THERAPY-RELATED LEUKEMIA--CLINICAL/BIOLOGIC PREDICTORS

治疗相关白血病——临床/生物预测因子

• 批准号: 2882496
• 负责人: Stella Margaret Davies
• 金额: $ 23.89万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2882496
• 关键词: DNA damage; Ewing's tumor; acute myelogenous leukemia; alkylating agents; antineoplastics; cancer risk; child (0-11); clinical research; drug metabolism; drug screening /evaluation; dyserythropoietic anemia; gene mutation; genetic markers; genetic polymorphism; genotype; glutathione transferase; glycophorin; hematopoiesis; human subject; human therapy evaluation; lymphoma; pediatric neoplasm /cancer; pediatric pharmacology; radiation genetics; skeletal disorder chemotherapy

DESCRIPTION: (Applicant's Abstract) Over the last 20 years marked improvements in survival from childhood cancer have been achieved, at least in part by significant increases in the dose intensity of chemotherapy administered. While this has improved survival from the primary malignancy, increases in dose intensity have been associated with a marked increase in the frequency of therapy-related acute myeloid leukemia or myelodysplasia (t-MDS/AML), with frequencies as high as 22% in a Children's Cancer Group (CCG) treatment protocol for children with Ewing's sarcoma. The applicant hypothesizes that it is possible to identify genetic markers of alkylator damage to predict risk of t-MDS/AML in children receiving high dose-alkylating agent chemotherapy for sarcoma. Additionally, she hypothesizes that host genetic polymorphisms in drug metabolizing enzymes will influence genetic susceptibility to t-MDS/AML and could be used in the future to guide therapy. In this study she will investigate markers of genetic susceptibility and increased risk of t-MDS/AML in 321 children enrolled on CCG sarcoma treatment protocols. She will ask whether genetic susceptibility to alkylating agent damage can be measured prospectively (using analysis of glutathione-S-transferase genotype and glycophorin A mutation frequency). She will look for early signs of development of myeloid malignancy (clonal hematopoiesis), and for acquisition of later genetic events associated with myeloid malignancy (presence of ras gene mutations in peripheral blood leukocytes) in patients who have completed intensive chemotherapy. The identification of markers of genetic susceptibility to t-MDS/AML will allow future modification of therapy for individual patients. The identification of markers of early progression to t-MDS/AML during or after therapy will also allow modification of therapy and/or the development of treatment with chemopreventive agents such as retinoids.

描述：（申请人的摘要）在过去的20年中 至少已经实现了儿童癌症生存的改善 在某种程度上，化学疗法的剂量强度显着升高 管理。 虽然这已经改善了主要恶性肿瘤的生存率，但 剂量强度的增加与明显增加有关 与治疗相关的急性髓样白血病或脊髓增生的频率 （T-MDS/AML），儿童癌组中的频率高达22％ （CCG）Ewing肉瘤儿童的治疗方案。 申请人 假设可以鉴定烷基遗传标记 损害预测受较高儿童的T-MDS/AML的风险 肉瘤的剂量 - 烷基化剂化疗。 另外，她 假设在药物代谢酶中宿主遗传多态性 将影响对T-MDS/AML的遗传敏感性，可用于 指导治疗的未来。 在这项研究中，她将调查 321名儿童的遗传敏感性和T-MDS/AML的风险增加 参加CCG肉瘤治疗方案。 她会问是否遗传 可以预期测量对烷基化剂损伤的敏感性 （使用谷胱甘肽-S-转移酶基因型和糖蛋白A的分析 突变频率）。 她将寻找早期发展的迹象 髓样恶性肿瘤（克隆造血），以便以后获得 与髓样恶性肿瘤相关的遗传事件（RAS基因的存在 已完成的患者的外周血白细胞突变） 强化化疗。 遗传标记的鉴定 对T-MDS/AML的敏感性将允许将来修改治疗 个别患者。 早期进步标记的标志 治疗期间或之后的T-MDS/AML也将允许修改治疗 和/或通过化学预防剂（例如 视网膜类似。