Prognostic impact of CEBPA mutational subgroups in adult AML

Abstract

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 (bZIP^InDel), frameshift InDel or nonsense mutations inducing translational stop (bZIP^STOP) or single base-pair missense alterations (bZIP^ms), and transcription activation domain (TAD) mutations) and the allelic state (single (smCEBPA) vs. double mutant (dmCEBPA)). Only bZIP^InDel 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 bZIP^InDel patients (e.g. GATA2, FLT3, WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS, whereas in non-bZIP^InDel patients, grouping according to ELN2022 recommendations added significant prognostic information. In conclusion, these results demonstrate bZIP^InDel 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 bZIP^ms).

Fig. 1. Illustration of type and localization of mutations affecting the bZIP region of the CEBPA gene.

Mutations in the bZIP region (AA272-358) are typically in-frame insertion or deletion mutations (bZIP^InDel), whereas frameshift insertions/deletions or nonsense mutations causing a premature translational termination (bZIP^STOP), and single base-pair missense mutations (bZIP^ms) are less common.

Fig. 2. Schematic illustration of the predominant mutational constellations in the eight different CEBPA-mutant subgroups.

Subgrouping was performed according to different types of mutations, i.e. TAD or bZIP mutations (in-frame insertions/deletions, frameshift insertions/deletions and nonsense mutations, missense mutations) and allelic status (double vs. single mutant).

Fig. 3. Age distribution of the different CEBPA-mutant subgroups.

Regarding the distribution of mutational subgroups within age decades, there is a clear decrease in the frequency of CEBPA bZIP^InDel mutations with increasing age.

Fig. 4. Frequency distribution of additional gene mutations identified in the different CEBPA-mutant subgroups.

Frequencies are shown for genes with a prevalence of at least 10% in the total CEBPA-mutant cohort.

Fig. 5. Impact of different CEBPA-mutant subgroups on outcome.

Kaplan Meyer estimates for RFS and OS in A Gr1-8 and B Gr1 and Gr5 (dmCEBPA bZIP^InDel and smCEBPA bZIP^InDel) vs. Gr2-4 and Gr6-8 (CEBPA^other). HR and p values were calculated by Cox regression analysis.

Fig. 6. Impact of ELN2022 risk factors in CEBPA-mutant subgroups.

Kaplan Meyer estimates for RFS and OS of A CEBPA bZIP^InDel patients with vs. without ELN2022 adverse risk factors and B different ELN2022 risk groups within CEBPA^other patients. HR and p values were calculated by Cox regression analysis.

Fig. 7. Re-grouping of CEBPA-mutant patients according to localization and type of mutation(s).

Illustration of the frequency of different CEBPA mutational subtypes and their allocation to the proposed subgroups CEBPA bZIP^InDel and CEBPA^other.