Project 4: Genomic Predictors of Early Relapse in Immunochemotherapy-Treated Follicular Lymphoma

摘要：项目4滤泡性淋巴瘤(FL)是最常见的惰性非霍奇金淋巴瘤和 有一个高度多变的临床过程。无症状和低肿瘤负担的患者最初可以通过 观察或利妥昔单抗治疗，而有症状和高肿瘤负担的患者通常是 确诊时以免疫化疗(IC)为标准治疗。我们已经证明IC治疗的FL 在24个月后达到无事件(即没有疾病进展或再次治疗)状态的患者 诊断(EFS24)有后续预期寿命的背景、年龄和性别匹配的一般 而那些未能实现EFS24的人患有侵袭性疾病，结果很差。其中一个 NCI驱动的外语进步新范式的最高优先事项是解决FL的早期事件，包括 了解潜在的生物学，识别预后和预测性标记，并最终发展 针对这些患者的新的治疗目标和管理策略。我们假设一本小说 生殖系(宿主)和体细胞(肿瘤)基因组生物标记物、肿瘤基因表达和临床的组合 因素，可以提高我们在诊断时预测IC治疗的FL患者将出现早期临床的能力 失败，定义为未能达到EFS24。为了检验这一假设，我们建议识别、验证和 临床翻译种系遗传生物标记物(Aim 1)、体细胞肿瘤基因组生物标记物(Aim 2)和 在IC治疗的FL中未能达到EFS24的表达签名(目标3)，然后开发和验证 新的综合模型(AIM 4)，将临床预后因素与下列生物标志物相结合 目标1-3。为了实现这些目标，我们组建了一支出色的跨学科团队，拥有广泛的 在拟议的研究中提供专业知识。这项研究利用了已建立的淋巴瘤孢子资源， 我们的横向合作(LLMPP、SWOG、Lysa)，以及我们在#年淋巴瘤流行病学方面的领先地位 结果(LEO)队列。我们的创新人口科学项目将是第一个全面 发现和验证种系遗传、肿瘤基因组和基因表达生物标记物未能实现 EFS24。我们设计了具有高内部有效性的研究，重点是使用大的患者队列 拥有高质量的生物标本、临床和结果数据；在生物样本处理方面进行广泛的质量控制 和化验；多阶段研究，外部验证结果，包括使用地理和 来自LEO队列研究的种族/民族多样化的IC治疗FL患者样本，这也增强了 我们结果的推广性。我们的发现-验证和临床翻译的综合方法 应该产生一个可靠的、多参数的预测模型，并有可能对管理层产生重大影响 IC治疗FL患者的最终目标是准确、个性化的患者管理以及新的 对淋巴瘤生物学的洞察也有助于确定治疗靶点。

ABSTRACT: Project 4. Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma and has a highly variable clinical course. Asymptomatic and low-tumor burden patients can initially be managed by observation or rituximab-monotherapy, while symptomatic and high-tumor burden patients are typically managed at diagnosis with immunochemotherapy (IC) as standard of care. We have shown that IC-treated FL patients who achieve event-free (i.e., no disease progression or re-treatment) status at 24 months after diagnosis (EFS24) have the subsequent life expectancy of the background age and sex matched general population, while those who fail to achieve EFS24 have aggressive disease with poor outcomes. One of the highest priorities for the new NCI-driven paradigm for progress in FL is to address early events in FL including understanding the underlying biology, identifying prognostic and predictive markers, and ultimately developing new therapeutic targets and management strategies for these patients. We hypothesize that a novel combination of germline (host) and somatic (tumor) genomic biomarkers, tumor gene expression, and clinical factors, can improve our ability to predict at diagnosis which IC-treated FL patients will have an early clinical failure, defined as failure to achieve EFS24. To test this hypothesis, we propose to identify, validate and clinically translate germline genetic biomarkers (Aim 1), somatic tumor genomic biomarkers (Aim 2), and gene expression signatures (Aim 3) for failure to achieve EFS24 in IC-treated FL and then develop and validate a novel integrative model (Aim 4) that combines clinical prognostic factors with the biomarkers identified from Aims 1-3. To address these aims, we have assembled an outstanding interdisciplinary team with extensive expertise in the proposed studies. The study leverages the established resources of the Lymphoma SPORE, our horizontal collaborations (LLMPP, SWOG, LYSA), and our leadership in the Lymphoma Epidemiology of Outcomes (LEO) cohort. Our innovative population science project will be the first to comprehensively discover and validate germline genetic, tumor genomic, and gene expression biomarkers for failure to achieve EFS24. We have designed studies that have high internal validity, with a focus on use of large patient cohorts with high quality biospecimens, clinical and outcome data; extensive quality control in biologic sample handling and assays; and multi-stage studies with external validation of results, including use of a geographically and racially/ethnically diverse sample of IC-treated FL patients from the LEO cohort study, which also enhances the generalizability of our results. Our comprehensive approach of discovery-validation and clinical translation should yield a reliable, multiparameter, prognostic model, with potential for major impact on the management of IC-treated FL patients with the ultimate goal of accurate, personalized patient management as well as new insights into lymphoma biology that can also aid in identification of therapeutic targets.