Theurich Sebastian, Fischmann Hans, Shimabukuro-Vornhagen Alexander, Chemnitz Jens M, Holtick Udo, Scheid Christof, Skoetz Nicole, von Bergwelt-Baildon Michael
Department I of Internal Medicine, Stem Cell Transplantation Program, University Hospital of Cologne, Cologne, Germany.
Cochrane Database Syst Rev. 2012 Sep 12(9):CD009159. doi: 10.1002/14651858.CD009159.pub2.
Allogeneic haematopoietic stem cell transplantation (HSCT) is an established treatment for many malignant and non-malignant haematological disorders. Graft-versus-host disease (GVHD), a condition frequently occurring after HSCT, is the result of host tissues being attacked by donor immune cells. One strategy for the prevention of GVHD is the administration of anti-thymocyte globulins (ATG), a set of polyclonal antibodies directed against a variety of immune cell epitopes, leading to immunosuppression and immunomodulation.
To assess the effect of ATG used for the prevention of graft-versus-host disease (GVHD) in patients undergoing allogeneic HSCT with regard to overall survival, incidence and severity of acute and chronic GVHD, incidence of relapse, incidence of infectious complications, non-relapse mortality, early mortality within 100 days of transplantation, progression-free survival, quality of life and adverse events.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), MEDLINE (January 1950 to February 2012), trials registries and conference proceedings. The search was conducted in October 2010 and was updated in July 2011 and February 2012. We did not apply any language restrictions.
We included randomised controlled trials (RCTs) investigating the impact of ATG on GVHD prophylaxis in adults suffering from haematological diseases and undergoing allogeneic HSCT. Treatment arms had to differ only in the addition of ATG to the standard GVHD prophylaxis regimen.
Two review authors screened abstracts, extracted data and analysed the data independently. We contacted study authors for additional information.
We included in the meta-analysis six RCTs which met the pre-defined selection criteria, involving a total of 568 participants. Quality of data reporting was heterogeneous among these studies with a lack of detailed information in the early studies.The primary outcome of overall survival was not significantly changed by the addition of ATG for the prophylaxis of GVHD (harms ratio (HR) 0.88; 95% CI 0.67 to 1.15, P = 0.33).The incidence of treatment-requiring or severe acute GVHD (grade II to IV) was significantly lower in patients who received ATG (risk ratio (RR) 0.68; 95% CI 0.55 to 0.85, P = 0.009; number needed to treat (NNT) 8). Also, the incidence of severe acute GVHD (grade III to IV) was significantly reduced (HR 0.53; 95% CI 0.33 to 0.85, P = 0.0005; NNT 7) but comparable data were available for rabbit ATG only. However, pooled study results regarding the incidence of acute GVHD of all grades (I to IV) showed no significant benefit of ATG treatment (RR 0.89; 95% CI 0.74 to 1.06, P = 0.20).Meta-analysis of data regarding the incidence of overall chronic GVHD (both, limited and extensive) was not possible. Nevertheless, studies reporting on extensive chronic GVHD (only studies evaluating rabbit ATG) suggested a lower incidence of extensive chronic GVHD whereas others that only reported on overall chronic GVHD did not show an advantage for ATG.Pooled results regarding the incidence of relapse were not significantly different (RR 1.13; 95% CI 0.75 to 1.68, P = 0.56), as well as pooled results regarding non-relapse mortality (HR 0.82; 95% CI 0.55 to 1.24, P = 0.35).Due to the lack of comparable data, we could not perform meta-analysis of data regarding the incidence of chronic GVHD, relapse-related mortality, progression-free survival, quality of life, adverse events and engraftment.
AUTHORS' CONCLUSIONS: Our systematic review suggests that the addition of ATG during allogeneic HSCT significantly reduces the incidence of severe grades (II to IV) of acute GvHD, whereas the incidence of overall acute GVHD (grades I to IV) was not significantly lowered. This indicates a reduction of the severity but not the incidence of acute GVHD. However, this effect did not lead to a significant improvement of overall survival, which may be due to the severe potential side effects of the consecutively increased immunosuppression.Furthermore, future research is needed to clarify the effect of ATG on the incidence and severity of chronic GVHD and consequently on all aspects of quality of life.From the currently available data, no recommendation on the general use of ATG in allogeneic HSCT can be supported. Therefore, a careful consideration of the use of ATG based on the patient's condition and the risk factors of the transplantation setting should be made.
