The Impact of Mutation of Myelodysplasia-Related Genes in De Novo Acute Myeloid Leukemia Carrying NPM1 Mutation †

SIMPLE SUMMARY: NPM1-mutated acute myeloid leukemia (AML) is one of the most common subtypes of AML in patients with a normal karyotype. In the recently introduced International Consensus Classification, detection of gene mutations typically associated with myelodysplastic syndrome (MDS) is considered an adverse biomarker in AML patients. However, the impact of these gene mutations occurring in the setting of AML with NPM1 mutation and without FLT3-ITD mutation, a favorable subtype, is unclear. Furthermore, correlation between minimal measurable disease (MMD) with survival in the context of these co-mutations also remains unclear. This study aims to address these issues. We found that patients with or without MDS-related gene mutations treated intensively had a similar MMD rate; however, the former group had a higher relapse rate and shorter progression-free survival (PFS). ABSTRACT: Background: The impact of gene mutations typically associated with myelodysplastic syndrome (MDS) in acute myeloid leukemia (AML) with NPM1 mutation is unclear. Methods: Using a cohort of 107 patients with NPM1-mutated AML treated with risk-adapted therapy, we compared survival outcomes of patients without MDS-related gene mutations (group A) with those carrying concurrent FLT3-ITD (group B) or with MDS-related gene mutations (group C). Minimal measurable disease (MMD) status assessed by multiparameter flow cytometry (MFC), polymerase chain reaction (PCR), and/or next-generation sequencing (NGS) were reviewed. Results: Among the 69 patients treated intensively, group C showed significantly inferior progression-free survival (PFS, p < 0.0001) but not overall survival (OS, p = 0.055) compared to group A. Though groups A and C had a similar MMD rate, group C patients had a higher relapse rate (p = 0.016). Relapse correlated with MMD status at the end of cycle 2 induction (p = 0.023). Survival of group C patients was similar to that of group B. Conclusion: MDS-related gene mutations are associated with an inferior survival in NPM1-mutated AML.