Indications and Limitations of Sirolimus in the Treatment of Vascular Anomalies—Insights From a Retrospective Case Series

Abstract

BackgroundDespite recent developments, the role of sirolimus in the heterogeneous spectrum of vascular anomalies is yet to be defined, in terms of indication, dosage, and therapy duration, recognizing both its potential and limitations.MethodsWe retrospectively analyzed 16 children with vascular anomalies treated with sirolimus in two pediatric centers between 2014 and 2020 [male: n = 7, the median age at diagnosis: 4.6 months (range, 0–281.4)]. In addition, repetitive volumetric analyses of the vascular anomalies were performed when possible (11 cases).ResultsTen patients were diagnosed with vascular malformations and 6 with vascular tumors. The mean therapy duration was 27.2 months (range, 3.5–65). The mean sirolimus level was 8.52 ng/ml (range, 5.38–12.88). All patients except one with central conducting lymphatic anomaly responded to sirolimus, with the most noticeable volume reduction in the first 4–6 months. Additional administration of vincristine was needed in five patients with kaposiform hemangioendothelioma and yielded a response, even in cases, refractory to sirolimus monotherapy. As a single agent, sirolimus led to impressive improvement in a patient with another vascular tumor—advanced epithelioid hemangioendothelioma. Complicated vascular malformations required long-term sirolimus therapy. Side effects of sirolimus included mucositis and laboratory abnormalities. No major infectious episodes were recorded. An infant with COVID-19, diagnosed while on sirolimus therapy, presented with a mild course.ConclusionIn the current series, we reported limitations of sirolimus as monotherapy, addressing the need to redefine its indications, and explore combination regimens and multimodal treatment strategies. Tools for objective evaluation of response trends over time could serve as a basis for the establishment of future therapeutic algorithms.

Clinical effectiveness and safety of sirolimus in pediatric patients with complex vascular anomalies: necessitating personalized and comprehensive approaches

“…This study conducted a retrospective analysis of the clinical effectiveness of sirolimus in pediatric patients with complex vascular anomalies, revealing a 60% rate of CR or PR. This rate is lower than the response rates reported in previous studies ( 2 , 3 , 6 – 8 ). The presence of selection bias in retrospective studies and potential ethnic differences should be considered.…”

“…Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has emerged as a promising therapeutic agent for refractory vascular anomalies ( 2 ). Sirolimus demonstrates potent immunosuppressive and anti-angiogenic properties, inhibiting the mTOR pathway, critical in angiogenesis and vascular endothelial cell proliferation ( 3 ). In preclinical studies, sirolimus has shown efficacy in inhibiting hemangioma growth by reducing endothelial cell proliferation, inducing apoptosis, and suppressing pro-angiogenic factors ( 4 ).…”

Sirolimus treatment for intractable lymphatic anomalies: an open-label, single-arm, multicenter, prospective trial

“…Despite these findings, low concentrations are not universally optimal for all cases. Karastaneva et al ( 17 ) reported that the most remarkable volume reductions were detected within the first 4–6 months of therapy. In all of our PR patients, the tumors had already reduced by >20% at 12 weeks, and a similar trend persisted at 24 and 52 weeks.…”

Barriers to Genetic Testing in Vascular Malformations

“…The introduction of sirolimus for the management of VM represented a paradigm shift in the approach to medical management . While sirolimus remains a critical part of the therapeutic armamentarium, data increasingly suggest that more precise targeting of gene variants may result in better outcomes . Because many of the genetic drivers of VM are shared with those found in cancers, most drugs under investigation have been borrowed from cancer treatments.…”

“… 7 , 8 While sirolimus remains a critical part of the therapeutic armamentarium, data increasingly suggest that more precise targeting of gene variants may result in better outcomes. 18 , 19 , 20 , 21 , 22 , 23 Because many of the genetic drivers of VM are shared with those found in cancers, most drugs under investigation have been borrowed from cancer treatments. Alpelisib (PIQRAY and Vijoice; Novartis), a drug that targets the PIK3CA gene, was approved in April 2022 by the US Food and Drug Administration for the treatment of a specific group of VM disorders: PIK3CA -Related Overgrowth Spectrum.…”