TY - JOUR
T1 - CEBPA mutations in 4708 patients with acute myeloid leukemia
T2 - differential impact of bZIP and TAD mutations on outcome
AU - Taube, Franziska
AU - Georgi, Julia Annabell
AU - for the Study Alliance Leukemia (SAL)
AU - Kramer, Michael
AU - Stasik, Sebastian
AU - Middeke, Jan Moritz
AU - Röllig, Christoph
AU - Krug, Utz
AU - Krämer, Alwin
AU - Scholl, Sebastian
AU - Hochhaus, Andreas
AU - Brümmendorf, Tim H.
AU - Naumann, Ralph
AU - Petzold, Andreas
AU - Mulet-Lazaro, Roger
AU - Valk, Peter J.M.
AU - Steffen, Björn
AU - Einsele, Hermann
AU - Schaich, Markus
AU - Burchert, Andreas
AU - Neubauer, Andreas
AU - Schäfer-Eckart, Kerstin
AU - Schliemann, Christoph
AU - Krause, Stefan W.
AU - Hänel, Mathias
AU - Noppeney, Richard
AU - Kaiser, Ulrich
AU - Baldus, Claudia D.
AU - Kaufmann, Martin
AU - Herold, Sylvia
AU - Stölzel, Friedrich
AU - Sockel, Katja
AU - von Bonin, Malte
AU - Müller-Tidow, Carsten
AU - Platzbecker, Uwe
AU - Berdel, Wolfgang E.
AU - Serve, Hubert
AU - Ehninger, Gerhard
AU - Bornhäuser, Martin
AU - Schetelig, Johannes
AU - Thiede, Christian
N1 - Funding Information: This study was supported in part by grants from the Federal Ministry of Education and Research 01GS0872 (C.T.).
Publisher Copyright: © 2022 American Society of Hematology
PY - 2022/1/6
Y1 - 2022/1/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85122257189&partnerID=8YFLogxK
U2 - 10.1182/blood.2020009680
DO - 10.1182/blood.2020009680
M3 - Article
C2 - 34320176
AN - SCOPUS:85122257189
SN - 0006-4971
VL - 139
SP - 87
EP - 103
JO - Blood
JF - Blood
IS - 1
ER -