November-December 2016, Volume 13, Issue 6
If We Could Turn Back Time: Danazol Preserves Telomere Length in Patients With Telomere Dysfunction
Published on: October 28, 2016
Townsley DM, Dumitriu B, Liu D, et al. Danazol treatment for telomere diseases. N Engl J Med. 2016;374:1922-1931.
Telomeres are specialized DNA-protein structures that protect chromosome ends from degradation and fusion. They are composed of long stretches of repetitive TTAGGG sequences that are bound by a group of proteins called shelterin. As the DNA replication machinery cannot fully copy to the ends of chromosomes, telomeres shorten progressively with each cell division, eventually triggering cell senescence. Telomerase is a ribonucleoprotein enzyme complex capable of de novo synthesis of telomeric repeats, and in association with a number of other protein functions, helps maintain the length of telomeres in some proliferating cell types including hematopoietic stem cells. However, this repair process is incomplete, and telomere length attrition occurs normally with each cell division.1 Telomere diseases, or short telomere syndromes, are a group of Mendelian disorders that share an underlying molecular finding of short telomere lengths. In effect, these patients age prematurely and clinically manifest with variable complications that can include bone marrow failure (purportedly due to stem cell exhaustion), and lung and liver disease. Premature telomere shortening is also observed in presumed, immunologically mediated, acquired aplastic anemia, potentially as a consequence of increased cell turnover and proliferation to compensate for hematopoietic stem cell depletion.
Androgens have been used to improve cytopenias in inherited and acquired bone marrow failure for decades.2 Recent case reports and retrospective case series confirm hematologic response to androgen therapy in patients with marrow failure due to short telomere disorders.3,4 Androgens upregulate telomerase reverse transcriptase expression (TERT) and telomerase activity,5,6 which may account for a component of this hematologic response.
Dr. Danielle M. Townsley and colleagues recently reported the results of the first prospective phase I/II study to evaluate the use of androgen therapy in short telomere disorders.7 All patients had age-adjusted telomere lengths at or below the first percentile, and/or a mutation in a telomere maintenance or repair gene; they also had at least a single-lineage cytopenia or pulmonary fibrosis, or both. Telomere length was measured in peripheral blood leukocytes by real-time quantitative polymerase chain reaction (qPCR), and in a subset of patients, also by fluorescent in situ hybridization (flow-FISH). Patients received 800 mg of oral danazol daily in divided doses. Twenty-seven patients were enrolled on the study. Twenty-four received treatment, and 12 of the 27 were evaluable at the 24-month endpoint. Of the 27 patients enrolled (10 withdrew from the study for various reasons, and five subjects had not reached the primary endpoint of two years owing to the study being halted early in April 2015), 10 had mutations in TERT, seven had mutations in TERC, three had mutations in DKC1, and one had a mutation in RTEL1. Among the 12 evaluable patients at 24 months, 10 carried pathogenic mutations in a telomere maintenance or repair gene.
The study was closed early due to the unanticipated high level of efficacy in achieving the primary efficacy endpoint of a reduction in telomere length attrition to 96 or fewer base pairs per year at 24 months follow-up; this was observed in 11 of 12 evaluable patients. This endpoint can be considered in the context of what the authors estimate as an expected rate of telomere loss of 60 base pairs per year in normal patients versus 120 base pairs per year in patients with telomerase gene mutations. Telomere elongation was noted at all time points during danazol treatment. The mean increase in telomere length compared with baseline was 386 base pairs (95% CI, 178-593) after 24 months of treatment. Patients also demonstrated increases in their peripheral blood counts. Specifically, a hematologic response (≥ 1.5 g/dL hemoglobin increase, new transfusion independence, > 50% reduction in transfusions, ≥ 20 × 109/L platelet count increase, or ≥ 0.5 × 109/L neutrophil count increase) was observed in 79, 81, 78, and 83 percent of patients after two, six, 12, and 24 months of treatment, respectively.
The study was not designed to assess the progression of pulmonary and liver fibrosis in treated patients. Limited data were reported for these outcomes, and thus no definitive conclusions surrounding efficacy can be drawn. Pulmonary fibrosis scores based on computed tomography scan findings during two years of treatment in all but one patient were reportedly stable, although further details were not provided. Pretreatment pulmonary function data were available in seven patients. By paired t-test analysis, these patients showed a significant 10 percent reduction in the diffusing capacity of the lungs for carbon monoxide (DLCO; adjusted for hemoglobin) between at least six months prior to study entry and study entry, whereas during danazol administration there was no significant decrease in DLCO.
The most common suspected treatment-related adverse events were elevations in liver enzyme levels in 11 (41%) of 27 patients, muscle spasm or cramps in nine (33%) of 27 patients, edema in seven (26%) of 27 patients, and high cholesterol in seven (26%) of 27 patients (all < grade 3 in severity).
The results of this prospective study confirm earlier studies dating to the mid-20th century that demonstrate that clinically relevant improvement in blood counts can be achieved through treatment with androgens in patients with short telomere syndromes. However, the observation of telomere elongation in circulating leukocytes in treated patients stands in contrast with an earlier retrospective study of androgen therapy in a small number of patients with short telomere disorders,3 potentially reflecting methodological differences between the studies. To this point, the authors reported marked differences in telomere length measurement on the same sample by qPCR and flow-FISH. In addition, the hematologic response and increase in telomere length in danazol treated patients was not permanent — both declined in the eight patients observed for six and 12 months after discontinuing danazol therapy, suggesting that ongoing therapy is required to maintain response.
Further studies with longer follow-up and more clinical assessments are needed to determine the efficacy of androgens to treat and/or prevent other disease manifestations associated with short telomere syndromes (e.g., pulmonary and liver dysfunction). These studies are also needed to address whether there are any long-term consequences of androgen therapy in these populations of patients who may be particularly susceptible to the adverse effects of androgens given their specific underlying genetic disorder. For example, the high incidence of liver function test abnormalities in this study was not observed in Fanconi anemia patients whose marrow failure was treated with androgen therapy,3 potentially reflecting a particular vulnerability to this toxicity among patients with short telomere syndromes; liver dysfunction is a known complication in short telomere syndromes.
Armanios M, Blackburn EH. The telomere syndromes. Nat Rev Genet. 2012;13:693-704.
Shahidi NT, Diamond LK. Testosterone-induced remission in aplastic anemia. AMA J Dis Child. 1959;98:293-302.
Islam A, Rafiq S, Kirwan M, et al. Haematological recovery in dyskeratosis congenita patients treated with danazol. Br J Haematol. 2013;162:854-856.
Khincha PP, Wentzensen IM, Giri N, et al. Response to androgen therapy in patients with dyskeratosis congenita. Br J Haematol. 2014;165:349-357.
Calado RT, Yewdell WT, Wilkerson KL, et al. Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells. Blood. 2009;114:2236-2243.
Bär C, Huber N, Beier F, et al. Therapeutic effect of androgen therapy in a mouse model of aplastic anemia produced by short telomeres. Haematologica. 2015;100:1267-1274.
Townsley DM, Dumitriu B, Young NS. Danazol treatment for telomere diseases. N Engl J Med. 2016;375:1095-1096.
Conflict of Interests
Dr. Keel indicated no relevant conflicts of interest.
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