BACKGROUND Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate regimens using either maraviroc, bortezomib, or post-transplantation cyclophosphamide for GvHD prophylaxis compared with controls receiving the combination of tacrolimus and methotrexate using a novel composite primary endpoint to identify the most promising intervention to be further tested in a phase 3 trial. METHODS In this prospective multicentre phase 2 trial, adult patients aged 18-75 years who received reduced-intensity conditioning HCT were randomly assigned (1:1:1) by random block sizes to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide (cyclophosphamide 50 mg/kg on days 3 and 4, followed by tacrolimus starting on day 5 and mycophenolate mofetil starting on day 5 at 15 mg/kg three times daily not to exceed 1 g from day 5 to day 35); tacrolimus, methotrexate, and bortezomib (bortezomib 1·3 mg/m2 intravenously on days 1, 4, and 7 after HCT); or tacrolimus, methotrexate, and maraviroc (maraviroc 300 mg orally twice daily from day -3 to day 30 after HCT). Methotrexate was administered as a 15 mg/m2 intravenous bolus on day 1 and 10 mg/m2 intravenous bolus on days 3, 6, and 11 after HCT; tacrolimus was given intravenously at a dose of 0·05 mg/kg twice daily (or oral equivalent) starting on day -3 (except the post-transplantation cyclophosphamide, as indicated), with a target level of 5-15 ng/mL. Tacrolimus was continued at least until day 90 and was tapered off by day 180. Each study group was compared separately to a contemporary non-randomised prospective cohort of patients (control group) who fulfilled the same eligibility criteria as the trial, but who were treated with tacrolimus and methotrexate at centres not participating in the trial. The primary endpoint (GvHD-free, relapse-free survival [GRFS]) was defined as the time from HCT to onset of grade 3-4 acute GvHD, chronic GvHD requiring systemic immunosuppression, disease relapse, or death. The study was analysed by modified intention to treat. The study is closed to accrual and this is the planned analysis. This trial is registered with ClinicalTrials.gov, number NCT02208037. FINDINGS Between Nov 17, 2014, and May 18, 2016, 273 patients from 31 US centres were randomly assigned to the three study arms: 89 to tacrolimus, methotrexate, and bortezomib; 92 to tacrolimus, methotrexate, and maraviroc; 92 to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; and six were excluded. Between Aug 1, 2014, and Sept 14, 2016, 224 controls received tacrolimus and methotrexate. Controls were generally well matched except for more frequent comorbidities than the intervention groups and a different distribution of types of conditioning regimens used. Compared with controls, the hazard ratio for GRFS was 0·72 (90% CI 0·54-0·94; p=0·044) for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide, 0·98 (0·76-1·27; p=0·92) for tacrolimus, methotrexate, and bortezomib, and 1·10 (0·86-1·41; p=0·49) for tacrolimus, methotrexate, and maraviroc. 238 patients experienced grade 3 or 4 toxicities: 12 (13%) had grade 3 and 67 (73%) grade 4 events with tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; ten (11%) had grade 3 and 68 (76%) had grade 4 events with tacrolimus, methotrexate, and bortezomib; and 18 (20%) had grade 3 and 63 (68%) had grade 4 events with tacrolimus, methotrexate, and maraviroc. The most common toxicities were haematological (77 [84%] for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; 73 [82%] for tacrolimus, methotrexate, and bortezomib; and 78 [85%] for tacrolimus, methotrexate, and maraviroc) and cardiac (43 [47%], 44 [49%], and 43 [47%], respectively). INTERPRETATION Tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding the best GRFS; this regimen is thus being prospectively compared with tacrolimus and methotrexate in a phase 3 randomised trial. FUNDING US National Health, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Disease; and Millennium Pharmaceuticals.

中文翻译：

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三种预防方案（他克莫司、吗替麦考酚酯和环磷酰胺；他克莫司、甲氨蝶呤和硼替佐米；或他克莫司、甲氨蝶呤和马拉韦罗）与他克莫司和甲氨蝶呤相比，用于预防低强度造血细胞移植移植物抗宿主病：一项具有非随机同期对照组的随机 2 期试验 (BMT CTN 1203)。

