Safety Profile of Sirolimus in All Age Groups: A Pooled Analysis of Two 10-Year Cohort Studies Comprising 1738 Patients With Tuberous Sclerosis and/or Lymphangioleiomyomatosis

Abstract

Background: Previously known as the anti-rejection drug, then famous for its efficacy on many mTOR-regulated diseases, sirolimus is now reported as the drug to reverse the process of many age-related diseases, rejuvenate immunity, and extend life span. However, its long-term safety profile for all-age groups is still a concern. Methods: Data were from two 10-year prospective cohort studies (ChiCTR-OOB-15006535，NCT031938), in which patients were diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. Indicators on growth, hematopoietic, liver and renal function, and blood lipid were all primary outcomes. GLM analysis and Chi-square test were used to reveal their changes between the baseline and five follow-up periods (< 6 months, 6 to < 12 months, 1 to < 2 years, 2 to < 4 years, and 4-to-10 years)). Four models with cross-validation were constructed for prediction. Descriptive adverse events and the change of regimens were also recorded (secondary outcomes). Findings: 1738 patients aging from 5 days to 69 years were included. The median follow-up period was 25 (12-43) months, and 380 patients were followed for more than four years. Z scores of height, weight, and BMI increased significantly throughout the follow-up (baseline versus 4-to-10-year follow-up: 0·24 vs 0·69, 0·25 vs 0·56, 0·14 vs 0·29). The dose of sirolimus was the only factor related to all the changes. No negative effects on hematopoietic, liver, and renal function were observed throughout the follow-up. On the contrary, the long-term use of sirolimus showed beneficial effects. The increase of blood lipids was mainly in the first six months. Stomatitis was the most common adverse event (920/1738, 52·9% ), and 48·5% of adult females were with menstrual disorders. The economic burden was the main reason for discontinuing therapy. Interpretation: For the first time, we observed the increase in height and weight brought by sirolimus. Also, the length of follow-up was associated with different safety profiles. Some beneficial effects were observed in a longer follow-up. Clinical Trial Registration Details: The pediatric patients in this study are from the Efficacy and Safety of Sirolimus in Pediatric Patients with Tuberous Sclerosis (ESOSIPT) study (Chinese Clinical Trial Registration, http://www.chictr.org.cn, No. ChiCTR-OOB-15006535). The adult patients re from A National Registry on Chinese Patients with Lymphangioleiomyomatosis (ClinicalTrials.gov, No. NCT03193892). Funding Information: This work was supported by grants from the National Key Research and Development Program of China (No. 2016YFC1000707，No.2016YFC0901502) and the National Natural Science Foundation of China (No. 81471329). Declaration of Interests: The authors have no conflicts of interest relevant to this article to disclose. Ethics Approval Statement: The Ethics Committee of Chinese PLA General Hospital approved the pediatric study (No. S2013-028-01). The Ethics Committee of Peking Union Medical College Hospital (PUMCH) approved the adult study(JS-1323).