基于CSF3R突变与治疗后微小残留病对CEBPA双突变急性髓系白血病预后再分层研究

Restratifying the prognosis of acute myeloid leukemia patients with CEBPA double mutations based on CSF3R mutations and measurable residual disease

目的研究CSF3R突变与治疗后微小残留病(MRD)在CEBPA双突变急性髓系白血病(AML)患者中的预后意义。方法回顾性分析2012年1月至2018年9月就诊于吉林大学第一医院血液科的66例具有完整二代基因测序结果且进行了系列MRD监测的AML患者,研究治疗前CSF3R突变和治疗后MRD水平与患者治疗疗效及长期预后的相关性。结果CSF3R突变患者的5年无复发生存(RFS)率和总生存(OS)率分别为15.2%和18.2%,明显低于无CSF3R突变患者的38.7%和60.6%(P值分别为0.006和0.038)。2个疗程化疗后MRD转阴患者的中位RFS与OS时间分别为64个月与未达到,明显长于MRD阳性患者的15个月和48个月(P值分别为0.004和0.050)。Cox风险比例模型分析显示,CSF3R突变(HR=0.317,95%CI 0.129~0.779,P=0.012)、WT1突变(HR=0.304,95%CI 0.115~0.804,P=0.016)、NRAS突变(HR=0.153,95%CI 0.061~0.385,P<0.001)为影响患者RFS的独立不良预后因素,CSF3R突变与MRD阳性趋向为OS的独立预后因素(P值分别为0.071与0.088)。基于CSF3R突变与治疗后MRD将患者分为野生型CSF3R且MRD转阴组、突变型CSF3R或MRD阳性组、突变型CSF3R且MRD阳性组,三组患者RFS(P<0.001)与OS(P=0.006)差异均有统计学意义。结论CSF3R突变与2个疗程化疗后MRD状态均可预测CEBPA双突变AML患者的长期预后,据此可对患者进行预后再分层。

Objective This investigation aims to assess the impact of CSF3R mutations and the presence of measurable residual disease(MRD)on the prognosis of patients with CEBPA double mutations who have acute myeloid leukemia(AML).Methods The prognostic significance of these two factors was examined in the present study,which included 66 patients with complete genetic mutations and sequential MRD information.Results Following the second course of chemotherapy,the MRD status and CSF3R mutations of these patients were linked to their long-term prognosis.CSF3R mutated patients showed inferior relapse-free survival(RFS)(5-year RFS:15.2%vs 38.7%,P=0.006)and overall survival(OS)(5-year OS:18.2%vs 60.6%,P=0.038)compared with those with wild-type CSF3R.After the second course of chemotherapy,patients with negative MRD had an RFS of 64 months and an OS of not reaching,which was significantly longer than that of patients with positive MRD(15 and 48 months,and the P value were 0.004 and 0.050,respectively).CSF3R mutations(HR=0.317,95%CI 0.129-0.779,P=0.012),WT1 mutations(HR=0.304,95%CI 0.115-0.804,P=0.016),and NRAS mutations(HR=0.153,95%CI 0.061-0.385,P<0.001)were all independently associated with a poor prognosis for RFS,and CSF3R mutations and positive MRD tended to be independently associated with a poor prognosis for OS,according to the results of a Cox proportional-hazards model analysis(P values were 0.071 and 0.088,respectively).The patients were divided into three groups based on their CSF3R mutation status and MRD status following treatment:wide-type CSF3R and negative MRD,mutated CSF3R or positive MRD,and mutated CSF3R and positive MRD,which showed significantly different RFS(P<0.001)and OS(P=0.006).Conclusion Both CSF3R mutations and positive MRD were associated with poor outcome in AML patients with CEBPA double mutations.An integrity model based on these two factors may be beneficial for accurately evaluating the prognosis of these patients.