Understanding and predicting relapse in acute myeloid leukemia

项目概要/摘要 复发仍然是白血病治愈的主要障碍。为什么有的患者会复发，而有的患者会痊愈？ 在明显的复发发生之前预测反应并干预替代疗法的能力可以 可能优化治疗，并可能改变特定患者疾病的自然史。我们会 使用 AML 作为模型疾病来证明检测可测量残留疾病 (MRD) 的能力 和基因表达特征来预测治疗反应。对于这些研究，我们将使用档案和 来自美国组间研究的前瞻性样本，以便我们能够准确地将基因变化与 临床特征和结果。在目标 1 中，我们将开发并测试一种新的测序方法，双工测序 测序，可以在一百万个野生动物背景中以一个突变等位基因的频率检测突变 型等位基因。在目标 2 中，我们将测试三个基因表达特征来预测短和长- 长期治疗反应，并发现反应组中不同的途径，这些途径可能是未来治疗的目标 药物治疗。在目标 3 中，我们将上述基因测试应用于同种异体移植环境中，以预测 非清髓性移植（因此直接流产治疗）后复发。我们实验室已经有 在 CML 和 ALL 中使用类似的工具取得了相当大的成功，事实上，这些疾病的 MRD 检测已经取得了巨大的成功。 演变为临床试验结果的替代品。我们同样相信，在反洗钱中，这些目标最终将 允许我们在治疗前预测结果，根据导致预测结果的可能途径选择治疗方法 不良反应，然后监测 MRD，如果 MRD 清除动力学是早期改变治疗 次优。

PROJECT SUMMARY/ABSTRACT Relapse remains the major obstacle to cure in leukemia. Why do some patients relapse, while others are cured? The ability to predict response, and intervene with alternative therapies before frank relapse occurs, can potentially optimize therapy, and potentially change the natural history of a particular patient’s disease. We will use AML as a model disease to demonstrate the power of the detection of measurable residual disease (MRD) and gene expression signatures in predicting treatment response. For these studies we will use archival and prospective samples from U.S. Intergroup studies so that we can accurately associate genetic changes with clinical characteristics and outcomes. In Aim 1 we will develop and test a new sequencing method, duplex sequencing, which can detect a mutation at a frequency of one mutant allele in a background of a million wild type alleles. In Aim 2, we will test three gene expression signatures head to head in predicting short and long- term treatment response, and discover pathways different in the response groups that may be future targets of drug therapy. In Aim 3, we will apply the above genetic tests to the allogeneic transplant setting, to predict relapse following non-myeloablative transplantation (and hence, direct abortive therapy). Our lab has had considerable success in using similar tools in CML and ALL, and indeed, MRD detection in these diseases have evolved to a surrogate for outcome in clinical trials. We likewise believe that in AML these aims will eventually allow us to predict outcome prior to therapy, pick therapies based on likely pathways responsible for the predicted unfavorable response, then monitor MRD, changing therapy early if the kinetics of MRD clearance are suboptimal.