CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome

Author:

Taube Franziska1,Georgi Julia Annabell1,Kramer Michael1,Stasik Sebastian1ORCID,Middeke Jan Moritz1,Röllig Christoph1ORCID,Krug Utz2,Krämer Alwin3,Scholl Sebastian4,Hochhaus Andreas4,Brümmendorf Tim H.5ORCID,Naumann Ralph6,Petzold Andreas7,Mulet-Lazaro Roger8ORCID,Valk Peter J. M.8,Steffen Björn9,Einsele Hermann10,Schaich Markus11,Burchert Andreas12ORCID,Neubauer Andreas12ORCID,Schäfer-Eckart Kerstin13,Schliemann Christoph14,Krause Stefan W.15ORCID,Hänel Mathias16,Noppeney Richard17,Kaiser Ulrich18,Baldus Claudia D.19,Kaufmann Martin20,Herold Sylvia21,Stölzel Friedrich1,Sockel Katja1,von Bonin Malte1,Müller-Tidow Carsten3,Platzbecker Uwe22ORCID,Berdel Wolfgang E.14ORCID,Serve Hubert9ORCID,Ehninger Gerhard23,Bornhäuser Martin124ORCID,Schetelig Johannes125ORCID,Thiede Christian126ORCID,

Affiliation:

1. Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus, Dresden, Germany;

2. Medizinische Klinik III, Klinikum Leverkusen, Leverkusen, Germany;

3. Universität Heidelberg, Medizinische Klinik und Poliklinik, Abteilung Innere Medizin V, Heidelberg, Germany;

4. Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany;

5. Medizinische Klinik IV, Uniklinik Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen, Aachen, Germany;

6. Medizinische Klinik III, St Marien-Krankenhaus Siegen, Siegen, Germany;

7. DRESDEN-Concept Genome Center, Center for Molecular and Cellular Bioengineering, Technische Universität (TU) Dresden, Dresden, Germany;

8. Department of Hematology, Erasmus Medical Center (MC) Cancer Institute, Rotterdam, The Netherlands;

9. Medizinische Klinik 2, Hämatologie/Onkologie, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany;

10. Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany;

11. Klinik für Hämatologie, Onkologie und Palliativmedizin, Rems-Murr-Klinikum Winnenden, Winnenden, Germany;

12. Klinik für Innere Medizin, Schwerpunkt Hämatologie, Onkologie und Immunologie, Philipps Universität Marburg, Marburg, Germany;

13. Klinikum Nürnberg, Paracelsus Medizinische Privatuniversität, Medizinische Klinik 5, Nürnberg, Germany;

14. Medizinische Klinik A, Universitätsklinikum Münster, Münster, Germany;

15. Medizinische Klinik 5, Universitätsklinikum Erlangen, Erlangen, Germany;

16. Klinik für Innere Medizin III, Klinikum Chemnitz, Chemnitz, Germany;

17. Klinik für Hämatologie, Universitätsklinikum Essen, Essen, Germany;

18. Medizinische Klinik II, St Bernward Krankenhaus, Hildesheim, Germany;

19. Klinik für Innere Medizin II, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany;

20. Abteilung für Hämatologie, Onkologie und Palliativmedizin, Robert-Bosch-Krankenhaus, Stuttgart, Germany;

21. Institut für Pathologie; Universitätsklinikum Carl Gustav Carus, Dresden, Germany;

22. Klinik und Poliklinik für Hämatologie, Zelltherapie und Hämostaseologie, Universitätsklinikum Leipzig, Leipzig, Germany;

23. GEMoaB Monoclonals GmbH, Dresden, Germany;

24. National Center for Tumor Diseases NCT, Dresden, Germany;

25. DKMS Clinical Trials Unit, Dresden, Germany; and

26. AgenDix GmbH, Dresden, Germany

Abstract

Abstract Biallelic mutations of the CEBPA gene (CEBPAbi) define a distinct entity associated with favorable prognosis; however, the role of monoallelic mutations (CEBPAsm) is poorly understood. We retrospectively analyzed 4708 adults with acute myeloid leukemia (AML) who had been recruited into the Study Alliance Leukemia trials, to investigate the prognostic impact of CEBPAsm. CEBPA mutations were identified in 240 patients (5.1%): 131 CEBPAbi and 109 CEBPAsm (60 affecting the N-terminal transactivation domains [CEBPAsmTAD] and 49 the C-terminal DNA-binding or basic leucine zipper region [CEBPAsmbZIP]). Interestingly, patients carrying CEBPAbi or CEBPAsmbZIP shared several clinical factors: they were significantly younger (median, 46 and 50 years, respectively) and had higher white blood cell (WBC) counts at diagnosis (median, 23.7 × 109/L and 35.7 × 109/L) than patients with CEBPAsmTAD (median age, 63 years, median WBC 13.1 × 109/L; P < .001). Co-mutations were similar in both groups: GATA2 mutations (35.1% CEBPAbi; 36.7% CEBPAsmbZIP vs 6.7% CEBPAsmTAD; P < .001) or NPM1 mutations (3.1% CEBPAbi; 8.2% CEBPAsmbZIP vs 38.3% CEBPAsmTAD; P < .001). CEBPAbi and CEBPAsmbZIP, but not CEBPAsmTAD were associated with significantly improved overall (OS; median 103 and 63 vs 13 months) and event-free survival (EFS; median, 20.7 and 17.1 months vs 5.7 months), in univariate and multivariable analyses. Additional analyses revealed that the clinical and molecular features as well as the favorable survival were confined to patients with in-frame mutations in bZIP (CEBPAbZIP-inf). When patients were classified according to CEBPAbZIP-inf and CEBPAother (including CEBPAsmTAD and non-CEBPAbZIP-inf), only patients bearing CEBPAbZIP-inf showed superior complete remission rates and the longest median OS and EFS, arguing for a previously undefined prognostic role of this type of mutation.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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