背景技术 预防移植物抗宿主病（GvHD）而不发生恶性复发是同种异体造血细胞移植（HCT）的总体目标。我们的目的是使用新型复合主要终点来评估使用马拉韦罗、硼替佐米或移植后环磷酰胺预防 GvHD 的方案与接受他克莫司和甲氨蝶呤联合治疗的对照组相比，以确定最有希望的干预措施，以便在 3 期试验中进一步测试。方法 在这项前瞻性多中心 2 期试验中，接受降低强度调理 HCT 的 18-75 岁成年患者按随机块大小随机分配 (1:1:1) 至他克莫司、吗替麦考酚酯和移植后环磷酰胺（环磷酰胺）第3天和第4天50mg/kg，随后从第5天开始使用他克莫司，从第5天开始使用吗替麦考酚酯，剂量为15mg/kg，每天3次，从第5天到第35天不超过1g)；他克莫司、甲氨蝶呤和硼替佐米（HCT 后第 1、4 和 7 天静脉注射硼替佐米 1·3 mg/m2）；或他克莫司、甲氨蝶呤和马拉韦罗（HCT 后第-3 天至第 30 天，每日两次口服马拉韦罗 300 mg）。HCT 后第 1 天以 15 mg/m2 静脉推注形式给予甲氨蝶呤，在第 3、6 和 11 天以 10 mg/m2 静脉推注形式给予甲氨蝶呤；从第-3天开始，以0·05 mg/kg的剂量每天两次（或口服等效剂量）静脉内给予他克莫司（移植后环磷酰胺除外，如所示），目标水平为5-15 ng/mL。他克莫司至少持续到第 90 天，并在第 180 天逐渐减量。每个研究组分别与当代非随机前瞻性患者队列（对照组）进行比较，这些患者符合与试验相同的资格标准，但接受了治疗在未参与试验的中心使用他克莫司和甲氨蝶呤。主要终点（无 GvHD、无复发生存期 [GRFS]）定义为从 HCT 到 3-4 级急性 GvHD、需要全身免疫抑制的慢性 GvHD 发作、疾病复发或死亡的时间。该研究通过修正意向治疗进行分析。该研究已结束权责发生制，这是计划的分析。该试验已在 ClinicalTrials.gov 注册，编号为 NCT02208037。结果 2014年11月17日至2016年5月18日期间，来自美国31个中心的273名患者被随机分配至三个研究组：89名患者接受他克莫司、甲氨蝶呤和硼替佐米；89名患者接受他克莫司、甲氨蝶呤和硼替佐米治疗；89名患者接受他克莫司、甲氨蝶呤和硼替佐米治疗。92 他克莫司、甲氨蝶呤和马拉维罗；92 他克莫司、吗替麦考酚酯和移植后环磷酰胺；六人被排除在外。2014年8月1日至2016年9月14日期间，224名对照者接受了他克莫司和甲氨蝶呤治疗。除了比干预组更常见的合并症以及所使用的预处理方案类型分布不同之外，对照组通常匹配良好。与对照组相比，他克莫司的 GRFS 风险比为 0·72 (90% CI 0·54-0·94；p=0·044)，吗替麦考酚酯和移植后环磷酰胺，他克莫司、甲氨蝶呤和硼替佐米为 0·98 (0·76-1·27；p=0·92)，1·10 (0·86-1·41；p= 0·49) 适用于他克莫司、甲氨蝶呤和马拉维罗。238 名患者出现 3 级或 4 级毒性：使用他克莫司、吗替麦考酚酯和移植后环磷酰胺时，12 名患者（13%）出现 3 级毒性，67 名患者（73%）出现 4 级毒性；使用他克莫司、甲氨蝶呤和硼替佐米时，10 名 (11%) 发生 3 级事件，68 名 (76%) 发生 4 级事件；使用他克莫司、甲氨蝶呤和马拉维罗时，18 名 (20%) 发生 3 级事件，63 名 (68%) 发生 4 级事件。最常见的毒性是血液学毒性（他克莫司、霉酚酸酯和移植后环磷酰胺为 77 [84%]；他克莫司、甲氨蝶呤和硼替佐米为 73 [82%]；他克莫司、甲氨蝶呤和马拉维罗为 78 [85%] ）和心脏（分别为 43 [47%]、44 [49%] 和 43 [47%]）。解释 他克莫司、吗替麦考酚酯和移植后环磷酰胺是最有希望的干预措施，产生最好的 GRFS；因此，正在一项 3 期随机试验中将该方案与他克莫司和甲氨蝶呤进行前瞻性比较。资助美国国家健康、肺脏和血液研究所；国家癌症研究所；国家过敏和传染病研究所；和千年制药公司。