背景:核蛋白1(NPM1)基因突变的急性髓性白血病(NPM1mutAML)被归类为预后良好的亚型。然而,一些患者在强化化疗后未能完全缓解或复发。伴随突变的遗传异常有助于NPM1mutAML患者的异质性预后。
方法:在本研究中,纳入91例NPM1突变和FLT3-ITD野生型(NPM1mut/FLT3-ITDwt)中等风险核型AML患者,以分析常见遗传共突变对化疗结果的影响。
结果:我们的数据显示TET1/2(52/91,57.1%)是NPM1mutAML患者中最普遍的共突变,其次是IDH1/2(36/91,39.6%),DNMT3A(35/91,38.5%),骨髓增生异常综合征相关基因(MDS相关基因)(ASXL1,BCOR,EZH2、RUNX1、SF3B1、SRSF2、STAG2、U2AF1和ZRSR2基因)(35/91,38.5%),FLT3-TKD(27/91,29.7%)和GATA2(13/91,14.3%)突变。TET1/2mut患者的无复发生存率(RFS)明显较差(中位数,28.7vs.未达到(NR)个月;p=0.0382)与TET1/2wt患者相比,而总生存期(OS)无显著差异(中位数,NRvs.NR;p=0.3035)。GATA2mut亚型与OS差相关(中位数,28vs.NR月;p<0.0010)和RFS(中位数,24vs.NR月;p=0.0224)与GATA2wt相比。通过多变量分析,GATA2mut和MDS相关基因mut与较差的生存率独立相关。
结论:发现TET1/2,GATA2和MDS相关基因的突变显着影响NPM1mutAML患者的化疗结局。我们的研究结果对于识别对一线化疗有不良反应的患者具有重要的临床意义,并为NPM1mut/FLT3-ITDwtAML患者的进一步预后分层提供了新的参考。
BACKGROUND: Nucleophosmin 1 (NPM1) gene-mutated acute myeloid leukemia (NPM1mut 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 NPM1mut AML patients.
METHODS: In this study, 91 NPM1-mutated and FLT3-ITD wild-type (NPM1mut/FLT3-ITDwt) 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 NPM1mut 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 TET1/2mut exhibited significantly worse relapse-free survival (RFS) (median, 28.7 vs. not reached (NR) months; p = 0.0382) compared to patients with TET1/2wt, while no significant difference was observed in overall survival (OS) (median, NR vs. NR; p = 0.3035). GATA2mut 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 GATA2wt. By multivariate analysis, GATA2mut and MDS-related genesmut were independently associated with worse survival.
CONCLUSIONS: Mutations in TET1/2, GATA2 and MDS-related genes were found to significantly influence the chemotherapeutic outcome of patients with NPM1mut 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 NPM1mut/FLT3-ITDwt AML patients.