BACKGROUND Previous trials testing prevention strategies for chronic graft versus host disease (GVHD) have measured its cumulative incidence. In this trial of anti-thymocyte globulin, we measured treatment-independence at a long-term timepoint as the primary endpoint. METHODS This was a randomised, open-label, multicentre, phase 3 trial done at ten centres in Canada and one in Australia. Eligible patients had a haematological malignancy (leukaemia, myelodysplastic syndrome, or lymphoma), were between 16 and 70 years of age, eligible for transplantation with a Karnofsky score of at least 60, and received an unrelated donor (fully matched or one-locus mismatched at HLA-A, HLA-B, HLA-C, or DRB1 loci) graft following myeloablative or non-myeloablative-reduced intensity conditioning. Patients were randomly assigned to receive anti-thymocyte globulin 4·5 mg/kg plus standard GVHD prophylaxis (cyclosporine or tacrolimus plus methotrexate or mycophenolate) or standard GVHD prophylaxis alone. The primary endpoint, freedom from immunosuppressive therapy without resumption at 12 months, was previously reported. Here we report on the prespecified 24-month analysis. Analyses were per-protocol, excluding those patients who did not proceed to transplantation. This trial is registered as ISRCTN 29899028 and NCT01217723, status completed. FINDINGS Between June 9, 2010, and July 8, 2013, we recruited and randomly assigned 203 eligible patients to receive anti-thymocyte globulin (n=101) or no additional treatment (n=102) along with standard GVHD prophylaxis. 7 (3%) patients did not receive a transplant and were excluded from the analysis. 38 (38%) of 99 evaluable patients in the anti-thymocyte globulin plus GVHD prophylaxis group were free from immunosuppressive therapy at 24 months compared with 18 (19%) of 97 patients in the standard GVHD prophylaxis group (adjusted odds ratio [OR] 3·49 [95% CI 1·60–7·60]; p=0·0016). At 24 months, the cumulative incidence of relapse was 16·3% (95% CI 8·9–23·7) in the anti-thymocyte globulin plus GVHD prophylaxis group compared with 17·5 (9·9–25·1) in the standard GVHD prophylaxis group (p=0·73) and non-relapse mortality was 21·2% (95% CI 13·2–29·2) versus 31·3% (21·9–40·7; p=0·15). The cumulative incidence of chronic GVHD at 24 months was 26·3% (95% CI 17·5–35·1) in the anti-thymocyte globulin group and 41·3% (31·3–51·3) in the standard GVHD prophylaxis group (p=0·032). Overall survival at 24 months was 70·6% (95% CI 60·6–78·6) in the anti-thymocyte globulin plus GVHD prophylaxis group compared with 53·3% (42·8–62·8) in the standard GVHD prophylaxis group (adjusted hazard ratio [HR] 0·56, 95% CI [0·35–0·90]; p=0·017). Symptoms of chronic GVHD by the Lee Scale were more prevalent in the standard GVHD prophylaxis group, with scores of 13·27 (SD 10·94) in the anti-thymocyte globulin plus GVHD prophylaxis group and 20·38 (SD 14·68) in the standard GVHD prophylaxis group (p=0·040). Depressive symptoms were more prominent in the standard GVHD prophylaxis group, the mean Center for Epidemiological Studies Depression scale (CES-D) scores were 10·40 (SD 9·88) in the anti-thymocyte globulin group and 14·62 (SD 12·26) in the standard GVHD prophylaxis group (p=0·034). Serious adverse events (CTCAE grade 4 or 5) occurred in 38 (38%) patients in the anti-thymocyte globulin group and in 49 (51%) in the standard GVHD prophylaxis group, the most common being infection and GVHD. One patient in the anti-thymocyte globulin plus GVHD prophylaxis group died of Epstein-Barr virus hepatitis, but no deaths were attributable to anti-thymocyte globulin. INTERPRETATION The results of this prespecified 24-month analysis suggest that pretreatment with anti-thymocyte globulin provides clinically meaningful benefits when added to standard GVHD prophylaxis in patients undergoing unrelated donor transplantation, including decreases in use of immunosuppressive therapy, chronic GVHD and its symptoms, depressive symptoms, and improved overall survival. Anti-thymocyte globulin should be included in the preparative regimens of patients with haematological malignancies selected for unrelated donor transplantation. FUNDING Canadian Institutes of Health Research and Sanofi.

