Sirolimus shrinks renal angiomyolipomas in tuberous sclerosis / lymphangioleiomyomatosis.
| Evidence tier | B Direct human evidence |
| Study type | 2 - Human Clinical Trial |
| Model system | Human (clinical trial) |
| Journal | The New England journal of medicine |
| Year | 2008 |
| Peer reviewed | Yes |
| Source | DOI 10.1056/NEJMoa063564 · PMID 18184959 · Free full text (PMC3398441) |
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. 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. Of the 25 patients enrolled, 20 completed the 12-month evaluation, and 18 completed the 24-month evaluation. The mean angiomyolipoma volume at 12 months was 53.2% of the baseline value (P<0.001) and at 24 months was 85.9% of the baseline value (P=0.005). During sirolimus therapy, among patients with lymphangioleiomyomatosis, FEV1, FVC and residual volume improved relative to baseline. One year after sirolimus was discontinued, some spirometric improvements persisted; cerebral lesions were unchanged. Five patients had six serious adverse events while receiving sirolimus, including diarrhea, pyelonephritis, stomatitis, and respiratory infections. Angiomyolipomas regressed somewhat during sirolimus therapy but tended to increase in volume after therapy was stopped. Suppression of mTOR signaling might constitute an ameliorative treatment in patients with the tuberous sclerosis complex or sporadic lymphangioleiomyomatosis. (ClinicalTrials.gov number, NCT00457808.)
| Intervention | Sirolimus (rapamycin) |
| Target | mTOR |
| Model | Human – open-label trial (TSC/LAM) |
| Effect | Sirolimus reduced angiomyolipoma volume during treatment; tumors regrew after stopping |