Effective low-dose sirolimus regimen for kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon in young infants
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Published on: November 8, 2015
Veroniek E M Harbers1, Nathalie van der Salm2, Sjoert A H Pegge1
1Radboud University Medical centre (Radboudumc), Nijmegen, Gelderland, the Netherlands.
Insights
Low-dose sirolimus effectively treats kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon in infants. This approach ensures therapeutic levels and resolves symptoms without serious adverse events, accounting for developing infant metabolism.
Area of Science:
- Pediatric Oncology
- Pharmacology
- Hematology
Background:
- Kaposiform haemangioendothelioma (KHE) with Kasabach-Merritt phenomenon presents management challenges in infants due to pharmacokinetic variations.
- Sirolimus is an effective treatment, but potential toxicities like interstitial pneumonitis are a concern.
- Infants exhibit low CYP3-enzyme activity, suggesting reduced sirolimus metabolism and potential for toxicity with standard dosing.
Purpose of the Study:
- To evaluate the safety and efficacy of a low-dose sirolimus regimen in infants with KHE and Kasabach-Merritt phenomenon.
- To investigate if reduced sirolimus dosage can achieve therapeutic levels while minimizing adverse effects in neonates and young infants.
Main Methods:
- Retrospective analysis of a case series of 5 infants diagnosed with KHE and Kasabach-Merritt phenomenon.
- Treatment involved a low dose of sirolimus (0.2 mg/m² every 24 or 48 hours) based on age.
- Prednisone was co-administered in 4 patients to enhance therapeutic effects.
Main Results:
- All infants achieved therapeutic sirolimus serum levels (4-6 ng/mL) with the low-dose regimen.
- Complete hematological response and normalization of coagulation profiles were observed in all patients.
- Kasabach-Merritt phenomenon resolved, and tumor size reduction was noted, all without serious adverse events.
Conclusions:
- Low-dose sirolimus is a safe and effective treatment for KHE with Kasabach-Merritt phenomenon in infants.
- Dosage should be carefully adjusted based on infant age and developing metabolic capacity to prevent toxicity.
- Understanding and accounting for immature drug metabolism in infants is crucial for optimizing sirolimus therapy.
Aims:
Management of kaposiform haemangioendotheliomas (KHE) with Kasabach-Merritt phenomenon is challenging in young infants who are subjected to developmental pharmacokinetic changes. Sirolimus, sometimes combined with corticosteroids, can be used as an effective treatment of KHE. Simultaneously, toxicities such as interstitial pneumonitis related to the use of sirolimus may be fatal. As infants have a very low CYP3-enzyme expression at birth, which rises during ageing, we hypothesize that a reduced metabolization of sirolimus might lead to high sirolimus serum levels and low dose may be sufficient without the side effects.
Methods:
A case series of 5 infants with kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon was analysed retrospectively. All infants were treated with sirolimus 0.2 mg/m2 every 24 or 48 hours according to their age. Prednisone was added to the therapy for additional effect in 4 patients.
Results:
In all patients, low dose of sirolimus led to therapeutic sirolimus levels (4-6 ng/mL). All infants (aged 4 days-7 months) had a complete haematological response, without serious adverse events. In all patients, the Kasabach-Merritt phenomenon resolved, the coagulation profile normalized and tumour size reduction was seen.
Conclusion:
Low-dose sirolimus treatment is safe for infants with kaposiform haemangioendothelioma and Kasabach-Merritt phenomenon. It is essential to realize that during the first months of life, metabolism is still developing and enzymes necessary to metabolise drugs like sirolimus still have to mature. To avoid toxic levels, the sirolimus dosage should be based on age and the associated pharmacological developments.
