Influence of genetic co‐mutation on chemotherapeutic outcome in NPM1‐mutated and FLT3‐ITD wild‐type AML patients

Abstract Background Nucleophosmin 1 ( NPM1 ) gene‐mutated acute myeloid leukemia ( NPM1 mut AML) is classified as a subtype with a favorable prognosis. However, some patients fail to achieve a complete remission or relapse after intensified chemotherapy. Genetic abnormalities in concomitant mutations contribute to heterogeneous prognosis of NPM1 mut AML patients. Methods In this study, 91 NPM1 ‐mutated and FLT3‐ITD wild‐type ( NPM1 mut /FLT3‐ITD wt ) AML patients with intermediate‐risk karyotype were enrolled to analyze the impact of common genetic co‐mutations on chemotherapeutic outcome. Results Our data revealed that TET1/2 (52/91, 57.1%) was the most prevalent co‐mutation in NPM1 mut AML patients, followed by IDH1/2 (36/91, 39.6%), DNMT3A (35/91, 38.5%), myelodysplastic syndrome related genes (MDS‐related genes) ( ASXL1 , BCOR , EZH2 , RUNX1 , SF3B1 , SRSF2 , STAG2 , U2AF1 and ZRSR2 genes) (35/91, 38.5%), FLT3‐TKD (27/91, 29.7%) and GATA2 (13/91, 14.3%) mutations. Patients with TET1/2 mut exhibited significantly worse relapse‐free survival (RFS) (median, 28.7 vs. not reached (NR) months; p = 0.0382) compared to patients with TET1/2 wt , while no significant difference was observed in overall survival (OS) (median, NR vs. NR; p = 0.3035). GATA2 mut subtype was associated with inferior OS (median, 28 vs. NR months; p < 0.0010) and RFS (median, 24 vs. NR months; p = 0.0224) compared to GATA2 wt . By multivariate analysis, GATA2 mut and MDS‐related genes mut were independently associated with worse survival. Conclusion Mutations in TET1/2 , GATA2 and MDS‐related genes were found to significantly influence the chemotherapeutic outcome of patients with NPM1 mut AML. The findings of our study have significant clinical implications for identifying patients who have an adverse response to frontline chemotherapy and provide a novel reference for further prognostic stratification of NPM1 mut /FLT3‐ITD wt AML patients.