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: 9925187
• 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 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925187
• 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; aggressive therapy; base; cancer cell differentiation; cancer diagnosis; chemotherapy; cost; cost effective; driver mutation; 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）是一种病态的疾病，每年有超过20,000例新病例和10,000例死亡