Objective: To evaluate the gene mutation profile and prognostic significance of adult cytogenetically normal acute myeloid leukemia (CN-AML) with CEBPA-bZIP mutation.
Methods: Targeted sequencing was implemented on the diagnostic bone marrow DNA samples of 141 adult CN-AML subjects with CEBPA-bZIP mutation. The nomogram model for leukemia-free survival (LFS) rate was generated by combining genetic abnormalities and clinical data. Risk stratification was conducted based on prognostic variables and the effect of risk-adjusted consolidation therapy was investigated by Kaplan-Meier method.
Results: Four variables were finally included in our nomogram model after multivariate Cox analysis, and an equation for risk score calculation was obtained, risk score=1.300 2×white blood cell (WBC) (≥18.77×109/L)+1.406 5×CSF3R mutation positive+2.648 9× KMT2A mutation positive+1.012 8×DNA methylation-related genes mutation positive. According to the nomogram model, patients were further divided into low-risk group (score=0, n=46) and high-risk group (score>0, n=95). Prognostic analysis showed that the 5-year LFS rate, 5-year overall survival (OS) rate, and 5-year cumulative incidence of relapse (CIR) of patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the high-risk group were 93.5%, 97.1%, and 3.5%, while those in patients who received maintenance chemotherapy were 32.9%, 70.5%, and 63.4%, respectively. The differences were statistically significant (all P < 0.05). Allo-HSCT could significantly improve the prognosis of patients in high-risk group. However, no corresponding benefit was observed in the low-risk group.
Conclusion: Adult CN-AML with CEBPA-bZIP mutation has a complex co-mutation pattern. The nomogram model based on mutations of CFS3R, KMT2A and DNA methylation-related genes together with WBC count can further divide this subset of patients into a relatively low-risk group and a relatively high-risk group. For individuals in the high-risk group, allo-HSCT is proposed as post-remission therapy. The above data will benefit the prognosis estimation and treatment decision for adult CN-AML with CEBPA-bZIP mutation.
题目: 基于多基因测序研究伴 CEBPA-bZIP突变的成人正常核型急性髓系白血病的基因突变谱及危险分层.
目的: 探讨伴 CEBPA-bZIP突变的成人正常核型急性髓系白血病（CN-AML）患者的基因突变谱及预后意义。.
方法: 对141例伴 CEBPA-bZIP突变的成人CN-AML初诊骨髓DNA样本进行靶区测序，结合突变信息及临床数据构建基于无白血病生存率的Nomogram模型。根据预后因素进行危险分层，采用Kaplan-Meier法探讨风险调整的缓解后治疗的获益程度。.
结果: 经多因素Cox分析后4个因素被纳入本研究的Nomogram模型，由此得到一个风险评分计算的方程：危险分数=1.300 2×WBC(≥18.77×109/L)+1.406 5×CSF3R 突变阳性+2.648 9× KMT2A 突变阳性+ 1.012 8×DNA甲基化相关基因突变阳性。根据该模型进一步将患者分为低风险组46例（分数=0）和高风险组95例 （分数>0），预后分析结果表明，高风险组中接受异基因造血干细胞移植的患者5年无白血病生存率、5年总体生存率和5年累积复发率分别93.5%、97.1%和3.5%，接受维持化疗的患者分别为32.9%、70.5%和63.4%，其差异均有统计学意义（均P < 0.05），异基因造血干细胞移植可显著改善患者的预后，而在低风险组中并未观察到类似的获益。.
结论: 伴 CEBPA-bZIP突变的成人CN-AML具有复杂的共突变模式，基于CFS3R、KMT2A 和DNA甲基化相关基因的突变情况联合白细胞水平构建的Nomogram模型可将该组患者进一步细分为相对低风险组和相对高风险组；对于高风险组患者，推荐异基因造血干细胞移植作为其缓解后的治疗方案。以上数据将有助于伴 CEBPA-bZIP突变的成人CN-AML的预后评估及治疗决策。.
Keywords:
next-generation sequencing; acute myeloid leukemia; normal karyotype;