Sirolimus is efficacious in treatment for extensive and/or complex slow-flow vascular malformations: a monocentric prospective phase II study

Abstract

Background: Extensive and complex vascular malformations often cause chronic pain and severe functional restraint. Conventional treatments, such as surgery and/or sclerotherapy, are rarely curative, underscoring the great need for new therapeutic modalities. Recent preclinical and clinical data demonstrated that sirolimus could offset the progression of vascular malformations and significantly improve quality of life of patients through inhibition of the Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian Target of Rapamycin (mTOR) pathway. The purpose of this prospective study was to assess the efficacy and safety of this treatment in patients with extensive or complex slow-flow vascular malformations.

Methods: Sirolimus was administered orally on a continuous dosing schedule with pharmacokinetic-guided target serum concentration level of 10 to 15 ng/ml. Patients were seen every month for the first three months and subsequently every three months. The primary endpoints were safety and efficacy, based on clinical, biological and radiological evaluations, as well as a quality of life questionnaire.

Results: Nineteen patients, from 3 to 64 years old, with lymphatic (LM), venous (VM) or complex slow-flow malformations, refractory to standard care, were enrolled and received sirolimus continuously. After 12 months of follow-up, 16 patients were available for assessment of efficacy and safety: all had a significant and rapid improvement of their symptoms and quality of life. In two patients, sirolimus treatment permitted sclerotherapy and surgery, initially evaluated unfeasible. Sirolimus was well tolerated, with mucositis as the most common (10% of patients) grade 3 adverse event.

Conclusions: Sirolimus was efficient in extensive LM, VM and/or complex malformations that were refractory to conventional treatments and was well tolerated.

Keywords: Complex vascular malformation; Extensive vascular anomaly; Lymphatic malformation; Rapamycin; Sirolimus; Slow-flow anomaly; Venous malformation.

Conflict of interest statement

Ethics approval and consent to participate

This study (NCT01811667; EudraCT 2012–001262-15) was approved by the Ethics Committee of the Cliniques universitaires Saint-Luc, Brussels, Belgium. Each patient or patient’s parent signed an informed consent after receiving a summary explaining the procedure of the study. The trial was also registered at clinicaltrials.gov under the name VASCA-LM.

Consent for publication

Each patient or patient’s parent signed a consent for publication.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

Patient #3 with a cervico-facial microcystic LM before initiation of sirolimus (a) and after 12 months of treatment (b)

Fig. 2

Patient #17 with a capillaro-lymphatico-venous malformation with hypertrophy (Klippel-Trenaunay syndrome) before initiation of sirolimus (a) and after 6 months of treatment (b)

Fig. 3

Visual Analogue Scale (continuous pain) results for all patients

Fig. 4

D-dimer levels

Fig. 5

Classical MRI sequences and 3D-volumes of the malformation (patient #15) before initiation of sirolimus (a, c) and after 12 months of treatment (b, d). Notice volume reduction from 14 cm3 to 12,3 cm3