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Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis
John J Bissler1, Francis X McCormack, Lisa R Young
1Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA. john.bissler@cchmc.org
Background:
Angiomyolipomas in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis are associated with mutations in tuberous sclerosis genes resulting in constitutive activation of the mammalian target of rapamycin (mTOR). The drug sirolimus suppresses mTOR signaling.
Methods:
We conducted a 24-month, nonrandomized, open-label trial to determine whether sirolimus reduces the angiomyolipoma volume in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. Sirolimus was administered for the first 12 months only. Serial magnetic resonance imaging of angiomyolipomas and brain lesions, computed tomography of lung cysts, and pulmonary-function tests were performed.
Results:
Of the 25 patients enrolled, 20 completed the 12-month evaluation, and 18 completed the 24-month evaluation. The mean (+/-SD) angiomyolipoma volume at 12 months was 53.2+/-26.6% of the baseline value (P<0.001) and at 24 months was 85.9+/-28.5% of the baseline value (P=0.005). At 24 months, five patients had a persistent reduction in the angiomyolipoma volume of 30% or more. During the period of sirolimus therapy, among patients with lymphangioleiomyomatosis, the mean forced expiratory volume in 1 second (FEV1) increased by 118+/-330 ml (P=0.06), the forced vital capacity (FVC) increased by 390+/-570 ml (P<0.001), and the residual volume decreased by 439+/-493 ml (P=0.02), as compared with baseline values. One year after sirolimus was discontinued, the FEV1 was 62+/-411 ml above the baseline value, the FVC was 346+/-712 ml above the baseline value, and the residual volume was 333+/-570 ml below the baseline value; cerebral lesions were unchanged. Five patients had six serious adverse events while receiving sirolimus, including diarrhea, pyelonephritis, stomatitis, and respiratory infections.
Conclusions:
Angiomyolipomas regressed somewhat during sirolimus therapy but tended to increase in volume after the therapy was stopped. Some patients with lymphangioleiomyomatosis had improvement in spirometric measurements and gas trapping that persisted after treatment. Suppression of mTOR signaling might constitute an ameliorative treatment in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. (ClinicalTrials.gov number, NCT00457808.)
Insights
Sirolimus therapy reduced angiomyolipoma volume in patients with tuberous sclerosis complex or lymphangioleiomyomatosis, with some lung function improvements persisting after treatment cessation.
Area of Science:
- Oncology
- Pulmonology
- Genetics
Background:
- Tuberous sclerosis complex (TSC) and sporadic lymphangioleiomyomatosis (S-LAM) are linked to TSC gene mutations, causing mammalian target of rapamycin (mTOR) overactivation.
- Sirolimus, an mTOR inhibitor, is investigated for its therapeutic potential in these conditions.
Purpose of the Study:
- To evaluate the efficacy of sirolimus in reducing angiomyolipoma volume in patients with TSC or S-LAM.
- To assess the impact of sirolimus on lung function and cerebral lesions in these patients.
Main Methods:
- A 24-month, open-label trial involving 25 patients with TSC or S-LAM.
- Sirolimus was administered for the initial 12 months.
- Serial MRI, CT scans, and pulmonary function tests were conducted throughout the study.
Main Results:
- Angiomyolipoma volume significantly decreased during sirolimus therapy (53.2% at 12 months, P<0.001) but showed a trend toward increase post-treatment (85.9% at 24 months, P=0.005).
- Five patients maintained a ≥30% reduction in angiomyolipoma volume at 24 months.
- Patients with S-LAM experienced improvements in FEV1, FVC, and residual volume during treatment, with some benefits persisting after discontinuation. Cerebral lesions remained unchanged.
Conclusions:
- Sirolimus demonstrates modest efficacy in reducing angiomyolipoma volume, though regression is not always sustained after treatment cessation.
- Sirolimus may offer sustained pulmonary function benefits for patients with S-LAM.
- mTOR pathway inhibition presents a potential therapeutic strategy for TSC and S-LAM.
