Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis

Abstract

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.)

Figure 1. Overview of Screening, Enrollment, and Follow-up of the Patients with the Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)

Angiomyolipoma volumes and pulmonary-function tests in patients with LAM were assessed during the period of sirolimus treatment, from baseline to 12 months, and during a post-treatment observation period, from 12 to 24 months. At baseline, 18 patients had LAM, but pulmonary data were uninterpretable in 2 patients because of chylothorax or pneumothorax. At the 12-month time point, one patient declined to undergo pulmonary-function tests, and four patients had withdrawn from the study. One patient withdrew during the second year.

Figure 2. Angiomyolipoma Volume in the Patients with the Tuberous Sclerosis Complex or Sporadic Lymphangioleiomyomatosis during the Study

Angiomyolipomas were visualized with the use of abdominal magnetic resonance imaging, and volumetric analysis was performed at baseline and at 2, 4, 6, 12, 18, and 24 months. The angiomyolipoma volume at each visit is expressed as a percentage of the baseline size. The dashed line represents 70% of the baseline value; data below the line indicate that the mean angiomyolipoma volume was reduced by 30% or more.

Figure 3. Renal Angiomyolipomas in the Abdomen of a Patient with the Tuberous Sclerosis Complex

Bilateral angiomyolipomas are shown at baseline and after 12 months of sirolimus therapy. Three lesions in the left kidney are identified by arrows; at 12 months, the top lesion had become reduced in size and the bottom two had become imperceptible. The images were obtained with the use of fast spin–echo T₂-weighted magnetic resonance imaging with fat suppression.

Figure 4. Pulmonary Function in Patients with Lymphangioleiomyomatosis

Panel A shows the forced expiratory volume in 1 second (FEV₁) for each patient. Panel B shows the forced vital capacity (FVC) for each patient. Panel C shows the mean change (in milliliters) from the baseline values for FEV₁ and for FVC. I bars indicate the standard errors. Panel D shows the residual volume for each patient.