异基因造血干细胞移植（HSCT）是治疗多种恶性和非恶性血液系统疾病的既定疗法。移植物抗宿主病（GVHD）是HSCT后经常出现的一种病症，是供体免疫细胞攻击宿主组织的结果。预防GVHD的一种策略是给予抗胸腺细胞球蛋白（ATG），这是一组针对多种免疫细胞表位的多克隆抗体，可导致免疫抑制和免疫调节。
评估在接受异基因HSCT的患者中，使用ATG预防移植物抗宿主病（GVHD）对总生存期、急慢性GVHD的发生率和严重程度、复发率、感染并发症发生率、非复发死亡率、移植后100天内的早期死亡率、无进展生存期、生活质量和不良事件的影响。
我们检索了Cochrane对照试验中央注册库（CENTRAL）（《Cochrane图书馆》2011年第3期）、MEDLINE（1950年1月至2012年2月）、试验注册库和会议论文集。检索于2010年10月进行，并于2011年7月和2012年2月更新。我们未设任何语言限制。
我们纳入了随机对照试验（RCT），这些试验研究了ATG对患有血液系统疾病并接受异基因HSCT的成年人预防GVHD的影响。各治疗组的差异仅在于在标准GVHD预防方案中添加了ATG。
两位综述作者独立筛选摘要、提取数据并分析数据。我们联系了研究作者以获取更多信息。
我们将六项符合预定义选择标准的RCT纳入荟萃分析，共涉及568名参与者。这些研究的数据报告质量参差不齐，早期研究缺乏详细信息。添加ATG预防GVHD并未显著改变总生存期这一主要结局（危害比（HR）0.88；95%置信区间0.67至1.15，P = 0.33）。接受ATG的患者中，需要治疗的或严重急性GVHD（II至IV级）的发生率显著更低（风险比（RR）0.68；95%置信区间0.55至0.85，P = 0.009；需治疗人数（NNT）8）。此外，严重急性GVHD（III至IV级）的发生率也显著降低（HR 0.53；95%置信区间0.33至0.85，P = 0.0005；NNT 7），但仅有兔源ATG的可比数据。然而，关于所有级别（I至IV级）急性GVHD发生率的汇总研究结果显示，ATG治疗并无显著益处（RR 0.89；95%置信区间0.74至1.06，P = 0.20）。关于总体慢性GVHD（局限性和广泛性）发生率的数据无法进行荟萃分析。尽管如此，报告广泛性慢性GVHD的研究（仅评估兔源ATG的研究）表明广泛性慢性GVHD的发生率较低，而其他仅报告总体慢性GVHD的研究未显示ATG有优势。关于复发率的汇总结果无显著差异（RR 1.13；95%置信区间0.75至1.68，P = 0.56），关于非复发死亡率的汇总结果也无显著差异（HR 0.82；95%置信区间0.55至1.24，P = 0.35）。由于缺乏可比数据，我们无法对慢性GVHD发生率、复发相关死亡率、无进展生存期、生活质量、不良事件和植入的数据进行荟萃分析。
我们的系统评价表明，在异基因HSCT期间添加ATG可显著降低严重级别（II至IV级）急性GVHD的发生率，而总体急性GVHD（I至IV级）的发生率并未显著降低。这表明急性GVHD的严重程度降低，但发生率未降低。然而，这种效果并未导致总生存期显著改善，这可能是由于持续增加的免疫抑制带来的严重潜在副作用。此外，需要进一步研究以阐明ATG对慢性GVHD发生率和严重程度的影响，进而对生活质量的各个方面的影响。根据目前可得的数据，无法支持在异基因HSCT中普遍使用ATG的建议。因此，应根据患者情况和移植环境的风险因素仔细考虑使用ATG。
