Impact of Oncologic Therapy on Clonal Hematopoiesis and Subsequent Risk of Therapy-Related Leukemia

肿瘤治疗对克隆造血的影响以及治疗相关白血病的后续风险

• 批准号: 10248480
• 负责人: Kelly Leigh Bolton
• 金额: $ 23.89万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10248480
• 关键词: Adenosine Diphosphate; Adenosine Diphosphate Ribose; Affect; Aftercare; Automobile Driving; Biological; Blood; Blood Banks; Blood Cells; Blood specimen; Cancer Patient; Cancer Survivor; Cancer Survivorship; Characteristics; Chemotherapy and/or radiation; Clinical; Clinical Treatment; Clonal Expansion; Collection; Constitutional; Data; Databases; Development; Disease; Drug Combinations; Exposure to; Future; Genes; Genetic; Genomics; Guidelines; Hematological Disease; Hematology; Hematopoiesis; Incidence; Individual; Intervention; Lead; Link; Malignant Neoplasms; Molecular; Molecular Profiling; Mutation; Myeloproliferative disease; Patients; Pattern; Persons; Polymerase; Population; Prevention Protocols; Prevention strategy; Primary Neoplasm; Radiation therapy; Recording of previous events; Regimen; Research; Research Proposals; Resistance; Resources; Risk; Risk Assessment; Sampling; Shapes; Site; Solid Neoplasm; Somatic Mutation; Testing; Topoisomerase-II Inhibitor; Translational Research; Treatment outcome; Treatment-Associated Neoplasms; Variant; Work; aged; base; blood treatment; cancer care; chemotherapy; clinical care; clinical decision support; cohort; deep sequencing; design; evidence base; high risk; inhibitor; insight; leukemia; patient population; patient subsets; predictive modeling; prospective; risk prediction model; risk stratification; survivorship; therapeutic development; therapy development; tumor

ABSTRACT Cancer survivors across most primary tumor types are at a heightened risk for secondary myeloid neoplasms (tMN), a highly lethal disease. However, the mechanism underlying this association and the patient populations at adequately high risk to warrant intervention are not well-established. Clonal hematopoiesis (CH) is a pre- leukemic state that confers a substantially increased risk of tMN. We have developed a database of 17,500 patients who have undergone targeted blood sequencing with associated comprehensive clinical annotation. Preliminary data from this cohort shows that exposure to specific oncologic therapies is associated with CH. We show that subsets of patients at high risk of tMN can be defined based on CH mutational and clinical characteristics. Our central hypothesis is that CH can be used to predict tMN risk and that this “high-risk” CH is promoted by exposure to specific oncologic therapies. First, we propose to characterize how prior exposure specific oncologic therapies is related to the presence of CH and clonal expansion. We will study this in 25,000 solid tumor patients who were tested for CH through routine clinical molecular profiling workup. We will compare CH mutational characteristics among previously treated (60%) and untreated (40%) solid tumor patients. Second, we will define the molecular and clinical features associated with myeloid neoplasm in solid tumor patients. This will be achieved though sequencing of tMN cases and matched controls selected from bio-banked blood samples of solid tumor patients. We hypothesize that consideration of CH molecular features in combination with clinical factors and treatment exposures predict development of myeloid neoplasm development in cancer patients. This will result in the development of a risk-prediction model for t-MN development in solid tumor patients. Third, we will define the timing of CH mutation acquisition in patients receiving high-risk therapy through serial mutational profiling. We hypothesize that exposure to high-risk therapy drives clonal expansion of pre-existing CH clones present in low levels in pre-treatment blood samples. To achieve this, prospective collection of pre-treatment, mid-treatment and post-treatment blood samples will be undertaken. Our research proposal is designed to deliver a statistically powered and evidence-based resource that will enable a detail understanding of the relationships between CH, treatment exposures and subsequent risk of tMN. Our findings will enable the development of genomic based risk assessment of tMN in solid tumor patients. This will guide rational treatment decisions for solid tumor patients across a variety of primary sites aimed at minimization of tMN risk, a major barrier to long-term survival.

抽象的 大多数原发肿瘤类型的癌症幸存者患继发性骨髓肿瘤的风险较高 (tMN)，一种高度致命的疾病。然而，这种关联的潜在机制和患者群体 风险足够高而需要干预的措施尚未确定。克隆造血（CH）是一种预 导致 tMN 风险显着增加的白血病状态。我们开发了一个包含 17,500 条信息的数据库 接受过靶向血液测序以及相关综合临床注释的患者。 该队列的初步数据表明，接受特定肿瘤治疗与 CH 相关。我们 表明 tMN 高风险患者的子集可以根据 CH 突变和临床来定义 特征。我们的中心假设是 CH 可用于预测 tMN 风险，并且这种“高风险”CH 是 通过接触特定的肿瘤治疗来促进。首先，我们建议描述先前暴露如何 特定的肿瘤治疗与 CH 的存在和克隆扩张有关。我们将在 25,000 年内研究这个 通过常规临床分子分析检查进行 CH 检测的实体瘤患者。我们会比较 既往治疗（60%）和未治疗（40%）实体瘤患者的 CH 突变特征。 其次，我们将定义实体瘤中与髓系肿瘤相关的分子和临床特征 患者。这将通过对 tMN 病例进行测序并从生物库中选择匹配的对照来实现 实体瘤患者的血液样本。我们假设考虑到 CH 分子特征 结合临床因素和治疗暴露可预测骨髓肿瘤的发展 癌症患者的发展。这将导致 t-MN 风险预测模型的开发 实体瘤患者的发展。第三，我们将定义患者获得CH突变的时间 通过连续突变分析接受高风险治疗。我们假设暴露于高风险治疗 驱动治疗前血液样本中低水平存在的现有 CH 克隆的克隆扩增。到 为了实现这一目标，将前瞻性地收集治疗前、治疗中和治疗后的血液样本 进行。我们的研究提案旨在提供统计支持和基于证据的资源 这将有助于详细了解 CH、治疗暴露和后续治疗之间的关系 tMN 的风险。我们的研究结果将有助于开发基于基因组的实体瘤 tMN 风险评估 患者。这将指导不同原发部位的实体瘤患者的合理治疗决策 旨在最大限度地降低 tMN 风险，这是长期生存的主要障碍。