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.

急性髓样白血病（AML）是病态病，每年有20,000例新病例和10,000例死亡 在美国，大多数患者可以缓解，但大多数患者的残留疾病量最小 （MRD）最终将导致退休。检测MRD的能力很重要，因为它的存在与 随着退休和死亡的风险增加，并且对调节治疗强度有很大的兴趣 根据MRD的存在或不存在。不幸的是，当前的MRD检测方法患有可变 敏感性，实验室之间的不均匀性能，并且对所有患者缺乏广泛的适用性。有 紧急，未满足的需要更好的MRD检测方法，该方法可以实质上使患者和 其他利益相关者。下一代测序（NGS）允许检测遗传畸变 亚克隆水平。实际上，NGS可能是“通用” MRD测定法的平台。 与其他检测方法不同，NGS会揭示特定的突变，并可能建议靶向疗法。 到目前为止 方法。双工测序是最准确的NGS技术，可以改变MRD检测的范例。 我们团队的成员开创了这项专有技术，并在主要验证研究中证明了 它可以准确地检测出极低水平的白血病克隆。在此快速应用程序的第一阶段，我们 将在我们的测序程序中完善步骤，以促进我们的MRD分析的工业规模部署 验证分析性能。在第二阶段，我们根据银行AML评估评估的绩效 样品。在AIM 1中，我们专注于我们的评估是否对疾病的预后进行了预后。在AIM 2中，我们比较我们的 测定流式细胞仪，这是MRD检测的当前金标准。在AIM 3中，我们比较了 我们对配对的骨髓和外周血样本的评估，以确定我们是否可以实现可比 结果不那么侵入性。最终产品将是一个强大的，具有成本效益且可实施的实验室 开发测试（LDT）准备进行商业部署。该产品将对患者广泛有用， 肿瘤学家和付款人都通过帮助最有可能受益的患者进行直接尖端疗法， 同时保留其他人不必要的医疗和财务毒性。它将允许研究人员和药品 公司可以快速评估新型疗法，使未来的临床试验较小且成本较小。 AML每年夺走数千名患者的生命。患者既死于疾病，也死于 积极的治疗。进行超准确的“通用”测试以检测MRD将允许改进 预后，将为更有效的个性化治疗铺平道路。我们从根本上 认为这样的测试是必要的，并且符合我们的范围，并且我们的团队的位置比任何人都要好 世界其他人将这一进步带给患者。