Safety and efficacy of mTOR inhibitor treatment in patients with tuberous sclerosis complex under 2 years of age – a multicenter retrospective study

Abstract

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.

Fetal cardiac rhabdomyomas treated with maternal sirolimus

“…The Food and Drug Association indications for initiation of mTOR inhibitors are subependymal giant cell astrocytomas (SEGA), refractory epilepsy, renal angiomyolipoma, and pulmonary lymphangiomyoleiomatosis. 37 There is no evidence in the postnatal literature to suggest that mTOR inhibitors affect tuber or nodule size. This infant was born with multiple nodules and tubers, an expected finding in 80% to 90% of patients with TSC, particularly with TSC2 mutations.…”

Everolimus for cardiac rhabdomyomas in children with tuberous sclerosis. The ORACLE study protocol (everOlimus for caRdiac rhAbdomyomas in tuberous sCLErosis): a randomised, multicentre, placebo-controlled, double-blind phase II trial

“…Everolimus is a known drug for children, and it is used in cardiac and hepatic transplantation with mild and moderate adverse events. 17,22 A positive randomised controlled study that proves that everolimus is a safe option for symptomatic cardiac rhabdomyomas in TSC, will be of a great value for these patients as a novel treatment to avoid cardiovascular surgery with the risk of major morbidity and mortality. This trial would lay the foundation for further phase III trials and raise interest in developing treatment alternatives for paediatric TSC, which being a rare disease.…”

“…Most frequent adverse events described with everolimus in paediatric population are stomatitis, upper respiratory tract infection, transient hypercholesterolaemia and transient leucopenia. 17,22 Titration, dose adjustments due to adverse events (Table 4), evaluation of interaction with food and other drugs, and method of administration will be performed according to the prescribing information of the product used during the trial.…”

Mechanistic target of rapamycin inhibitors: successes and challenges as cancer therapeutics

“…RADIANT-4 (NCT01524783) [62,63] Tuberous sclerosis complex NCT00457808 [47] ; NCT00490789 [48,49] ; NCT00411619 [50] ; NCT00126672 [51] ; EXIST-1 (NCT00789828) [52] ; [53] Potential clinical benefit Biliary tract cancer RADiChol study (NCT00973713) [64] ; EUDRACT 2008-007152-94 [125] Thyroid cancer (in patients refractory to other agents) NCT01263951 [126] ; NCT00936858 [127] No clinical benefit seen Gastric cancer GRANITE-1, NCT00879333 [ mTORC1 activity also cross-talks with, as well as negatively regulates, the catabolic process of autophagy. While rapamycin treatment is often less effective at re-activating autophagy in mammalian cells than in yeast [80] , mTORC1 inhibition could permit some reactivation of autophagy in cancer cells, thus allowing them to recycle macromolecules more effectively, maintain homeostasis and survive.…”