Background

We previously showed that human anti-T-lymphocyte globulin (ATLG) plus ciclosporin and methotrexate given to patients with acute leukaemia in remission, having allogeneic haemopoietic stem-cell transplantation with peripheral blood stem cells from an HLA-identical sibling donor after myeloablative conditioning, significantly reduced 2-year chronic graft-versus-host disease (cGVHD) incidence and severity, without increasing disease relapse and infections, and improves cGVHD-free and relapse-free survival (cGRFS). The aim of an extended follow-up study was the assessment of long-term outcomes, which are, in this context, scarcely reported in the literature. We report unpublished data on quality of life (QoL) from the original study and the results of a follow-up extension.

Methods

In the original open-label study, patients with acute myeloid and lymphoblastic leukaemia in first or subsequent remission, having sibling HLA-identical allogeneic peripheral blood stem-cell transplantation, were randomly assigned (1:1) to receive ATLG plus standard GVHD prophylaxis with ciclosporin and short-term methotrexate (ATLG group) or standard GVHD prophylaxis without ATLG (non-ATLG group). Conditioning regimens were cyclophosphamide 120 mg/kg with either total body irradiation (12 Gy) or busulfan (12·8 mg/kg intravenously or 16 mg/kg orally), with or without etoposide (30–60 mg/kg). Randomisation was stratified according to centre and disease risk. The primary endpoint was cumulative incidence of cGVHD at 2 years. The primary and secondary endpoints, excluding QoL, have been published. QoL, assessed using European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-HDC29 questionnaires, was an unpublished secondary endpoint, which we now report here. A follow-up extension was then done, with the primary endpoint cumulative incidence of cGVHD. Enrolment has been completed for both studies. The original trial (number, NCT00678275) and follow-up extension (number, NCT03042676) are registered at ClinicalTrials.gov.

Findings

In the original study, from Dec 14, 2006, to Feb 2, 2012, 161 patients were enrolled and 155 were randomly assigned to either the ATLG group (n=83) or to the non-ATLG group (n=72). In the follow-up study, which started on Feb 7, 2017, and was completed on June 30, 2017, 61 patients were included in the ATLG group and 53 were included in the non-ATLG group. Global health status showed a more favourable time course in the ATLG group compared with the non-ATLG group (p=0·02; treatment by visit interaction). ATLG was descriptively superior to non-ATLG at 24 months for physical function (points estimate −14·8 [95% CI −26·4 to −3·1]; p=0·014) and social function (–19·1 [–38·0 to −0·2]; p=0·047), gastrointestinal side-effects (8·8 [2·5–15·1]; p=0·008) and effect on family (13·5 [1·2–25·8]; p=0·032). Extended follow-up (median 5·9 years [IQR 1·7–7·9]) confirmed a lower 5-year cGVHD incidence (30·0% [95% CI 21·4–41·9] vs 69·1% [59·1–80·1]; analysis for entire follow-up, p<0·001), no increase in relapses (35·4% [26·4–47·5] vs 22·5% [14·6–34·7]; p=0·09), improved cGRFS (34·3% [24·2–44·5] vs 13·9% [7·1–22·9]; p=0·005), and fewer patients still in immunosuppression (9·6% vs 28·3%; p=0·017) in the ATLG group compared with the non-ATLG group. 5-year overall survival, relapse-free survival, and non-relapse mortality did not differ significantly between groups.

Interpretation

The addition of ATLG to standard GVHD prophylaxis improves the probability of surviving without disease relapse and cGVHD after myeloablative peripheral blood stem-cell transplantation from an HLA-identical sibling donor for patients with acute leukaemia in remission. Further additional benefits are better QoL and shorter immunosuppressive treatment compared with standard GVHD prophylaxis without ATLG. Therefore, in this setting, ATLG plus standard GVHD prophylaxis should be preferred over the standard GVHD prophylaxis alone.

Funding

Neovii Biotech.

