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PROGNOSTIC IMPACT OF SOMATIC CEBPA BZIP DOMAIN MUTATIONS IN ACUTE MYELOID LEUKEMIA
Author(s): ,
Frank G. Ruecker
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Allemagne;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Deutschland;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germania;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Alemania;Department of Int
,
Andrea Corbacioglu
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Allemagne;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Deutschland;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germania;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Alemania;Department of Int
,
Frauke Theis
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Allemagne;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Deutschland;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germania;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Alemania;Department of Int
,
Maximilian Christopeit
Affiliations:
Medical Clinic, Department of Hematology, Oncology, Clinical Immunology and Rheumatology,University Hospital Tübingen,Tübingen,Allemagne;Medical Clinic, Department of Hematology, Oncology, Clinical Immunology and Rheumatology,University Hospital Tübingen,Tübingen,Deutschland;Medical Clinic, Department of Hematology, Oncology, Clinical Immunology and Rheumatology,University Hospital Tübingen,Tübing
,
Ulrich Germing
Affiliations:
Department of Hematology, Oncology and Clinical Immunology,Heinrich Heine University,Düsseldorf,Allemagne;Department of Hematology, Oncology and Clinical Immunology,Heinrich Heine University,Düsseldorf,Deutschland;Department of Hematology, Oncology and Clinical Immunology,Heinrich Heine University,Düsseldorf,Germania;Department of Hematology, Oncology and Clinical Immunology,Heinrich Heine Univers
,
Gerald Wulf
Affiliations:
University Medical Center Göttingen,Göttingen,Allemagne;University Medical Center Göttingen,Göttingen,Deutschland;University Medical Center Göttingen,Göttingen,Germania;University Medical Center Göttingen,Göttingen,Germany;University Medical Center Göttingen,Göttingen,Alemania;University Medical Center Göttingen,Göttingen,Duitsland;University Medical Center Göttingen,Göttingen,Alemanha;University
,
Maisun Abu Samra
Affiliations:
Department of Internal Medicine IV,University Hospital of Gießen,Gießen,Allemagne;Department of Internal Medicine IV,University Hospital of Gießen,Gießen,Deutschland;Department of Internal Medicine IV,University Hospital of Gießen,Gießen,Germania;Department of Internal Medicine IV,University Hospital of Gießen,Gießen,Germany;Department of Internal Medicine IV,University Hospital of Gießen,Gießen,A
,
Lino Teichmann
Affiliations:
Department of Medicine and Polyclinic III,Bonn University Hospital,Bonn,Allemagne;Department of Medicine and Polyclinic III,Bonn University Hospital,Bonn,Deutschland;Department of Medicine and Polyclinic III,Bonn University Hospital,Bonn,Germania;Department of Medicine and Polyclinic III,Bonn University Hospital,Bonn,Germany;Department of Medicine and Polyclinic III,Bonn University Hospital,Bonn,A
,
Michael Lübbert
Affiliations:
Department of Hematology, Oncology and Stem Cell Transplantation,University of Freiburg Medical Center,Freiburg,Allemagne;Department of Hematology, Oncology and Stem Cell Transplantation,University of Freiburg Medical Center,Freiburg,Deutschland;Department of Hematology, Oncology and Stem Cell Transplantation,University of Freiburg Medical Center,Freiburg,Germania;Department of Hematology, Oncolog
,
Michael W.M. Kühn
Affiliations:
Department of Hematology, Medical Oncology and Pneumology,University Medical Center Mainz,Mainz,Allemagne;Department of Hematology, Medical Oncology and Pneumology,University Medical Center Mainz,Mainz,Deutschland;Department of Hematology, Medical Oncology and Pneumology,University Medical Center Mainz,Mainz,Germania;Department of Hematology, Medical Oncology and Pneumology,University Medical Cent
,
Martin Bentz
Affiliations:
Department of Internal Medicine III,Hospital of Karlsruhe,Karlsruhe,Allemagne;Department of Internal Medicine III,Hospital of Karlsruhe,Karlsruhe,Deutschland;Department of Internal Medicine III,Hospital of Karlsruhe,Karlsruhe,Germania;Department of Internal Medicine III,Hospital of Karlsruhe,Karlsruhe,Germany;Department of Internal Medicine III,Hospital of Karlsruhe,Karlsruhe,Alemania;Department o
