Prognostic impact of CEBPA mutational subgroups in adult AML.
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Georgi Julia-Annabell, Stasik Sebastian, Kramer Michael, Meggendorfer Manja, Röllig Christoph, Haferlach Torsten, Valk Peter, Linch David, Herold Tobias, Duployez Nicolas, Taube Franziska, Middeke Jan Moritz, Platzbecker Uwe, Serve Hubert, Baldus Claudia D, Muller-Tidow Carsten, Haferlach Claudia, Koch Sarah, Berdel Wolfgang E, Woermann Bernhard J, Krug Utz, Braess Jan, Hiddemann Wolfgang, Spiekermann Karsten, Boertjes Emma L, Hills Robert K, Burnett Alan, Ehninger Gerhard, Metzeler Klaus, Rothenberg-Thurley Maja, Dufour Annika, Dombret Hervé, Pautas Cecile, Preudhomme Claude, Fenwarth Laurene, Bornhäuser Martin, Gale Rosemary, Thiede Christian
Аннотация
Despite recent refinements in the diagnostic and prognostic assessment of CEBPA mutations in AML, several questions remain open, i.e. implications of different types of basic region leucin zipper (bZIP) mutations, the role of co-mutations and the allelic state. Using pooled primary data analysis on 1010 CEBPA-mutant adult AML patients, a comparison was performed taking into account the type of mutation (bZIP: either typical in-frame insertion/deletion (InDel) mutations (bZIPInDel), frameshift InDel or nonsense mutations inducing translational stop (bZIPSTOP) or single base-pair missense alterations (bZIPms), and transcription activation domain (TAD) mutations) and the allelic state (single (smCEBPA) vs. double mutant (dmCEBPA)). Only bZIPInDel patients had significantly higher rates of complete remission and longer relapse free and overall survival (OS) compared with all other CEBPA-mutant subgroups. Moreover, co-mutations in bZIPInDel patients (e.g. GATA2, FLT3, WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS, whereas in non-bZIPInDel patients, grouping according to ELN2022 recommendations added significant prognostic information. In conclusion, these results demonstrate bZIPInDel mutations to be the major independent determinant of outcome in CEBPA-mutant AML, thereby refining current classifications according to WHO (including all dmCEBPA and smCEBPA bZIP) as well as ELN2022 and ICC recommendations (including CEBPA bZIPms).