Discovery and Optimization of AML Prognostic Biomarkers

描述（由申请人提供）：AML是最常见和最致命的造血恶性肿瘤之一。目前，有必要提高现有预后生物标志物的预测性质，并开发更精确的AML患者风险分层方法。为了满足这些需求，我们将通过检测AML原细胞亚群中的这些生物标志物来确定生物标志物检测是否可以显著改进。此外，我们将开发结合生物标志物结果和其他预后因素的风险评估模型，以更准确地预测临床结果。具体目标确定在AML原细胞富集人群中测量生物标志物是否能显著提高其预测准确性。诊断样本将从小儿（N = 250）和成人（N = 192） AML患者中获得。先前确认的基因组（如FLT3等）和转录本(如；将在这些诊断样本中的4个细胞群中检测生物标志物：单个核细胞（MNCs）、总AML原细胞、高分化AML原细胞和低分化AML原细胞。纳入其他预后因素影响的多变量分析将用于确定与临床结果的独立关联。性能特征的比较分析将用于确定在富集的AML原细胞群体（包括分化程度较低的AML原细胞）中测量生物标志物是否能显著提高生物标志物的预测准确性。具体目标2。开发和验证用于预测AML患者临床结果的新型风险评估模型。利用Specific Aim 1产生的数据，我们将开发以下临床结果的风险评估模型：完全缓解（CR）、耐药（RD）、无复发生存（RFS）和总生存（OS）。这些模型将结合最具预测性的生物标志物的结果，无论是否在AML原细胞富集群体中，以及其他风险因素（年龄、细胞遗传学、性能状态等）。我们最初将为每个结果和两种患者群体（即儿童和成人，分别）独立开发这些模型。然而，我们也将研究是否可以建立一个综合的风险评估模型，预测儿科和成人人群的多种临床结果（CR、RD、RFS和OS）。然后，我们将在类似治疗的儿童（N = 250）和成人（N = 191）患者中验证这些预测模型。

DESCRIPTION (provided by applicant): AML is one of the most common and lethal hematopoietic malignancies. Currently, there is a need to improve the predictive nature of available prognostic biomarkers and to develop more precise methods for risk- stratifying AML patients. In keeping with these needs, we will determine whether biomarker assays can be significantly improved by examining these biomarkers in subpopulations of AML blasts. Furthermore, we will develop risk-assessment models using a combination of biomarker results and other prognostic factors that will more accurately predict clinical outcomes. Specific Aim 1. Determine if measuring biomarkers in enriched populations of AML blasts significantly improves their predictive accuracy. Diagnostic samples will be obtained from pediatric (N = 250) and adult (N = 192) patients with AML. Previously recognized genomic (e.g., FLT3, etc.) and transcript(e.g., BAALC, etc.) biomarkers will be examined in 4 cell populations from these diagnostic samples: mononuclear cells (MNCs), total AML blasts, more differentiated AML blasts, and less differentiated AML blasts. Multivariate analyses, incorporating the effects of other prognostic factors, will be used to identify independent associations with clinical outcomes. Comparative analyses of performance characteristics will be used to determine if measuring the biomarker in enriched populations of AML blasts, including the less differentiated AML blasts, significantly improves the predictive accuracy of the biomarker. Specific Aim 2. Develop and validate novel risk-assessment models for predicting clinical outcomes for AML patients. Using the data generated from Specific Aim 1, we will develop risk-assessment models for the following clinical outcomes: complete response (CR), resistant disease (RD), relapse-free survival (RFS), and overall survival (OS). These models will combine the results from the most predictive biomarkers, whether in enriched populations of AML blasts or not, with other risk factors (age, cytogenetics, performance status, etc.). We will initially develop these models independently for each outcome and the two populations of patients (i.e., children and adult, separately). However, we will also examine whether a comprehensive risk- assessment model can be developed, which predicts for multiple clinical outcomes (CR, RD, RFS, and OS) across both pediatric and adult populations. We will then validate these predictive models in similarly treated populations of pediatric (N = 250) and adult (N = 191) patients.