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

Anna Karastaneva; Paolo Gasparella; Sebastian Tschauner; Roman Crazzolara; Gabriele Kropshofer; Manfred Modl; Andreas Pfleger; Ante Burmas; Mirjam Pocivalnik; Raphael Ulreich; Werner Zenz; Wolfgang Schwinger; Besiana P Beqo; Christian Urban; Emir Q Haxhija; Herwig Lackner; Martin Benesch

doi:10.3389/fped.2022.857436

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

Front Pediatr. 2022 May 23:10:857436. doi: 10.3389/fped.2022.857436. eCollection 2022.

Authors

Anna Karastaneva¹, Paolo Gasparella², Sebastian Tschauner³, Roman Crazzolara⁴, Gabriele Kropshofer⁴, Manfred Modl⁵, Andreas Pfleger⁵, Ante Burmas⁶, Mirjam Pocivalnik⁷, Raphael Ulreich⁷, Werner Zenz⁸, Wolfgang Schwinger¹, Besiana P Beqo^{2

9}, Christian Urban¹, Emir Q Haxhija², Herwig Lackner¹, Martin Benesch¹

Affiliations

¹ Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, Medical University of Graz, Graz, Austria.
² Department of Pediatric and Adolescent Surgery, Medical University of Graz, Graz, Austria.
³ Department of Radiology, Medical University of Graz, Graz, Austria.
⁴ Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria.
⁵ Division of Pediatric Pulmonology and Allergology, Department of Pediatric and Adolescent Medicine, Medical University of Graz, Graz, Austria.
⁶ Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Medical University of Graz, Graz, Austria.
⁷ Pediatric Intensive Care Unit, Department of Pediatric and Adolescent Medicine, Medical University of Graz, Graz, Austria.
⁸ Division of General Pediatrics, Department of Pediatric and Adolescent Medicine, Medical University of Graz, Graz, Austria.
⁹ Global Clinical Scholars Research Training, Department of Postgraduate Medical Education, Harvard Medical School, Boston, MA, United States.

Abstract

Background: Despite 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.

Methods: We 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).

Results: Ten 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.

Conclusion: In 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.

Keywords: COVID-19; Kasabach–Merritt phenomenon; central conducting lymphatic anomaly (CCLA); epithelioid hemangioendothelioma (EHE); sirolimus; vascular anomalies; vincristine.