title: Sirolimus plus prednisone for Erdheim-Chester disease: an open-label trial.
abstract: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, to whose pathogenesis neoplastic and immune-mediated mechanisms contribute. Mammalian target of rapamycin (mTOR)-inhibitors have antiproliferative and immunosuppressive properties. We tested in this study, the efficacy and safety of the mTOR-inhibitor sirolimus (SRL) plus prednisone (PDN) in patients with ECD. PDN was given initially at 0.75 mg/kg per day, tapered to 5 to 2.5 mg per day by month 6. Target SRL blood levels were 8 to 12 ng/mL. Treatment was continued for at least 24 months in patients who showed disease stabilization or improvement. Ten patients were enrolled; 8 achieved stable disease or objective responses, whereas 2 had disease progression. Responses were mainly observed at the following sites: retroperitoneum in 5/8 patients (62.5%), cardiovascular in 3/4 (75%), bone in 3/9 (33.3%), and central nervous system (CNS) in 1/3 (33.3%). The median follow-up was 29 months (interquartile range, 16.5-74.5); 2 patients died of progressive CNS disease and small-cell lung cancer, respectively. Treatment-related toxicity was mild. Using immunohistochemistry and immunofluorescence on ECD biopsies, we detected expression in foamy histiocytes of the phosphorylated forms of mTOR and of its downstream kinase p70S6K, which indicated mTOR pathway activation. In conclusion, SRL and PDN often induce objective responses or disease stabilization and may represent a valid treatment of ECD. The trial is registered at the Australia-New Zealand Clinical Trial Registry as #ACTRN12613001321730.
authors.affiliation: Nephrology Unit, Department of Emergency and Clinical Medicine, University Hospital, Parma, Italy;
authors.forename: Davide
authors.initials: D
authors.lastname: Gianfreda
authors.affiliation: Nephrology Unit, Department of Emergency and Clinical Medicine, University Hospital, Parma, Italy;
authors.forename: Maria
authors.initials: M
authors.lastname: Nicastro
authors.affiliation: Nephrology Unit, Department of Emergency and Clinical Medicine, University Hospital, Parma, Italy; Italian Workers' Compensation Authority Research Center, Department of Clinical and Experimental Medicine.
authors.forename: Maricla
authors.initials: M
authors.lastname: Galetti
authors.affiliation: Nephrology Unit, Department of Emergency and Clinical Medicine, University Hospital, Parma, Italy;
authors.forename: Federico
authors.initials: F
authors.lastname: Alberici
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences, Unit of Pathology, University of Parma, Parma, Italy;
authors.forename: Domenico
authors.initials: D
authors.lastname: Corradi
authors.affiliation: Department of Biomedical, Biotechnological and Translational Sciences, Unit of Pathology, University of Parma, Parma, Italy;
authors.forename: Gabriella
authors.initials: G
authors.lastname: Becchi
authors.affiliation: Nuclear Medicine Unit.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Baldari
authors.affiliation: Radiology Service, and.
authors.forename: Massimo
authors.initials: M
authors.lastname: De Filippo
authors.affiliation: Urology Unit, University Hospital, Parma, Italy;
authors.forename: Stefania
authors.initials: S
authors.lastname: Ferretti
authors.affiliation: Nephrology Unit, Policlinico Hospital, Milan, Italy;
authors.forename: Gabriella
authors.initials: G
authors.lastname: Moroni
authors.affiliation: Rheumatology Unit, University Hospital Policlinico Vittorio Emanuele, Catania, Italy;
authors.forename: Rosario
authors.initials: R
authors.lastname: Foti
authors.affiliation: Rheumatology Unit, University Hospital Policlinico Vittorio Emanuele, Catania, Italy;
authors.forename: Marcella
authors.initials: M
authors.lastname: Di Gangi
authors.affiliation: Nephrology Unit, University Hospital, Brescia, Italy;
authors.forename: Guido
authors.initials: G
authors.lastname: Jeannin
authors.affiliation: Biochemistry and Molecular Biology Department, Paul Brousse Hospital, APHP, Villejuif, France; and.
authors.forename: Raphael
authors.initials: R
authors.lastname: Saffroy
authors.affiliation: EA4340 and Pathology Department, Versailles University and Ambroise Paré Hospital, Boulogne, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Emile
authors.affiliation: Nephrology Unit, Department of Emergency and Clinical Medicine, University Hospital, Parma, Italy;
authors.forename: Carlo
authors.initials: C
authors.lastname: Buzio
authors.affiliation: Nephrology Unit, Department of Emergency and Clinical Medicine, University Hospital, Parma, Italy;
authors.forename: Augusto
authors.initials: A
authors.lastname: Vaglio
mesh_terms: D000328:Adult; D000368:Aged; D031249:Erdheim-Chester Disease / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011241:Prednisone / Q000627:therapeutic use*; D020123:Sirolimus / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D011241:Prednisone; D020123:Sirolimus