen in 92% ( n = 11/12) of patients. In nine patients pain complaints returned. Seven out of nine of them (78%) again experienced a reduction of symptoms after restarting sirolimus treatment. Despite low target levels, these response rates are comparable to those found in the literature using higher target levels of sirolimus. However, significantly less serious AEs were observed with low dose sirolimus, suggesting low dose sirolimus might be safer. Unfortunately, young adolescent female patients developed serious menstrual disturbances during treatment with low dose sirolimus. We describe this adverse event for the first time in patients with congenital vascular malformations and this might be specifically related to low dose sirolimus. Conclusions Low dose sirolimus showed a high efficacy in patients with therapy-resistant and low-flow malformation, with a lower incidence of serious adverse events. At the same time a new adverse event, namely menstrual cycle disturbance, was observed in young adolescents, indicating the need for caution when sirolimus is given. This is extremely relevant to patients with low-flow vascular malformation, who are likely to require lifelong treatment for their condition. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01758-y.

Efficacy and safety of oral sirolimus for high‐flow vascular malformations in real clinical practice

“…It has previously been suggested, based on animal studies with mouse models, that low doses of rapamycin (1–5 ng/mL) would be optimal to block intracellular angiogenesis pathways 17 . Our good clinical results support this theory, and in previous publications on low‐flow vascular malformations, similar results have been reported with sirolimus levels lower than those considered the gold standard 18,19 …”

“…17 Our good clinical results support this theory, and in previous publications on low-flow vascular malformations, similar results have been reported with sirolimus levels lower than those considered the gold standard. 18,19 Pneumocystis carinii pneumonia (PCP) is a potentially serious AE in patients treated with sirolimus, but no cases were seen in our study, which was possibly due to all patients receiving prophylaxis. However, other authors have published similar data without prophylaxis and only two cases of PCP have been reported in patients receiving sirolimus for a vascular malformation.…”

Combination therapy for pediatric patients with Kasabach–Merritt phenomenon: A single-center retrospective study

“…In a phase II clinical trial, Adams et al [5] demonstrated the effectiveness of sirolimus in treating pediatric patients with complicated vascular anomalies without apparent BM toxicity. A more recent report by Harbers et al [19] suggested that low-dose sirolimus successfully cured therapy-resistant patients with congenital vascular malformation, although adverse events such as menstrual cycle disturbances were observed in young adult patients. In addition, Sirolimus does have side effects, including immune suppression, hyperlipidemia, and oral ulcers.…”

Effective low–dose sirolimus regimen for kaposiform haemangioendothelioma with Kasabach–Merritt phenomenon in young infants

“…This is also seen in our case series of patients with low flow vascular malformations showing that low-dose sirolimus led to less (serious) AEs compared to intermediate-high dose sirolimus. 28 In some case series of KHE patients described in the literature, a dose of 0.8 mg/m 2 twice daily was prescribed, based on standard dosing for off label treatment of vascular anomalies (such as vascular malformation). This dose regimen led to supratherapeutic levels of >30 ng/mL in patients with KHE, which in turn led to serious AEs or even were fatal.…”

“…This is also seen in our case series of patients with low flow vascular malformations showing that low‐dose sirolimus led to less (serious) AEs compared to intermediate‐high dose sirolimus. 28 …”