Development of a Universal Assay for Minimal Residual Disease in Acute Myeloid Leukemia using Duplex Sequencing

使用双重测序开发急性髓系白血病微小残留病的通用检测方法

• 批准号: 9892103
• 负责人: Jerald Patrick Radich
• 金额: $ 69.02万
• 依托单位: TWINSTRAND BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-16 至 2021-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892103
• 关键词: Acute Myelocytic Leukemia; Aspirate substance; Biological; Biological Assay; Blood specimen; Bone Marrow; Caring; Cessation of life; Clinical Trials; Collection; Cytogenetics; DNA; DNA sequencing; Detection; Development; Diagnostic; Diagnostic Services; Disease; Disease remission; Evaluation; Fingerprint; Flow Cytometry; Frequencies; Future; Genetic; Gold; Incidence; Industrialization; Insurance Carriers; Laboratories; Lead; Leukemic Cell; Marrow; Measures; Medical; Medicine; Methods; Microscope; Morphology; Mutation; New Drug Approvals; Normal Cell; Oncologist; Patients; Performance; Pharmacologic Substance; Phase; Pilot Projects; Positioning Attribute; Predictive Value; Procedures; Recurrence; Recurrent disease; Regulation; Relapse; Reproducibility; Research Personnel; Residual Neoplasm; Residual Tumors; Residual state; Running; Sales; Sampling; Small Business Innovation Research Grant; Stem cell transplant; Surrogate Endpoint; Technology; Technology Assessment; Testing; Time; United States; Variant; Work; actionable mutation; base; cancer cell differentiation; cancer diagnosis; chemotherapy; cost; cost effective; drug development; exome; financial toxicity; high risk; improved; improved outcome; interest; leukemia; light microscopy; member; mortality; next generation; next generation sequencing; novel therapeutics; patient subsets; peripheral blood; personalized medicine; prognostic; prognostic value; relapse prediction; relapse risk; sample collection; service providers; survival outcome; targeted treatment; tool; virtual

Acute myeloid leukemia (AML) is a morbid condition, with over 20,000 new cases and 10,000 deaths annually in the U.S. While the majority of patients achieve remission, most harbor minimal amounts of residual disease (MRD) that will ultimately lead to relapse. The ability to detect MRD is important as its presence is associated with increased risk of relapse and death, and there is considerable interest in modulating treatment intensity based on the presence or absence of MRD. Unfortunately, current MRD detection methods suffer from variable sensitivity, non-uniform performance across laboratories, and lack of broad applicability to all patients. There is an urgent, unmet need for a better MRD detection method, which could substantially benefit patients as well as other stakeholders. Next generation sequencing (NGS) permits detection of genetic aberrations on the subclonal level. As virtually all AML harbors mutations, NGS could be a platform for a “universal” MRD assay. Unlike other detection methods, NGS would reveal specific mutations and could suggest targeted therapies. Enthusiasm for NGS for MRD detection has, until now, been tempered by the relatively poor sensitivity of this method. Duplex Sequencing, the most accurate NGS technology, can change the paradigm for MRD detection. Members of our team pioneered this proprietary technology and demonstrated in proof-of-principal studies that it can accurately detect leukemic clones at extremely low levels. In Phase I of this Fast Track application, we will refine steps in our sequencing procedures to facilitate industrial-scale deployment of our MRD assay and validate analytical performance. In Phase II, we assess our assay's performance based on banked AML samples. In Aim 1, we focus on whether our assay is prognostic of disease relapse. In Aim 2, we compare our assay to flow cytometry, the current gold standard for MRD detection. In Aim 3, we compare performance of our assay on paired bone marrow and peripheral blood samples to determine if we can achieve comparable results less invasively. The final product will be a robust, cost-effective, and implementable Laboratory Developed Test (LDT) ready for commercial deployment. This product will be widely useful for patients, oncologists, and payers alike by helping direct cutting-edge therapies to the patients most likely to benefit, while sparing others unnecessary medical and financial toxicities. It will allow researchers and pharmaceutical companies to rapidly evaluate novel therapies, permitting future clinical trials to be smaller and less costly. AML takes the lives of thousands of patients every year. Patients die both from the disease and from the aggressive treatment. Having an ultra-accurate “universal” test to detect MRD would allow for improved prognostication and would pave the way for more efficacious personalized treatment. We fundamentally believe that such a test is necessary and well within our reach, and that our team is positioned better than any other in the world to bring this advance to patients.

急性髓性白血病（AML）是一种病态，每年有超过20，000例新发病例和10，000例死亡 在美国，虽然大多数患者获得缓解，但大多数患者存在少量残留疾病 (MRD)最终会导致复发检测MRD的能力很重要，因为其存在与 复发和死亡的风险增加，并且对调节治疗强度有相当大的兴趣 基于MRD的存在或不存在。不幸的是，目前的MRD检测方法受到可变的 灵敏度、实验室间的不一致性能以及缺乏对所有患者的广泛适用性。有 迫切需要一种更好的MRD检测方法，这种方法可以使患者受益， 其他利益攸关方。下一代测序（NGS）允许检测基因组上的遗传畸变。 亚克隆水平由于几乎所有AML都含有突变，NGS可以成为“通用”MRD测定的平台。 与其他检测方法不同，NGS将揭示特定的突变，并可能建议靶向治疗。 到目前为止，由于灵敏度相对较差，人们对NGS用于MRD检测的热情有所减弱 法双链测序是最准确的NGS技术，可以改变MRD检测的范式。 我们的团队成员率先开发了这项专有技术，并在主要研究证明中证明， 它可以在极低的水平上准确地检测白血病克隆。在此快速通道申请的第一阶段，我们 将完善我们测序程序中的步骤，以促进我们MRD检测的工业规模部署， 验证分析性能。在第二阶段，我们根据库存AML评估我们的检测性能 样品在目标1中，我们重点关注我们的检测方法是否可以预测疾病复发。在目标2中，我们比较了 流式细胞术是目前MRD检测的金标准。在目标3中，我们比较了 我们对配对的骨髓和外周血样本进行检测，以确定我们是否可以达到可比的 侵入性更低。最终产品将是一个强大的、具有成本效益的和可实施的实验室 已开发测试（LDT）可用于商业部署。该产品将广泛用于患者， 肿瘤学家和付款人都通过帮助最有可能受益的患者直接进行尖端治疗， 同时避免其他人不必要的医疗和财务毒性。它将允许研究人员和制药公司 公司快速评估新的疗法，允许未来的临床试验规模更小，成本更低。 AML每年夺去数千名患者的生命。病人死于这种疾病和 积极治疗有一个超准确的“通用”测试来检测MRD将允许改善 这将为更有效的个性化治疗铺平道路。我们从根本上 我相信这样的测试是必要的，也是我们力所能及的，我们的团队比任何人都更有能力 将这一进步带给患者。