Arsenic Trioxide in Primary Curative APL Therapy

描述（由申请人提供）：尽管自纳入所有反式维甲酸（ATRA）以来，急性早幼粒细胞白血病（APL）患者的预后有显著改善，但仍有多达30%的患者未通过初始治疗治愈。继发性白血病和骨髓增生异常综合征的报道越来越多，根据目前的治疗方案，包括三个或更多周期的巩固化疗。因此，在保持或提高治愈率的同时，尽量减少过量细胞毒性药物的暴露必须成为未来发展APL治疗的优先目标。三氧化二砷（ATO）对复发性APL表现出非凡的单药活性，在70 - 90%的患者中诱导完全缓解。本研究旨在探讨将ATO纳入新诊断APL的主要治疗方法。将进行一项II期多中心临床试验，在一个强化巩固周期内用ATO代替依托泊苷。该试验基于先前的一项试验，在该试验中，单次强化巩固治疗似乎产生了与更传统的方案相当的缓解，后者包括两到三个周期的巩固治疗，可能最大限度地减少短期和长期毒性，包括继发性恶性肿瘤。总的假设是，在一个巩固化疗周期中，用ATO替代活性较低的依托泊苷将导致相同的持久缓解和治愈，短期和长期毒性较小。为了能够在快速的时间框架内评估该试点方法的成功，本研究的主要终点将是确定pml - rar α转录物在10 E-4（预测复发的阈值）以上仍未检测到的一年内维持缓解的频率。这项试验将利用一种新的定量rt-PCR技术来监测外周血样本，以确定持续缓解的充分性和早期复发的证据。这项检测将大大减轻疾病监测的负担，目前患者每3 - 6个月接受一次骨髓移植。该分析还将能够确定由于这种新的巩固方法导致的肿瘤污染的对数减少。该试验取得成功后，可能会在III期试验中对更常规和更广泛的APL治疗方案进行测试。

DESCRIPTION (provided by applicant): Despite the remarkable improvement in outcome for patients with acute promyelocytic leukemia (APL) since the incorporation of all trans-retinoic acid (ATRA), as many as 30% of patients are not cured with primary therapy. Secondary leukemias and myelodysplastic syndromes are increasingly reported following treatment according to current protocols that include three or more cycles of consolidation chemotherapy. Thus, minimizing exposure to excessive cytotoxic agents while maintaining or increasing the cure rate must represent priority goals for future developmental APL therapy. Arsenic trioxide (ATO) has demonstrated extraordinary single-agent activity against relapsed APL, inducing complete remissions in 70 - 90% of patients. The research proposed in this application investigates the incorporation of ATO into the primary curative therapy of newly diagnosed APL. A Phase II multicenter clinical trial will be performed in which ATO is substituted for etoposide during a single intensive consolidation cycle. This trial is based on a prior trial in which a single intensive consolidation appeared to yield comparable remissions to more conventional regimens which include two to three cycles of consolidation therapy, potentially minimizing short- and long-term toxicity, including secondary malignancies. The overall hypothesis is that substitution of ATO for the less active etoposide in a single cycle of consolidation chemotherapy will lead to equivalent durable remissions and cures, with less short- and long-term toxicity. To enable assessment of the success of this pilot approach in a rapid time frame, the primary endpoint of this study will be the determination of the frequency of maintenance of remissions at one year in which PML-RARalpha transcript remains undetectable above 10 E-4, the threshold which predicts relapse. This trial will utilize a novel quantitative rt-PCR technique to monitor samples of peripheral blood for adequacy of ongoing remission and evidence of early relapse. This assay will greatly ease the burden of disease monitoring for patients, who currently undergo bone marrow aspirations every three - six months. This assay will also enable determination of the log-reduction of tumor contamination attributable to this novel consolidation approach. Success of this trial will potentially be followed by the testing of regimen against more conventional and more extensive treatment for APL in a Phase III trial.