Sirolimus significantly reduces pain, oozing, and bleeding in Slow-Flow Malformations in Children: PERFORMUS Trial
CAPTION
Propranolol treatment contributes to reduced number and size of cerebral cavernous malformations. Panel A shows a brain section of vehicle treated mouse. The lesions are outlined in green.
CREDIT
Joppe Oldenburg
Vascular anomalies include a heterogeneous group of disorders divided into vascular tumors (characterized by vascular cell hyperplasia) and vascular malformations (due to defective embryologic vasculogenesis). Slowflow vascular malformations include capillary malformations, venous malformations (VMs), lymphatic malformations (LMs), or combinations of these malformations. Several pathogenic, somatic, activating variants in the genes involved in vascular angiogenesis and lymphangiogenesis have been identified in vascular malformations.
Venous malformations and LMs are usually present at birth, although they are not always apparent at this stage. Apart from macrocystic LMs, which may resolve spontaneously after common infections of infancy,8 the natural history of VMs and LMs consists mainly of slow progressive increases in size and the occurrence of complications, such as pain, bleeding, and oozing, which are associated with functional impairment and have a negative impact on quality of life (QoL).
Management of VMs and LMs includes observation, physiotherapy, sclerotherapy, complete or partial resection, and medical therapies, such as mammalian target of rapamycin (mTOR) inhibitors.
The mTOR inhibitors, especially sirolimus (rapamycin), usually indicated as immunosuppressive agents for preventing rejection of a transplanted organ have been increasingly used for treating complicated vascular anomalies. They directly inhibit mTOR, which is regulated by phosphoinositide-3-kinase and acts as a master switch in numerous cellular processes, such as cell growth and proliferation and angiogenesis and lymphangiogenesis. Contrary to high flow vascular malformations, for which sirolimus seems poorly effective as treatment, slow-flow vascular malformations showed promising although mixed results in previous observational reports, but with heterogeneous sirolimus doses and outcomes.
Annabel Maruani and team performed a observational-phase randomized clinical trial (PERFORMUS [Superficial Slow-Flow Vascular Malformations Treated With Sirolimus]) to assess the efficacy and safety of sirolimus for children with complicated slow-flow vascular malformations.
This multicenter, open-label, observational-phase randomized clinical trial included 59 children aged 6 to 18 years with a slow-flow vascular malformation who were recruited between September 28, 2015, and March 22, 2018, in 11. Patients underwent an observational period, then switched to an interventional period when they received oral sirolimus (target serum levels, 4-12 ng/mL). The switch time was randomized from month 4 to month 8, and the whole study period lasted 12 months for each patient.
The primary outcome was change in the volume of vascular malformations detected on magnetic resonance imaging scan (with centralized interpretation) per unit of time (ie, between the interventional period and the observational period). Secondary outcomes included subjective end points: pain, bleeding, oozing, quality of life, and safety.
Among the participants (35 girls [59.3%]; mean [SD] age, 11.6 [3.8] years), 22 (37.3%) had a pure venous malformation, 18 (30.5%) had a cystic lymphatic malformation, and 19 (32.2%) had a combined malformation, including syndromic forms. Variations in the volume of vascular malformations detected on magnetic resonance imaging scans associated with the duration period were not overall significantly different between the interventional period and the observational period (all vascular malformations: mean [SD] difference, –0.001 [0.007]; venous malformations: mean [SD] difference, 0.001 [0.004]; combined malformations: mean [SD] difference, 0.001 [0.009]). However, a significant decrease in volume was observed for children with pure lymphatic malformations (mean [SD] difference, –0.005 [0.005]). Overall, sirolimus had positive effects on pain, especially for combined malformations, and on bleeding, oozing, self-assessed efficacy, and quality of life. During sirolimus treatment, 56 patients experienced 231 adverse events (5 serious adverse events, none life-threatening). The most frequent adverse event was an oral ulcer (29 patients [49.2%]).
The study showed that sirolimus treatment had no effect on volume changes detected on MRI scans of slow-flow vascular malformations overall associated with the duration period in slow-flow vascular malformations but significantly decreased the volume of LMs when analyzing subgroups. In no case was complete regression observed. Sirolimus treatment also had positive effects on end points associated with symptoms such as pain (especially in combined malformations), bleeding, oozing, and QoL.
This study allows for clarifying the goals of patients and families when starting sirolimus therapy for children older than 6 years. Lymphatic malformations seem to be the best indication because we found evidence of an effect of sirolimus treatment on decreasing LM volume, oozing, and bleeding and improving QoL. In combined malformations, sirolimus treatment significantly reduced pain, oozing, and bleeding. Benefits, also based on symptoms only, seemed lower with pure VMs than the 2 other subgroups. Questions remain on the optimal age to initiate sirolimus therapy to potentially prevent an increase in the volume of vascular malformations and on how long treatment must be maintained.
Source: Annabel Maruani, Elsa Tavernier, Olivia Boccara et al; JAMA Dermatol. 2021;157(11):1289-1298. doi:10.1001/jamadermatol.2021.3459
