Danazol for Genetic Bone Marrow and Lung Disorders
Danazol for Genetic Bone Marrow and Lung Disorders
Background:

 - Some people have bone marrow and lung disorders that are caused by genetic problems. These
 problems often involve damage to the ends of the chromosomes that pass down genes. One of
 these disorders is aplastic anemia. This is a disorder in which the bone marrow does not make
 enough blood cells. Currently, doctors use a male hormone-based drug called Danazol to
 improve bone marrow function and treat aplastic anemia. More information is needed on whether
 Danazol can help repair the damaged chromosomes that cause aplastic anemia and similar
 disorders that cause low blood cell counts or lung problems.

 Objectives:

 - To study the safety and effectiveness of Danazol for bone marrow and lung disorders caused
 by damaged genes.

 Eligibility:

 - Individuals at least 2 years of age who have low blood cell counts or lung fibrosis caused
 by damaged genes.

 Design:

 -  Participants will be screened with a physical exam and medical history. Then they will
 have blood and urine tests, imaging studies, and a lung function test. They will also
 take a 6-minute walking test and have a bone marrow biopsy.

 -  Participants will receive Danazol to take twice a day for the duration of the study.

 -  Participants will have regular study visits at 6, 12, and 24 months, with blood tests,
 imaging studies, a lung function test, and a 6-minute walking test. A bone marrow sample
 will be collected at the 12-month visit.

 -  Participants will remain on the study for up to 2 years. Researchers will follow up with
 them for 2 years after the end of the study.
Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder characterized
 by pancytopenia and a hypocellular bone marrow. Telomeres were reported to be short in up to
 one-third of patients with SAA.Initially this occurrence was presumed to be secondary to
 hematopoietic stress. However, the discovery of loss-of-function mutations in genes of the
 telomerase complex (TERC, TERT) established a genetic etiology for telomere attrition in some
 patients with marrow failure who did not have the stigmata associated to an inherited bone
 marrow failure syndrome. These findings implicated telomerase dysfunction in failed
 hematopoiesis. In family members of probands with SAA, telomerase mutations have been
 observed which were associated to varying degrees of cytopenias, idiopathic pulmonary
 fibrosis (IPF) and/or cirrhosis.

 Telomere length has been associated with human cancer. Telomere attrition has been implicated
 in a variety of solid organ malignancies including esophageal and colon adenocarcinoma. In a
 longitudinal population based study, shorter telomere length associated to a higher cancer
 mortality risk overtime. It is plausible that a shorter telomere length is not just a
 biomarker associated to development of cancer, but involved in its pathogenesis. Ample
 experimental data supports an important role of critically short telomere length in genomic
 instability. Furthermore, our laboratory data (unpublished) shows that similar chromosome
 instability occurs in bone marrow cells of mutant patients, confirming the experimental data.
 Thus, a common molecular mechanism appears to underlie risk for cancer and a range of
 clinical entities.

 In vitro studies suggest that telomere length could, in theory, be modulated with sex
 hormones.15 Exposure of normal peripheral blood lymphocytes and human bone marrow derived
 CD34+ cells to androgens increased telomerase activity in vitro and androgens increased low
 baseline telomerase activity in individuals carrying a loss-of-function TERT mutation to
 normal levels. In retrospect, the beneficial effects of sex hormones on telomerase activity
 may be the mechanism by which SAA patients treated over 40 years ago with male hormones
 showed hematologic improvement in some cases.

 In recent years we have seen patients referred to our clinic with varying degree of
 cytopenia(s) who had significant family history for cytopenia(s), IPF and/or cirrhosis. We
 have identified very short telomeres in these patients and in some mutations in TERC and
 TERT. We hypothesize that male hormone therapy might modulate telomere attrition in vivo and
 ameliorate progression or reverse the clinical consequences of accelerated telomere
 attrition. Therefore, we propose male hormone therapy in patients with cytopenia(s) and/or
 IPF who show evidence of telomere dysfunction by a short age adjusted telomere length
 associated to telomerase gene mutations. The primary biologic endpoint will be delay of
 telomere attrition over time compared to known rates of telomere erosion in normal
 individuals and in those who carry mutation in the telomerase genes. The main clinical
 endpoint will be tolerability of oral danazol over two years. Secondary endpoints will be
 improvement in blood counts and/or pulmonary function. The small sample size, lack of control
 groups, and variable clinical course among those with marrow failure and IPF, will not allow
 for definitive assessment of clinical benefit. Nevertheless, we believe this protocol will
 provide insight into the possible effects of androgen therapy on telomere attrition in humans
 and of possible clinical benefit in telomere related disorders, and serve as hypothesis
 generating for further larger controlled studies.
-  INCLUSION CRITERIA:

 1. Short age-adjusted telomere length in the first percentile and/or a mutation in
 telomerase genes

 2. One or more of the following cytopenia(s).

 -  Anemia

 1. Symptomatic anemia with a hemoglobin < 9.5 g/dL or red cell transfusion
 requirements > 2 units/month for at least 2 months

 2. Reticulocyte count < 60,000 /microL

 -  Thrombocytopenia

 1. Platelet count < 30,000 /microL or < 50,000 /microL associated with bleeding

 2. Decreased megakaryocytic precursors in the bone marrow

 -  Neutropenia

 1. Absolute neutrophil count < 1,000 /microL

 OR

 3. Idiopathic pulmonary fibrosis diagnosed by either a lung biopsy of high
 resolution computed tomography scan of the chest according to guidelines from the
 American Thoracic Society and European Respiratory Society

 4. Age greater than or equal to 2 years

 5. Weight > 12 kg

 EXCLUSION CRITERIA:

 1. Moribund status or concurrent hepatic, renal, cardiac, neurologic,
 pulmonary, infectious, or metabolic disease of such severity that it would
 preclude the patient s ability to tolerate protocol therapy, or that death
 within 30 days is likely

 2. Potential subjects with cancer who are on active chemotherapeutic treatment

 3. Current pregnancy, or unwillingness to avoid pregnancy if of childbearing
 potential

 4. Not able to understand the investigational nature of the study or give
 informed consent or does not have a legally authorized representative or
 surrogate that can provide informed consent.