IDH2基因突变对急性髓系白血病患者的临床特征及预后影响

Effects of IDH2 Gene Mutation on Clinical Characteristics and Prognostic of Patients with Acute Myeloid Leukemia

目的:分析异柠檬酸脱氢酶2(IDH2)基因突变在急性髓系白血病(AML)中的发生率、临床特征及预后意义。方法:收集2015年1月至2018年10月经MICM分型确诊的223例初治AML患者的骨髓标本,采用PCR扩增产物直接测序法检测IDH2基因4号外显子的突变情况,分析AML中IDH2基因突变的发生率及类型,分析伴IDH2基因突变AML患者的临床特征并评估其治疗疗效。结果:223例AML患者中,23例患者存在IDH2基因突变,突变率为10.31%,其中IDH2R140Q15例(65.22%),IDH2R172K6例(26.09%),IDH2R140W2例(8.70%)。IDH2基因突变组中位年龄高于未突变组中位年龄(P=0.008),初诊血小板计数高于未突变组血小板计数(P=0.010)。IDH2基因突变组FAB分型与非突变组相比无明显统计学差异(P>0.05),但是IDH2基因突变组M4和M5的发生率较高。IDH2基因突变在正常核型组和NPM1基因突变组的发生率较高,其中IDH2R140Q突变亚型与NPM1基因突变有相关性,但是IDH2R172K突变亚型与NPM1基因突变无相关性。IDH2突变组化疗完全缓解(CR)率为57.14%,低于非突变组的80.46%(χ^2=5.927,P=0.015),其中IDH2R140Q突变组化疗完全缓解率,与非突变组相比差异无统计学意义(P>0.05),但IDH2R172K突变组化疗完全缓解率明显低于非突变组(χ^2=7.734,P=0.005)。不伴有NPM1突变的患者中,IDH2突变组2年总生存(OS)率为36.36%,低于非突变组2年总生存率66.40%(χ^2=3.958,P=0.047),其中IDH2R172K突变组2年总生存率明显低于非突变组(P>0.05);所有随访患者中,IDH2突变组2年总生存率为50%,与非突变组2年总生存率(66.88%)相比无明显统计学差异(P>0.05),但是IDH2R172K突变组2年总生存率明显低于非突变组(P>0.05);在正常核型患者中或伴有NPM1突变的患者中,IDH2突变组2年总生存率与非突变组2年总生存率相比,均无明显统计学差异(P>0.05)。结论:IDH2基因突变是AML患者较常见的基因突变,IDH2基因突变患者年龄较大,血小板计数较高。IDH2基因突变易发生于正常核型患者,在FAB分型M4和M5的发生率较高。IDH2基因突变与NPM1基因突变有相关性,但是IDH2R172K突变亚型与NPM1基因突变无相关性。IDH2基因突变与患者的预后有一定相关性,其中IDH2R140Q突变对AML患者的预后无影响,IDH2R172K突变可能是AML患者预后不良的分子标志。

Objective:To analyze the prevalence,clinical characteristics and prognostic significance of the isocitrate dehydrogenase 2( IDH2) mutations in patients with acute myeloid leukemia( AML).Methods:The bone marrow samples of 223 patients with newly diagnosed AML confirmed by MICM typing from January 2015 to October 2018 were collected.The mutation of exon 4 of IDH2 gene was detected by direct sequancing of PCR product;the incidence and types of IDH2 gene mutation in AML patients were analyzed;the clinical characteristics of AML patients with IDH2 gene mutation were analyzed and the therapeutic efficacy for these patients was evaluated.Results:In a cohort of 223 AML patients,IDH2 mutations were detected in 23 ( 10.31%) patients,among them,15 with R140Q mutations ( 65. 22%),6 with R172K mutations( 26.09%) and 2 with R140W mutations( 8.70%).The median age in IDH2 mutated group was older than that in non-mutated group( P = 0.008).The platelet level at initial diagnosis in IDH2 mutated group was higher than that in non-mutated group( P = 0.010).There was no significant statistical difference between IDH2 mutated group and non-mutated group in FAB subtypes of AML( P > 0.05).But the rate of IDH2 mutation in M4 and M5 was higher.The rate of IDH2 mutations was higher in AML with normal karyotype and in AML with NPM1 mutations.R140Q mutations associated with NPM1 mutations (χ^2 = 8.481,P = 0.004),but R172K mutations not associated with NPM1 mutation ( P > 0.05).IDH2 mutated patients had a lower complete remission rate than nonmutated patients( 57.14% vs 80.46%,χ^2 = 5.927,P = 0.015).The complete remission rate of R140Q mutated patients was not significantly statistically different from non-mutated patients.The complete remission rate of R172K mutated patients was very significantly lower than non-mutated patients(χ^2 = 7.734,P = 0.005).In the patients without NPM1 mutation,the 2 years overall survival in IDH2 mutated group was lower than in non-mutated group ( 36.36% vs 66. 40%,χ^2 = 3.958,P = 0.047),the 2 years overall survival of R172K mutated group was significantly lower than nonmutated group( although P > 0.05).In all patients,the 2 years overall survival between IDH2 mutated group and nonmutated group was not statistically different( 50% vs 66.88%,P > 0.05),the 2 years overall survival of R172K mutated group was significantly lower than non-mutated group( although P > 0.05).In the patients with normal karyotype or with mutated NPM1,the 2 years overall survival between IDH2 mutated group and non-mutated group was not statistically different( P > 0.05 ).Conclusion:IDH2 gene mutations are more common in AML patients at older age,higher platelets level and normal karyotype.The rate of IDH2 mutation in M4 and M5 is higher.IDH2 gene mutations associate with NPMl gene mutations,but R172K mutations not associates with NPM1mutation.IDH2 gene mutations associate with prognosis of AML patients,R140Q mutations have no effect on prognosis of patients,but R172K mutations may be the molecular markers for poor prognosis in AML patients.