A Randomized Trial Assessing the Role of Arsenic Trioxide and/or ATRA During Consolidation Course in Newly Diagnosed Acute Promyelocytic Leukemia (APL)
试验速览
- 阶段
- 3 期
- 入组人数
- 800
- 试验地点
- 2
- 主要终点
- For Patients aged 70 years or less with WBC<10.000/mm3, The primary end point will be event free survival at 2 years from CR achievement
研究概览
简要总结
To assess the role of Arsenic trioxide and/or ATRA during consolidation course in APL. It is hoped that the investigational arms will further increase the event-free survival at 2 years, with reduced toxicity and without increasing the relapse rate by comparison with a classical anthracycline-AraC consolidation regimen.
详细描述
Definition: Extended description of the protocol, including information not already contained in other fields, such as comparison(s) studied.
APL is a specific type of acute myeloid leukemia (AML) characterized by its morphology (M3 or M3v in the FAB classification), t(15;17) translocation leading to PML-RARa fusion gene, and by a specific coagulopathy combining D.I.C., fibrinolysis and non specific proteolysis. ATRA can differentiate APL blasts in VITRO and in vivo. The combination of ATRA and anthracycline based chemotherapy yields CR rates greater than 90% in newly diagnosed APL. With early introduction of anthracycline AraC chemotherapy during induction treatment, and maintenance combining continuous 6MP and MTX to intermittent ATRA, the relapse risk in APL therefore now appears to be in the range of 10 to 15%.
Nevertheless, 5 to 10% of the patients do not achieve CR and 10% to 15% still relapse. Another subset of patients (5 to 7% in APL 93 trial including 17% of patients aged greater than 65 years) die in CR, from complications of the consolidation treatment phase, mainly from infection during chemotherapy induced aplasia. Failure to achieve CR with current treatment approaches is almost exclusively due to early death during induction treatment. Causes of death are predominantly bleeding, ATRA syndrome and less often infection. Early deaths predominate in elderly patients and patients with high WBC counts. Reducing the amount of chemotherapy administered to newly diagnosed APL patients diminishes this toxicity. The Spanish PETHEMA group reported results of two successive phase II trials in newly diagnosed APL with ATRA and chemotherapy with intercalating agents (idarubicin and mitoxantrone) without AraC followed by maintenance combining ATRA and low dose chemotherapy (LPA96 and LPA99 trials). Results appeared similar to those of the best arm of APL 93 trial, but with less toxicity and only 2 to 3 % death in CR were seen, including in elderly patients.
Arsenic trioxide (As2O3 or ATO) is an effective agent in relapsing or refractory APL, which induced 85% hematological and 79% molecular CR rates in a pivotal US study. The interest of ATO in the front-line therapy of newly-diagnosed APL has been strongly suggested in three studies which showed high complete remission rate, low incidence of relapse and limited toxicity.
In this study, patients will be stratified based on age (≤ 70 years and > 70 years) and WBC count at diagnosis (WBC<10.000/mm3 and >10.000 /mm3).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of APL based on morphological grounds, which will have to be confirmed by the presence of t(15;17) and/or PML-RARA rearrangement with characterization of the bcr subtype (PML-RAR characterization).
- •Untreated patients.
- •No contraindication to intensive chemotherapy (especially well documented cardiac contraindication to idarubicin).
- •In female patients: absence of pregnancy and adequate contraceptive methods (due to teratogenetic effects of ATRA in early pregnancy).
- •Absence of Hypersensitivity to Arsenic derivatives.
- •No QT interval prolongation or complete atria-ventricular block.
- •Written informed consent.
排除标准
- •Patients already treated.
- •Patients with contraindication to intensive chemotherapy, especially well documented cardiac contraindication to Idarubicin.
- •In female patients: pregnancy or absence of adequate contraceptive Methods
- •QT interval prolongation or complete atria-ventricular block.
- •Hypersensitivity to Arsenic derivatives.
结局指标
主要结局
For Patients aged 70 years or less with WBC<10.000/mm3, The primary end point will be event free survival at 2 years from CR achievement
时间窗: during de study
For Patients aged 70 years or less with WBC\<10.000/mm3, The primary end point
For patients older than 70 years with WBC>10.000 /mm3, The primary end point will be EFS at 2 years from diagnosis
时间窗: during the study
For patients older than 70 years with WBC\>10.000 /mm3, The primary end point will be EFS at 2 years from diagnosis
次要结局
- event free survival at 2 years from CR achievement(during the study)
- For Patients older than 70 years with WBC<10.000 /mm3(during the study)
- For Patients aged 70 years or less with WBC<10.000/mm3 :(during the study)
- Relapse (molecular or hematological).(during the study)
- Survival at 2 years.(during the study)
- Days on antibiotics, transfusion requirement and nights spent in Hospital(during the study)
- For Patients aged 70 years or less with WBC>10.000/mm3(during the study)
- Relapse and survival at 2 years.(during the study)
- Side effects of the treatment, including treatment-related mortality and morbidity of consolidation treatment.(during the study)
- Side effects of the treatment, including mortality and morbidity of consolidation treatment.(during the study)
- For patients older than 70 years with WBC>10.000 /mm3(during the study)
- Kinetics of decrease of PML-RARA transcript level during and after consolidation course.(during the study)