Sirolimus plus prednisone for Erdheim-Chester disease: An open-label trial

Davide Gianfreda, Maria Nicastro, Maricla Galetti, Federico Alberici, Domenico Corradi, Gabriella Becchi, Giorgio Baldari, Massimo De Filippo, Stefania Ferretti, Gabriella Moroni, Rosario Foti, Marcella Di Gangi, Guido Jeannin, Raphael Saffroy, Jean François Emile, Carlo Buzio, Augusto Vaglio

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1163-1171
Number of pages9
JournalBlood
Volume126
Issue number10
DOIs
Publication statusPublished - Sep 3 2015

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Erdheim-Chester Disease
Sirolimus
Prednisone
Labels
Neurology
Non-Langerhans-Cell Histiocytosis
70-kDa Ribosomal Protein S6 Kinases
Stabilization
Histiocytes
Central Nervous System Diseases
Small Cell Lung Carcinoma
Immunosuppressive Agents
New Zealand
Biopsy
Fluorescent Antibody Technique
Registries
Disease Progression
Phosphotransferases
Therapeutics
Central Nervous System

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Gianfreda, D., Nicastro, M., Galetti, M., Alberici, F., Corradi, D., Becchi, G., ... Vaglio, A. (2015). Sirolimus plus prednisone for Erdheim-Chester disease: An open-label trial. Blood, 126(10), 1163-1171. https://doi.org/10.1182/blood-2015-01-620377

Sirolimus plus prednisone for Erdheim-Chester disease : An open-label trial. / Gianfreda, Davide; Nicastro, Maria; Galetti, Maricla; Alberici, Federico; Corradi, Domenico; Becchi, Gabriella; Baldari, Giorgio; De Filippo, Massimo; Ferretti, Stefania; Moroni, Gabriella; Foti, Rosario; Di Gangi, Marcella; Jeannin, Guido; Saffroy, Raphael; Emile, Jean François; Buzio, Carlo; Vaglio, Augusto.

In: Blood, Vol. 126, No. 10, 03.09.2015, p. 1163-1171.

Research output: Contribution to journalArticle

Gianfreda, D, Nicastro, M, Galetti, M, Alberici, F, Corradi, D, Becchi, G, Baldari, G, De Filippo, M, Ferretti, S, Moroni, G, Foti, R, Di Gangi, M, Jeannin, G, Saffroy, R, Emile, JF, Buzio, C & Vaglio, A 2015, 'Sirolimus plus prednisone for Erdheim-Chester disease: An open-label trial', Blood, vol. 126, no. 10, pp. 1163-1171. https://doi.org/10.1182/blood-2015-01-620377
Gianfreda D, Nicastro M, Galetti M, Alberici F, Corradi D, Becchi G et al. Sirolimus plus prednisone for Erdheim-Chester disease: An open-label trial. Blood. 2015 Sep 3;126(10):1163-1171. https://doi.org/10.1182/blood-2015-01-620377
Gianfreda, Davide ; Nicastro, Maria ; Galetti, Maricla ; Alberici, Federico ; Corradi, Domenico ; Becchi, Gabriella ; Baldari, Giorgio ; De Filippo, Massimo ; Ferretti, Stefania ; Moroni, Gabriella ; Foti, Rosario ; Di Gangi, Marcella ; Jeannin, Guido ; Saffroy, Raphael ; Emile, Jean François ; Buzio, Carlo ; Vaglio, Augusto. / Sirolimus plus prednisone for Erdheim-Chester disease : An open-label trial. In: Blood. 2015 ; Vol. 126, No. 10. pp. 1163-1171.
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AU - Gianfreda, Davide

AU - Nicastro, Maria

AU - Galetti, Maricla

AU - Alberici, Federico

AU - Corradi, Domenico

AU - Becchi, Gabriella

AU - Baldari, Giorgio

AU - De Filippo, Massimo

AU - Ferretti, Stefania

AU - Moroni, Gabriella

AU - Foti, Rosario

AU - Di Gangi, Marcella

AU - Jeannin, Guido

AU - Saffroy, Raphael

AU - Emile, Jean François

AU - Buzio, Carlo

AU - Vaglio, Augusto

PY - 2015/9/3

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N2 - 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.

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