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Sirolimus for the treatment of lymphangioleiomyomatosis

ABSTRACT Introduction: Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease that is associated with recurrent pneumothorax, abdominal tumors including lymphangioleiomyomas and angiomyolipomas, chylous fluid accumulations and progressive respiratory failure. Sirolimus has been shown to slow the progression of disease. Areas covered: In this review, the current evidence, indications, precautions, and practical use of sirolimus therapy in patients with LAM is discussed. Expert opinion: In LAM, the lung becomes diffusely infiltrated with smooth muscle-like cells containing mechanistic target of rapamycin complex (mTOR) activating mutations in tuberous sclerosis genes which drive destructive parenchymal remodeling. LAM cells arise from an unknown source, migrate to the lung and express vascular endothelial growth factor D (VEGF-D). In the laboratory, mTOR inhibitors block destructive LAM cell behaviors including abnormal growth, migration and metalloproteinase production and induce tumor regression in animal models. The MILES trial demonstrated that sirolimus, stabilizes lung function, reduces VEGF-D and improves measures of functional performance. Based on MILES, sirolimus was approved by the United States Food and Drug Administration for the treatment of LAM in 2015. Available mTOR inhibitor therapies are suppressive, requiring chronic or even lifelong exposure for continued benefit. Multiple trials are underway to refine the use of mTOR inhibitors in LAM.