地西他滨联合白消安-环磷酰胺对比白消安-环磷酰胺清髓性预处理在异基因造血干细胞移植前用于降低中国成人KMT2A重排白血病复发风险：一项开放标签、多中心、随机III期试验。
完整摘要 · 中文译文
背景：对于成人KMT2A重排白血病患者，在同种异体造血干细胞移植（HSCT）前仍存在对最佳清髓性预处理方案的未满足需求。我们研究了地西他滨联合白消安-环磷酰胺（DAC-BuCy）预处理与白消安-环磷酰胺（BuCy）预处理相比是否降低复发风险。 方法：在这项于中国八个移植中心开展的非盲、随机、3期试验中，符合条件的患者年龄为14-65岁，经形态学确诊为KMT2A重排白血病，东部肿瘤协作组体能状态评分为0-2。患者在HSCT前按1:1随机分配至DAC-BuCy组（第-14天至第-10天静脉注射地西他滨20 mg/m2每日一次，第-7天至第-4天静脉注射白消安3·2 mg/kg每日一次，第-3天至第-2天静脉注射环磷酰胺60 mg/kg每日一次）或BuCy组（白消安和环磷酰胺的剂量和疗程相同）。随机化采用置换区组（区组大小为四），未进行分层，并通过独立的、交互式网络应答系统实施。主要终点为意向治疗人群的2年累积复发率。安全性在所有接受治疗的患者中评估。本试验已在ClinicalTrials.gov注册（NCT03596892），且已完成。 结果：2019年5月1日至2023年1月31日期间，130例患者被随机分配接受DAC-BuCy方案（n=65；34例[52%]女性，31例[48%]男性）或BuCy方案（n=65；29例[45%]女性，36例[55%]男性）。中位随访时间为34·7个月（IQR 30·2-52·5）。DAC-BuCy组的2年累积复发率为12%（95% CI 6-22），BuCy组为29%（19-41）（风险比0·41 [0·20-0·87]；p=0·017）。最常见的3-5级不良事件为感染或寄生虫侵染（DAC-BuCy组27例[42%]，BuCy组25例[38%]）、急性移植物抗宿主病（DAC-BuCy组23例[35%]，BuCy组22例[34%]）以及胃肠道疾病（DAC-BuCy组14例[22%]，BuCy组15例[23%]）。DAC-BuCy组有4例（6%）患者、BuCy组有5例（8%）患者因不良事件死亡，其中2例死于方案相关毒性：DAC-BuCy组1例神经系统疾病，BuCy组1例心脏疾病。 解读：在BuCy预处理方案中加入地西他滨可降低KMT2A重排白血病成人患者的复发风险，且安全性可接受，可能成为该人群的合适治疗选择。 资助：国家自然科学基金、国家重点研发计划、广东省科技计划项目、慢性非传染性疾病国家科技重大专项、广东省自然科学基金、广州市科技计划项目，以及南方医科大学南方医院优秀青年培养计划。 翻译：本摘要的中文翻译见补充材料部分。
完整摘要 · 英文原文
BACKGROUND: An unmet need persists for optimal myeloablative conditioning before allogeneic haematopoietic stem cell transplantation (HSCT) in adult KMT2A‑rearranged leukaemia. We investigated whether decitabine plus busulfan-cyclophosphamide (DAC-BuCy) conditioning reduced the risk of relapse compared with busulfan-cyclophosphamide (BuCy) conditioning. METHODS: In this open-label, randomised, phase 3 trial at eight transplantation centres in China, eligible patients were aged 14-65 years, had morphologically confirmed KMT2A-rearranged leukaemia, and had an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned (1:1) before HSCT to DAC-BuCy (intravenous decitabine 20 mg/m2 once a day on days -14 to -10, intravenous busulfan 3·2 mg/kg once a day on days -7 to -4, and intravenous cyclophosphamide 60 mg/kg once a day on days -3 to -2) or BuCy (same dose and duration of busulfan and cyclophosphamide). Randomisation was done with permuted blocks (block size four) with no stratification and was implemented through an independent, interactive, web-based response system. The primary endpoint was 2-year cumulative incidence of relapse in the intention-to-treat population. Safety was assessed in all patients who received treatment. This trial is registered with ClinicalTrials.gov (NCT03596892) and is complete. FINDINGS: Between May 1, 2019, and Jan 31, 2023, 130 patients were randomised to receive a DAC-BuCy (n=65; 34 [52%] female and 31 [48%] male) or BuCy (n=65; 29 [45%] female and 36 [55%] male) regimen. Median follow-up was 34·7 months (IQR 30·2-52·5). 2-year cumulative incidence of relapse was 12% (95% CI 6-22) in the DAC-BuCy group and 29% (19-41) in the BuCy group (hazard ratio 0·41 [0·20-0·87]; p=0·017). The most common grade 3-5 adverse events were infections or infestations (DAC-BuCy group 27 [42%] and BuCy group 25 [38%]), acute graft-versus-host disease (DAC-BuCy group 23 [35%] and BuCy group 22 [34%]), and gastrointestinal disorders (DAC-BuCy group 14 [22%] and BuCy group 15 [23%]). Four (6%) patients in the DAC-BuCy group and five (8%) patients in the BuCy group died from adverse events, of which two were due to regimen-related toxicities: one nervous system disorder in the DAC-BuCy group and one cardiac disorder in the BuCy group. INTERPRETATION: The addition of decitabine to BuCy conditioning reduced the risk of relapse with an acceptable safety profile in adult patients with KMT2A‑rearranged leukaemia and could be a suitable therapeutic option for this population. FUNDING: The National Natural Science Foundation of China, the National Key Research and Development Program of China, the Science and Technology Program of Guangdong Province, the Non-communicable Chronic Diseases-National Science and Technology Major Project, the Natural Science Foundation of Guangdong Province, the Science and Technology Planning Project of Guangzhou, and the Outstanding Youth Cultivation Program of Nanfang Hospital, Southern Medical University. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.