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

Elissa R Engel; Adrienne Hammill; Denise Adams; Roderic J Phillips; Michael Jeng; Megha M Tollefson; Ionela Iacobas; Deborah Schiff; Shoshana Greenberger; Michael Kelly; Ilona Frieden; Nibal Zaghloul; Beth Drolet; Amy Geddis; Dov Goldenberg; Kiersten Ricci

doi:10.1002/pbc.30215

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

Pediatr Blood Cancer. 2023 Apr;70(4):e30215. doi: 10.1002/pbc.30215. Epub 2023 Jan 18.

Authors

Elissa R Engel¹, Adrienne Hammill², Denise Adams³, Roderic J Phillips⁴, Michael Jeng⁵, Megha M Tollefson⁶, Ionela Iacobas⁷, Deborah Schiff⁸, Shoshana Greenberger⁹, Michael Kelly¹⁰, Ilona Frieden¹¹, Nibal Zaghloul¹², Beth Drolet¹³, Amy Geddis¹⁴, Dov Goldenberg¹⁵, Kiersten Ricci²

Affiliations

¹ Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
² Division of Hematology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
³ Division of Oncology, Comprehensive Vascular Anomalies Program, Children's Hospital of Philadelphia and Perelman School of Medicine and the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁴ Department of Paediatrics Monash University, Royal Children's Hospital, Melbourne, New South Wales, Australia.
⁵ Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California, USA.
⁶ Department of Dermatology and Pediatrics, Mayo Clinic and Mayo Clinic Children's Center, Rochester, Minnesota, USA.
⁷ Department of Pediatric Hematology-Oncology, Texas Children's Hospital, Houston, Texas, USA.
⁸ Department of Pediatrics, University of California San Diego, La Jolla, California, USA.
⁹ Department of Dermatology, Sheba Medical Center Sackler Faculty of Medicine and Tel-Aviv University, Tel Aviv, Israel.
¹⁰ Department of Pediatrics, Northeast Ohio Medical University, Akron, Ohio, USA.
¹¹ Departments of Dermatology and Pediatrics, University of California School of Medicine San Francisco, San Francisco, California, USA.
¹² Division of Pediatric Hematology/Oncology, The Children's Hospital at Saint Peter's University Hospital, New Brunswick, New Jersey, USA.
¹³ Departments of Dermatology and Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
¹⁴ Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, Washington, USA.
¹⁵ Divisions of Plastic Surgery and General Surgery, Hospital das Clinicas, University of Sao Paulo Medical School, Sao Paulo, Sao Paulo, Brazil.

PMID: 36651691
DOI: 10.1002/pbc.30215

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.

Keywords: CLOVES; Klippel-Trenaunay syndrome (KTS); PIK3CA-related overgrowth spectrum (PROS); capillary lymphatic venous malformation (CLVM); mammalian target of rapamycin (mTOR); sirolimus (rapamycin).

Publication types

Evaluation Study

MeSH terms

Child
Humans
Klippel-Trenaunay-Weber Syndrome* / diagnosis
Klippel-Trenaunay-Weber Syndrome* / genetics
Prospective Studies
Quality of Life
Retrospective Studies
Sirolimus
Vascular Malformations* / diagnosis
Young Adult

Substances

Sirolimus