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TP53 mutation and survival in aggressive B cell lymphoma
Authors:Thorsten Zenz  Markus Kreuz  Maxi Fuge  Wolfram Klapper  Heike Horn  Annette M. Staiger  Doris Winter  Hanne Helfrich  Jennifer Huellein  Martin‐Leo Hansmann  Harald Stein  Alfred Feller  Peter M?ller  Norbert Schmitz  Lorenz Trümper  Markus Loeffler  Reiner Siebert  Andreas Rosenwald  German Ott  Michael Pfreundschuh  Stephan Stilgenbauer  for the German High‐Grade Non‐Hodgkin Lymphoma Study Group
Affiliation:1. Molecular Therapy in Haematology and Oncology and Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (dkfz), Heidelberg, Germany;2. Dept. of Medicine V, University Hospital Heidelberg, Heidelberg, Germany;3. Dept. of Internal Medicine III, University of Ulm, Ulm, Germany;4. Institute for Medical Informatics, Statistics and Epidemiology, Universit?t Leipzig, Leipzig, Germany;5. Institute of Pathology, Hematopathology Section and Lymph Node Registry, Universit?tsklinikum Schleswig‐Holstein, Campus Kiel, Kiel, Germany;6. Department of Clinical Pathology, Robert‐Bosch‐Krankenhaus, and Dr. Margarete Fischer‐Bosch‐Institute of Clinical Pharmacology, and University of Tübingen, Stuttgart, Germany;7. Dr. Senckenberg Institute of Pathology, Universit?tsklinikum Frankfurt, Frankfurt, Germany;8. Pathodiagnostik Berlin, Berlin, Germany;9. Institute of Pathology, University Hospital Schleswig‐Holstein, Campus Lübeck, and H?matopathologie Lübeck, Germany;10. Institute of Pathology, Universit?tsklinikum Ulm, Ulm, Germany;11. Department of Hematology, Oncology and Pneumonology, University Hospital of Muenster, Muenster, Germany;12. Department of Hematology and Oncology, Georg‐August Universit?t, G?ttingen, Germany;13. Institute of Human Genetics, University of Ulm, Ulm, Germany;14. Institute of Pathology, and Comprehensive Cancer Center Mainfranken (CCC MF), University of Würzburg, Würzburg, Germany;15. Department of Clinical Pathology, Robert‐Bosch‐Krankenhaus, Stuttgart, Germany;16. Internal Medicine I, Saarland University Medical School, Homburg, Germany
Abstract:TP53 is mutated in 20–25% of aggressive B‐cell lymphoma (B‐NHL). To date, no studies have addressed the impact of TP53 mutations in prospective clinical trial cohorts. To evaluate the impact of TP53 mutation to current risk models in aggressive B‐NHL, we investigated TP53 gene mutations within the RICOVER‐60 trial. Of 1,222 elderly patients (aged 61–80 years) enrolled in the study and randomized to six or eight cycles of CHOP‐14 with or without Rituximab (NCT00052936), 265 patients were analyzed for TP53 mutations. TP53 mutations were demonstrated in 63 of 265 patients (23.8%). TP53 mutation was associated with higher LDH (65% vs. 37%; p < 0.001), higher international prognostic index‐Scores (IPI 4/5 27% vs. 12%; p = 0.025) and B‐symptoms (41% vs. 24%; p = 0.011). Patients with TP53 mutation were less likely to obtain a complete remission CR/CRu (CR unconfirmed) 61.9% (mut) vs. 79.7% (wt) (p = 0.007). TP53 mutations were associated with decreased event‐free (EFS), progression‐free (PFS) and overall survival (OS) (median observation time of 40.2 months): the 3 year EFS, PFS and OS were 42% (vs. 60%; p = 0.012), 42% (vs. 67.5%; p < 0.001) and 50% (vs. 76%; p < 0.001) for the TP53 mutation group. In a Cox proportional hazard analysis adjusting for IPI‐factors and treatment arms, TP53 mutation was shown to be an independent predictor of EFS (HR 1.5), PFS (HR 2.0) and OS (HR 2.3; p < 0.001). TP53 mutations are independent predictors of survival in untreated patients with aggressive CD20+ lymphoma. TP53 mutations should be considered for risk models in DLBCL and strategies to improve outcome for patients with mutant TP53 must be developed.
Keywords:DLBCL  R‐CHOP  p53  TP53 mutation
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