,
Jörg Westermann
Affiliations:
Department of Hematology, Oncology and Tumor Immunology,Charité University Medicine,Berlin,Allemagne;Department of Hematology, Oncology and Tumor Immunology,Charité University Medicine,Berlin,Deutschland;Department of Hematology, Oncology and Tumor Immunology,Charité University Medicine,Berlin,Germania;Department of Hematology, Oncology and Tumor Immunology,Charité University Medicine,Berlin,Germa
,
Lars Bullinger
Affiliations:
Department of Hematology, Oncology and Tumor Immunology,Charité University Medicine,Berlin,Allemagne;Department of Hematology, Oncology and Tumor Immunology,Charité University Medicine,Berlin,Deutschland;Department of Hematology, Oncology and Tumor Immunology,Charité University Medicine,Berlin,Germania;Department of Hematology, Oncology and Tumor Immunology,Charité University Medicine,Berlin,Germa
,
Verena I. Gaidzik
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Allemagne;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Deutschland;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germania;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Alemania;Department of Int
,
Ekaterina Jahn
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Allemagne;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Deutschland;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germania;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Alemania;Department of Int
,
Maximilian Gröger
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Allemagne;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Deutschland;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germania;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Alemania;Department of Int
,
Silke Kapp-Schwoerer
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Allemagne;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Deutschland;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germania;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Alemania;Department of Int
,
Daniela Weber
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Allemagne;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Deutschland;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germania;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Alemania;Department of Int
,
Felicitas Thol
Affiliations:
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,Hannover Medical School, Hannover,Hannover,Allemagne;Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,Hannover Medical School, Hannover,Hannover,Deutschland;Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,Hannover Medical School, Hannover,Hannover,Germania;Departmen
,
Michael Heuser
Affiliations:
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,Hannover Medical School, Hannover,Hannover,Allemagne;Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,Hannover Medical School, Hannover,Hannover,Deutschland;Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,Hannover Medical School, Hannover,Hannover,Germania;Departmen
,
Arnold Ganser
Affiliations:
Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,Hannover Medical School, Hannover,Hannover,Allemagne;Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,Hannover Medical School, Hannover,Hannover,Deutschland;Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation,Hannover Medical School, Hannover,Hannover,Germania;Departmen
,
Hartmut Döhner
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Allemagne;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Deutschland;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germania;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Alemania;Department of Int
Konstanze Döhner
Affiliations:
Department of Internal Medicine III,University Hospital of Ulm,Ulm,Allemagne;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Deutschland;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germania;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Germany;Department of Internal Medicine III,University Hospital of Ulm,Ulm,Alemania;Department of Int
(Abstract release date: 05/12/22) EHA Library. G. Ruecker F. 06/10/22; 357311; P448
Dr. Frank G. Ruecker
Dr. Frank G. Ruecker
Contributions
Abstract
Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P448

