S130: NPM1 MUTATED AML: IMPACT OF CO-MUTATIONAL PATTERNS - RESULTS OF THE EUROPEAN HARMONY ALLIANCE

Background: Acute myeloid leukemia (AML) is a heterogeneous disease in terms of clinical features, outcomes and genetics. While mutations of NPM1 are usually considered as a favorable prognostic marker, the vast majority of the patients carry several co-mutations that might influence the prognosis. Therefore, a better understanding of the NPM1^mut AML mutational landscape is warranted. The large cohort of AML patients collected within the European HARMONY Alliance provides an excellent basis for this purpose.

Aims: To identify clinically significant co-mutational patterns in NPM1^mut AML in order to establish a revised risk stratification model.

Methods: From the HARMONY Alliance AML database, a total of 1001 NPM1^mut intensively treated patients were selected. Clinically significant co-mutations were evaluated using graphical patterns created with the Gephi tool and confirmed by detailed survival analysis using Kaplan-Meier and Cox regression models. Finally, a novel multi-state risk stratification model for NPM1^mut AML was established.

Results: The study population of 1001 NPM1^mut AML patients included 57% females and median age was 53 years. Regarding ELN2017 classification, 68% of patients were classified into the favorable, 29% intermediate and 3% adverse risk groups. The most frequent co-mutations were DNMT3A (54%), followed by FLT3-ITD (38%). In total, 24% of patients presented with a high allelic mutant-to-wildtype ratio ≥0.5 (FLT3-ITD^high) while 14% had low allelic ratio <0.5 (FLT3-ITD^low). Other frequent co-mutations were NRAS (21%), TET2 (20%) and PTPN11 (15%).

The triple mutation pattern of NPM1^mut + FLT3-ITD^high + DNMT3A^mut identified a subgroup with adverse prognosis (2-year OS of 25%), similar to NPM1^mut + TP53^mut. The combination of FLT3-ITD^low + DNMT3A^mut or FLT3-ITD^high + DNMT3A^wt was associated with intermediate prognosis (2-year OS of 45% and 53% respectively). Notably, mutations of NRAS, KRAS, PTPN11 or RAD21 were identified to be associated with better OS. However, in the context of NPM1^mut + DNMT3A^mut these mutations did not affect the prognosis when a FLT3-ITD was present. This information is summarized in a 3-category risk classification model (Figure 1).

The revised NPM1^mut favorable group presented with a 2-year OS of 73%, while for intermediate and adverse groups the OS was 54% and 27% respectively (p<0.001). Regarding relapse free survival (RFS), the median was not reached in the favorable group, while it was 23 months for intermediate and 6 months for adverse group (p<0.001). It should be noted that 171 patients in the NPM1^mut intermediate group would be considered as favorable according to the ELN2017 criteria, as well as 162 patients in the NPM1^mut adverse group were previously classified as intermediate risk. Therefore, our model was able to reclassify 33% of NPM1^mut AML patients in comparison to ELN2017 criteria.

Multivariate analysis of OS in NPM1^mut AML identified the following independent prognostic factors: NPM1^mut model (taking favorable group as reference, HR 1.6 for intermediate and HR 2.7 for adverse group, p<0.001); secondary or therapy-related AML (HR 1.8, p<0.001), WBC at diagnosis >100x10³/μL (HR 1.5, p<0.001) and age >60 years (HR 1.4, p<0.001).

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Summary/Conclusion: Analysis of large NPM1^mut AML cohorts allows the discovery of co-mutation patterns associated with prognostic outcome. In accordance, we propose a new genetic stratification model for NPM1^mut AML that identifies 3 groups with different OS and RFS. This model improves ELN2017 criteria as it is able to correctly reclassify 33% of NPM1^mut AML patients.