Massachusetts General Hospital, Boston, Massachusetts.
Dana-Farber Cancer Institute, Boston, Massachusetts.
Cancer. 2019 Feb 15;125(4):541-549. doi: 10.1002/cncr.31729. Epub 2018 Nov 13.
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.
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 × 10 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.
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.
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.
急性髓系白血病（AML）细胞中存在异柠檬酸脱氢酶 1（IDH1）和异柠檬酸脱氢酶 2（IDH2）突变，会产生致癌代谢物 2-羟基戊二酸（2HG）。本研究前瞻性评估了新诊断为 AML 的患者接受标准化疗时的 2HG 水平、IDH1/2 突变状态和结局。
收集新诊断为 AML 的患者的血清、尿液和骨髓抽吸物的连续样本，并使用质谱法测量 2HG 水平。基线血清 2HG 水平大于 1000ng/ml 或骨髓沉淀 2HG 水平大于 1000ng/2×10^6 个细胞的患者，提示存在 IDH1/2 突变，进行了连续检测。鉴定 IDH1/2 突变和估计的变异等位基因频率。采用 Wilcoxon 检验和 Fisher 确切检验比较 AML 特征。采用对数秩检验和 Cox 回归评估无病生存和总生存（OS）。
202 例患者接受 AML 治疗；51 例存在 IDH1/2 突变。与野生型患者相比，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 水平显著升高。血清 2HG 水平大于 534.5ng/ml 对 IDH1/2 突变的存在具有 98.8%的特异性。接受 7+3 诱导的 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的完全缓解率、EFS 或 OS 无差异。在多变量分析中，基线时血清 2HG 水平降低至第 14 天的比例与 EFS（P=0.047）和 OS（P=0.019）的改善显著相关。
在 IDH1/2 突变的 AML 患者中，2HG 水平高度特异于诊断时的突变状态，在接受标准化疗的患者中具有预后意义。
