Elimination of Chemotherapy in Newly-Diagnosed APL

新诊断 APL 患者无需化疗

• 批准号: 6646916
• 负责人: ELIHU ESTEY
• 金额: $ 26.4万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6646916
• 关键词: acute myelogenous leukemia; all trans retinol; antineoplastics; arsenic; clinical research; clinical trials; combination chemotherapy; drug adverse effect; gene expression; gene mutation; human subject; longitudinal human study; minimal residual disease; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; oxides; patient oriented research; polymerase chain reaction; relapse /recurrence

DESCRIPTION (provided by applicant): Administration of all-transretinoic acid (ATRA) + myelotoxic chemotherapy results in long-term remission in 70% of patients with newly diagnosed acute promyelocytic leukemia (APL). It is becoming clear however that this approach is associated with development, several years later, of myelodysplastic syndromes and AML. The demonstration of the effectiveness of arsenic trioxide (ATO) in APL makes it feasible to assess, in newly diagnosed APL, whether the combination of ATO + ATRA will enable elimination of myelotoxic therapy. To test this hypothesis (SA#1) we will conduct a trial of ATO + ATRA, with myelotoxic therapy added only if minimal residual disease (MRD), as judged by the standard manual PCR assay, persists or recurs. For safety monitoring we will use a published Bayesian "multiple outcome" design that allows early termination if the rates of either CR, or PCR negativity at 6 months from CR date, are too low. More effective means of measuring MRD would obviously make similar trials more feasible in the future, and SA#2 tests the hypothesis that use of high sensitivity quantitative real-time PCR, rather than the standard assay, and blood rather than marrow will increase the accuracy of current methods. Similarly, understanding of mechanisms underlying resistance to ATRA would increase the possibility of eliminating myelotoxic therapy, and SA#3 tests the hypothesis that addition of ATO to ATRA, while decreasing the overall relapse rate, increases the frequency of missense mutations in the PML-RAR( gene among patients who do relapse.

描述（申请人提供）：全反式维甲酸（ATRA）+骨髓毒性化疗可使70%新诊断的急性早幼粒细胞白血病（APL）患者获得长期缓解。然而，越来越清楚的是，这种方法与几年后骨髓增生异常综合征和AML的发展有关。三氧化二砷（ATO）在APL中的有效性的证明使得在新诊断的APL中评估ATO + ATRA的组合是否能够消除骨髓毒性治疗是可行的。 为了检验这一假设（SA#1），我们将进行一项ATO + ATRA试验，仅当通过标准手动PCR检测判断的微小残留病（MRD）持续存在或复发时，才添加骨髓毒性治疗。对于安全性监测，我们将使用已发表的贝叶斯“多结局”设计，如果CR或CR后6个月PCR阴性率过低，则允许提前终止研究。更有效的测量MRD的方法显然会使类似的试验在未来变得更加可行，SA#2测试了使用高灵敏度定量实时PCR而不是标准测定和血液而不是骨髓将提高当前方法准确性的假设。类似地，了解ATRA耐药的潜在机制将增加消除骨髓毒性治疗的可能性，并且SA#3检验了以下假设：ATRA中添加ATO，同时降低总体复发率，增加复发患者中PML-RAR基因中错义突变的频率。