title: Danazol Treatment for Telomere Diseases.
abstract: BACKGROUND
  Genetic defects in telomere maintenance and repair cause bone marrow failure, liver cirrhosis, and pulmonary fibrosis, and they increase susceptibility to cancer. Historically, androgens have been useful as treatment for marrow failure syndromes. In tissue culture and animal models, sex hormones regulate expression of the telomerase gene.
  
  
  METHODS
  In a phase 1-2 prospective study involving patients with telomere diseases, we administered the synthetic sex hormone danazol orally at a dose of 800 mg per day for a total of 24 months. The goal of treatment was the attenuation of accelerated telomere attrition, and the primary efficacy end point was a 20% reduction in the annual rate of telomere attrition measured at 24 months. The occurrence of toxic effects of treatment was the primary safety end point. Hematologic response to treatment at various time points was the secondary efficacy end point.
  
  
  RESULTS
  After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary end point; in the intention-to-treat analysis, 12 of 27 patients (44%; 95% confidence interval [CI], 26 to 64) met the primary efficacy end point. Unexpectedly, almost all the patients (11 of 12, 92%) had a gain in telomere length at 24 months as compared with baseline (mean increase, 386 bp [95% CI, 178 to 593]); in exploratory analyses, similar increases were observed at 6 months (16 of 21 patients; mean increase, 175 bp [95% CI, 79 to 271]) and 12 months (16 of 18 patients; mean increase, 360 bp [95% CI, 209 to 512]). Hematologic responses occurred in 19 of 24 patients (79%) who could be evaluated at 3 months and in 10 of 12 patients (83%) who could be evaluated at 24 months. Known adverse effects of danazol--elevated liver-enzyme levels and muscle cramps--of grade 2 or less occurred in 41% and 33% of the patients, respectively.
  
  
  CONCLUSIONS
  In our study, treatment with danazol led to telomere elongation in patients with telomere diseases. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01441037.).
authors.affiliation: From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Townsley
authors.affiliation: From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Dumitriu
authors.affiliation: From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.
authors.forename: Delong
authors.initials: D
authors.lastname: Liu
authors.affiliation: From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.
authors.forename: Angélique
authors.initials: A
authors.lastname: Biancotto
authors.affiliation: From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.
authors.forename: Barbara
authors.initials: B
authors.lastname: Weinstein
authors.affiliation: From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.
authors.forename: Christina
authors.initials: C
authors.lastname: Chen
authors.affiliation: From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.
authors.forename: Nathan
authors.initials: N
authors.lastname: Hardy
authors.affiliation: From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Mihalek
authors.affiliation: From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Lingala
authors.affiliation: From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.
authors.forename: Yun Ju
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yao
authors.affiliation: From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Jones
authors.affiliation: From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.
authors.forename: Bernadette R
authors.initials: BR
authors.lastname: Gochuico
authors.affiliation: From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.
authors.forename: Theo
authors.initials: T
authors.lastname: Heller
authors.affiliation: From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.
authors.forename: Colin O
authors.initials: CO
authors.lastname: Wu
authors.affiliation: From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.
authors.forename: Rodrigo T
authors.initials: RT
authors.lastname: Calado
authors.affiliation: From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.
authors.forename: Phillip
authors.initials: P
authors.lastname: Scheinberg
authors.affiliation: From the Hematology Branch (D.M.T., B.D., D.L., B.W., C.C., N.H., N.S.Y.), the Cardiopulmonary Branch (A.D.M.), and the Office of Biostatistics Research (C.O.W.), National Heart, Lung, and Blood Institute, the Center for Human Immunology, Autoimmunity, and Inflammation (A.B.), the Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (S.L., Y.J.K., T.H.), Radiology and Imaging Sciences, Clinical Center (J.Y., E.J.), and the Medical Genetics Branch, National Human Genome Research Institute (B.R.G.), National Institutes of Health, Bethesda, MD; and the Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto (R.T.C.), and Clinical Hematology, Antônio Ermírio de Moraes Cancer Center, Hospital São José and Beneficência Portuguesa (P.S.), São Paulo.
authors.forename: Neal S
authors.initials: NS
authors.lastname: Young
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D001855:Bone Marrow Diseases / Q000188:drug therapy*; D003613:Danazol / Q000627:therapeutic use*; D004965:Estrogen Antagonists / Q000627:therapeutic use*; D005260:Female; D006200:Hair Color / Q000235:genetics; D006801:Humans; D008103:Liver Cirrhosis / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D011658:Pulmonary Fibrosis / Q000188:drug therapy*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000187:drug effects* / Q000648:ultrastructure; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D004965:Estrogen Antagonists; D019098:Telomerase; D003613:Danazol