Efficacy and safety of DANAZOL for pulmonary fibrosis or bone-marrow failure associated with telomere-related gene mutation

Telomere-related gene (TRG) pathogenic variants are detected in ∼30% of familial pulmonary fibrosis (PF) cases. Danazol, a synthetic sex hormone with androgenic properties, has been found associated with telomere elongation and hematologic response in patients with short telomeres. The objective of the ANDROTELO multicenter, prospective, open-label single-arm phase II clinical trial ( NCT03710356 ) was to evaluate the efficacy and safety of danazol in carriers of TRG mutations with PF or bone-marrow failure (BMF).Included patients were carriers of a pathogenic or likely pathogenic TRG variant and presented a PF lung involving ≥10% parenchymal involvement on chest CT (PF group) and/or severe BMF (BMF group). Treatment was danazol 400 mg twice a day for 12 months. We included 25 patients with PF (16 males) and 5 with BMF (2 males). One PF patient withdrew consent. At inclusion, the median age in the PF group was 62.5 years, FVC 69% (interquartile range 40;120) and DLCO 44% (29;84). Ten of 24 PF patients (42%) completed the 12-month treatment. Causes of premature treatment discontinuation were side effects (n=9), death (n=3), lung transplantation (n=1), and disease progression (n=1). Fourteen PF patients were evaluated at month 12: 8 showed a relative decline of FVC of <5%. The median relative decrease in FVC and DLCO was −10% (interquartile range −14;−2) and −10.3% (−22.7;4.2). The 5 patients in the BMF group completed the 12-month treatment and exhibited at least partial response. Danazol was poorly tolerated in patients with TRG-related PF in this study, thus precluding efficacy assessment.

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Journal
ERJ Open Research
Published
2025-11-09
DOI
https://doi.org/10.1183/23120541.00905-2025
Primary Topic
Telomeres, Telomerase, and Senescence
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article
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article

Efficacy and safety of DANAZOL for pulmonary fibrosis or bone-marrow failure associated with telomere-related gene mutation

Aurélie Plessier, Élodie Lainey, Vincent Cottin, Flore Sicre de Fontbrune et al.
ERJ Open Research
Telomeres, Telomerase, and Senescence
article

Efficacy and safety of DANAZOL for pulmonary fibrosis or bone-marrow failure associated with telomere-related gene mutation

Aurélie Plessier, Élodie Lainey, Vincent Cottin, Flore Sicre de Fontbrune, S. Marchand‐Adam, Matthieu Resche‐Rigon, Lucie Biard, Ibrahima Ba, Hilario Nunès, Louis Terriou, Anne Bergeron, S. Jouneau, Caroline Kannengiesser, Bruno Crestani, Ambroise Marçais, Raphaël Borie, Marie‐Pierre Debray, Grégoire Prévôt, Kristell Desseaux
article en

Abstract

Telomere-related gene (TRG) pathogenic variants are detected in ∼30% of familial pulmonary fibrosis (PF) cases. Danazol, a synthetic sex hormone with androgenic properties, has been found associated with telomere elongation and hematologic response in patients with short telomeres. The objective of the ANDROTELO multicenter, prospective, open-label single-arm phase II clinical trial ( NCT03710356 ) was to evaluate the efficacy and safety of danazol in carriers of TRG mutations with PF or bone-marrow failure (BMF).Included patients were carriers of a pathogenic or likely pathogenic TRG variant and presented a PF lung involving ≥10% parenchymal involvement on chest CT (PF group) and/or severe BMF (BMF group). Treatment was danazol 400 mg twice a day for 12 months. We included 25 patients with PF (16 males) and 5 with BMF (2 males). One PF patient withdrew consent. At inclusion, the median age in the PF group was 62.5 years, FVC 69% (interquartile range 40;120) and DLCO 44% (29;84). Ten of 24 PF patients (42%) completed the 12-month treatment. Causes of premature treatment discontinuation were side effects (n=9), death (n=3), lung transplantation (n=1), and disease progression (n=1). Fourteen PF patients were evaluated at month 12: 8 showed a relative decline of FVC of <5%. The median relative decrease in FVC and DLCO was −10% (interquartile range −14;−2) and −10.3% (−22.7;4.2). The 5 patients in the BMF group completed the 12-month treatment and exhibited at least partial response. Danazol was poorly tolerated in patients with TRG-related PF in this study, thus precluding efficacy assessment.

ERJ Open Research
Université Claude Bernard Lyon 1 (FR), Université de Tours (FR), University of Geneva (CH), Hôpital Necker-Enfants Malades (FR), Inserm (FR), Université de Lyon (FR), Université Paris Cité (FR), Centre Hospitalier Universitaire de Lille (FR), Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR), Sorbonne Paris Cité (FR), Hôpital Beau-Séjour (CH), Centre Hospitalier Universitaire de Tours (FR), Assistance Publique – Hôpitaux de Paris (FR), Lung Institute (US), Institut de Recherche en Santé, Environnement et Travail (FR), Hôpital Pontchaillou (FR), Hôpital Robert-Debré (FR), Hôpital Larrey (FR), Hôpital Avicenne (FR), Centre de Recherche sur l'Inflammation (FR), Hôpital Louis Pradel (FR), Hôpital Saint-Louis (FR), Hôpital Bichat-Claude-Bernard (FR), Centre Hospitalier Universitaire de Rennes (FR)
Openalex Percentile: Top 59%
Telomeres, Telomerase, and Senescence
DOIOpen Access PDFOpenAlex
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