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. 2023 Feb;102(2):337-347.
doi: 10.1007/s00277-022-05033-0. Epub 2022 Nov 15.

Measurable residual disease detected by flow cytometry independently predicts prognoses of NPM1-mutated acute myeloid leukemia

Yun-Wei Zhang  1 , Long Su #  1 , Ye-Hui Tan  1 , Hai Lin  1 , Xiao-Liang Liu  1 , Qiu-Ju Liu  1 , Jing-Nan Sun  1 , Ming Zhang  1 , Ya-Zhe Du  1 , Fei Song  1 , Wei Han  1 , Su-Jun Gao  2
Affiliations

Measurable residual disease detected by flow cytometry independently predicts prognoses of NPM1-mutated acute myeloid leukemia

Yun-Wei Zhang et al. Ann Hematol. 2023 Feb.

Abstract

Acute myeloid leukemia (AML) with NPM1 mutation is a distinct genetic entity with favorable outcomes. Nevertheless, emerging evidence suggests that NPM1-mutated AML is still a highly heterogeneous disorder. In this study, 266 patients with AML with NPM1 mutations were retrospectively analyzed to evaluate the associations between variant allele frequency (VAF) of NPM1 mutations, co-mutated genes, measurable residual disease (MRD), and patient outcomes. Multiparameter flow cytometry (MFC) and real-time quantitative polymerase chain reaction (RT-PCR) were used for monitoring MRD. Ultimately, 106 patients were included in the long-term follow-up period. Patients with high NPM1 VAF (≥ 42.43%) had poorer 2-year relapse-free survival (RFS) (55.7% vs. 70.2%, P = 0.017) and overall survival (OS) (63.7% vs. 82.0%, P = 0.027) than those with low VAF. DNMT3A mutations negatively influenced the outcomes of patients with NPM1 mutations. Patients with high DNMT3A VAF or NPM1/DNMT3A/FLT3-ITD triple mutations had shorter RFS and significantly lower OS than that in controls. After two cycles of chemotherapy, patients with positive MFC MRD results had lower RFS (MRD+ vs. MRD-:44.9% vs. 67.6%, P = 0.007) and OS (61.5% vs. 76.6%, P = 0.011) than those without positive MFC MRD results. In multivariate analysis, high NPM1 VAF (hazard ratio [HR] = 2.045; P = 0.034) and positive MRD after two cycles of chemotherapy (HR = 3.289; P = 0.003) were independent risk factors for RFS; MRD positivity after two cycles of chemotherapy (HR = 3.293; P = 0.008) independently predicted the OS of the patients. These results indicate that VAF of both NPM1 gene itself or certain co-occurring gene pre-treatment and MRD post-treatment are potential markers for restratifying the prognoses of patients AML having NPM1 mutations.

Keywords: Acute myeloid leukemia; Measurable residual disease; NPM1 mutations; Next-generation sequencing; Prognoses.

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