中文翻译：

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在不相关捐赠者移植的血液系统恶性肿瘤患者中，将抗胸腺细胞球蛋白添加到标准的移植物抗宿主病预防与单独的标准治疗中：一项随机，开放标签，多中心，3期试验的最终分析。

背景技术先前测试慢性移植物抗宿主病（GVHD）预防策略的试验已经测量了其累积发生率。在这项抗胸腺细胞球蛋白试验中，我们以长期时间点作为主要终点，测量了治疗独立性。方法这是一项在加拿大的十个中心和在澳大利亚的一个中心进行的随机，开放标签，多中心，3期临床试验。符合条件的患者具有血液系统恶性肿瘤（白血病，骨髓增生异常综合症或淋巴瘤），年龄在16至70岁之间，有资格接受Karnofsky评分至少60的移植，并接受了无关的供体（完全匹配或单位错配） HLA-A，HLA-B，HLA-C或DRB1基因座）移植后进行清髓性或非清髓性降低强度调节 患者被随机分配接受抗胸腺细胞球蛋白4·5 mg / kg加上标准的GVHD预防（环孢霉素或他克莫司加甲氨蝶呤或霉酚酸酯）或单独的标准GVHD预防。先前报道了主要终点，即在12个月内无需恢复免疫抑制治疗而无需恢复。在这里，我们报告了预先指定的24个月分析。分析是按方案进行的，不包括那些未进行移植的患者。该试验已注册为ISRCTN 29899028和NCT01217723，状态为已完成。结果在2010年6月9日至2013年7月8日之间，我们招募并随机分配了203名符合标准的GVHD预防措施接受抗胸腺细胞球蛋白（n = 101）或不接受其他治疗（n = 102）的合格患者。7名（3％）患者未接受移植，因此被排除在分析之外。抗胸腺细胞球蛋白加GVHD预防组中99例可评估患者中有38例（38％）在24个月时未接受免疫抑制治疗，而标准GVHD预防组中97例患者中有18例（19％）（校正比值比[OR] 3·49 [95％CI 1·60-7·60]； p = 0·0016）。抗胸腺细胞球蛋白加GVHD预防组在24个月时的复发累积发生率为16·3％（95％CI 8·9–23·7），而17·5（9·9–25·1）在标准的GVHD预防组中（p = 0·73），非复发死亡率分别为21·2％（95％CI 13·2–29·2）和31·3％（21·9-40·7; p = 0·15）。抗胸腺细胞球蛋白组在24个月时慢性GVHD的累积发生率为26·3％（95％CI 17·5–35·1），标准为41·3％（31·3–51·3） GVHD预防组（p = 0·032）。抗胸腺细胞球蛋白加GVHD预防组24个月的总生存率为70·6％（95％CI 60·6-78·6），而标准组为53·3％（42·8-62·8）预防GVHD组（风险比调整后[HR] 0·56，95％CI [0·35-0·90]； p = 0·017）。Lee量表显示的慢性GVHD症状在标准的GVHD预防组中更为普遍，抗胸腺细胞球蛋白加GVHD预防组的得分为13·27（SD 10·94），而得分为20·38（SD 14·68）。在标准的GVHD预防组中（p = 0·040）。在标准的GVHD预防组中，抑郁症状更为明显，抗胸腺细胞球蛋白组的流行病学研究中心抑郁平均评分（CES-D）得分为10·40（SD 9·88），而14·62（SD 12） ·26）在标准的GVHD预防组中（p = 0·034）。抗胸腺细胞球蛋白组的38名患者（38％）和标准的GVHD预防组的49名患者（51％）发生了严重的不良事件（CTCAE 4或5级），最常见的是感染和GVHD。抗胸腺细胞球蛋白加GVHD预防组的1例患者死于爱泼斯坦-巴尔病毒性肝炎，但没有死亡可归因于抗胸腺细胞球蛋白。解释这项预先规定的24个月分析结果表明，将抗胸腺细胞球蛋白预处理在不相关供体移植的患者中加入标准GVHD预防措施可提供临床上有意义的益处，包括减少免疫抑制疗法的使用，慢性GVHD及其症状，抑郁症症状，并改善整体生存率。抗胸腺细胞球蛋白应包括在选择进行无关供体移植的血液系统恶性肿瘤患者的治疗方案中。资金加拿大卫生研究所和赛诺菲。