Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial
Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial
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DOI：
10.1016/s2352-3026(15)00115-5
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发表时间：
2015-09-01
影响因子：
24.7
通讯作者：
Seymour, John F.
中科院分区：
文献类型：
--
作者：
Iland, Harry J.;Collins, Marnie;Seymour, John F.
急性早幼粒细胞白血病的初始治疗传统上包括维甲酸（全反式维甲酸）联合蒽环类药物的风险适应性化疗，复发时首选三氧化二砷治疗。为了尽量减少复发率，我们结合三氧化二砷与维甲酸和依达鲁肽在诱导治疗，并使用三氧化二砷与维甲酸作为巩固therapy.Methods与以前未经治疗的基因证实的急性早幼粒细胞白血病患者有资格参加这项研究。合格还需要东部肿瘤协作组体能状态0-3，年龄大于1岁，左心室射血分数正常，Q-Tc间期小于500 ms，无严重合并症，以及书面知情同意书。急性早幼粒细胞白血病（PML以外的基因与RARA融合）的遗传变异患者不合格。诱导包括在第1-36天口服45 mg/m2维甲酸，每天分4次给药，在第2、4、6和8天静脉注射6-12 mg/m2依达罗肽，根据年龄调整，在第9-36天静脉注射0.15 mg/kg三氧化二砷，每天一次。支持性治疗包括用于方案规定的止血目标的血液制品，以及每日1 mg/kg泼尼松预防分化综合征。维甲酸和三氧化二砷的两个巩固周期后，口服维甲酸，6-巯基嘌呤和甲氨蝶呤维持治疗2年。研究的主要终点是无复发和早期死亡（治疗开始后36天内），我们评估了与2年中期结果相比的改善。为了评估缓解的持久性，我们比较了APML 4的主要终点和5年时的无病生存期和总生存期与2年中期APML 4数据和排除三氧化二砷的APML 3治疗方案。本研究在澳大利亚新西兰临床试验注册处注册，编号ACTRN 12605000070639。结果2004年11月10日至2009年9月23日期间入组了124例患者，数据截止日期为2012年3月15日。4例（3%）患者早期死亡。中位随访4.2年（IQR，3.2-5.2）后，5年无复发率为95%（95%CI 89-98），无疾病生存率为95%（89-98），无事件生存率为90%（83-94），总生存率为94%（89-97）。与APML 3数据的比较显示，风险比为0.23（95% CI 0.08-0.64，p=0.002）无复发，0.21（0.07-0.59，p=0.001），无病生存率为0.34（0.16-0.69，p=0.002）无事件生存期，0.35（0.14-0.91，p=0.02）。与历史对照组相比，在急性早幼粒细胞白血病的初始治疗诱导和巩固中加入三氧化二砷可降低复发风险。这种改善，加上早期死亡的非显著减少和缓解期无死亡，转化为更好的无事件生存期和总生存期。
Background Initial treatment of acute promyelocytic leukaemia traditionally involves tretinoin (all-trans retinoic acid) combined with anthracycline-based risk-adapted chemotherapy, with arsenic trioxide being the treatment of choice at relapse. To try to reduce the relapse rate, we combined arsenic trioxide with tretinoin and idarubicin in induction therapy, and used arsenic trioxide with tretinoin as consolidation therapy.Methods Patients with previously untreated genetically confirmed acute promyelocytic leukaemia were eligible for this study. Eligibilty also required Eastern Cooperative Oncology Group performance status 0-3, age older than 1 year, normal left ventricular ejection fraction, Q-Tc interval less than 500 ms, absence of serious comorbidity, and written informed consent. Patients with genetic variants of acute promyelocytic leukaemia (fusion of genes other than PML with RARA) were ineligible. Induction comprised 45 mg/m(2) oral tretinoin in four divided doses daily on days 1-36, 6-12 mg/m(2) intravenous idarubicin on days 2, 4, 6, and 8, adjusted for age, and 0.15 mg/kg intravenous arsenic trioxide once daily on days 9-36. Supportive therapy included blood products for protocol-specified haemostatic targets, and 1 mg/kg prednisone daily as prophylaxis against differentiation syndrome. Two consolidation cycles with tretinoin and arsenic trioxide were followed by maintenance therapy with oral tretinoin, 6-mercaptopurine, and methotrexate for 2 years. The primary endpoints of the study were freedom from relapse and early death (within 36 days of treatment start) and we assessed improvement compared with the 2 year interim results. To assess durability of remission we compared the primary endpoints and disease-free and overall survival at 5 years in APML4 with the 2 year interim APML4 data and the APML3 treatment protocol that excluded arsenic trioxide. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12605000070639.Findings 124 patients were enrolled between Nov 10, 2004, and Sept 23, 2009, with data cutoff of March 15, 2012. Four (3%) patients died early. After a median follow-up of 4.2 years (IQR, 3.2-5.2), the 5 year freedom from relapse was 95% (95% CI 89-98), disease-free survival was 95% (89-98), event-free survival was 90% (83-94), and overall survival was 94% (89-97). The comparison with APML3 data showed that hazard ratios were 0.23 (95% CI 0.08-0.64, p=0.002) for freedom from relapse, 0.21 (0.07-0.59, p=0.001) for disease-free survival, 0.34 (0.16-0.69, p=0.002) for event-free survival, and 0.35 (0.14-0.91, p=0.02) for overall survival.Interpretation Incorporation of arsenic trioxide in initial therapy induction and consolidation for acute promyelocytic leukaemia reduced the risk of relapse when compared with historical controls. This improvement, together with a non-significant reduction in early deaths and absence of deaths in remission, translated into better event-free and overall survival.