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The hypomorphic TERT A1062T variant is associated with increased treatment-related toxicity in acute myeloid leukemia

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Abstract

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.

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Acknowledgements

This study was supported by grant nos. DJCLS H 06/04v and H 09/01f from the Deutsche-José-Carreras Leukämie-Stiftung e.V. and grant nos. 01GI0378 (Kompetenznetz “Akute und chronische Leukämien”) and 01KG0605 from the Bundesministerium für Bildung und Forschung and the Dieter-Schlag-Stiftung. The authors would like to thank Elvira Lux, Sylvia Horter, Diana Dudacy, Monika Bischoff, and Patricia Hanel for their excellent technical support.

Author contribution

A.B., J.K., and K.W. designed the research. A.B., J.K., F.D., F.T., M.H., and K.W. performed research and analyzed data. G.G. and B.S. performed the cytogenetic studies. O.O., M.L., M.W., L.K., G.S., A.R., W.F., H.K., W.B., G.H., and A.G. contributed patient samples and clinical data. A.B., J.K., A.G., and K.W. wrote the paper. All authors read and agreed to the final version of the manuscript.

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Authors and Affiliations

  1. Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany

    Anna Both, Jürgen Krauter, Frederik Damm, Felicitas Thol, Michael Heuser, Gerhard Heil, Arnold Ganser & Katharina Wagner

  2. Institute of Medical Microbiology, Virology and Hygiene, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Anna Both

  3. Department Hematology and Oncology, Klinikum Braunschweig, Braunschweig, Germany

    Jürgen Krauter

  4. Department Hematology, Oncology, and Tumor Immunology, Charité—University Medicine, Berlin, Germany

    Frederik Damm

  5. Institute of Molecular and Cellular Pathology, Hannover Medical School, Hannover, Germany

    Gudrun Göhring & Brigitte Schlegelberger

  6. Department Internal Medicine II, University of Frankfurt, Frankfurt, Germany

    Oliver Ottmann

  7. Department Internal Medicine I, University of Freiburg, Freiburg, Germany

    Michael Lübbert

  8. Department Hematology/Oncology, Ev. Krankenhaus Essen-Werden, Essen, Germany

    Mohammed Wattad

  9. Department Internal Medicine II, University of Tübingen, Tübingen, Germany

    Lothar Kanz

  10. Department Internal Medicine II, Klinikum Augsburg, Augsburg, Germany

    Günter Schlimok

  11. Department Internal Medicine I, HELIOS-Klinikum Wuppertal, Wuppertal, Germany

    Aruna Raghavachar

  12. Department of Internal Medicine II, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    Walter Fiedler

  13. Department Hematology/Oncology, Hospital Siloah, Hannover, Germany

    Hartmut Kirchner

  14. Department Hematology/Oncology, Schwarzwald-Baar Klinikum, Villingen-Schwenningen, Germany

    Wolfram Brugger

  15. Department of Internal Medicine V, Klinikum Lüdenscheid, Lüdenscheid, Germany

    Gerhard Heil

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  1. Anna Both
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  2. Jürgen Krauter
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Correspondence to Katharina Wagner.

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Katharina Wagner and Arnold Ganser contributed equally to this work.

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Both, A., Krauter, J., Damm, F. et al. The hypomorphic TERT A1062T variant is associated with increased treatment-related toxicity in acute myeloid leukemia. Ann Hematol 96, 895–904 (2017). https://doi.org/10.1007/s00277-017-2967-0

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