Pretransplant FLT3-ITD levels predict outcome after allogeneic hematopoietic cell transplantation for AML patients in the first remission.
Pretransplant FLT3-ITD levels predict outcome after allogeneic hematopoietic cell transplantation for AML patients in the first remission.
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移植前 FLT3-ITD 水平可预测 AML 患者异基因造血细胞移植后首次缓解的结果。
DOI：
10.1038/s41409-019-0576-3
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发表时间：
2020
影响因子：
4.8
通讯作者：
Liu Yuejun
中科院分区：
文献类型：
--
作者：
Wan Li;Xu Mingzhu;Chen Jia;Yang Zuyi;Xu Mimi;Shen Hongjie;Wu Xiaojin;Xue Shengli;Ma Xiao;Han Yue;Tang Xiaowen;Qiu Huiying;Wu Depei;Liu Yuejun
携带FLT 3-ITD突变的AML患者结局较差，在首次完全缓解（CR 1）期间被广泛认为是异基因造血细胞移植（allo-HCT）的候选者[1]。然而，HCT后的疾病复发仍然是这些患者治疗失败的主要原因，值得进一步研究以早期预测复发。尽管具有普遍适用性，但通过多参数流式细胞术（MRDMFC）检测的可测量残留疾病（MRD）在用作移植后结局的预测因子时仍存在固有的局限性[2]。越来越多的证据证明了特定突变水平作为AML患者MRD标志物的价值[2]。作为AML中常见的白血病特异性遗传畸变，FLT 3-ITD突变已被确定为预测缓解后结局的高度敏感手段[3，4]。然而，很少有研究关注HCT前FLT 3-ITD突变水平对CR 1患者移植后结局的影响。因此，我们进行了一项回顾性研究，以探讨在HCT前使用FLT 3-ITD等位基因频率作为MRD标志物（MRDFLT 3-ITD）预测移植结局的有效性，并招募了84例在2012年1月至2017年6月期间在苏州大学附属第一医院首次缓解期间接受allo-HCT的患者。排除急性早幼粒细胞白血病患者或在移植前和/或移植后接受FLT 3抑制剂治疗的患者。所有受者和供者均提供了书面知情同意书，该方案得到了我院伦理委员会的批准，移植前治疗、预处理方案、GVHD预防和移植后管理均按前述进行[5]。用于FLT 3-ITD检测和MFC的样本从相同的预处理骨髓抽吸中获得，中位时间为HCT前18天（范围12-28）。如前所述进行MRDMFC和MRDFLT 3-ITD的检测，MRDMFC的临界值为0.1%，MRDFLT 3-ITD的临界值为2.5%[6-8]。诊断时FLT 3-ITD突变等位基因频率> 33%定义为FLT 3-ITDhi [9]。生存概率、复发和非复发死亡率以及风险分析分别通过Kaplan-Meier法、竞争风险模型和考克斯比例风险模型计算。单变量分析P值< 0.1的相关因素纳入多变量分析。所有统计分析均采用SPSS19.0和R2.15软件包进行。1软件包。对于入组本研究的84例受体（特征见表S1），诊断时检测到的FLT 3-ITD突变等位基因范围为0.5%-90.8%。在HCT前频率范围为0.9%至60.1%的15例患者中，12例患者被确定为MRDFLT 3-ITD阳性（等位基因频率≥ 2.5%），而28例患者为MRDMFC阳性。在12例MRDFLT 3-ITD阳性患者中，7例患者复发，中位时间为5.2个月。
Patients with AML harboring FLT3-ITD mutations have a poorer outcome and are widely considered to be candidates for allogeneic hematopoietic cell transplant (allo-HCT) during their first complete remission (CR1)[1]. However, disease recurrence following HCT remains the main cause of treatment failure among these patients, which merits further investigation for early predicting relapse. Despite the general applicability, measurable residual disease (MRD) detected by multiparameter flow cytometry (MRDMFC) still exhibits inherent limitations when employed as a predictor for posttransplant outcomes [2]. Increasing evidences have proven the value of specific mutation levels as MRD marker for AML patients [2]. As a common leukemia-specific genetic aberration in AML, FLT3-ITD mutations have been identified as a highly sensitive means of predicting postremission outcomes [3, 4]. Nevertheless, few studies focused on the impact of pre-HCT FLT3-ITD mutant levels on the posttransplant outcomes for patients in CR1. Hence, we conducted a retrospective study to investigate the efficacy of using FLT3-ITD allele frequencies as MRD marker (MRDFLT3-ITD) pre-HCT, for predicting transplant outcomes, and enrolled 84 patients who received allo-HCT during their first remission in the First Affiliated Hospital of Soochow University between January 2012 and June 2017. Patients with acute promyelocytic leukemia or who had received FLT3 inhibitors before and/or after transplantation were excluded. All recipients and donors provided written informed consent for the protocol, which was approved by our hospital’s Ethics Committee.Treatment before transplantation, conditioning regimen, GVHD prophylaxis, and posttransplant management were carried out as described previously [5]. Samples used for FLT3-ITD detection and MFC were acquired from the same preconditioning marrow aspiration with the median time of 18 (range 12–28) days before HCT. Detection of MRDMFC and MRDFLT3-ITD was performed as described previously, with the cutoff value of 0.1% for MRDMFC and 2.5% for MRDFLT3-ITD [6–8]. FLT3-ITD mutant allele frequencies> 33% at diagnosis were defined as FLT3-ITDhi [9]. The probabilities of survival, relapse and nonrelapse mortality, and risk analyses were calculated via the Kaplan–Meier method, competing risk model, and Cox proportional hazard model, respectively. Factors associated with a P value< 0.1 by univariate analysis were included in the multivariate analysis. All statistical analyses were performed with SPSS 19.0 and R 2.15. 1 software packages. For the 84 recipients enrolled in this study (characteristics shown in Table S1), FLT3-ITD mutant alleles were detected ranging from 0.5% to 90.8% at diagnosis. In 15 patients with frequencies ranging from 0.9% to 60.1% pre-HCT, 12 patients were determined as MRDFLT3-ITD positive (with allele frequencies≥ 2.5%), whereas 28 patients were MRDMFC positive. Among the 12 MRDFLT3-ITD-positive patients, 7 patients relapsed which occurred at a median time of 5.2 months.