The hypomorphic TERT A1062T variant is associated with increased treatment-related toxicity in acute myeloid leukemia.
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.
Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.|Institute of Medical Microbiology, Virology and Hygiene, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Anna
A
Both
Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.|Department Hematology and Oncology, Klinikum Braunschweig, Braunschweig, Germany.
Jürgen
J
Krauter
Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.|Department Hematology, Oncology, and Tumor Immunology, Charité-University Medicine, Berlin, Germany.
Frederik
F
Damm
Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.
Felicitas
F
Thol
Institute of Molecular and Cellular Pathology, Hannover Medical School, Hannover, Germany.
Gudrun
G
Göhring
Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.
Michael
M
Heuser
Department Internal Medicine II, University of Frankfurt, Frankfurt, Germany.
Oliver
O
Ottmann
Department Internal Medicine I, University of Freiburg, Freiburg, Germany.
Michael
M
Lübbert
Department Hematology/Oncology, Ev. Krankenhaus Essen-Werden, Essen, Germany.
Mohammed
M
Wattad
Department Internal Medicine II, University of Tübingen, Tübingen, Germany.
Lothar
L
Kanz
Department Internal Medicine II, Klinikum Augsburg, Augsburg, Germany.
Günter
G
Schlimok
Department Internal Medicine I, HELIOS-Klinikum Wuppertal, Wuppertal, Germany.
Aruna
A
Raghavachar
Department of Internal Medicine II, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Walter
W
Fiedler
Department Hematology/Oncology, Hospital Siloah, Hannover, Germany.
Hartmut
H
Kirchner
Department Hematology/Oncology, Schwarzwald-Baar Klinikum, Villingen-Schwenningen, Germany.
Wolfram
W
Brugger
Institute of Molecular and Cellular Pathology, Hannover Medical School, Hannover, Germany.
Brigitte
B
Schlegelberger
Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.|Department of Internal Medicine V, Klinikum Lüdenscheid, Lüdenscheid, Germany.
Gerhard
G
Heil
Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany.
Arnold
A
Ganser
Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Str. 1, 30625, Hannover, Germany. wagner.katharina@mh-hannover.de.
Katharina
http://orcid.org/0000-0002-4057-2666
K
Wagner
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy; D003967:Diarrhea / Q000209:etiology; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D052016:Mucositis / Q000209:etiology; D015337:Multicenter Studies as Topic; D015999:Multivariate Analysis; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011446:Prospective Studies; D033581:Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D016019:Survival Analysis; D019098:Telomerase / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult
D019098:Telomerase
Acute myeloid leukemia; Gene mutations; Karyotype; Prognostic factors; Telomerase