急性髓细胞白血病IDH基因突变临床特征及预后意义

Clinical characteristics and prognostic significance in adult acute myeloid leukemia with isocitrate dehydrogenase gene mutation

目的基因突变在急性髓系白血病(acute myelocytic leukemia,AML)患者预后判断方面具有重要意义,其中异柠檬酸脱氢酶(isocitrate dehydrogenase,IDH)基因突变与AML的临床特征和预后密切相关。本研究探讨AML患者IDH基因突变的发生率、临床特征及预后意义。方法选取滨州医学院附属医院2015-01-01-2017-01-31经MICM分型确诊的120例初治AML患者,采用骨髓单个核细胞基因组DNA,PCR方法扩增IDHl、IDH2基因4号外显子,基因测序检测IDHl及IDH2基因突变,分析患者临床特征并评估其疗效。结果 120例AML患者中16例检测到IDH基因突变,突变率为13.33%,其中IDHl突变5例(4.17%),IDH2突变11例(9.17%)。未发现有患者同时获得IDHl和IDH2突变。突变组中位年龄55岁,未突变组中位年龄40岁,差异有统计学意义,P=0.000 4;初诊外周血血小板计数为77×10~9 L^(-1),明显高于未突变组的33×10~9 L^(-1),差异有统计学意义,P=0.000 2。IDH突变均发生在AML-M4/M5中,未见其他AML亚型。IDH基因突变与正常核型、NPMl基因突变,尤其是NPMl基因突变未伴FLT3-ITD基因突变的基因型相关。突变组的化疗完全缓解率为50.00%,低于未突变组的79.59%,差异有统计学意义,P<0.01。不伴NPM1基因突变的患者中,IDH基因突变组1年总生存率为50.00%,低于未突变组的86.42%,差异有统计学意义,P<0.01。所有患者中,IDH基因突变组1年总生存率为71.43%,低于未突变组的86.73%,但差异无统计学意义,P>0.05;在正常核型和伴NPM1突变患者中,IDH基因突变组与未突变组1年总生存率差异均无统计学意义,均P>0.05。结论 IDH基因突变更多见于正常核型的AML患者,常与NPMl基因突变相伴随,与患者治疗疗效具有一定相关性,提示是预后不良的分子标志。

OBJECTIVE To explore the prevalence,clinical characteristics and prognostic significance of isocitrate dehydrogenase gene mutations in acute myeloid leukemia（AMID patients. METHODS Polymerase chain reaction （PCR） and direct sequencing were used to sequence exon 4 of IDH gene in 120 AML patients from January 1,2015 to January 31, 2017 in Affiliated hospital of Binzhou medical university. RESULTS In a cohort of 120 AML patients,IDH gene muta- tion was found in 16（13.33%） patients. IDH1 and IDH2 mutations were detected in 5（4.17%） patients and 11（9.17%） patients, respectively. None of them had the combined mutations of IDH1 and IDH2. The median age was 55 years in muta- ted group versus 40 years in wild-type group（P〈0.01）. Blood platelets median level was 77 × 109 L-1 versus 33 ×109 L-1 （P〈0.01）. IDH mutations all occurred in AML-M4/MS,other AML subtypes were not observed. IDH gene mutations were associated with cytogenetically normal（CN）AML, NPM1 mutations and particularly the genotype of mutated NPM1 without FLT3-ITD. IDH mutated patients had a lower complete remission rate than unmutated patients （50.00% vs 79.59 %, P〈0.01）. And in the patients without mutated NPM1, IDH gene mutations were associated with a shorter over- all survival than non-mutations （50.00 % vs 86.42 %, P〈0.01 ）. In all patients, the overall survival in IDH gene mutation group was lower than in non-mutation group, but the difference was not statistically significant （71.43% vs 86.73% ,P〉 0.05）. In the patients with normal karyotype, the overall survival between IDH gene mutation group and non-mutation group was not statistically different （P〈0.0,5）,the same result was obtained in tile patients with mutated NPM1. CON- CLUSlONS IDH gene mutations are more common in AMI, patients with normal karyotype and are associated with NPM1 gene mutation. IDH gene mutations may be poor molecular markers in AML.