IDH不同突变亚型及伴发基因突变对急性髓系白血病患者的预后意义

目的探讨IDH不同突变亚型及伴发不同基因突变在非M3型急性髓系白血病(AML)患者中的预后意义。方法采用二代测序技术检测2016年6月至2018年12月就诊于郑州大学第一附属医院的389例AML患者的22种基因突变情况,通过Kaplan-Meier法及Cox回归模型分析影响预后的因素。结果 389例AML患者中,IDH1及IDH2的突变率分别为6.2%、8.7%,未发现IDH1与IDH2共突变的情况。IDH2突变型患者年龄偏大、骨髓原始细胞比例高、正常核型多见、常合并RUNX1突变及SRSF2突变。单因素方差分析发现,IDH1突变型组较野生型组的中位总生存(OS)及无进展生存(PFS)时间明显缩短(P值均<0.05);IDH2突变作为一个单变量对预后无显著影响,不同突变位点对预后的影响不同,IDH2R140突变对预后无显著影响,IDH2R172突变型患者较IDH2野生型患者完全缓解(CR)率明显减低、中位OS及PFS时间明显缩短(P值均<0.05)。在正常核型或年龄≥50岁的患者中,IDH不同突变亚型显示出同样的预后意义。74.1%(43/58)IDH突变患者同时携带其他基因突变,伴发基因突变数目对患者的预后无显著影响,IDH突变患者中伴NPM1突变者的CR率明显高于不伴NPM1突变者(81.8%对36.4%,P=0.014),伴DNMT3A突变者的中位OS时间短于不伴DNMT3A突变者4.0(95%CI 3.8~4.2)个月对6.3(95%CI 2.4~10.2)个月,P=0.041]。多因素分析显示:年龄≥60岁、WBC≥100×109/L是影响患者OS及PFS的独立危险因素,2个疗程内CR、造血干细胞移植是影响患者OS及PFS的独立有利因素。结论在AML(非M3型)患者中,IDH基因突变常与其他基因突变共存,IDH不同突变亚型及伴发基因突变显示出不同的预后意义。

Prognostic significance of different IDH mutations and accompanying gene mutations in patients with acute myeloid leukemia

Objective To investigate the prognostic significance of different IDH mutations and accompanying gene mutations in patients with non-M3 acute myeloid leukemia(AML).Methods Second-generation sequencing was performed to detect the mutations of 22 genes in 389 patients with AML in the First Affiliated Hospital of Zhengzhou University from June 2016 to December 2018,and Kaplan-Meier and Cox regression models were used to analyze the prognostic factors.Results The mutation frequency of IDH1 and IDH2 was 6.2%and 8.7%,respectively,in all patients without co-mutation.The IDH2 mutant group had an older age,higher proportion of bone marrow primitive cells,more common normal karyotype,and more common RUNX1 and SRSF2 mutations compared with IDH2 wild-type group.Univariate analysis of variance showed that the median OS and PFS of IDH1 mutation group were significantly shorter than those of the wild-type group(P<0.05).IDH2 mutation as a single variable and IDH2R140 mutation had no significant effect on the prognosis,while different mutation sites had different effects.Compared with the IDH2 wild-type group,the IDH2R172 mutation group had lower complete remission(CR)rate and shorter median OS and PFS(P<0.05).In patients with normal karyotypes or aged≥50 years,IDH2 mutation as a single variable had no significant effect on the prognosis,IDH1 mutation and IDH2R172 mutation were associated with poor OS and PFS(P<0.05),and IDH2R140 mutation had no significant effect on OS and PFS.Approximately 74.1%(43/58)of patients with IDH mutation simultaneously carried other gene mutations;however,the number of accompanying gene mutations had no significant effect on the prognosis.Among 58 patients with IDH mutation,the CR rate of patients with NPM1 mutation was significantly higher than that of patients in the NPM1 wild-type group(81.8%vs 36.4%,P=0.014),the median OS in patients with DNMT3A mutation was lower than that of patients with DNMT3A wild type4.0 months(95%CI 3.8-4.2)vs 6.3 months(95%CI 2.4-10.2),(P=0.041)].Multivariate analysis showed that age≥60 years and white blood cell count≥100×109/L were independent risk factors for OS and PFS,while CR after two courses of treatment and hematopoietic stem cell transplantation were independent prognostic favorable factors for OS and PFS.Conclusion In patients with AML(non-M3),IDH gene mutations often coexisted with other gene mutations,and different subtypes and accompanying gene mutations of IDH have different prognostic significance.