BACKGROUND Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population. METHODS We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18-70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts <5% in bone marrow) or myelodysplastic syndrome (blast counts <20% in bone marrow), Karnofsky index of 60% or higher, and were indicated for allogeneic HSCT but considered at an increased risk for standard myeloablative preparative regimens based on age (≥50 years), an HSCT-specific comorbidity index of more than 2, or both. Patients were randomly assigned (1:1) to receive either intravenous 10 g/m2 treosulfan daily applied as a 2-h infusion for 3 days (days -4 to -2) or 0·8 mg/kg busulfan applied as a 2-h infusion at 6-h intervals on days -4 and -3. Both groups received 30 mg/m2 intravenous fludarabine daily for 5 days (days -6 to -2). The primary outcome was event-free survival 2 years after HSCT. The non-inferiority margin was a hazard ratio (HR) of 1·3. Efficacy was assessed in all patients who received treatment and completed transplantation, and safety in all patients who received treatment. The study is registered with EudraCT (2008-002356-18) and ClinicalTrials.gov (NCT00822393). FINDINGS Between June 13, 2013, and May 3, 2016, 476 patients were enrolled (240 in the busulfan group received treatment and transplantation, and in the treosulfan group 221 received treatment and 220 transplanation). At the second preplanned interim analysis (Nov 9, 2016), the primary endpoint was met and trial was stopped. Here we present the final confirmatory analysis (data cutoff May 31, 2017). Median follow-up was 15·4 months (IQR 8·8-23·6) for patients treated with treosulfan and 17·4 months (6·3-23·4) for those treated with busulfan. 2-year event-free survival was 64·0% (95% CI 56·0-70·9) in the treosulfan group and 50·4% (42·8-57·5) in the busulfan group (HR 0·65 [95% CI 0·47-0·90]; p<0·0001 for non-inferiority, p=0·0051 for superiority). The most frequently reported grade 3 or higher adverse events were abnormal blood chemistry results (33 [15%] of 221 patients in the treosulfan group vs 35 [15%] of 240 patients in the busulfan group) and gastrointestinal disorders (24 [11%] patients vs 39 [16%] patients). Serious adverse events were reported for 18 (8%) patients in the treosulfan group and 17 (7%) patients in the busulfan group. Causes of deaths were generally transplantation-related. INTERPRETATION Treosulfan was non-inferior to busulfan when used in combination with fludarabine as a conditioning regimen for allogeneic HSCT for older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. The improved outcomes in patients treated with the treosulfan-fludarabine regimen suggest its potential to become a standard preparative regimen in this population. FUNDING medac GmbH.

中文翻译：

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对于年龄较大的急性髓细胞性白血病或骨髓增生异常综合症患者（MC-FludT.14 / L），在异体造血干细胞移植之前，用硫代硫丹或白消安加氟达拉滨作为调理治疗（MC-FludT.14 / L）：一项随机，非劣效性的3期临床试验。

背景技术对于越来越多的患有急性髓样白血病或骨髓增生异常综合症的年龄较大或合并症的患者，同种异体造血干细胞移植（HSCT）之前制备方案的进一步改善是医学上尚未满足的需求。我们旨在评估在该人群中与降低强度的白消安加氟达拉滨相比，用硫代硫丹加氟达拉滨进行调理的有效性和安全性。方法我们在法国，德国，匈牙利，意大利和波兰的31个移植中心进行了一项开放标签，随机，非劣效的3期临床试验。符合条件的患者年龄为18-70岁，在首次或连续的完全血液学缓解（骨髓中的爆炸计数<5％）或骨髓增生异常综合症（骨髓中的爆炸计数<20％）中患有急性髓细胞性白血病，Karnofsky指数为60％或更高，且已被指定用于异基因HSCT，但考虑到基于年龄（≥50岁），HSCT特异性合并症指数大于2或二者兼有的标准清髓性制备治疗方案的风险较高。患者被随机分配（1：1）接受静脉滴注10 g / m2硫代硫丹，每天2h输注，持续3天（第4到-2天），或接受0·8 mg / kg丁硫丹，以2-h的速度输注在第-4天和-3天以6小时间隔输注h。两组均每天接受30 mg / m2的静脉注射氟达拉滨治疗，共5天（第-6至-2天）。主要结果是HSCT 2年后无事件生存。非劣质性边缘的危险比（HR）为1·3。评估所有接受治疗并完成移植的患者的疗效，以及所有接受治疗的患者的安全性。该研究已在EudraCT（2008-002356-18）和ClinicalTrials.gov（NCT00822393）中注册。结果在2013年6月13日至2016年5月3日之间，招募了476例患者（白消安组中的240例接受了治疗和移植，而硫磺an组中的221例接受了治疗和220例移植）。在第二次预先计划的中期分析（2016年11月9日）中，达到了主要终点并停止了试验。在这里，我们介绍了最终的验证性分析（数据截止日期：2017年5月31日）。接受硫代硫丹治疗的患者中位随访时间为15·4个月（IQR 8·8-23·6），接受白消安治疗的患者中位随访时间为17·4个月（6·3-23·4）。在硫代硫丹组中，两年无事件生存率为64·0％（95％CI 56·0-70·9），在环丙硫磷组中为50·4％（42·8-57·5）（HR 0· 65 [95％CI 0·47-0·90]； p <0·0001（非劣等），p = 0·0051）。最常报告的3级或更高级别的不良事件是血液化学结果异常（硫丹组221例患者中33例[15％]，白消安组240例患者35例[15％]）和胃肠道疾病（24例[11％ ]患者vs 39 [16％]患者）。据报道，硫代硫丹组有18（8％）名患者出现严重不良事件，而白消安组则有17（7％）名患者出现严重不良事件。死亡原因通常与移植有关。解释对于年龄较大或合并症的急性髓细胞性白血病或骨髓增生异常综合症患者，与氟达拉滨联合用作异基因HSCT的条件治疗方案时，硫代硫磺不亚于白消安。使用海藻糖-氟达拉滨方案治疗的患者预后有所改善，表明其有可能成为该人群的标准制备方案。