Correspondence
Sirolimus Therapy in Tuberous Sclerosis or Sporadic Lymphangioleiomyomatosis
N Engl J Med 2008; 358:200-203January 10, 2008
- Article
To the Editor:
Tuberous sclerosis is an autosomal dominant disorder characterized by hamartomatous growths in many organs and caused by inherited mutations of the TSC1 or TSC2 gene. Acquired (somatic) mutations of either gene occur within pathologic cells in patients with sporadic lymphangioleiomyomatosis. Renal angiomyolipomas occur in both disorders, resulting in substantial morbidity and mortality.1 The proteins TSC1 and TSC2 regulate signaling through the mammalian target of rapamycin (mTOR) pathway to control processes including growth, cell-cycle progression, apoptosis, and autophagy. Constitutive activation of mTOR and its downstream targets occurs in lesions associated with tuberous sclerosis or lymphangioleiomyomatosis, suggesting that mTOR inhibitors might have potential as molecularly targeted therapies in patients with these conditions.1 Case studies have shown shrinkage of tuberous sclerosis–associated angiomyolipomas and subependymal giant-cell astrocytomas in response to treatment with the mTOR inhibitor sirolimus.2,3 We are conducting a multicenter, phase 2 trial to investigate the efficacy and safety of sirolimus in adults with tuberous sclerosis or lymphangioleiomyomatosis. Patients are being treated for 2 years; here, we report our interim findings in 13 patients treated for up to 1 year.
Eligible patients had one or more renal angiomyolipomas that were more than 2 cm in the longest diameter on magnetic resonance imaging (MRI). The study was approved by a U.K. multicenter research ethics committee and by the ethics review board of each participating center. Patients received daily oral doses of sirolimus to achieve initial trough blood levels of 3 to 6 ng per milliliter, with an increase to 6 to 10 ng per milliliter at 2 months, unless all measured angiomyolipomas showed a reduction in the longest diameter of 10% or more. The sum of the longest diameters of up to five target angiomyolipomas (each with an initial longest diameter >2 cm) in each kidney was calculated after MRI at baseline, at 2 months, at 6 months, and at 12 months (Table 1Table 1
Changes in Size of Renal Angiomyolipomas and Results of Lung-Function Testing in Seven Patients with Tuberous Sclerosis (TSC) and Six Patients with Lymphangioleiomyomatosis (LAM) during Treatment with Sirolimus.). Respiratory function was measured at baseline, at 4 months, at 6 months, and at 12 months in patients with tuberous sclerosis–associated or sporadic lymphangioleiomyomatosis. Shrinkage of angiomyolipomas was seen in all patients and the mean (±SD) reduction in the sum of the longest diameters at 12 months was 26.1±10.3%. However, no clear improvement in lung function was observed.All patients had grade 1 or 2 adverse events (including mouth ulcers, hyperlipidemia, and peripheral edema) that, in all but one patient, resulted in periods of dose reduction or cessation of therapy. Similar problems have been reported in renal-transplant recipients treated with sirolimus for immunosuppression.4 Sirolimus crosses the blood–brain barrier and impairs memory in rats.5 Its potential neuropsychological effects in patients with tuberous sclerosis have not been studied. We are monitoring memory and executive skills in our patients and have found no evidence of clinically significant deterioration.
Our trial of targeted therapy for an inherited disorder is among the early studies based on new genomic knowledge. Our results indicate that the inhibition of mTOR may hold promise as a treatment for angiomyolipoma in patients with tuberous sclerosis or lymphangioleiomyomatosis.
D. Mark Davies, M.B.
Cardiff University, Cardiff CF14 4XN, United KingdomSimon R. Johnson, D.M.
Anne E. Tattersfield, M.D.
University of Nottingham, Nottingham NG7 2UH, United KingdomJ. Chris Kingswood, F.C.R.P.
Jane A. Cox, M.Sc.
Royal Sussex County Hospital, Brighton BN2 5BE, United KingdomDeborah L. McCartney, B.A.
University of Cambridge, Cambridge CB2 2AH, United KingdomTim Doyle, L.R.C.P. & S., L.R.C.P. & S.
Royal Sussex County Hospital, Brighton BN2 5BE, United KingdomFrances Elmslie, M.D.
Anand Saggar, M.B.
St George's Hospital Medical School, London SW17 0RE, United KingdomPetrus J. de Vries, M.B., Ph.D.
University of Cambridge, Cambridge CB2 2AH, United KingdomJulian R. Sampson, D.M., F. Med. Sci., D.M., F. Med. Sci.
Cardiff University, Cardiff CF14 4XN, United Kingdom
sampson@cf.ac. uk Supported by grants from the Tuberous Sclerosis Association, the James Tudor Foundation, and the Welsh Assembly Government for the Wales Gene Park.
Drs. Davies and Sampson report receiving grant support and lecture fees from Wyeth. No other potential conflict of interest relevant to this letter was reported.
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