Specific Molecular Mutations with Prognostic Relevance in AML with Normal Karyotype Are Also Associated with Outcome in AML with Aberrant Karyotype: A Study on 1981 Cases,

The karyotype and molecular mutations are well established prognostic parameters in AML. However, the impact on outcome of molecular mutations has been evaluated mainly in the subset of AML with normal karyotype (NK). The aim of this study was 1. to determine the frequency of NPM1 mutations (NPM1 mut), partial tandem duplications within the MLL gene (MLL -PTD), length mutations within the FLT3 gene (FLT3 -ITD) and CEPBA mutations (CEPBA mut) in distinct cytogenetic subgroups and 2. to evaluate the prognostic impact of these mutations in relation to chromosome abnormalities. Patients and Methods: 1981 patients with AML and evaluable cytogenetics were included. Mutation data was available in the majority of cases: NPM1: 1646, CEPBA: 1324, FLT3 -ITD: 1726 and MLL -PTD: 1656. Based on the karyotype the cohort was subdivided according to revised MRC criteria (Grimwade et al. Blood 2010) and in addition into distinct cytogenetic subgroups. Results: According to cytogenetics 170 cases were assigned to the favorable MRC class (MRCF), 1414 to the intermediate MRC (MRCI) and 397 to the unfavorable MRC subset (MRCU). The frequency of NPM1 mut, CEPBA mut, MLL -PTD and FLT3 -ITD differed significantly between MRC classes and distinct cytogenetic groups.

In the MRCI subset we evaluated overall survival (OS) between patients with normal or aberrant karyotype (AK) within the respective mutation groups. Within NPM1 mut, CEPBA mut, MLL -PTD+ and FLT3 -ITD+ patients no significant differences in OS were observed between patients with NK or AK. When separating CEPBA mut into biallelic (n=52) and monoallelic cases (n=40) also no difference in OS was observed between pats with NK or AK. Next we tested the prognostic impact of the respective molecular mutations within MRCI including 966 cases with NK and 448 cases with AK. OS was significantly longer in patients with NPM1 mut or CEPBA mut (median OS (mOS) 49.6 months (mo) vs 18.6 mo, p=0.003; not reached (n.r.) vs 21.1 mo, p=0.016) and significantly worse for patients with MLL -PTD or FLT3 -ITD (mOS 10.8 vs 23.0 mo, p=0.039; 13.8 vs 24.9 mo, p=0.003). Analyzing biallelic and monoallelic CEPA mut separately revealed that only biallelic CEPBA mut was associated with a longer OS (p=0.006). Restricting the analysis to MRCI patients with aberrant karyotype revealed a longer OS for patients with NPM1 mut/FLT3 -ITD-, and a shorter OS for patients with FLT3 -ITD (mOS n.r. vs 18.0 mo, p=0.033; 5.7 vs 23.0 mo, p=0.015). A trend towards better OS was observed for biallelic CEBPA mut. Conclusions: 1. The frequency of molecular mutations varies significantly between distinct cytogenetic subsets. They are particularly common in AK within MRCI. NPM1 mut, CEBPA mut and MLL -PTD were not observed in MRCF, in AML with 11q23/MLL -rearrangements, or in 3q26/EVI1 -rearrangements. Their frequency was below 5% in AML with complex karyotype. 2. The outcome of NPM1 mut, CEPBA mut and MLL -PTD+ cases was not different in AML with normal or aberrant karyotype within MRCI. 3. This data suggest to extend mutation screening for NPM1 mut, CEPBA mut, MLL -PTD and FLT3 -ITD to all AML with intermediate risk cytogenetics, as they are significantly associated with outcome not only in AML with normal karyotype but also in AML with cytogenetic abnormalities assigned to MRCI. This consequently will lead to better characterization of a reasonable number of cases from MRCI with important implication on treatment.

Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Alpermann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.