THERAPY-RELATED LEUKEMIA--CLINICAL/BIOLOGIC PREDICTORS

描述：(申请人摘要)在过去的20年中标记 至少，儿童癌症的存活率已经取得了改善 部分原因是化疗剂量强度显著增加 管理。虽然这提高了原发恶性肿瘤的存活率， 剂量强度的增加与显著增加的 与治疗相关的急性髓系白血病或骨髓发育不良的发生率 (T-MDS/AML)，在儿童癌症组中频率高达22% (CCG)治疗儿童尤文氏肉瘤的方案。申请人 假设有可能识别烷基化子的遗传标记 损伤预测高危儿童t-MDS/AML的风险 肉瘤的剂量-烷化剂化疗。此外，她还 药物代谢酶存在遗传多态的假说 将影响t-MDS/AML的遗传易感性，并可用于 指导未来的治疗。在这项研究中，她将研究 321名儿童t-MDS/AML的遗传易感性和风险增加 登记参加CCG肉瘤治疗方案。她会问基因是否 对烷化剂损伤的敏感性可以前瞻性地进行测量 谷胱甘肽-S-转移酶基因分型和血糖蛋白A分析 突变频率)。她将寻找发展的早期迹象 髓系恶性肿瘤(克隆性造血)，以及后来的获得性 与髓系恶性肿瘤相关的遗传事件(存在ras基因 外周血白细胞突变) 强化化疗。遗传标记的鉴定 对t-MDS/AML的敏感性将允许未来修改治疗 个别病人。肿瘤早期进展的标志物鉴定 T-MDS/AML在治疗期间或治疗后也将允许修改治疗 和/或发展化学预防药物的治疗，如 维甲酸。

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.