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

Abstract

Background Capillary lymphatic venous malformations (CLVM) and associated syndromes, including Klippel–Trenaunay syndrome (KTS) and congenital lipomatous overgrowth, vascular malformation, epidermal nevi, skeletal, and spinal syndrome (CLOVES), are underrecognized disorders associated with high morbidity from chronic pain, recurrent infections, bleeding, and clotting complications. The rarity of these disorders and heterogeneity of clinical presentations make large‐scale randomized clinical drug trials challenging. Identification of PIK3CA (phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha [gene]) mutations in CLVM has made targeted medications, such as sirolimus, attractive treatment options. The aim of this study was to investigate the safety and efficacy of sirolimus therapy in CLVM. Procedure A combined prospective and retrospective cohort of pediatric and young adult patients with CLVM treated with sirolimus was evaluated for disease response, including symptom improvement, quality of life (QOL), and radiologic response. Sirolimus dosing regimens and toxicities were also assessed. Results Twenty‐nine patients with CLVM, including KTS and CLOVES, were included. Ninety‐three percent of patients reported improved QOL, and 86% had improvement in at least one symptom. Most significantly, improvement was noted in 100% of patients with bleeding and 89% with thrombotic complications with corresponding decreases in mean D‐dimer (p = .008) and increases in mean fibrinogen (p = .016). No patients had progressive disease on sirolimus. Most common side effects included neutropenia, lymphopenia, infection, and aphthous ulcers/stomatitis. No toxicities were life‐threatening, and none required long‐term discontinuation of sirolimus. Conclusion Sirolimus appears to be effective at reducing complications and improving QOL in patients with CLVM and associated syndromes. In this patient cohort, sirolimus was well tolerated and resulted in few treatment‐related toxicities.

Gastrointestinal Manifestations of CLOVES Syndrome

“…It has been shown to modestly decrease areas of lymphatic overgrowth 18 and lesion-associated bleeding in pediatric patients with PI3K-related overgrowth syndromes. 19 The efficacy of these inhibitors in the prevention or treatment of acute bleeding from gastrointestinal lesions has yet to be determined.…”

Diagnosis and treatment of lymphatic malformations: experience of the surgical department for newborns and infants

“…В своём исследовании мы опирались на рекомендации по дозированию сиролимуса у новорождённых [44], однако терапевтического коридора концентраций препарата в плазме крови в некоторых случаях мы достигали при меньших дозировках. Рекомендации по длительности курса иммуносупрессивной терапии у больных с ЛМФ пока не разработаны [45,46].…”

Anticoagulation and vascular anomalies

“…These superficial thrombi can cause significant pain and loss of function of the involved area. The term LIC is used to describe a distinct coagulopathy that occurs in approximately 40% to 60% of patients with SFVM and is characterized primarily by elevated D-dimer, but in more severe cases, patients may also have varying degrees of thrombocytopenia and hypofibrinogenemia, occasionally with prolongation of prothrombin time and partial thromboplastin time [ [4] , [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] , [13] ]. This more severe form of LIC occurs in about 10% of patients, carries a high risk of bleeding, and is usually seen with larger venous malformations or following procedures or interventions that involve the abnormal vasculature ( Figure 1 ) [ 5 , 12 , 14 ].…”