Prospective Minimal Residual Disease Monitoring to Predict Relapse of Acute Promyelocytic Leukemia and to Direct Pre-Emptive Arsenic Trioxide Therapy
Prospective Minimal Residual Disease Monitoring to Predict Relapse of Acute Promyelocytic Leukemia and to Direct Pre-Emptive Arsenic Trioxide Therapy
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DOI：
10.1200/jco.2008.20.1533
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发表时间：
2009-08-01
影响因子：
45.3
通讯作者：
Burnett, Alan K.
中科院分区：
文献类型：
--
作者：
Grimwade, David;Jovanovic, Jelena V.;Burnett, Alan K.
目的分子诊断和早期评估治疗反应，使用能够检测亚显微疾病的方法，可以区分不同复发风险的白血病患者亚组。这些信息正在被纳入风险分层协议;然而，很少有数据涉及前瞻性使用序贯微小残留病（MRD）监测，以更准确地确定那些注定要复发的患者，这将允许更有针对性的治疗。（即PML-RARA、RARA-PML）前瞻性分析了6例，来自406例新诊断的急性早幼粒细胞白血病（APL）患者的727份连续血液和骨髓样本，这些患者正在接受全反式维甲酸和蒽环类药物治疗，结果根据推荐的时间表进行MRD监测成功地识别了大多数复发患者，并提供了无复发生存率最有力的预测因子（RFS）（风险比，17.87; 95%CI，6.88至46.41; P < .0001）; MRD监测远上级目前广泛用于指导治疗的WBC（风险比，1.02; 95%CI，1.00至1.03; P = .02）。在根据MRD监测预测会复发的患者中，大多数患者的三氧化二砷早期治疗干预可防止进展为明显复发，分子复发后1年的RFS率为73%。通过使用这种策略，3年的临床复发的累积发病率只有5%，在医学研究理事会AML 15 trial.ConclusionRigorous顺序RQ-PCR监测提供了最强的预测RFS在APL，再加上先发制人的治疗，提供了一个有效的策略，以减少临床复发率。这为开发更个性化的方法来管理其他分子定义的急性白血病亚型提供了一个模型。J Clin Oncol 27：3650-3658. (C)2009年美国临床肿瘤学会
PurposeMolecular diagnostics and early assessment of treatment response that use methodologies capable of detecting submicroscopic disease can distinguish subgroups of patients with leukemia at differing relapse risk. Such information is being incorporated into risk-stratified protocols; however, there are few data concerning prospective use of sequential minimal residual disease (MRD) monitoring to identify more precisely those patients destined to experience relapse, which would allow more tailored therapies.MethodsReal-time quantitative polymerase chain reaction (RQ-PCR) assays to detect leukemia-specific transcripts (ie, PML-RARA, RARA-PML) were used to prospectively analyze 6,727 serial blood and marrow samples from 406 patients with newly diagnosed acute promyelocytic leukemia (APL) who were receiving all-trans-retinoic acid and anthracycline-based chemotherapy.ResultsMRD monitoring according to the recommended schedule successfully identified the majority of patients subject to relapse and provided the most powerful predictor of relapse-free survival (RFS) in multivariable analysis (hazard ratio, 17.87; 95% CI, 6.88 to 46.41; P < .0001); MRD monitoring was far superior to presenting WBC (hazard ratio, 1.02; 95% CI, 1.00 to 1.03; P = .02), which is currently widely used to guide therapy. In patients who were predicted to experience relapse on the basis of MRD monitoring, early treatment intervention with arsenic trioxide prevented progression to overt relapse in the majority, and the RFS rate at 1 year from molecular relapse was 73%. By using this strategy, 3-year cumulative incidence of clinical relapse was only 5% in the Medical Research Council AML15 trial.ConclusionRigorous sequential RQ-PCR monitoring provides the strongest predictor of RFS in APL and, when coupled with pre-emptive therapy, provides a valid strategy to reduce rates of clinical relapse. This provides a model for development of a more individualized approach to management of other molecularly defined subtypes of acute leukemia. J Clin Oncol 27: 3650-3658. (C) 2009 by American Society of Clinical Oncology