Elimination of Chemotherapy in Newly-Diagnosed APL

描述（由申请人提供）：在70%的新诊断的急性早幼粒细胞白血病（APL）患者中，全经维甲酸(ATRA) +髓毒性化疗可导致长期缓解。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，使得评估ATO + ATRA是否能够消除新诊断的APL的骨髓毒性治疗成为可能。为了验证这一假设（SA#1），我们将进行ATO + ATRA的试验，仅当通过标准手工PCR检测判断的最小残留疾病（MRD）持续或复发时，才添加髓毒性治疗。对于安全监测，我们将使用已发表的贝叶斯“多结果”设计，如果CR或PCR阴性在CR日期后6个月的比率过低，则允许早期终止。更有效的MRD测量方法显然会使未来类似的试验更加可行，SA#2验证了这样一个假设，即使用高灵敏度的实时定量PCR而不是标准的测定方法，使用血液而不是骨髓将提高当前方法的准确性。同样，了解ATRA耐药机制将增加消除骨髓毒性治疗的可能性，SA#3验证了在ATRA中加入ATO的假设，虽然降低了总体复发率，但增加了复发患者PML-RAR基因错义突变的频率。

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.