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

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 1 mg/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 2 mg). 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.

Keywords: Adverse events; Physical growth; Safety; Sirolimus; Tuberous sclerosis.

Fig. 1

Study design. * The data collection is still ongoing. The date of the first visit in some patients made them fail to participate in a visit on January 20, 2021. ξ If no data can be used in the safety set, the piece of observation will be deleted

Fig. 2

Mapping distribution of patients’ height, weight, and BMI among peers at first and last follow-up. The shaded area around the distribution fitting curve represents the 95% CI. The dashed lines from top to bottom indicate different percentiles of growth levels (97%, 95%, 85%, 50%, 15%, 5%, 3%). The green solid line represents the curve at the first visit, and the bluish-purple solid line represents the curve at the last visit

Fig. 3

Changes in 13 safety-related indicators throughout the follow-up period. The green line represents the fitting curve for adults, while the red line represents the fitting curve for children. The gray scatter points represent the specific value distribution for adult females, and the orange scatter points represent the specific value distribution for children