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Sirolimus (Rapamycin) for Slow-Flow Malformations in Children: The Observational-Phase Randomized Clinical PERFORMUS
Annabel Maruani1,2,3, Elsa Tavernier1,3, Olivia Boccara4
1University of Tours, University of Nantes, Institut National de la Santé et de la Recherche Médicale, SPHERE U1246, Tours, France.
Insights
Sirolimus shows promise for treating pediatric vascular malformations, particularly lymphatic types, improving symptoms like pain and bleeding. Further research is needed to fully establish its efficacy and safety in children.
Area of Science:
- Pediatric vascular anomalies
- Pharmacological treatment of malformations
- Rare disease research
Background:
- Sirolimus is increasingly used for vascular anomalies, but evidence is limited.
- Slow-flow vascular malformations in children require effective treatment options.
Purpose of the Study:
- To evaluate sirolimus efficacy and safety in children with slow-flow vascular malformations.
- To define optimal indications for sirolimus therapy in pediatric patients.
Main Methods:
- Multicenter, observational-phase randomized clinical trial involving 59 children (aged 6-18).
- Patients received oral sirolimus (target serum levels 4-12 ng/mL) after an observational period.
- Primary outcome: change in vascular malformation volume; secondary outcomes: pain, bleeding, quality of life, safety.
Main Results:
- No significant overall volume change in malformations, but a decrease in pure lymphatic malformations.
- Sirolimus improved pain (especially in combined malformations), bleeding, oozing, and quality of life.
- Most frequent adverse event was oral ulcers; 5 serious adverse events occurred.
Conclusions:
- Pure lymphatic malformations are a strong indication for sirolimus therapy.
- Sirolimus effectively reduced pain, oozing, and bleeding in combined malformations.
- Benefits were less pronounced in pure venous malformations compared to other types.
Importance:
Sirolimus is increasingly being used to treat various vascular anomalies, although evidence of its efficacy is lacking.
Objective:
To assess the efficacy and safety of sirolimus for children with slow-flow vascular malformations to better delineate the indications for treatment.
Design, Setting And Participants:
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 French tertiary hospital centers. Statistical analysis was performed on an intent-to-treat basis from December 4, 2019, to November 10, 2020.
Interventions:
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.
Main Outcomes And Measures:
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.
Results:
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%]).
Conclusions And Relevance:
This observational-phase randomized clinical trial allows for clarifying the goals of patients and families when starting sirolimus therapy for children older than 6 years. Pure lymphatic malformations seem to be the best indication for sirolimus therapy because evidence of decreasing lymphatic malformation volume per unit of time, oozing, and bleeding and increasing quality of life was found. In combined malformations, sirolimus significantly reduced pain, oozing, and bleeding. Benefits seemed lower for pure venous malformations than for the 2 other subgroups, also based on symptoms.
Trial Registration:
ClinicalTrials.gov Identifier: NCT02509468; clinicaltrialsregister.eu Identifier: 2015-001096-43.
