Arsenic Trioxide in Primary Curative APL Therapy

描述（由申请人提供）：尽管由于全反式维甲酸（ATRA）的掺入，急性早幼粒细胞白血病（APL）患者的结局显著改善，但多达30%的患者不能用初级治疗治愈。继发性白血病和骨髓增生异常综合征的报告越来越多的治疗后，根据目前的协议，包括三个或更多个周期的巩固化疗。因此，尽量减少暴露于过量的细胞毒性药物，同时保持或增加治愈率必须代表未来发展APL治疗的优先目标。三氧化二砷（ATO）已被证明对复发的APL具有非凡的单药活性，在70 - 90%的患者中诱导完全缓解。本申请中提出的研究调查了ATO纳入新诊断APL的主要治愈性治疗。将进行一项II期多中心临床试验，其中ATO在单个强化巩固周期中替代依托泊苷。这项试验是基于先前的试验，其中一个单一的强化巩固似乎产生了可比的缓解更传统的方案，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，在一个周期的巩固化疗中，ATO替代活性较低的依托泊苷将导致等效的持久缓解和治愈，具有较低的短期和长期毒性。为了能够在快速的时间范围内评估这种试点方法的成功，本研究的主要终点将是确定在一年时维持缓解的频率，其中PML-RAR α转录物在高于10 E-4（预测复发的阈值）时保持不可检测。本试验将利用一种新的定量rt-PCR技术来监测外周血样本的持续缓解充分性和早期复发的证据。这种检测方法将大大减轻患者的疾病监测负担，目前患者每三到六个月接受一次骨髓穿刺。该测定还将能够确定可归因于这种新的巩固方法的肿瘤污染的对数减少。这项试验的成功将有可能在III期试验中测试针对APL的更传统和更广泛的治疗方案。

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.