Safety and Efficacy of mTOR Inhibitor Treatment in Patients with Tuberous Sclerosis Complex under 2 Years of Age

Objective: Tuberous sclerosis complex (TSC) is a multisystem disease with prominent neurologic manifestations such as epilepsy, cognitive impairment and autism spectrum disorder. mTOR inhibitors have successfully been used to treat TSC-related manifestations in older children and adults. However, data on safety and efficacy in infants and young children are scarce. The objective of this study is to assess the utility and safety of mTOR inhibitor treatment in children with TSC under the age of 2 years.

Material and Methods: Patients from 12 different TSC clinics were included in this study. Inclusion criteria were a definitive diagnosis of TSC according to the 2012 International TSC Consensus Conference criteria and initiation of mTOR inhibitor treatment within the first 2 years of life. Clinical, radiological and developmental data, as well as information on therapies were included in the evaluation.

Results: A total of 17 children (median age at study inclusion 2.4 years (0–6); 12 male, 5 female) with TSC who received early mTOR inhibitor therapy were studied. mTOR inhibitor treatment was started at a median age of 5 months (0–19). Reasons for initiation of treatment were cardiac rhabdomyomas (6 cases), subependymal giant cell astrocytomas (SEGA, 5 cases), the combination of cardiac rhabdomyomas and SEGA (1 case), refractory epilepsy (4 cases) and congenital focal lymphedema (1 case). In all cases everolimus was used. Adverse events (AE) were classified according to the Common Terminology Criteria of Adverse Events (CTCAE, Version 5.0). Grade 1–2 AE occurred in 12 patients and included mild dermatologic manifestations, laboratory changes without clinical relevance and recurrent infections. No serious AE (grade 3–4) were reported. Treatment is currently continued in 13/17 patients. Benefits were seen in 14/17 patients and included volume reduction of cardiac rhabdomyoma and SEGA size, improvement of arrhythmia, reduction of seizure frequency and regression of congenital focal lymphedema and associated complaints. Everolimus therapy could not improve refractory epilepsy in 2 patients and 1/5 SEGA showed no radiological response in terms of volume reduction.

Discussion: This retrospective multicenter study provides data for good tolerability of mTOR inhibitor treatment with everolimus in TSC patients under the age of 2 years and confirms positive effects on cardiac manifestations, giant cell astrocytomas and early epilepsies.

Conclusion: mTOR inhibitors are a useful therapy option with acceptable safety profile for very young patients with TSC.

Reference

1. Saffari A, Brösse I, Wiemer-Kruel A, et al. Safety and efficacy of mTOR inhibitor treatment in patients with tuberous sclerosis complex under 2 years of age - a multicenter retrospective study. Orphanet J Rare Dis 2019;14(1):96