TY - JOUR
T1 - Safety and efficacy of mTOR inhibitor treatment in patients with tuberous sclerosis complex under 2 years of age - A multicenter retrospective study
AU - Saffari, Afshin
AU - Brösse, Ines
AU - Wiemer-Kruel, Adelheid
AU - Wilken, Bernd
AU - Kreuzaler, Paula
AU - Hahn, Andreas
AU - Bernhard, Matthias K.
AU - Van Tilburg, Cornelis M.
AU - Hoffmann, Georg F.
AU - Gorenflo, Matthias
AU - Hethey, Sven
AU - Kaiser, Olaf
AU - Kölker, Stefan
AU - Wagner, Robert
AU - Witt, Olaf
AU - Merkenschlager, Andreas
AU - Möckel, Andreas
AU - Roser, Timo
AU - Schlump, Jan Ulrich
AU - Serfling, Antje
AU - Spiegler, Juliane
AU - Milde, Till
AU - Ziegler, Andreas
AU - Syrbe, Steffen
N1 - Funding Information:
We kindly thank all patients and their families for participating in the study. We further thank the German TSC Centers and Tuberöse Sklerose Deutschland e.V. (TSD e.v) for their support and collaboration. We acknowledge financial support by Deutsche Forschungsgemeinschaft within the funding programme Open Access Publishing, by the Baden-Württemberg Ministry of Science, Research and the Arts and by Ruprecht-Karls-Universität Heidelberg.
Funding Information:
A.S. received grants from Biogen. I.B. declares that she has no competing interests. A.W-K. received research funding from Novartis and Nutricia, and honoraria from Novartis, Desitin, Nutricia, Vitaflo and UCB. B.W. declares that he has no competing interests. P.K. declares that she has no competing interests. A.H. declares that he has no competing interests. M.K.B. received honoraria from PTC Therapeutics. C.v.T. participated at advisory boards of Novartis and Bayer Vital GmbH. G.F.H. declares that he has no competing interests. M.G. declares that he has no competing interests. S.H. declares that he has no competing interests. O.K. reports honoraria from Novartis. S.K. declares that he has no competing interests. O.W. declares that he has no competing interests. A.Me. declares that he has no competing interests. A.M. declares that he has no competing interests. T.R. declares that he has no competing interests. J.U.S. declares that he has no competing interests. A.Se. declares that she has no competing interests. J.S. declares that she has no competing interests. T.M. declares that he has no competing interests. A.Z. declares that he has no competing interests. S.S. received one travel grant from Novartis.
Funding Information:
The Dietmar Hopp Stiftung provided financial support for this study (Grant 1DH1813319 to Steffen Syrbe).
Publisher Copyright:
© 2019 The Author(s).
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/5/3
Y1 - 2019/5/3
N2 - Background: 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 their 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 TSC patients under the age of 2 years. Results: A total of 17 children (median age at study inclusion 2.4 years, range 0-6; 12 males, 5 females) with TSC who received early mTOR inhibitor therapy were studied. mTOR inhibitor treatment was started at a median age of 5 months (range 0-19 months). Reasons for initiation of treatment were cardiac rhabdomyomas (6 cases), subependymal giant cell astrocytomas (SEGA, 5 cases), combination of cardiac rhabdomyomas and SEGA (1 case), refractory epilepsy (4 cases) and disabling congenital focal lymphedema (1 case). In all cases everolimus was used. Everolimus therapy was overall well tolerated. Adverse events were classified according to the Common Terminology Criteria of Adverse Events (CTCAE, Version 5.0). Grade 1-2 adverse events occurred in 12 patients and included mild transient stomatitis (2 cases), worsening of infantile acne (1 case), increases of serum cholesterol and triglycerides (4 cases), changes in serum phosphate levels (2 cases), increase of cholinesterase (2 cases), transient neutropenia (2 cases), transient anemia (1 case), transient lymphopenia (1 case) and recurrent infections (7 cases). No grade 3-4 adverse events were reported. Treatment is currently continued in 13/17 patients. Benefits were reported in 14/17 patients and included decrease of cardiac rhabdomyoma size and improvement of arrhythmia, decrease of SEGA size, reduction of seizure frequency and regression of congenital focal lymphedema. Despite everolimus therapy, two patients treated for intractable epilepsy are still experiencing seizures and another one treated for SEGA showed no volume reduction. Conclusion: This retrospective multicenter study demonstrates that mTOR inhibitor treatment with everolimus is safe in TSC patients under the age of 2 years and shows beneficial effects on cardiac manifestations, SEGA size and early epilepsy.
AB - Background: 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 their 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 TSC patients under the age of 2 years. Results: A total of 17 children (median age at study inclusion 2.4 years, range 0-6; 12 males, 5 females) with TSC who received early mTOR inhibitor therapy were studied. mTOR inhibitor treatment was started at a median age of 5 months (range 0-19 months). Reasons for initiation of treatment were cardiac rhabdomyomas (6 cases), subependymal giant cell astrocytomas (SEGA, 5 cases), combination of cardiac rhabdomyomas and SEGA (1 case), refractory epilepsy (4 cases) and disabling congenital focal lymphedema (1 case). In all cases everolimus was used. Everolimus therapy was overall well tolerated. Adverse events were classified according to the Common Terminology Criteria of Adverse Events (CTCAE, Version 5.0). Grade 1-2 adverse events occurred in 12 patients and included mild transient stomatitis (2 cases), worsening of infantile acne (1 case), increases of serum cholesterol and triglycerides (4 cases), changes in serum phosphate levels (2 cases), increase of cholinesterase (2 cases), transient neutropenia (2 cases), transient anemia (1 case), transient lymphopenia (1 case) and recurrent infections (7 cases). No grade 3-4 adverse events were reported. Treatment is currently continued in 13/17 patients. Benefits were reported in 14/17 patients and included decrease of cardiac rhabdomyoma size and improvement of arrhythmia, decrease of SEGA size, reduction of seizure frequency and regression of congenital focal lymphedema. Despite everolimus therapy, two patients treated for intractable epilepsy are still experiencing seizures and another one treated for SEGA showed no volume reduction. Conclusion: This retrospective multicenter study demonstrates that mTOR inhibitor treatment with everolimus is safe in TSC patients under the age of 2 years and shows beneficial effects on cardiac manifestations, SEGA size and early epilepsy.
UR - http://www.scopus.com/inward/record.url?scp=85065261089&partnerID=8YFLogxK
U2 - 10.1186/s13023-019-1077-6
DO - 10.1186/s13023-019-1077-6
M3 - Journal articles
C2 - 31053163
AN - SCOPUS:85065261089
SN - 1750-1172
VL - 14
JO - Orphanet Journal of Rare Diseases
JF - Orphanet Journal of Rare Diseases
IS - 1
M1 - 96
ER -