Arsenic Trioxide in Primary Curative APL Therapy

描述(申请人提供)：尽管自纳入全反式维甲酸(ATRA)以来，急性早幼粒细胞白血病(APL)患者的预后有了显著改善，但多达30%的患者无法通过初级治疗治愈。根据目前的治疗方案，包括三个或更多的巩固化疗周期，继发性白血病和骨髓增生异常综合征的报告越来越多。因此，在保持或提高治愈率的同时，最大限度地减少过量细胞毒剂的暴露，必须成为未来APL开发治疗的优先目标。三氧化二砷(ATO)对复发的APL显示出非凡的单药活性，可使70%-90%的患者完全缓解。本申请中提出的研究旨在探讨ATO在新诊断的APL的主要治疗中的作用。将进行第二阶段多中心临床试验，在单一强化巩固周期中用ATO取代依托泊苷。这项试验是基于先前的一项试验，在该试验中，单一强化巩固似乎产生了与更传统的方案类似的缓解，包括两到三个周期的巩固治疗，潜在地将短期和长期毒性降至最低，包括继发性恶性肿瘤。总体假设是，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同等持久的缓解和治愈，且短期和长期毒性较小。为了能够在快速的时间范围内评估这一试点方法的成功，这项研究的主要终点将是确定PML-RARpha转录本在10E-4以上仍未被检测到的一年的缓解维持频率，10E-4是预测复发的阈值。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，以了解持续缓解的充分性和早期复发的证据。这项检测将极大地减轻患者的疾病监测负担，目前患者每三到六个月进行一次骨髓抽吸。这项检测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。这项试验的成功之后，可能会在第三阶段试验中测试治疗APL的更常规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.