# Prognostic impact of myelodysplasia-related gene mutations in FLT3-ITD-mutated acute myeloid leukemia

## TL;DR

Myelodysplasia-related gene mutations in FLT3-ITD-mutated AML have a prognostic impact that depends on whether NPM1 is also mutated.

## Contribution

This study identifies that the prognostic value of MRG mutations in FLT3-ITD AML is influenced by NPM1 co-mutation status.

## Key findings

- MRG mutations are not independently associated with survival in FLT3-ITD-mutated AML overall.
- In FLT3-ITD/NPM1 wildtype AML, MRG mutations predict shorter relapse-free and overall survival.
- The prognostic relevance of MRG mutations mirrors findings in AML without FLT3-ITD mutations.

## Abstract

The inclusion of nine myelodysplasia-related gene (MRG) mutations (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) as adverse risk factors in the ELN risk classification has reshaped classification in acute myeloid leukemia (AML). AML with FLT3-ITD mutations and co-occurring MRG alterations is now classified to the ELN adverse risk group although supporting evidence remains limited. Among 4,078 patients with AML with available molecular information included in the HARMONY platform, 862 harbored FLT3-ITD mutations and underwent intensive chemotherapy. Of these, 171 (20%) exhibited co-occurring MRG mutations at diagnosis. In this cohort, MRGs were not independently associated with relapse-free survival (RFS) or overall survival (OS). In the FLT3-ITD/NPM1 co-mutated subgroup, MRG mutations were rare (9%) and showed no prognostic impact. Conversely, in FLT3-ITD/NPM1 wildtype AML, MRG mutations were predictive of shorter RFS (HR 1.37, 95%CI 1.01 – 1.88, p = 0.046) and OS (HR 1.34, 95%CI 1.02–1.74, p = 0.032) in multivariable analysis with survival times comparable to the ELN adverse risk category. The allelic ratio of FLT3-ITD did not further stratify OS and RFS in this subgroup. These findings suggest that the prognostic relevance of MRG mutations in FLT3-ITD AML is modulated by NPM1 co-mutational status and mirror findings in AML lacking FLT3-ITD.