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.