THERAPY-RELATED LEUKEMIA--CLINICAL/BIOLOGIC PREDICTORS

治疗相关白血病——临床/生物预测因子

• 批准号: 2451173
• 负责人: Stella Margaret Davies
• 金额: $ 24.4万
• 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/2451173
• 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 20 年里 至少已经实现了儿童癌症生存率的提高 部分原因是化疗剂量强度的显着增加 管理。 虽然这提高了原发恶性肿瘤的生存率， 剂量强度的增加与显着增加有关 治疗相关的急性髓系白血病或骨髓增生异常的频率 (t-MDS/AML)，在儿童癌症组中发生率高达 22% (CCG) 尤文氏肉瘤儿童的治疗方案。 申请人 假设有可能识别烷化剂的遗传标记 损害预测接受高剂量治疗的儿童患 t-MDS/AML 的风险 肉瘤的剂量烷化剂化疗。 此外，她 药物代谢酶中存在遗传多态性的假设 将影响对 t-MDS/AML 的遗传易感性，可用于 未来指导治疗。 在这项研究中，她将研究 321 名儿童的遗传易感性和 t-MDS/AML 风险增加 参加 CCG 肉瘤治疗方案。 她会询问是否遗传 可以前瞻性地测量对烷化剂损害的敏感性 （使用谷胱甘肽-S-转移酶基因型和血型糖蛋白 A 的分析 突变频率）。 她将寻找发展的早期迹象 骨髓恶性肿瘤（克隆造血），以及用于后来获得 与骨髓恶性肿瘤相关的遗传事件（存在 ras 基因） 外周血白细胞突变）已完成的患者 强化化疗。 遗传标记的鉴定 对 t-MDS/AML 的易感性将允许未来对治疗进行修改 个别患者。 早期进展标志物的鉴定 治疗期间或治疗后的 t-MDS/AML 也将允许调整治疗 和/或开发化学预防剂治疗，例如 类维生素A。