P404: PROGNOSTIC IMPACT OF CEBPA-MUTATIONAL SUBGROUPS IN ADULT AML – RESULTS OF A LARGE METAANALYSIS IN MORE THAN 1000 CEBPA-MUTANT PATIENTS

Abstract

Background:CEBPA double mutations (dm) are included in the current AML WHO-classification as a favorable-risk independent entity, but recent data suggest this might be limited to those approximately 90% of patients (pts) with in-frame mutations in the basic leucine zipper (bZIP) domain, and that bZIP single allele mutations (sm) might also be favorable. Aims: To investigate further, we performed a meta-analysis involving detailed sequencing data from 1010 CEBPA-mutant pts. Methods: Primary pt data was obtained from six study groups: 98 from ALFA, 104 AMLCG, 191 HOVON, 200 MLL, 240 SAL, 177 UK(MRC/NCRI). All pts were treated with curative intention using age and risk-adapted strategies. CEBPA sequences were classified by localization (bZIP vs transactivation domains [TAD] 1 + 2), allelic status (sm vs dm), and type of mutation (in-frame [if] or frameshift [fs] insertions/deletions [InDel] or missense [ms]). Data for GATA2, WT1, FLT3, NPM1 co-mutations were available for most pts. Results: Overall, 546 (54%) had dm and 464 (46%) sm CEBPA (289 TAD1/2; 175 bZIP). To study the impact of the different mutations, we generated 8 groups: dmCEBPA pts with 1/more bZIPInDel-if (Gr1), bZIPInDel-fs (Gr2) or bZIPms (Gr3) mutation or 2 TAD mutations (Gr4), as well as the corresponding sm groups (Gr5-8). Of note, dm/sm pts with bZIPInDel-if mutations (Gr1 + 5) were significantly younger and predominantly had de novo AML (Tab.1) whereas Gr2-4 and Gr6-8 pts were older with higher incidence of sAML. GATA2 and WT1 mutations were more common in Gr1 + 5 pts; mutations in NPM1, spliceosome (SF3B1, U2AF1, SRSF2 and ZRSR2) and DNA-methylation (ASXL1, DNMT3A, TET2, IDH1/2) associated genes were confined to the other groups. Pts in Gr1 showed the highest rate of CR1 (Tab.1), better RFS and OS (Fig. 1), whereas dmCEBPA pts in Gr2-4 did significantly worse. Outcome of Gr5 pts was less favorable than Gr1, but still better than for the other subgroups (Gr2-4 and 6-8). In a combined analysis of Gr2-4 and Gr6-8, prognostic factors according to ELN2017 identified three clearly separated subgroups, with the favorable subgroup predominantly associated with mut. NPM1; Fig. 1B). The prognostic impact of Gr1 for CR, OS and RFS was confirmed in multivariable analyses taking into account the individual study groups. - dmCEB P AbZIPInDel-fs dmCEBPAbZIPInDel-if n=425Gr1 dmCEBPAbZIPInDel-fs n=26Gr2 dmCEBPAXbZIPmsnn=35Gr3 dmCEBPANNTADNNNn=60Gr4 smCEBPAbZIPInDel-if n=66Gr5 smCEBPAbZIPInDel-fs n=55Gr6 smCEBPAXbZIPmsnn=54Gr7 smCEBPANNTADN.Nn=289Gr8 p.value BPANDN289 Median age, years 42 60 57 64 47 59 52 58 <.001 AML type, % <.001 de novo 98 81 94 88 92 96 90 90 sAML/tAML 2 20 6 13 8 4 10 10 FLT3-ITD mut ,.% 11 8 9 7 8 29 9 32 <.001 NPM1 mut , % 1 12 9 13 3 29 15 44 <.001 GATA2 mut , % 39 8 12 9 33 10 12 4 <.001 WT1 mut , % 20 4 15 3 13 4 6 8 <.001 Spliceosome mut., % 2 29 6 40 5 39 25 25 <.001 Methylation mut., % 25 83 69 71 35 74 46 63 <.001 CR1, % 94.3 73.9 78.1 73.1 92.1 77.6 79.6 73.5 <.001 Median RFS, months 152 9 15 16 64 9 16 22 <.001 Median OS, months 215 16 40 22 126 70 30 41 <.001 Image:Summary/Conclusion: The results of this large metaanalysis confirm our previous results that only dmCEBPA with InDel-if mutations show a specific biology and very favorable prognostic implications, and further supports the notion that the subgroups with other dm pts differ substantially and have a significantly worse outcome. SmCEBPA bZIPInDel-if mutant pts and those with other CEBPA mutations and favorable ELN2017 genotype also show an improved outcome.