中文翻译：

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缓解后急性髓样白血病患者同种异体患者从HLA进行同种异体异基因造血造血干细胞移植后的急性GVHD预防加ATLG：3期随机研究的最终生活质量和长期结果分析

背景

我们以前表明，人抗T淋巴细胞球蛋白（ATLG）加环孢素和给予患者甲氨蝶呤急性白血病缓解，具有与异基因造血干细胞移植的外周血干细胞清髓性预处理后来自HLA相合同胞供体，显着降低了2年期慢性移植物抗宿主病（cGVHD）的发生率和严重程度，而没有增加疾病的复发和感染，并且改善了无cGVHD和无复发生存期（cGRFS）。延长随访研究的目的是评估长期结果，在这种情况下，文献中几乎没有报道。我们报告了原始研究和后续扩展结果中未发表的生活质量（QoL）数据。

方法

在最初的开放标签研究中，首次或之后缓解并具有同胞HLA相同同种异体外周血干细胞移植功能的急性髓样和淋巴细胞性白血病患者被随机分配（1：1）接受ATLG联合标准GVHD预防环孢素和短期甲氨蝶呤（ATLG组）或没有ATLG的标准GVHD预防（非ATLG组）。条件治疗为环磷酰胺120 mg / kg，全身照射（12 Gy）或环丁砜（静脉内12·8 mg / kg或口服16 mg / kg），有或没有依托泊苷（30-60 mg / kg）。根据中心和疾病风险将随机分组。主要终点是2年时cGVHD的累积发生率。主要和次要端点（不包括QoL）已发布。使用欧洲癌症研究与治疗组织QLQ-C30和QLQ-HDC29问卷评估的QoL是未发布的次要终点，我们现在在此报告。然后进行了后续扩展，主要终点是cGVHD的累积发生率。两项研究均已完成注册。原始试验（编号NCT00678275）和后续扩展（编号NCT03042676）已在ClinicalTrials.gov上注册。

发现

在原始研究中，从2006年12月14日到2012年2月2日，招募161位患者，并将155位患者随机分为ATLG组（n = 83）或非ATLG组（n = 72）。在2017年2月7日开始并于2017年6月30日完成的随访研究中，ATLG组包括61例患者，非ATLG组包括53例。与非ATLG组相比，ATLG组的总体健康状况显示出更有利的时程（p = 0·02；通过访视互动进行治疗）。24个月时，ATLG在身体功能（点估计值−14·8 [95％CI -26·4至-3·1]； p = 0·014）和社交功能（–19·1）方面在描述上优于非ATLG。 [–38·0至−0·2]； p = 0·047），胃肠道副作用（8·8 [2·5-15·1]； p = 0·008）和对家庭的影响（13·5 [1·2-25·8]； p = 0·032）。延长随访期（中位5·9年[IQR 1·7-7·9]）证实5年cGVHD发生率较低（30·0％[95％CI 21·4–41·9]与69·1 ％[59·1–80·1]；整个随访分析，p <0·001），复发无增加（35·4％[26·4–47·5] vs 22·5％[14] ·6–34·7]； p = 0·09），改善了cGRFS（34·3％[24·2-44·5] vs 13·9％[7·1-22·9]； p = 0· 005），与非ATLG组相比，ATLG组中仍处于免疫抑制状态的患者更少（9·6％对28·3％； p = 0·017）。各组之间的5年总生存率，无复发生存率和非复发死亡率无显着差异。

解释

在标准的GVHD预防措施中增加ATLG可提高从HLA相同的同胞供者进行清髓性外周血干细胞移植后缓解疾病的急性白血病患者中无疾病复发和cGVHD存活的可能性。与没有ATLG的标准GVHD预防措施相比，进一步的其他好处是更好的QoL和更短的免疫抑制治疗。因此，在这种情况下，ATLG加标准的GVHD预防应优于单独的标准GVHD预防。

资金

Neovii Biotech。