异柠檬酸脱氢酶 1 和 2 突变亚组对异基因造血干细胞移植后急性髓系白血病患者的影响。

Impact of IDH1 and IDH2 mutational subgroups in AML patients after allogeneic stem cell transplantation.

机构信息

Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus, Dresden, Germany.

Laboratory for Leukemia Diagnostics, Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.

出版信息

J Hematol Oncol. 2022 Sep 5;15(1):126. doi: 10.1186/s13045-022-01339-8.

BACKGROUND

The role of allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML) with mutated IDH1/2 has not been defined. Therefore, we analyzed a large cohort of 3234 AML patients in first complete remission (CR1) undergoing alloHCT or conventional chemo-consolidation and investigated outcome in respect to IDH1/2 mutational subgroups (IDH1 R132C, R132H and IDH2 R140Q, R172K).

METHODS

Genomic DNA was extracted from bone marrow or peripheral blood samples at diagnosis and analyzed for IDH mutations with denaturing high-performance liquid chromatography, Sanger sequencing and targeted myeloid panel next-generation sequencing, respectively. Statistical as-treated analyses were performed using R and standard statistical methods (Kruskal-Wallis test for continuous variables, Chi-square test for categorical variables, Cox regression for univariate and multivariable models), incorporating alloHCT as a time-dependent covariate.

RESULTS

Among 3234 patients achieving CR1, 7.8% harbored IDH1 mutations (36% R132C and 47% R132H) and 10.9% carried IDH2 mutations (77% R140Q and 19% R172K). 852 patients underwent alloHCT in CR1. Within the alloHCT group, 6.2% had an IDH1 mutation (43.4% R132C and 41.4% R132H) and 10% were characterized by an IDH2 mutation (71.8% R140Q and 24.7% R172K). Variants IDH1 R132C and IDH2 R172K showed a significant benefit from alloHCT for OS (p = .017 and p = .049) and RFS (HR = 0.42, p = .048 and p = .009) compared with chemotherapy only. AlloHCT in IDH2 R140Q mutated AML resulted in longer RFS (HR = 0.4, p = .002).

CONCLUSION

In this large as-treated analysis, we showed that alloHCT is able to overcome the negative prognostic impact of certain IDH mutational subclasses in first-line consolidation treatment and could pending prognostic validation, provide prognostic value for AML risk stratification and therapeutic decision making.

背景

异基因造血细胞移植（alloHCT）在伴有突变 IDH1/2 的急性髓系白血病（AML）中的作用尚未明确。因此，我们分析了 3234 例在首次完全缓解（CR1）期接受 alloHCT 或常规化疗巩固治疗的 AML 患者的大型队列，并根据 IDH1/2 突变亚组（IDH1 R132C、R132H 和 IDH2 R140Q、R172K）研究了预后。

方法

从骨髓或外周血样本中提取基因组 DNA，分别采用变性高效液相色谱法、Sanger 测序和靶向髓系 panel 下一代测序分析 IDH 突变。使用 R 和标准统计方法（连续变量的 Kruskal-Wallis 检验，分类变量的卡方检验，单变量和多变量模型的 Cox 回归）进行基于治疗的统计分析，将 alloHCT 作为时变协变量。

结果

在 3234 例达到 CR1 的患者中，7.8%存在 IDH1 突变（36%为 R132C，47%为 R132H），10.9%存在 IDH2 突变（77%为 R140Q，19%为 R172K）。852 例患者在 CR1 期接受 alloHCT。在 alloHCT 组中，6.2%存在 IDH1 突变（43.4%为 R132C，41.4%为 R132H），10%存在 IDH2 突变（71.8%为 R140Q，24.7%为 R172K）。IDH1 R132C 和 IDH2 R172K 突变与仅接受化疗相比， alloHCT 对 OS（p=0.017 和 p=0.049）和 RFS（HR=0.42，p=0.048 和 p=0.009）有显著获益。alloHCT 可改善 IDH2 R140Q 突变 AML 的 RFS（HR=0.4，p=0.002）。