Long-term safety and influence on growth in patients receiving sirolimus: a pooled analysis. (2024)

Affiliation

• Wang YY; Department of Pediatrics, The First Medical Center of PLA General Hospital, Chinese PLA General Hospital, Beijing, 100853, China.
• Zou LP; Department of Pediatrics, The First Medical Center of PLA General Hospital, Chinese PLA General Hospital, Beijing, 100853, China. zouliping21@hotmail.com.
• Xu KF; Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing, 100069, China. zouliping21@hotmail.com.
• Xu WS; Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China. xukf@pumch.cn.
• Zhang MN; Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China.
• Lu Q; Department of Pediatrics, The First Medical Center of PLA General Hospital, Chinese PLA General Hospital, Beijing, 100853, China.
• Tian XL; Department of Pediatrics, The First Medical Center of PLA General Hospital, Chinese PLA General Hospital, Beijing, 100853, China.
• Pang LY; Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100730, China.
• He W; Department of Neurology, Hebei Children's Hospital, Hebei, China.
• Wang QH; Department of Pediatrics, The First Medical Center of PLA General Hospital, Chinese PLA General Hospital, Beijing, 100853, China.
• Gao Y; Department of Pediatrics, The First Medical Center of PLA General Hospital, Chinese PLA General Hospital, Beijing, 100853, China.
• Liu LY; Deyang People's Hospital, Sichuan, China.
• Chen XQ; Department of Pediatrics, The First Medical Center of PLA General Hospital, Chinese PLA General Hospital, Beijing, 100853, China.
• Ma SF; Department of Pediatrics, The 904th Hospital of Joint Logistic Support Force, Jiangsu, China.
• Chen HM; Department of Pediatrics, Binzhou Medical University Hospital, Shandong, China.
• Dun S; Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing, 100069, China.
• Yang XY; Department of Pediatrics, The First Medical Center of PLA General Hospital, Chinese PLA General Hospital, Beijing, 100853, China.
• Luo XM; Department of Pediatrics, The First Medical Center of PLA General Hospital, Chinese PLA General Hospital, Beijing, 100853, China.
• Huang LL; Center of Epilepsy, Beijing Institute for Brain Disorders, Beijing, 100069, China.
• Li YF; Department of Pediatrics, Zhujiang Hospital of Southern Medical University, Guangdong, China.

ABSTRACT

BACKGROUND:

Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients.

METHODS:

This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded.

RESULTS:

Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217).

CONCLUSIONS:

Sirolimus's long-term administration is not associated with adverse effects on children's physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration. TRIAL REGISTRATION Pediatric patients Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients ClinicalTrials, No. NCT03193892.

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11325711
• https://dx.doi.org/10.1186/s13023-024-03243-5