IDH1 and IDH2 Mutations Are Frequent Genetic Alterations in Acute Myeloid Leukemia and Confer Adverse Prognosis in Cytogenetically Normal Acute Myeloid Leukemia With NPM1 Mutation Without FLT3 Internal Tandem Duplication
IDH1 and IDH2 Mutations Are Frequent Genetic Alterations in Acute Myeloid Leukemia and Confer Adverse Prognosis in Cytogenetically Normal Acute Myeloid Leukemia With NPM1 Mutation Without FLT3 Internal Tandem Duplication
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DOI：
10.1200/jco.2010.28.3762
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发表时间：
2010-08-01
影响因子：
45.3
通讯作者：
Doehner, Konstanze
中科院分区：
文献类型：
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作者：
Paschka, Peter;Schlenk, Richard F.;Doehner, Konstanze
目的分析异柠檬酸脱氢酶1（IDH 1）和异柠檬酸脱氢酶2（IDH 2）突变在急性髓性白血病（AML）中的频率和预后影响。患者和方法我们研究了805名患有AML的成年人（年龄范围，16至60岁），参加了德国-奥地利AML研究小组（AMLSG）治疗试验AML HD 98 A和APL HD 95，以检测IDH 1和IDH 2外显子4突变。还研究了患者的NPM 1、FLT 3、MLL和CEBPA突变。中位随访生存期为6.3 years.ResultsIDH突变被发现在129例（16.0%）-IDH 1的61例（7.6%），IDH 2的70例（8.7%）。两名患者同时具有IDH 1和IDH 2突变。除一个IDH 1突变外，所有IDH 1突变均引起残基R132的取代; IDH 2突变引起R140（n = 48）或R172（n = 22）的变化。IDH突变与年龄较大相关（P < .001;仅IDH 2产生的影响）; WBC较低（P = .04）;血小板较高（P < .001）;细胞遗传学正常（CN）-AML（P <.001）;和NPM 1突变，特别是无FLT 3内部串联重复（ITD; P < .001）的突变NPM 1基因型。在具有后一种基因型的CN-AML患者中，IDH突变对无复发生存期（RFS; P = .02）和总生存期（P = .03）产生不利影响，而在缺乏该基因型的CN-AML患者中，结果不受影响。在CN-AML中，多变量分析显示IDH突变和无FLT 3-ITD的突变NPM 1基因型之间存在显著的相互作用（即IDH突变的不利影响[ RFS]; P = 0.046仅限于该患者亚群）。它们构成了具有突变的NPM 1而无FLT 3-ITD的CN-AML的不良预后因素，这允许对该AML子集进行精细的风险分层。
PurposeTo analyze the frequency and prognostic impact of isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) mutations in acute myeloid leukemia (AML).Patients and MethodsWe studied 805 adults (age range, 16 to 60 years) with AML enrolled on German-Austrian AML Study Group (AMLSG) treatment trials AML HD98A and APL HD95 for mutations in exon 4 of IDH1 and IDH2. Patients were also studied for NPM1, FLT3, MLL, and CEBPA mutations. The median follow-up for survival was 6.3 years.ResultsIDH mutations were found in 129 patients (16.0%) -IDH1 in 61 patients (7.6%), and IDH2 in 70 patients (8.7%). Two patients had both IDH1 and IDH2 mutations. All but one IDH1 mutation caused substitutions of residue R132; IDH2 mutations caused changes of R140 (n = 48) or R172 (n = 22). IDH mutations were associated with older age (P < .001; effect conferred by IDH2 only); lower WBC (P = .04); higher platelets (P < .001); cytogenetically normal (CN) -AML (P < .001); and NPM1 mutations, in particular with the genotype of mutated NPM1 without FLT3 internal tandem duplication (ITD; P < .001). In patients with CN-AML with the latter genotype, IDH mutations adversely impacted relapse-free survival (RFS; P = .02) and overall survival (P = .03), whereas outcome was not affected in patients with CN-AML who lacked this genotype. In CN-AML, multivariable analyses revealed a significant interaction between IDH mutation and the genotype of mutated NPM1 without FLT3-ITD (ie, the adverse impact of IDH mutation [ RFS]; P = .046 was restricted to this patient subset).ConclusionIDH1 and IDH2 mutations are recurring genetic changes in AML. They constitute a poor prognostic factor in CN-AML with mutated NPM1 without FLT3-ITD, which allows refined risk stratification of this AML subset.