Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
Erdheim-Chester disease (ECD) is an extremely rare form of non-Langerhans cell histiocytosis. The pathogenesis of ECD is unclear: while most authors suggest the hypothesis of an inflammatory disease, others claim it is a neoplastic disorder. ECD often has a fatal course (3-year mortality 25-60%) and has no established treatment. Interferon-α is often used but it has severe toxicity and poor efficacy on CNS and cardiovascular lesions.
The mTOR inhibitor sirolimus (SRL) is an immunosuppressive drug with known anti-neoplastic properties. We tested the efficacy and safety of prednisone (PDN) and SRL in a series of patients with multisystemic, active ECD. We also assessed mTOR activity in patients’ biopsies as a potential predictor of treatment efficacy.
Methods:
We enrolled all patients with active, multisystemic ECD (either at first diagnosis or with progressive disease refractory to other treatments) referred to our Department between 2003 and 2011.
PDN was given at the initial dose of 0.75 mg/kg/day for 1 month, tapered to 2.5-5 mg/day over 6 months; SRL was given at a daily dose of 2-3 mg, with a target trough level of 8-10 ng/mL. If disease stabilization or remission was achieved, treatment was continued chronically.
Where available, frozen tissue biopsies were used to assess mTOR activity: for this purpose, the levels of phospho-p70S6K (Thr389) and phospho-mTOR (ser 2448) in total proteins extracted from the biopsies were determined by Western blotting.
Results:
Nine consecutive ECD patients were enrolled; six were newly diagnosed and untreated, the remaining three were refractory to previous treatments (interferon-α, PDN and colchicine, PDN and cyclophosphamide). The median follow-up from diagnosis was 41 months (range 12-164). At the end of the follow-up, seven patients were alive and experienced quiescent disease; of the remaining two, one died 12 months after diagnosis because of progressive CNS involvement, and one 25 months after diagnosis because of small cell lung cancer.
One of two patients had a complete cardiac response (complete remission of pericarditis), 1/2 a complete response in the lungs and 2/5 a complete remission in cutaneous lesions. Partial responses were observed at the following sites: long bones in 2/8 cases, CNS in 1/2 cases, retroperitoneum-perirenal space in 5/7 cases, hypothalamic-pituitary axis in 1/4 cases, skin in 1/5 cases. One patient had a progression in retroperitoneal involvement.
Treatment-related toxicity was mild; only one patient had to stop treatment because of sirolimus-related pneumonia.
The three available biopsies (2 retroperitoneal, 1 skin) exhibited high levels of phospho-p70S6K and phospho-mTOR, confirming that the mTOR pathway is activated in ECD. Given the paucity of available frozen tissue samples, we could not evaluate whether mTOR activity was a predictor of response to SRL.
Conclusion: The combination of PDN and SRL is a potential treatment for multisystemic ECD; it usually induces disease stabilization and in some cases objective responses, and has a good tolerability. The mTOR pathway seems to be activated in ECD lesions; further studies are needed to explore whether phospho-p70S6K and phospho-mTOR tissue expression predict response to SRL therapy.
Disclosure:
D. Gianfreda,
None;
F. Alberici,
None;
M. Galetti,
None;
M. Nicastro,
None;
C. Buzio,
None;
A. Vaglio,
None.
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