NYMC Faculty Publications

Safety and Efficacy of Combined Resveratrol and Sirolimus in Lymphangioleiomyomatosis

Nishant Gupta, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, OH; Medical Service, Veterans Affairs Medical Center, Cincinnati, OH. Electronic address: guptans@ucmail.uc.edu.
Bin Zhang, Department of Pediatrics, University of Cincinnati, Cincinnati, OH; Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Yuan Zhou, Department of Mathematical Sciences, University of Cincinnati, Cincinnati, OH.
Francis X. McCormack, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, OH; Medical Service, Veterans Affairs Medical Center, Cincinnati, OH.
Rebecca Ingledue, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, OH.
Nathan Robbins, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH.
Elizabeth J. Kopras, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, OH.
Susan McMahan, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, OH.
Abhishek Singla, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, Cincinnati, OH.
Jeffrey Swigris, Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health, Denver, CO.
Adam G. Cole, Division of Pulmonary and Critical Care Medicine, Lexington VA Medical Center, Lexington, KY; Department of Medicine, University of Kentucky College of Medicine, Lexington, KY.
Marina K. Holz, Department of Cell Biology and Anatomy, New York Medical College, New York, NY.

Author Type(s)

Faculty

Journal Title

Chest

First Page

1144

Last Page

1155

Document Type

Article

Publication Date

5-1-2023

Department

Cell Biology and Anatomy

Abstract

BACKGROUND: A critical need exists to develop remission-inducing therapies for lymphangioleiomyomatosis. RESEARCH QUESTION: Is the addition of resveratrol safe and more efficacious than sirolimus alone in patients with lymphangioleiomyomatosis? STUDY DESIGN AND METHODS: We conducted a phase 2, dose-escalating, open-label trial of resveratrol in patients with lymphangioleiomyomatosis receiving a stable regimen of sirolimus. Resveratrol was started at 250 mg/d and escalated every 8 weeks to maximum dose of 1,000 mg/d over 24 weeks. The primary outcome was ≥ 42% decline in serum vascular endothelial growth factor D (VEGF-D) levels on combined therapy compared with baseline VEGF-D levels on sirolimus. Secondary objectives included an assessment of the safety profile and the effect on lung function and health-related quality of life (HRQOL). Longitudinal change in outcome measures was assessed using linear mixed models. Adverse effects were tabulated using the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4. RESULTS: Twenty-five patients with lymphangioleiomyomatosis with a median age of 51 years were enrolled. Pulmonary function parameters at study inclusion were: FEV: median absolute, 1.72 L; 64% predicted; FVC: median absolute, 2.99 L; 96% predicted; and diffusing capacity of the lungs for carbon monoxide: median absolute, 14.68 mL/mm Hg/min; 37% predicted. The median serum VEGF-D value at baseline was 617 pg/mL. Patients entered the study with a median sirolimus dose of 2 mg/d with median trough level of 6.3 ng/mL. Despite some GI side effects, the addition of resveratrol was well tolerated. Although the primary outcome was not met, a statistically significant reduction in serum VEGF-D levels and improvement in HRQOL during the study was found. INTERPRETATION: The addition of resveratrol was safe and well tolerated in patients with lymphangioleiomyomatosis taking sirolimus and was associated with modest improvement in HRQOL. Larger controlled trials of this combination might be warranted to assess definitively the usefulness of resveratrol as an additive therapy in lymphangioleiomyomatosis. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03253913; URL: www. CLINICALTRIALS: gov.

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