The hypomorphic TERT A1062T variant is associated with increased treatment-related toxicity in acute myeloid leukemia
Autor: | Aruna Raghavachar, Jürgen Krauter, Walter Fiedler, Michael Heuser, Gerhard Heil, Felicitas Thol, Frederik Damm, Gudrun Göhring, Hartmut Kirchner, Mohammed Wattad, Anna Both, Lothar Kanz, Michael Lübbert, Arnold Ganser, Wolfram Brugger, Günter Schlimok, Brigitte Schlegelberger, Katharina Wagner, Oliver G. Ottmann |
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Rok vydání: | 2017 |
Předmět: |
Adult
Diarrhea Male Mucositis 0301 basic medicine medicine.medical_specialty Adolescent Biology Gene mutation Polymorphism Single Nucleotide Gastroenterology Young Adult 03 medical and health sciences 0302 clinical medicine Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans Multicenter Studies as Topic Point Mutation Prospective Studies Risk factor Adverse effect Telomerase Clinical Trials as Topic Hematology Induction chemotherapy Myeloid leukemia General Medicine Middle Aged Prognosis medicine.disease Combined Modality Therapy Survival Analysis Leukemia Treatment Outcome 030104 developmental biology Leukemia Myeloid 030220 oncology & carcinogenesis Acute Disease Multivariate Analysis Toxicity Immunology Female Stem Cell Transplantation |
Zdroj: | Annals of Hematology. 96:895-904 |
ISSN: | 1432-0584 0939-5555 |
Popis: | Hypomorphic germline variants in TERT, the gene encoding the reverse transcriptase component of the human telomerase complex, occur with a frequency of 3-5% in acute myeloid leukemia. We analyzed the clinical and prognostic impact of the most common TERT A1062T variant in younger patients with acute myeloid leukemia intensively treated within two prospective multicenter trials. Four hundred and twenty patients (age 17-60 years) were analyzed for the TERT A1062T variant by direct sequencing. Fifteen patients (3.6%) carried the TERT A1062T variant. Patients with the TERT A1062T variant had a trend towards less favorable and more intermediate 2/adverse karyotypes/genotypes according to the European Leukemia Net classification. In univariate and multivariate analysis, patients with the TERT A1062T variant had a significantly inferior overall survival compared to wild-type patients (6-year overall survival 20 vs. 41%, p = 0.005). Patients with the TERT A1062T variant showed a high rate of treatment-related mortality: 5/15 (33%) died during induction therapy or in complete remission as compared to 62/405 (15%) of the wild-type patients. In patients with the TERT variant, 14/15 (93%) suffered from non-hematological/non-infectious grade 3/4 adverse events (mostly hepatic and/or mucosal) as compared to 216/405 (53%) wild-type patients (p = 0.006). In multivariate analysis, the TERT A1062T variant was an independent risk factor predicting for adverse events during induction chemotherapy. In conclusion, the TERT A1062T variant is an independent negative prognostic factor in younger patients with acute myeloid leukemia and seems to predispose those patients to treatment-related toxicity. |
Databáze: | OpenAIRE |
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