AML-MutationCounter, a tool to detect residual and recurrent leukemia

AML-MutationCounter，检测残留和复发性白血病的工具

基本信息

批准号：
9255447
负责人：
William K. Kaufmann
金额：
$ 22.01万
依托单位：
ASYSTBIO LABORATORIES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9255447
关键词：
Academic Medical Centers Acute Myelocytic Leukemia Affect Alleles American Applications Grants Big Data Biological Biopsy Biopsy Specimen Blast Cell Blood Cells Bone Marrow Bone Marrow Stem Cell Bone Marrow Transplantation Calibration Cell Line Cells Chimerism Clinic Clinical Clinical Trials Collaborations Computational Science Cytopathology DNA Sequence DNA sequencing Data Data Analytics Detection Detection of Minimal Residual Disease Development Disease Disease remission Drug Targeting Flow Cytometry Frequencies Gene Frequency Gene Mutation Gene Targeting Genes Goals Hospitals Ions Laboratories Leukocytes Malignant Neoplasms Marketing Marrow Measurement Medical Medical center Molecular Monitor Mutation NPM1 gene Neoadjuvant Therapy North Carolina Oncologist Outcome Patient Care Patient-Focused Outcomes Patients Pharmaceutical Preparations Phase Polymerase Chain Reaction Protons Reagent Recurrence Recurrent disease Recurrent tumor Reference Standards Relapse Reproducibility Research Personnel Residual Tumors Residual state Salvage Therapy Sampling Small Business Technology Transfer Research Somatic Mutation Specimen Speed Techniques Technology Testing Time Transplantation Universities Work actionable mutation base burden of illness chemotherapy clinical practice clinical remission commercial application commercialization computer program cost improved innovation leukemia literature citation mutant neoplastic cell next generation next generation sequencing patient stratification prognostic research clinical testing response sequencing platform targeted treatment tool

项目摘要

Abstract AsystBio LLC proposes to market a molecular tool kit called AML-MutationCounter to count somatic mutations in genes that contribute to the development of acute myeloid leukemia (AML). We have developed a set of reagents and computer programs for application of next-generation sequencing to count AML gene mutations. The tool kit is versatile and can be used with either of the two major DNA sequencing platforms, Illumina Hi- Seq and ThermoFisher Ion Proton. Every year AML afflicts 20,000 Americans with nearly 10,000 dying from the disease. Many patients respond to primary therapy and achieve clinical remission. Remission is currently determined by a reduction of leukemic blasts in bone marrow to <5% of cells. A more sensitive and specific test for remission may guide clinicians to achieve more durable remission and improve stratification of patients for likelihood of relapse. One recent study found that forty eight percent of patients in remission retained AML gene mutations in >2.5% of marrow or blood cells and these patients’ survival was on average 25% of that seen in patients who cleared mutations to <2.5% during remission. Thus the presence or absence of residual disease at remission is highly prognostic. Patients who receive a bone marrow transplant after remission sometimes display emerging clones of host bone marrow, termed bone marrow chimerism. It is important to determine whether these emerging clones represent recurrent leukemia as early as possible to implement salvage therapies. Our advisory panel of oncologists at the University of North Carolina and NC Memorial Hospital expresses enthusiasm for a sensitive, accurate, rapid and low-cost test for residual and recurrent leukemia. Studies in this Phase I STTR grant application will involve a collaboration between AsystBio LLC and the University of North Carolina at Chapel Hill to produce a molecular tool kit for measurement of AML- associated somatic gene mutations in bone marrow specimens. Studies in Aim 1 will establish the accuracy, sensitivity and reproducibility of the kit for quantification of mutant allele frequencies using simulated data and a standard reference cell line. Studies in Aim 2 will apply the tool kit to 10 patient samples that were collected at the time of remission before a subsequent recurrence of leukemia. Samples are selected to include the NPM1 leukemia-driver gene mutation in the primary cancer. The presence of mutations in NPM1 in remission samples is a poor prognostic sign. We will show that our kit detects mutations in NPM1 and other AML- associated genes at remission in patients that were destined to relapse. This phase I project demonstrates the feasibility of AML-MutationCounter for detection of minimal residual and recurrent disease in AML. Our phase II commercialization plan will include a clinical trial to establish the utility of the test kit as well as active marketing of the test kit to academic medical centers and commercial test laboratories.

抽象的 AsystBio LLC 提议销售一种名为 AML-MutationCounter 的分子工具套件，用于计数体细胞突变我们开发了一套有助于急性髓系白血病 (AML) 发展的基因。应用下一代测序来计数 AML 基因突变的试剂和计算机程序。该工具套件用途广泛，可与两个主要 DNA 测序平台 Illumina Hi- 一起使用。 Seq 和 ThermoFisher Ion Proton 每年都会影响 20,000 名美国人，其中近 10,000 人因此死亡。许多患者对主要治疗有反应，目前已达到临床缓解。通过将骨髓中的白血病细胞减少至 <5% 来测定，更加灵敏和特异。缓解测试可能有助于实现更持久的缓解并改善患者分层最近的一项研究发现，48% 的缓解期患者保留了 AML。 >2.5% 的骨髓或血细胞发生基因突变，这些患者的生存率平均为 25% 见于缓解期间突变清除率<2.5%的患者，因此存在或不存在残留。病情缓解后接受骨髓移植的患者预后良好。有时会出现宿主骨髓的新克隆，称为骨髓嵌合现象，这一点很重要。尽早确定这些新出现的克隆是否代表复发性白血病我们的北卡罗来纳大学和北卡罗来纳大学纪念馆的肿瘤学家顾问小组。医院对灵敏、准确、快速且低成本的残留和复发检测表示热情这一阶段 STTR 拨款申请的研究将涉及 AsystBio LLC 和北卡罗来纳大学教堂山分校生产用于测量 AML 的分子工具包目标 1 中的相关体细胞基因突变研究将确定准确性，使用模拟数据量化突变等位基因频率的试剂盒的灵敏度和重现性目标 2 中的研究将将该工具包应用于收集的 10 个患者样本。在随后白血病复发之前的缓解时选择样本以包括原发性癌症中 NPM1 白血病驱动基因突变缓解期 NPM1 中存在突变。样本是一个不良的预后标志，我们将证明我们的试剂盒可检测 NPM1 和其他 AML 的突变。注定会复发的患者在缓解时的相关基因这一阶段的项目证明了这一点。 AML-MutationCounter 用于检测 AML 中微小残留和复发性疾病的可行性。商业化计划将包括建立测试套件实用性的临床试验以及积极的营销将该测试套件提供给学术医疗中心和商业测试实验室。