Isocitrate dehydrogenase 1 and 2 mutations, 2-hydroxyglutarate levels, and response to standard chemotherapy for patients with newly diagnosed acute myeloid leukemia
Isocitrate dehydrogenase 1 and 2 mutations, 2-hydroxyglutarate levels, and response to standard chemotherapy for patients with newly diagnosed acute myeloid leukemia
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DOI：
10.1002/cncr.31729
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发表时间：
2019-02-15
期刊：
影响因子：
6.2
通讯作者：
Fathi, Amir T.
中科院分区：
文献类型：
--
作者：
Brunner, Andrew M.;Neuberg, Donna S.;Fathi, Amir T.
背景 携带异柠檬酸脱氢酶 1 (IDH1) 和异柠檬酸脱氢酶 2 (IDH2) 突变的急性髓系白血病 (AML) 细胞会产生致癌代谢物 2-羟基戊二酸 (2HG)。本研究前瞻性评估了接受标准化疗的新诊断 AML 患者的 2HG 水平、IDH1/2 突变状态和结果。方法收集初诊AML患者的血清、尿液和骨髓抽吸物系列样本，采用质谱法测定2HG水平。基线血清 2HG 水平大于 1000 ng/mL 或骨髓颗粒 2HG 水平大于 1000 ng/2 x 10(6) 细胞（表明存在 IDH1/2 突变）的患者接受了系列检测。确定了 IDH1/2 突变和估计的变异等位基因频率。将 AML 特征与 Wilcoxon 检验和 Fisher 精确检验进行比较。通过对数秩检验和 Cox 回归评估无病生存率和总生存率 (OS)。结果 202 名 AML 患者接受治疗； 51 人携带 IDH1/2 突变。 IDH1/2 突变患者的血清、尿液、骨髓抽吸物和抽吸细胞沉淀中的 2HG 水平显着高于野生型患者。血清 2HG 水平大于 534.5 ng/mL 时，对 IDH1/2 突变的存在具有 98.8% 的特异性。采用 7+3 诱导治疗的 IDH1/2 突变 AML 患者的 2 年无事件生存 (EFS) 率为 44%，2 年 OS 率为 57%。 IDH1/2 突变型和野生型患者之间的完全缓解率、EFS 或 OS 没有差异。在多变量分析中，第 14 天血清 2HG 水平占基线的下降与 EFS (P = .047) 和 OS (P = .019) 的改善显着相关。结论 在 IDH1/2 突变的 AML 患者中，2HG 水平对于诊断时的突变状态具有高度特异性，并且与接受标准化疗的患者具有预后相关性。
Background Acute myeloid leukemia (AML) cells harboring mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) produce the oncometabolite 2-hydroxyglutarate (2HG). This study prospectively evaluated the 2HG levels, IDH1/2 mutational status, and outcomes of patients receiving standard chemotherapy for newly diagnosed AML. Methods Serial samples of serum, urine, and bone marrow aspirates were collected from patients newly diagnosed with AML, and 2HG levels were measured with mass spectrometry. Patients with baseline serum 2HG levels greater than 1000 ng/mL or marrow pellet 2HG levels greater than 1000 ng/2 x 10(6) cells, which suggested the presence of an IDH1/2 mutation, underwent serial testing. IDH1/2 mutations and estimated variant allele frequencies were identified. AML characteristics were compared with the Wilcoxon test and Fisher's exact test. Disease-free survival and overall survival (OS) were evaluated with log-rank tests and Cox regression. Results Two hundred and two patients were treated for AML; 51 harbored IDH1/2 mutations. IDH1/2-mutated patients had significantly higher 2HG levels in serum, urine, bone marrow aspirates, and aspirate cell pellets than wild-type patients. A serum 2HG level greater than 534.5 ng/mL was 98.8% specific for the presence of an IDH1/2 mutation. Patients with IDH1/2-mutated AML treated with 7+3-based induction had a 2-year event-free survival (EFS) rate of 44% and a 2-year OS rate of 57%. There was no difference in complete remission rates, EFS, or OS between IDH1/2-mutated and wild-type patients. Decreased serum 2HG levels on day 14 as a proportion of the baseline were significantly associated with improvements in EFS (P = .047) and OS (P = .019) in a multivariate analysis. Conclusions Among patients with IDH1/2-mutated AML, 2HG levels are highly specific for the mutational status at diagnosis, and they have prognostic relevance in patients receiving standard chemotherapy.