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Monoallelic CEBPA mutations in normal karyotype acute myeloid leukemia: independent favorable prognostic factor within NPM1 mutated patients

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Abstract

We and others have shown that cytogenetically normal (CN)-AML patients with biallelic CEBPA gene mutations (biCEBPA) represent a molecularly distinct group with a favorable prognosis. Patients carrying a monoallelic CEBPA mutation (moCEBPA), however, show no different outcome compared to patients with wildtype CEBPA, and these mutations are frequently associated with mutated NPM1 or FLT3-ITD. So far, no molecular or clinical hallmark has been identified to prognostically distinguish moCEBPA patients from patients with wildtype CEBPA. Therefore, we used the data of 663 CN-AML patients treated within the AMLCG 1999 trial to explore the prognostic value of moCEBPA in the context of concomitant clinical and molecular markers (mutated NPM1, FLT3-ITD). Multiple Cox regression in 515 patients adjusting for all available potential confounders revealed that the NPM1 mutation modified the prognostic value of moCEBPA with respect to overall survival (OS, p = 0.017) and event-free survival (EFS, p = 0.011). MoCEBPA was beneficial in NPM1 mutated patients: adjusted OS–hazard ratio (HR) 0.09, 95% confidence interval (CI) 0.01–0.63, p = 0.016; EFS–HR (95% CI) 0.16 (0.04–0.65), p = 0.010. In contrast, moCEBPA had no prognostic impact in patients with wildtype NPM1: OS–HR (95% CI) 1.08 (0.59–1.97), p = 0.804; EFS–HR (95% CI) 1.12 (0.64–1.96), p = 0.682. We found no prognostic effect modification for moCEBPA by FLT3-ITD. The presence of a moCEBPA mutation was shown to be associated with prolonged survival in NPM1 mutated CN-AML patients. Confirmation of these results in larger studies will clarify whether an additional moCEBPA mutation influences the risk stratification of patients with an NPM1 mutated/FLT3-ITD positive genotype.

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Acknowledgements

The authors would like to thank Evelyn Zellmeier and Gudrun Mellert for excellent technical assistance.

Conflict of interest

The authors indicate no potential conflict of interest.

Author information

Authors and Affiliations

  1. Laboratory for Leukemia Diagnostics, Department of Medicine III, University of Munich-Grosshadern, Marchioninistr.15, 81377, Munich, Germany

    Annika Dufour, Friederike Schneider, Tobias Benthaus, Bianka Ksienzyk, Stephanie Schneider, Purvi M. Kakadia, Marion Subklewe, Wolfgang Hiddemann, Stefan K. Bohlander & Karsten Spiekermann

  2. Clinical Cooperative Group “Leukemia”, Helmholtz Center Munich for Environmental Health, Munich, Germany

    Wolfgang Hiddemann, Stefan K. Bohlander & Karsten Spiekermann

  3. Institutes for Medical Informatics, Biometry and Epidemiology, University of Munich-Grosshadern, Munich, Germany

    Eva Hoster

  4. Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany

    Maria-Cristina Sauerland

  5. Department of Medicine A, Hematology and Oncology, University of Münster, Münster, Germany

    Wolfgang E. Berdel & Thomas Büchner

  6. Department of Hematology and Oncology, Municipal Hospital, Braunschweig, Germany

    Bernhard Wörmann

  7. Department of Oncology and Hematology, Hospital “Barmherzige Brüder”, Regensburg, Germany

    Jan Braess

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  1. Annika Dufour
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  2. Friederike Schneider
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for the AML CG study group

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Correspondence to Annika Dufour.

Additional information

Annika Dufour and Friederike Schneider contributed equally to this manuscript.

Appendix

Appendix

Selection

Patients with a complete molecular status of CEBPA, NPM1 and FLT3-ITD were selected out of a total of 802 patients. The selected patients (n = 663) had a significantly higher percentage of bone marrow blasts and leucocytes compared to non-selected patients (n = 139). Other clinical parameters and the frequency of molecular markers were similar in selected versus unselected patients. OS, EFS and RFS did not significantly differ between both tested and untested groups (p = 0.342, p = 0.219, p = 0.600, respectively) (data not shown).

