Sirolimus (Rapamycin) for Slow-Flow Malformations in Children

Abstract

IMPORTANCESirolimus 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 PARTICIPANTSThis 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 MEASURESThe 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 malformation...

Response to sirolimus in capillary lymphatic venous malformations and associated syndromes: Impact on symptomatology, quality of life, and radiographic response

“…Clinical response to sirolimus, including symptomatology and QOL, in CLVM patients has previously been reported in small case reports and case series with similar results 18,19 . Additionally, the PERFORMUS Trial, as a secondary outcome, reported improvements in pain and bleeding in patients with CLVM treated with sirolimus 20 …”

“…18,19 Additionally, the PERFORMUS Trial, as a secondary outcome, reported improvements in pain and bleeding in patients with CLVM treated with sirolimus. 20 Some patients with CLVM have overgrowth of bone and/or soft tissue due to the gain-of-function PIK3CA mutation in those affected tissues. While sirolimus is known to decrease cystic components of LM, its ability to adequately control tissue overgrowth in PROS remains questionable and was not specifically evaluated in this study.…”

French national diagnosis and care protocol (PNDS, protocole national de diagnostic et de soins): cystic lymphatic malformations

“…Sirolimus (or rapamycin) inhibits lymphangiogenesis by interfering with the PI3K/AKT/mTOR signaling pathway. It has been used in complicated LMs for 10 years [31][32][33][34][35][36][37][38][39]. Many studies have confirmed its effectiveness, albeit partial (up to 90%), delayed (after 2 weeks to 6 months of treatment) and suspensive.…”

“…Regular clinical and biological monitoring (approximately 1 month after treatment initiation, then every 2-3 months) is required. Sirolimus trough concentration should be measured for dose adjustment (target concentration approximately 3-12 ng/ml) Drug interactions should be routinely checked [34][35][36][37][38][39].…”

Commentary on “Doxycycline Sclerotherapy of Head and Neck Lymphatic Malformations: Intermediate Report of 27 Cases”

“…It is also incumbent upon us to consider the adjunctive use of medical therapies such as the mTOR inhibitor Sirolimus and more recently Alpelisib, targeting the PIK3CA mutation, a somatic mutation associated with overgrowth and lymphatic malformations. These targeted therapies may work synergistically with sclerotherapy to affect a greater response especially in mixed lesions and those that have airway compromise [7].…”