Type: Poster presentation

Session title: Acute myeloid leukemia - Biology & Translational Research

Background

Mutations of CEBPA (CEBPAmut) are present in ~5-10% of newly diagnosed adult acute myeloid leukemia (AML), and approximately half of the patients (pts) exhibit biallelic mutations (CEBPAbi). CEBPAbi defines a distinct entity within the 2016 WHO classification and is categorized as favorable in the 2017 risk stratification by the European LeukemiaNet. CEBPAmut can be divided into basic leucine zipper domain (bZIP) or transcription activation domains (TAD) mutations, respectively. Recent studies have demonstrated CEBPAbZIP mutations, in particular in-frame mutations (CEBPAbZIP-inf), to be associated with favorable outcome, regardless of mono- or biallelic status.

Aims
To evaluate the prognostic impact of CEBPAbZIP, in particular CEBPAbZIP-inf mutations in AML.

Methods

Investigating a cohort of 454 intensively treated CEBPA mutated AML pts entered into the AMLSG BiO Registry study (NCT01252485).

Results

Of the 454 pts, 223 had CEBPAbi and 231 monoallelic CEBPA mutations (CEBPAsm) affecting bZIP in 78 pts or TAD in 153 pts. Genotypes differed significantly with regard to clinical and genetic features: CEBPAbi pts were younger than CEBPAsmbZIP and CEBPAsmTAD (median age in yrs: 52 vs 59 vs 60; P<.001), had a higher rate of de novo AML (97% vs 81% vs 84%; P<.001), lower platelet counts  (median G/l 36 vs 57 vs 52; P<.001), higher peripheral blood (PB) blast counts (median 71% vs 60% vs 44%; P<.001), and showed an inverse correlation with FLT3 internal tandem duplication (FLT3-ITD) and NPM1 mutation (NPM1mut) (6% vs 21% vs 35% and 0% vs 26% vs 50%; P<.001 each).

Outcome analysis revealed a significant improved overall (OS) and event-free survival (EFS) for CEBPAbi with no difference between CEBPAsmbZIP and CEBPAsmTAD (5-year OS: 62% vs 42% vs 51%; P<.001, 5-year EFS: 47% vs 27% vs 43%; P<.022). Subgroup specific analysis within CEBPAsmbZIP revealed an improved outcome for CEBPAbZIP-inf pts (n=46) (5-year OS: 52% vs 29%; P=.001, and 5-year EFS: 34% vs 18%; P=.018).

To further address the impact of CEBPAbZIP-inf, pts were categorized as CEBPAbZIP-inf (n=250), irrespective of the allelic status, vs all others (CEBPAother) (n=204). CEBPAbZIP-inf pts were younger (median age in yrs: 52 vs 62; P<.001), had a higher rate of de novo AML (97% vs 81%; P<.001), lower platelet counts (median G/l 36 vs 53; P<.001), higher white blood cell (WBC) (median G/l 25.4 vs 16.1; P=.029), and higher PB blast counts (median 72% vs 46%; P<.001); FLT3-ITD and NPM1mut were less common in CEBPAbZIP-inf pts (9% vs 30% and 3% vs 44%; P<.001 each). CEBPAbZIP-inf exhibited a significant improved OS (5-year OS: 60% vs 48%; P<.001) and EFS (5-year EFS: 47% vs 37%; P=.007); in multivariate Cox models for OS and EFS, including allogeneic hematopoietic cell transplantation (HCT) in first complete remission as time-dependent covariate, age (HR: 1.50; P<.001), WBC (HR: 1.40; P=.018), and adverse cytogenetics (HR: 2.33; P=.010) were unfavorable factors for OS, whereas NPM1mut (HR: 0.63; P=.040), HCT (HR: 0.46; P=.010), and CEBPAbZIP-inf (HR: 0.59; P=.007) revealed as favorable. For EFS, age (HR: 1.19; P=.002), WBC (HR: 1.30; P=.028), and FLT3-ITD (HR: 1.83; P=.003) were unfavorable, whereas NPM1mut (HR: 0.65; P=.028) and HCT (HR: 0.33; P<.001) were favorable.

Conclusion

In this cohort of 454 CEBPA mutated adult AML pts, CEBPAbZIP-inf was associated with specific clinical and genetic characteristics. Furthermore, CEBPAbZIP-inf pts had a significantly superior outcome irrespective of the allelic status. This study confirms recent findings suggesting a prognostic role of this mutation type.

 

FGR and AC contributed equally

Keyword(s): Acute myeloid leukemia, C/EBP, Outcome, Prognostic factor

Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P448

Type: Poster presentation

Session title: Acute myeloid leukemia - Biology & Translational Research

Background

Mutations of CEBPA (CEBPAmut) are present in ~5-10% of newly diagnosed adult acute myeloid leukemia (AML), and approximately half of the patients (pts) exhibit biallelic mutations (CEBPAbi). CEBPAbi defines a distinct entity within the 2016 WHO classification and is categorized as favorable in the 2017 risk stratification by the European LeukemiaNet. CEBPAmut can be divided into basic leucine zipper domain (bZIP) or transcription activation domains (TAD) mutations, respectively. Recent studies have demonstrated CEBPAbZIP mutations, in particular in-frame mutations (CEBPAbZIP-inf), to be associated with favorable outcome, regardless of mono- or biallelic status.