List of participating centers within the AML CG 1999 study

Study coordinators: T. Büchner, W. Hiddemann, W.E. Berdel, B. Wörmann

Statisticians: A. Heinecke, M.C. Sauerland, F. Schneider, E. Hoster, M. Unterhalt

Cytogenetic and molecular genetic review: C. Haferlach, S. Schnittger, P.M. Kakadia, SK. Bohlander, A. Dufour, K. Spiekermann

Cytology review: T. Haferlach, J. Braess, K Spiekermann

Contributing centers and investigators:

University Hospital, Aachen (T.H. Ittel)

Municipal Hospital Augsburg (C. Schmid, D. Oruzio)

Municipal Hospital, Bad Saarow (H. Fu)

Vinzenz-Pallotti-Hospital, Bergisch-Gladbach (S. Korsten, D. Hennesser)

Municipal Hospital Neukölln, Berlin (A. Mayr, A. Grüneisen)

University Hospital Charité Mitte, Berlin (K. Possinger, J. Blau)

University Hospital Charité, Berlin (R. Arnold, B. Dörken, G. Maschmeyer)

St Hedwig Hospital, Berlin (C. Boewer, M. Derwahl, H.J. Englisch)

University Hospital Benjamin Franklin, Berlin (M. Notter, E. Thiel)

University Hospital Robert Rössle, Berlin (W.D. Ludwig, D. Schöndube)

Vivantes Klinikum, Berlin (E. Späth-Schwalbe, S. Hesse)

Vivantes Klinikum Berlin Neukölln (A. Grüneisen)

Ev. Hospital Spandau, Berlin (J. Potenberg)

Municipal Hospital, Bielefeld (A.J. Weh, A. Zumsprekel)

Knappschaft Hospital, Bochum (C. Teschendorf, M. Stechstor)

Knappschaft Hospital, Bottrop (G. Trenn)

Municipal Medical Center, Braunschweig (B. Wörmann)

Municipal Hospital, St Jürgenstrasse, Bremen (B. Hertenstein, H. Thomssen, A. Peyn)

University Hospital, Cologne (M. Hallek, P. Staib, KA Kreuzer)

Municipal Hospital, Dortmund (M. Heike, A. Niederste-Hollenberg)

St Johannes Hospital, Dortmund (H. Pielken, H. Hindahl)

University Hospital, Düsseldorf (A. Wehmeyer, A. Heyll)

St Johannes Hospital, Duisburg (C. Aul, C. Giagounidis)

Johanniter Hospital Rheinhausen, Duisburg (W. Lange, S.E. Kuhlemann)

Municipal Hospital, Düren (M. Flasshove, J. Karow)

St Antonius Hospital, Eschweiler (R. Fuchs, F. Schlegel)

University Hospital, Frankfurt/Oder (M. Kiehl)

St Joseph-Hospital, Gelsenkirchen (G. Meckenstock, G. Giagounidis)

University Hospital, Göttingen (D. Haase, L. Trümper, F. Griesinger)

Municipal Hospital, Gütersloh (C. Gropp, R. Depenbusch)

Municipal Hospital, Hagen (H. Eimermacher, Lindemann)

Municipal Hospital Martha-Maria, Halle (W. Schütte, U. Haak)

General Hospital Altona, Hamburg (D. Braumann)

Protestant Hospital, Hamm (L. Balleisen)

District Hospital, Herford (J.G. Lange, U. Schmitz-Hubner)

Municipal Hospital, Idar-Oberstein (A. Fauser)

Municipal Hospital, Kassel (M. Wolf, B. Ritter)

Municipal Hospital, Kaiserslautern (H. Link)

University Hospital I, Kiel (U.R. Fölsch)

University Hospital II, Kiel (M. Kneba)

Municipal Hospital, Köln (A. Dormann)

Municipal Hospital, Krefeld (Th. Frieling, M. Planker)

Hospital Lippe-Lemgo, Lemgo (F. Hartmann, H. Middeke, C.Gründgens,C.Constantin)

Trinity Hospital, Lippstadt (K.-A. Jost)

University Hospital, Lübeck (Th. Wagner)

Municipal Hospital South Lübeck, Lübeck (S. Fetscher, J. Schmielau)

Municipal Hospital, Ludwigshafen (M. Uppenkamp, M. Hoffmann)

University Hospital, Mannheim (R. Hehlmann, E. Lengfelder)

St Walburga Hospital, Meschede (M. Schwonzen, H. Spangenberg)

Maria-Hilf-Hospital, Mönchengladbach (D. Graeven, D. Kohl, T. Heuer)

University Hospital Muenster (WE. Berdel)

University Hospital Innenstadt, Munich (B. Emmerich, R. Dengler, B. Schlag)

University Hospital Grosshadern, Munich (W. Hiddemann, J. Braess, K. Spiekermann, S.K. Bohlander, C. Buske)

Municipal Hospital Neuperlach, Munich (K. Nibler, D. Fleckenstein)

Municipal Hospital Harlaching, Munich (M. Hentrich, X. Schiel)

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Dufour, A., Schneider, F., Hoster, E. et al. Monoallelic CEBPA mutations in normal karyotype acute myeloid leukemia: independent favorable prognostic factor within NPM1 mutated patients. Ann Hematol 91, 1051–1063 (2012). https://doi.org/10.1007/s00277-012-1423-4

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  • DOI: https://doi.org/10.1007/s00277-012-1423-4

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