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

摘要 大多数原发肿瘤类型的癌症幸存者患继发性髓系肿瘤的风险较高 (TMN)，一种高度致命的疾病。然而，这种联系背后的机制和患者群体 存在足够高的风险，需要进行干预，这是不成立的。克隆性造血(CH)是一种前造血系统。 白血病状态会显著增加患TMN的风险。我们已经开发了一个有17,500人的数据库 接受了靶向血液测序的患者，并有相关的全面临床注释。 来自该队列的初步数据显示，暴露于特定的肿瘤治疗与CH有关。我们 表明TMN高危患者的亚群可以基于CH突变和临床来定义 特点。我们的中心假设是CH可以用来预测TMN风险，并且这种“高风险”的CH是 通过接触特定的肿瘤治疗而促进。首先，我们建议描述以前的暴露是如何 特异性的肿瘤治疗与CH的存在和克隆性扩张有关。我们将在25,000人中研究这一点 实体瘤患者通过常规的临床分子图谱检查进行CH检测。我们会比较一下 既往治疗(60%)和未治疗(40%)实体瘤患者的CH突变特征。 第二，我们将定义与实体瘤中髓系肿瘤相关的分子和临床特征。 病人。这将通过对TMN病例和从生物库中选择的匹配对照进行排序来实现 实体瘤患者的血液样本。我们假设，在考虑CH分子特征的情况下 结合临床因素和治疗暴露预测髓系肿瘤的发展 癌症患者的发展。这将导致针对t-MN的风险预测模型的开发 实体瘤患者的发展。第三，我们将确定患者获取CH突变的时间 通过序列突变图谱接受高风险治疗。我们假设暴露在高风险疗法中 推动在治疗前血液样本中低水平存在的预先存在的CH克隆的克隆性扩展。至 要做到这一点，预期将收集治疗前、治疗中期和治疗后的血液样本 承担了。我们的研究提案旨在提供统计数据支持和基于证据的资源 这将使我们能够详细了解CH、治疗暴露和随后 患TMN的风险。我们的发现将使基于基因组的实体瘤TMN风险评估的发展成为可能 病人。这将指导跨各种原发部位的实体肿瘤患者的合理治疗决定 旨在将TMN风险降至最低，这是长期生存的主要障碍。

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.