Aims
To evaluate the prognostic impact of CEBPAbZIP, in particular CEBPAbZIP-inf mutations in AML.

Methods

Investigating a cohort of 454 intensively treated CEBPA mutated AML pts entered into the AMLSG BiO Registry study (NCT01252485).

Results

Of the 454 pts, 223 had CEBPAbi and 231 monoallelic CEBPA mutations (CEBPAsm) affecting bZIP in 78 pts or TAD in 153 pts. Genotypes differed significantly with regard to clinical and genetic features: CEBPAbi pts were younger than CEBPAsmbZIP and CEBPAsmTAD (median age in yrs: 52 vs 59 vs 60; P<.001), had a higher rate of de novo AML (97% vs 81% vs 84%; P<.001), lower platelet counts  (median G/l 36 vs 57 vs 52; P<.001), higher peripheral blood (PB) blast counts (median 71% vs 60% vs 44%; P<.001), and showed an inverse correlation with FLT3 internal tandem duplication (FLT3-ITD) and NPM1 mutation (NPM1mut) (6% vs 21% vs 35% and 0% vs 26% vs 50%; P<.001 each).

Outcome analysis revealed a significant improved overall (OS) and event-free survival (EFS) for CEBPAbi with no difference between CEBPAsmbZIP and CEBPAsmTAD (5-year OS: 62% vs 42% vs 51%; P<.001, 5-year EFS: 47% vs 27% vs 43%; P<.022). Subgroup specific analysis within CEBPAsmbZIP revealed an improved outcome for CEBPAbZIP-inf pts (n=46) (5-year OS: 52% vs 29%; P=.001, and 5-year EFS: 34% vs 18%; P=.018).

To further address the impact of CEBPAbZIP-inf, pts were categorized as CEBPAbZIP-inf (n=250), irrespective of the allelic status, vs all others (CEBPAother) (n=204). CEBPAbZIP-inf pts were younger (median age in yrs: 52 vs 62; P<.001), had a higher rate of de novo AML (97% vs 81%; P<.001), lower platelet counts (median G/l 36 vs 53; P<.001), higher white blood cell (WBC) (median G/l 25.4 vs 16.1; P=.029), and higher PB blast counts (median 72% vs 46%; P<.001); FLT3-ITD and NPM1mut were less common in CEBPAbZIP-inf pts (9% vs 30% and 3% vs 44%; P<.001 each). CEBPAbZIP-inf exhibited a significant improved OS (5-year OS: 60% vs 48%; P<.001) and EFS (5-year EFS: 47% vs 37%; P=.007); in multivariate Cox models for OS and EFS, including allogeneic hematopoietic cell transplantation (HCT) in first complete remission as time-dependent covariate, age (HR: 1.50; P<.001), WBC (HR: 1.40; P=.018), and adverse cytogenetics (HR: 2.33; P=.010) were unfavorable factors for OS, whereas NPM1mut (HR: 0.63; P=.040), HCT (HR: 0.46; P=.010), and CEBPAbZIP-inf (HR: 0.59; P=.007) revealed as favorable. For EFS, age (HR: 1.19; P=.002), WBC (HR: 1.30; P=.028), and FLT3-ITD (HR: 1.83; P=.003) were unfavorable, whereas NPM1mut (HR: 0.65; P=.028) and HCT (HR: 0.33; P<.001) were favorable.

Conclusion

In this cohort of 454 CEBPA mutated adult AML pts, CEBPAbZIP-inf was associated with specific clinical and genetic characteristics. Furthermore, CEBPAbZIP-inf pts had a significantly superior outcome irrespective of the allelic status. This study confirms recent findings suggesting a prognostic role of this mutation type.

 

FGR and AC contributed equally

Keyword(s): Acute myeloid leukemia, C/EBP, Outcome, Prognostic factor

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