Impact of myelodysplasia‐related and additional gene mutations in intensively treated patients with NPM1‐mutated AML

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ABSTRACT This study aimed to evaluate the impact of the myelodysplasia‐related gene (MRG) as well as additional gene mutations on outcomes in intensively treated patients with NPM1‐mutated (NPM1mut) AML. Targeted DNA sequencing of 263 genes was performed in 568 NPM1mut AML patients (median age: 59 years) entered into the prospective AMLSG 09‐09 treatment trial. Most commonly co‐mutated genes were DNMT3A (49.8%), FLT3‐TKD (25.9%), PTPN11 (24.8%), NRAS (22.7%), TET2 (21.7%), IDH2 (21.3%), IDH1 (18%), and FLT3‐ITD (17.3%). MRG mutations were identified in 18.1% of cases (18–60 years: 9.8%; >60 years: 28.7%). When focusing on the 470 patients with 2022 ELN favorable‐risk NPM1mut AML, multivariable analysis for event‐free survival (EFS) identified age (p < 0.001), DNMT3AR882 (p < 0.001), IDH1 (p = 0.007), and MRG mutations (p = 0.03) as unfavorable factors, cohesin gene co‐mutations (p = 0.001) and treatment with gemtuzumab ozogamicin (p = 0.007) as favorable factors. Restricting the analysis to a subset of CR/CRi patients with available data on NPM1mut measurable residual disease (MRD) status in blood post cycle 2 in the model, MRG mutations lost their significant effect, whereas DNMT3AR882, MYC, and cohesin gene mutations retained the adverse and favorable effects. For OS, age (p < 0.001), DNMT3AR882 (p = 0.042), IDH1 (p = 0.045), and KRAS (0.003) mutations were unfavorable factors, sole favorable factor was IDH2 co‐mutation (p = 0.037). In 2022 ELN favorable‐risk NPM1mut AML, MRG mutations are associated with inferior EFS; however, this effect is no longer present when considering NPM1mut MRD status post cycle 2; DNMT3AR882 and MYC mutations remained adverse, and cohesin gene mutations favorable prognostic factors independent of the NPM1mut MRD status.

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