THERAPY-RELATED LEUKEMIA--CLINICAL/BIOLOGIC PREDICTORS

描述：（申请人的摘要）在过去的20年里， 儿童癌症存活率的提高至少已经实现， 部分原因是化疗剂量强度的显著增加 管理。 虽然这提高了原发性恶性肿瘤的生存率， 剂量强度的增加与 治疗相关急性髓细胞白血病或骨髓增生异常的频率 （t-MDS/AML），在儿童癌症组中的频率高达22% (CCG)尤文氏肉瘤患儿的治疗方案 申请人 假设有可能鉴定烷化剂的遗传标记， 损害，以预测儿童接受高剂量的t-MDS/AML的风险 剂量烷化剂化疗肉瘤。 她还 假设宿主药物代谢酶的遗传多态性 将影响对t-MDS/AML的遗传易感性，并可用于 未来，指导治疗。 在这项研究中，她将调查 321例儿童t-MDS/AML的遗传易感性和风险增加 CCG肉瘤治疗方案的患者。 她会问是否遗传 对烷基化剂损害的敏感性可以前瞻性地测量 （使用谷胱甘肽-S-转移酶基因型和血型糖蛋白A分析） 突变频率）。 她将寻找早期的发展迹象， 骨髓恶性肿瘤（克隆性造血），并为收购后 与骨髓恶性肿瘤相关的遗传事件（ras基因的存在 外周血白细胞中的突变）， 强化化疗 遗传标记的鉴定 对t-MDS/AML的易感性将允许未来修改治疗， 个别患者。 识别早期进展到 治疗期间或治疗后的t-MDS/AML也允许调整治疗 和/或用化学预防剂治疗的发展， 类维生素A。

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.