Evaluating Efficacy and Safety of Danazol in Severe Hematologic or Pulmonary Disease Related to Telomeropathy

Assistance Publique - Hôpitaux de Paris40 enrolled

Overview

Constitutional mutations of genes involved in telomere repair and maintenance are responsible for "telomeropathy" (" Congenital Dyskeratosis "). Attrition of telomeres promotes cell senescence and genetic instability. The penetrance and severity of organ damage (pulmonary, hematological, liver, and neurological) is variable, depending on the gene involved, the generation concerned (anticipation phenomenon) and also environmental factors. In cases of bone marrow failure, the only curative treatment is hematopoietic stem cell transplant, often limited by pulmonary and / or hepatic involvement or the absence of a suitable HLA match donor. The pulmonary phenotype is most often that of idiopathic pulmonary fibrosis. In severe forms, a lung transplant is proposed in the absence of contraindications. Anti-fibrotic treatments are not very effective or not evaluated. The observed decrease in the vital capacity of these patients is 300 ml / year, abnormally high compared to idiopathic forms. Evolution without transplant is in both situations rapidly unfavorable; the prognosis after lung or marrow transplant is also worse than that of similar transplants without telomeres disease. Danazol has been used for over 4 decades in acquired and constitutional bone marrow failure in the absence of a therapeutic alternative. In telomeropathy, retrospective data on small cohorts indicate a haematological response rate of 60-70%. A prospective study in the United States recently showed a haematological response at 1 year in 78% of cases (10 of 12 evaluable patients) with stabilization of vital capacity. Retrospective data (unpublished) on patients treated in France have shown more side effects and more frequent treatment interruptions and eventually weaker haematological response rate. This study aim to evaluate the benefit of danazol at 12 months on the clinical response.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Eligibility

Sex: ALLMin age: 15 Years

Medical Language ↔ Plain English

Inclusion Criteria: * with telomeropathy defined by the existence of a deleterious constitutional mutation of a gene involved in telomere maintenance (TERT, TERC, DKC1, TINF2, RTEL1, PARN, ACD, NHP2, NOP10, NAF1, WRAP53, CTC1, ERCC6L2, USB1, POT1, DNAJC21 or a newly identified gene responsible for telomeropathy ), * 15 years or older, * with severe haematological involvement (platelets \< 20 G/L or ANC \< 0.5 G/L and/or hemoglobin \< 8 g/dL and/or transfusion needs) and/or pulmonary fibrosis with parenchymal involvement greater than 10% on the CT scan. * being able to give informed consent for patients 18 years and older, * being able to give consent and have the consent of the holder (s) of parental authority for children over 15 years, * being a beneficiary of social security scheme. Exclusion Criteria: * with HIV infection or active hepatitis B or C infection, * with severe hepatic disease: ASAT and/or ALAT \> 5N, or direct bilirubinemia \> 30 μmol/L, TP \<50% (except vitamin K deficiency), * having an active or treated tumor pathology for less than 5 years with the exception of a basocellular carcinoma or a in situ carcinoma of the cervix, * with a history of organ or hematopoietic stem cell transplantation or with an indication of hematopoietic stem cell or organ transplantation within 6 months of inclusion, * with an absolute contraindication to treatment with danazol: active thrombosis or history of thromboembolic disease, porphyria, severe renal or cardiac insufficiency (NYHA stage III or IV), androgen-dependent tumor, uncharacterized mammary nodules, pathological genital hemorrhage of undetermined etiology, * who have already received danazol for the treatment of telomeropathy, * having received another androgen within a period of less than 6 months, * receiving another experimental treatment, * receiving another hormonal therapy, * receiving simvastatin, * having a pregnancy plan and not committing to effective contraception while taking the treatment, * breastfeeding, * under guardianship or curators.

Outcomes

Primary Outcomes

Hematological response or Pulmonary response at M12

Response at 12 months is defined according to the initial pathology. Responses is defined as a composite outcome. At least one of the following item should be validated to observe response. * For patients with bone marrow failure, the hematological response at 12 months depending on initial cytopenia(s) is defined by * 1.5 g/dL increase in hemoglobin without transfusion for 2 months * And/or increase of 20.10\^9/L in platelet count without transfusion for 2 months * And/or increase of 0.5.10\^9/L in neutrophils count. * For patients with pulmonary fibrosis, a decrease of less than 5% in forced vital capacity at 12 months

Time frame: 12 months