title: Sirolimus therapy for angiomyolipoma in tuberous sclerosis and sporadic lymphangioleiomyomatosis: a phase 2 trial.
abstract: OBJECTIVE
  Renal angiomyolipomas are a frequent manifestation of tuberous sclerosis and sporadic lymphangioleiomyomatosis (LAM). These disorders are associated with mutations of TSC1 or TSC2 that lead to overactivation of mTOR complex 1 (mTORC1), suggesting an opportunity for targeted therapy by using mTORC1 inhibitors. This study investigated the efficacy and safety of the mTORC1 inhibitor sirolimus for treatment of renal angiomyolipomas in patients with these disorders.
  
  
  METHODS
  In this multicenter phase 2 nonrandomized open label trial, 16 patients with tuberous sclerosis or sporadic LAM and renal angiomyolipoma(s) were treated with oral sirolimus for up to 2 years. Steady-state blood levels were 3 to 10 ng/mL. The primary outcome was change in size of renal angiomyolipomas measured by MRI and assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes included safety, neurocognitive function, and pulmonary function.
  
  
  RESULTS
  The response rate, by RECIST criteria, was 50%. Summated angiomyolipoma diameters were reduced in all 16 patients and by 30% or more in eight (all from the per protocol group of 10). Forty-one of 48 angiomyolipomas were smaller at the last measurement than at baseline. Most shrinkage occurred during the first year of treatment. There was little change in pulmonary function. Recall memory improved in seven of eight patients with tuberous sclerosis. Adverse events were consistent with the known toxicities of sirolimus.
  
  
  CONCLUSIONS
  This study showed sustained regression of renal angiomyolipomas in patients with tuberous sclerosis or sporadic LAM receiving 2 years of sirolimus treatment. Possible effects on pulmonary function and neurocognition require further investigation.
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
authors.forename: D Mark
authors.initials: DM
authors.lastname: Davies
authors.forename: Petrus J
authors.initials: PJ
authors.lastname: de Vries
authors.forename: Simon R
authors.initials: SR
authors.lastname: Johnson
authors.forename: Deborah L
authors.initials: DL
authors.lastname: McCartney
authors.forename: Jane A
authors.initials: JA
authors.lastname: Cox
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Serra
authors.forename: Peter C
authors.initials: PC
authors.lastname: Watson
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Howe
authors.forename: Tim
authors.initials: T
authors.lastname: Doyle
authors.forename: Kate
authors.initials: K
authors.lastname: Pointon
authors.forename: Justin J
authors.initials: JJ
authors.lastname: Cross
authors.forename: Anne E
authors.initials: AE
authors.lastname: Tattersfield
authors.forename: J Chris
authors.initials: JC
authors.lastname: Kingswood
authors.forename: Julian R
authors.initials: JR
authors.lastname: Sampson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018207:Angiomyolipoma / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D008168:Lung / Q000503:physiopathology; D018192:Lymphangioleiomyomatosis / Q000150:complications* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D020123:Sirolimus / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014402:Tuberous Sclerosis / Q000150:complications* / Q000473:pathology*; D055815:Young Adult
chemical_list: D020123:Sirolimus