Clonal hematopoiesis and therapy-emergent myeloid neoplasms in patients with ovarian cancer

摘要 大多数被诊断为卵巢癌的妇女都接受了多轮化疗和 多年来经常服用一种PARP抑制剂药物进行“维持”治疗。这些疗法有 延长转移性卵巢癌患者的生命，但代价是毒性增加。 一种长期的毒性是白血病或其他血液疾病的发展，通常被称为 与治疗相关的髓系肿瘤(TMN)。这些继发性恶性肿瘤是一种已知的 化疗，而卵巢癌幸存者的TMN发生率是所有组中最高的之一 癌症幸存者。TMN的诊断通常是致命的，生存时间以几个月为单位。 TMN几乎总是在癌前状态下作为血细胞的克隆性增殖而被检测到 几年后才能做出临床诊断。非恶性克隆性白血球增殖症 称为不确定潜能克隆性造血(CHIP)。芯片和芯片之间的间隔 血癌的发展是多年的，提供了一个更好地了解 TMN的自然发展，也许是干预和预防的窗口。克隆性 在正常的衰老过程中也会出现造血(CH)，但只有一小部分进展到 血癌。更好地了解卵巢癌的自然发展过程 幸存者需要量身定做安全有效的卵巢癌治疗方法。我们的团队由以下人员共同领导 卵巢癌遗传学和血液系统恶性疾病方面的专家，将于2000年招生 全国范围内卵巢癌的幸存者，包括200名CH患者。我们将遵循这些原则 连续抽血的慢性丙型肝炎患者在至少3年内每6个月采集一次血 明确CH向TMN进展的风险因素。对于一部分患者来说，他们已经获得了 TMN在研究期间，我们将评估克隆动力学以及遗传和染色体 随着时间的推移，单细胞水平的变化，这将提供关于变化的新数据 发生在髓系细胞恶性转化中，对细胞毒治疗的反应。在这 通过这种方式，我们将了解谁有感染TMN的风险，并制定监测和 预防这种致命的长期治疗毒性。这些研究将改善以下方面的结果 卵巢癌患者，也将适用于幸存者或多种癌症类型， 也面临着TMN的风险。

ABSTRACT Most women diagnosed with ovarian cancer are treated with many rounds of chemotherapy and often years of a an oral PARP inhibitor drug for “maintenance” therapy. These therapies have extended life for women with metastatic ovarian cancer, but at the cost of increased toxicity. One long term toxicity is the development of leukemia or other blood disorders, often called therapy related myeloid neoplasia (TMN). These secondary malignancies are a known risk of chemotherapy, and ovarian cancer survivors have one of the highest rates of TMN of any group of cancer survivors. The diagnosis of TMN is usually fatal, with survival measured in months. TMN is nearly always detectable in a pre-malignant state as a clonal expansion of blood cells years before a clinical diagnosis. Non-malignant clonal expansion of white blood cells is often termed clonal hematopoiesis of indeterminate potential (CHIP). The interval between CHIP and development of blood cancers is many years, providing an opportunity to better understand the natural progression of TMN and perhaps a window for intervention and prevention. Clonal hematopoiesis (CH) can also arise during normal aging, but only a small fraction progress to a blood cancer. A better understanding of the natural progression of CH in ovarian cancer survivors is needed to tailor safe and effective ovarian cancer therapies. Our team is co-led by experts in ovarian cancer genetics and hematological malignancies and will enroll 2000 survivors across the country with ovarian cancer, including 200 with CH. We will follow these individuals with CH with serial blood draws obtained every 6 months for at least 3 years to define risk factors for progression of CH to TMN. For a subset of patients with acquisition of TMN during the study, we will evaluate clonal dynamics and genetic and chromosomal alterations over time at the single cell level, which will provide novel data on the changes that occur in the malignant transformation of myeloid cells in response to cytotoxic therapy. In this way, we will learn who is at risk of TMN and develop strategies for the monitoring and prevention of this deadly long-term treatment toxicity. These studies will improve outcomes for patients with ovarian cancer and also will be applicable to survivors or many cancer types, who are also at risk for TMN.