Sirolimus in the Treatment of Vascular Anomalies

Abstract

Aim of the Study mTOR inhibitors are showing promising results in the management of vascular anomalies. Although current controlled trials remain to be completed, many individual experiences are being published. We present our series of children with complex vascular anomalies treated with sirolimus. Patients and Methods A retrospective review of 41 patients treated with sirolimus between January 2011 and December 2015 was performed: 15% (n ¼ 6) had vascular tumors (4 kaposiform hemangioendotheliomas, 1 PTEN) and 85% (n ¼ 35) had malformations (13 generalized lymphatic anomalies/Gorham-Stout diseases [GSD], 1 kaposiform lymphangiomatosis [KLA], 11 large lymphatic malformations (LMs) in critical areas, 2 lymphedemas, 4 venous malformations, and 4 aggressive arteriovenous malformations [AVM]). Several variables were collected: type of vascular anomaly, duration of treatment, dosage, response, and secondary effects. Results There was a female predominance (1.4:1). All patients received sirolimus, at initial dosage of 0.8 mg/m 2 /12 hour. Overall successful response rate was 80.4% of cases, presenting improvement in radiologic imaging and reduction of symptoms, at a median time of 10 weeks. Patients showing no response included four AVMs, one GSD, one LM, one KLA, and one unknown tumor. Sirolimus was well tolerated, even in neonates, with insignificant side effects. No patients had complete resolution and no patients worsened on therapy. Thirty patients remain under treatment at the present moment. Conclusion Sirolimus has become a new therapeutic option for patients with vascular anomalies that do not respond to other treatments. Unfortunately, important questions as what is the most appropriate dosage and for how long should the patient be treated remain unanswered. An international registry followed by customized controlled trials is mandatory to clarify the future of this therapy.

Early Adjuvant Medication With the mTOR Inhibitor Sirolimus in a Preterm Neonate With Compressive Cystic Lymphatic Malformation

“…The choice of this therapeutic target was made in concentration with the local referring center for vascular malformations. However in the literature, the usual therapeutic target is frequently lower ( 2 , 7 , 10 , 17 ). We can hypothesize that a lower serum level of sirolimus could have prevented from those adverse events in our patient.…”

“…The mTOR signaling pathway is involved in cell proliferation, and is also a regulator of immune response, implicated in a vast number of diseases ( 1 ). Inhibitors of mTOR as sirolimus have long been indicated as anti-transplantation rejection medication, but recently several studies have also reported its use in the management of vascular malformations and in particular cystic lymphatic malformations ( 2 ).…”

Lymphatics in bone arise from preexisting lymphatics

“…found to be an effective treatment for lymphatic anomalies such as GLA and GSD (Adams et al, 2016;Cramer et al, 2016;Hammill et al, 2011;Ricci et al, 2019;Rodriguez-Laguna et al, 2019;Triana et al, 2017). A recent study examined the effect of rapamycin on disease response in 13 individuals with GLA and five individuals with GSD (Ricci et al, 2019).…”

“…GLA and GSD are often difficult to treat and usually require a multidisciplinary medical team and multiple strategies. In recent years, rapamycin has become a popular treatment for GLA and GSD, and it has been reported to be effective at stabilizing or reducing signs and symptoms of disease (Adams et al, 2016;Cramer et al, 2016;Hammill et al, 2011;Ricci et al, 2019;Rodriguez-Laguna et al, 2019;Triana et al, 2017). Next-generation sequencing studies have been performed with samples from individuals with GLA and GSD to identify the genetic mutations responsible for these diseases.…”

Pancreatic Kaposiform Hemangioendothelioma Not Responding to Sirolimus

“…6 7 Sirolimus treatment in cutaneous KHE has been described as successful in the literature, as well as in our own experience; however, it failed in our patient with visceral KHE. 8 9 Side effects of medical therapy and recurrence rates of KHE are not described well; therefore, long-term follow-up is mandatory in these patients. …”