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

• 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
• 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

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.

摘要 AsystBio LLC提议销售一种名为AML-MutationCounter的分子工具包，用于计算体细胞突变 急性髓细胞白血病（AML）的发病基因。我们开发了一套 用于应用下一代测序来计数AML基因突变的试剂和计算机程序。 该工具包是通用的，可以与两个主要的DNA测序平台，Illumina Hi- Seq和ThermoFisher Ion Proton。每年有2万名美国人患有AML，其中近1万人死于AML。 这种疾病许多患者对初级治疗有反应并达到临床缓解。缓解目前 通过骨髓中白血病母细胞减少至<5%的细胞来确定。一个更敏感和具体的 缓解测试可以指导临床医生获得更持久的缓解并改善患者分层 复发的可能性最近的一项研究发现，48%的缓解期患者保留了AML 在>2.5%的骨髓或血细胞中存在基因突变，这些患者的存活率平均为25%。 在缓解期间清除突变<2.5%的患者中观察到。因此，残留物的存在或不存在 疾病缓解时是高度预后的。缓解后接受骨髓移植的患者 有时显示宿主骨髓的新克隆，称为骨髓嵌合体。重要的是要 尽早确定这些新出现的克隆是否代表复发性白血病， 补救疗法我们在北卡罗来纳州和NC纪念大学的肿瘤学家顾问小组 医院表示对残留和复发的敏感，准确，快速和低成本测试的热情 白血病在第一阶段STTR资助申请中的研究将涉及AsystBio LLC和 位于查佩尔山的北卡罗来纳州大学，生产用于测量AML的分子工具包， 相关的体细胞基因突变。目标1中的研究将确定准确度， 使用模拟数据定量突变等位基因频率的试剂盒的灵敏度和重现性， 标准参考细胞系。目标2中的研究将工具包应用于收集的10份患者样本 在随后的白血病复发之前的缓解期。选择样本以包括 原发性癌症中的NPM 1白血病驱动基因突变缓解期NPM 1突变的存在 样本是一个预后不良的迹象。我们将展示我们的试剂盒检测NPM 1和其他AML中的突变， 在缓解期的相关基因，注定要复发的患者。第一阶段项目展示了 AML-MutationCounter检测AML微小残留和复发疾病的可行性。我们的第二阶段 商业化计划将包括一项临床试验，以确定测试试剂盒的实用性以及积极的市场营销 测试套件的学术医疗中心和商业测试实验室。