Real-Time Quantitative Polymerase Chain Reaction Detection of Minimal Residual Disease by Standardized WT1 Assay to Enhance Risk Stratification in Acute Myeloid Leukemia: A European LeukemiaNet Study
Real-Time Quantitative Polymerase Chain Reaction Detection of Minimal Residual Disease by Standardized WT1 Assay to Enhance Risk Stratification in Acute Myeloid Leukemia: A European LeukemiaNet Study
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DOI：
10.1200/jco.2009.22.4865
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发表时间：
2009-11-01
影响因子：
45.3
通讯作者：
Grimwade, David
中科院分区：
文献类型：
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作者：
Cilloni, Daniela;Renneville, Aline;Grimwade, David
急性髓细胞白血病（AML）的危险分层目前是基于治疗前的特征。通过评估微小残留病（MRD）是否可以更好地预测复发风险仍有待确定。一个建议的标志物是Wilms肿瘤基因WT 1，这是在大多数AML患者过表达，从而提供了一个假定的免疫治疗的目标，虽然在没有一个标准化的测定，其效用MRD监测仍然存在争议。将最佳性能的测定应用于诊断AML样品（n = 620）、来自129名用强化联合化疗治疗的患者的随访样品和204名正常外周血（PB）和骨髓（BM）对照。结果考虑到在正常PB和BM中检测到的相对表达水平，根据相应的随访样本来源，WT 1在46%和13%的AML患者中充分过表达，以区分转录本减少>= 2-log。在这个信息组中，诱导后WT 1转录物的减少更大，预测复发风险降低（风险比，每对数减少0.54; 95%CI，0.36至0.83; P = 0.004），当调整年龄，WBC计数和细胞遗传学时仍然显着。在巩固治疗结束时，如果WT 1转录水平不能降低到正常对照组定义的阈值以下，也预示着复发风险增加（P = 0.004）结论应用标准化WT 1检测可提供AML的独立预后信息，支持纳入MRD的早期评估，以开发更可靠的风险评分，增强风险分层，并确定可能从同种异体移植中受益的患者。
PurposeRisk stratification in acute myeloid leukemia (AML) is currently based on pretreatment characteristics. It remains to be established whether relapse risk can be better predicted through assessment of minimal residual disease (MRD). One proposed marker is the Wilms tumor gene WT1, which is overexpressed in most patients with AML, thus providing a putative target for immunotherapy, although in the absence of a standardized assay, its utility for MRD monitoring remains controversial.Patients and MethodsNine published and in-house real-time quantitative polymerase chain reaction WT1 assays were systematically evaluated within the European LeukemiaNet; the best-performing assay was applied to diagnostic AML samples (n = 620), follow-up samples from 129 patients treated with intensive combination chemotherapy, and 204 normal peripheral blood (PB) and bone marrow (BM) controls.ResultsConsidering relative levels of expression detected in normal PB and BM, WT1 was sufficiently overexpressed to discriminate >= 2-log reduction in transcripts in 46% and 13% of AML patients, according to the respective follow-up sample source. In this informative group, greater WT1 transcript reduction after induction predicted reduced relapse risk (hazard ratio, 0.54 per log reduction; 95% CI, 0.36 to 0.83; P = .004) that remained significant when adjusted for age, WBC count, and cytogenetics. Failure to reduce WT1 transcripts below the threshold limits defined in normal controls by the end of consolidation also predicted increased relapse risk (P = .004).ConclusionApplication of a standardized WT1 assay provides independent prognostic information in AML, lending support to incorporation of early assessment of MRD to develop more robust risk scores, to enhance risk stratification, and to identify patients who may benefit from allogeneic transplantation.