Long-term outcomes of sirolimus therapy in sporadic and tuberous sclerosis complex–associated lymphangioleiomyomatosis: a retrospective cohort study

INTRODUCTION: Sirolimus is the standard disease-modifying therapy for lymphangioleiomyomatosis (LAM), but long-term routine-care data integrating pulmonary, lymphatic, extrapulmonary, and biomarker outcomes remain limited. OBJECTIVES: To assess long-term effectiveness and safety of sirolimus in routine clinical practice. PATIENTS AND METHODS: We retrospectively analyzed consecutive adults with definite LAM treated with sirolimus at a national tertiary referral center in Poland between 2010 and 2020. RESULTS: Seventy-one patients were included (70 women; 57/71 [80%] with sporadic LAM and 14/71 [20%] with TSC-associated disease). The median duration of available functional follow-up was 5.0 years [IQR, 2.0-5.0], and mean trough sirolimus concentration was 7.85 (2.36) ng/mL. Baseline chylous pleural and/or peritoneal effusions were present in 15/71 (21%), renal angiomyolipomas in 33/71 (46%), and lymphangioleiomyomas in 28/71 (39%) patients. FEV1 increased at 12 months by a median Δ of 0.03 L [IQR, -0.10 to 0.30] from baseline (n=66; P=0.03). FVC and 6-minute walk distance also improved during early follow-up, while TLCO remained generally stable. Chylous effusions resolved in all affected patients by 12 months without recurrence, and renal angiomyolipoma and lymphangioleiomyoma volumes decreased significantly in patients with paired MRI measurements. Higher baseline VEGF-D was associated with lymphatic involvement, and VEGF-D decreased during treatment. Adverse events were mostly mild; permanent discontinuation occurred in approximately 6%. CONCLUSIONS: In routine practice, sirolimus was associated with long-term stabilization of lung function, marked improvement of lymphatic disease, reduction of angiomyolipoma burden, and acceptable tolerability. VEGF-D aligned with lymphatic phenotype and declined with treatment, supporting its role as a monitoring biomarker.