Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis.
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.)
Bissler
John J
JJ
Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229-3039, USA. john.bissler@cchmc.org
McCormack
Francis X
FX
Young
Lisa R
LR
Elwing
Jean M
JM
Chuck
Gail
G
Leonard
Jennifer M
JM
Schmithorst
Vincent J
VJ
Laor
Tal
T
Brody
Alan S
AS
Bean
Judy
J
Salisbury
Shelia
S
Franz
David N
DN
D000328:Adult; D018207:Angiomyolipoma / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D001921:Brain / Q000473:pathology; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007674:Kidney Diseases / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology; D008168:Lung / Q000000981:diagnostic imaging / Q000503:physiopathology; D008175:Lung Neoplasms / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D018192:Lymphangioleiomyomatosis / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism; D011859:Radiography; D012129:Respiratory Function Tests; D020123:Sirolimus / Q000009:adverse effects / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases; D014402:Tuberous Sclerosis / Q000150:complications* / Q000235:genetics
D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus