Fisher Sheila A, Cutler Antony, Doree Carolyn, Brunskill Susan J, Stanworth Simon J, Navarrete Cristina, Girdlestone John
Systematic Review Initiative, NHS Blood and Transplant, Level 2, John Radcliffe Hospital, Headington, Oxford, Oxon, UK, OX3 9BQ.
Cochrane Database Syst Rev. 2019 Jan 30;1(1):CD009768. doi: 10.1002/14651858.CD009768.pub2.
Recipients of allogeneic haematopoietic stem cell transplants (HSCT) can develop acute or chronic, or both forms of graft-versus-host disease (a/cGvHD), whereby immune cells of the donor attack host tissues. Steroids are the primary treatment, but patients with severe, refractory disease have limited options and a poor prognosis. Mesenchymal stromal cells (MSCs) exhibit immunosuppressive properties and are being tested in clinical trials for their safety and efficacy in treating many immune-mediated disorders. GvHD is one of the first areas in which MSCs were clinically applied, and it is important that the accumulating evidence is systematically reviewed to assess whether their use is favoured.
To determine the evidence for the safety and efficacy of MSCs for treating immune-mediated inflammation post-transplantation of haematopoietic stem cells.
We searched for randomised controlled trials (RCTs) in the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library 2018, Issue 12), MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1937), Web of Science: Conference Proceedings Citation Index-Science (CPCI-S) (from 1990) and ongoing trial databases to 6 December 2018. No constraints were placed on language or publication status.
We included RCTs of participants with a haematological condition who have undergone an HSCT as treatment for their condition and were randomised to MSCs (intervention arm) or no MSCs (comparator arm), to prevent or treat GvHD. We also included RCTs which compared different doses of MSCs or MSCs of different sources (e.g. bone marrow versus cord). We included MSCs co-transplanted with haematopoietic stem cells as well as MSCs administered post-transplantation of haematopoietic stem cells.
We used standard methodological procedures expected by Cochrane.We employed a random-effects model for all analyses due to expected clinical heterogeneity arising from differences in participant characteristics and interventions.
We identified 12 completed RCTs (879 participants), and 13 ongoing trials (1532 enrolled participants planned). Of 12 completed trials, 10 compared MSCs versus no MSCs and two compared different doses of MSCs. One trial was in people with thalassaemia major, the remaining trials were for haematological malignancies. Seven trials administered MSCs to prevent GvHD, whereas five trials gave MSCs to treat GvHD.In the comparison of MSCs with no MSCs, cells were administered at a dose of between 10 and 10 cells/kg in either a single dose (six trials) or in multiple doses (four trials) over a period of three days to four months. The dose-comparison trials compared 2 x 10 cells/kg with 8 x 10 cells/kg in two infusions, or 1 x 10 cells/kg with 3 x 10 cells/kg in a single infusion.The median duration of follow-up in seven trials which administered MSCs prophylactically ranged from 10 to 60 months. In three trials of MSCs as treatment for aGvHD, participants were followed up for 90 or 100 days. In two trials of MSCs as treatment for cGvHD, the mean duration of follow-up was 13.4 months (MSC group) and 23.6 months (control group) in one trial, and 56 weeks in the second trial. Five trials included adults only, six trials included adults and children, and one trial included children only. In eight trials which reported the gender distribution, the percentage of females ranged from 20% to 59% (median 35.8%).The overall quality of the included studies was low: randomisation methods were poorly reported and several of the included studies were subject to a high risk of performance bias and reporting bias. One trial which started in 2008 has not been published and the progress of this trial in unknown, leading to potential publication bias. The quality of evidence was therefore low or very low for all outcomes due to a high risk of bias as well as imprecision due to the low number of overall participants, and in some cases evidence based on a single study. We found that MSCs may make little or no difference in the risk of all-cause mortality in either prophylactic trials (HR 0.85, 95% CI 0.50 to 1.42; participants = 301; studies = 5; I = 34% ; low-quality evidence) or therapeutic trials (HR 1.12, 95% CI 0.80 to 1.56; participants = 244; studies = 1; very low-quality evidence), and no difference in the risk of relapse of malignant disease (prophylactic trials: RR 1.08, 95% CI 0.73 to 1.59; participants = 323; studies = 6; I = 0%; low-quality evidence) compared with no MSCs. MSCs were well-tolerated, no infusion-related toxicity or ectopic tissue formation was reported. No study reported health-related quality of life. In prophylactic trials, MSCs may reduce the risk of chronic GvHD (RR 0.66, 95% CI 0.49 to 0.89; participants = 283; studies = 6; I = 0%; low-quality evidence). This means that only 310 (95% CI 230 to 418) in every 1000 patients in the MSC arm are expected to develop chronic GvHD compared to 469 in the control arm. However, MSCs may make little or no difference to the risk of aGvHD (RR 0.86, 95% CI 0.63 to 1.17; participants = 247; studies = 6; I = 0%; low-quality evidence). In GvHD therapeutic trials, we are very uncertain whether MSCs improve complete response of either aGvHD (RR 1.16, 95% CI 0.79 to 1.70, participants = 260, studies = 1; very low-quality evidence) or cGvHD (RR 5.00, 95%CI 0.75 to 33.21, participants = 40, studies = 1; very low-quality evidence).In two trials which compared different doses of MSCs, we found no evidence of any differences in outcomes.
AUTHORS' CONCLUSIONS: MSCs are an area of intense research activity, and an increasing number of trials have been undertaken or are planned. Despite a number of reports of positive outcomes from the use of MSCs for treating acute GvHD, the evidence to date from RCTs has not supported the conclusion that they are an effective therapy. There is low-quality evidence that MSCs may reduce the risk of cGvHD. New trial evidence will be incorporated into future updates of this review, which may better establish a role for MSCs in the prevention or treatment of GvHD.
同种异体造血干细胞移植（HSCT）受者可能发生急性或慢性，或两种形式的移植物抗宿主病（a/cGvHD），即供体免疫细胞攻击宿主组织。类固醇是主要治疗方法，但患有严重难治性疾病的患者选择有限且预后不良。间充质基质细胞（MSCs）具有免疫抑制特性，目前正在临床试验中测试其在治疗多种免疫介导疾病方面的安全性和有效性。GvHD是MSCs首次临床应用的领域之一，系统回顾积累的证据以评估其使用是否有利很重要。
确定MSCs治疗造血干细胞移植后免疫介导炎症的安全性和有效性证据。
我们在Cochrane对照试验中心注册库（CENTRAL，Cochrane图书馆2018年第12期）、MEDLINE（1946年起）、Embase（1974年起）、CINAHL（1937年起）、科学网会议论文被引频次索引-科学版（CPCI-S）（1990年起）以及截至2018年12月6日的正在进行的试验数据库中搜索随机对照试验（RCTs）。对语言或出版状态未设限制。
我们纳入了患有血液系统疾病并接受HSCT治疗的参与者的RCTs，这些参与者被随机分配至MSCs组（干预组）或无MSCs组（对照组），以预防或治疗GvHD。我们还纳入了比较不同剂量MSCs或不同来源MSCs（如骨髓与脐带）的RCTs。我们纳入了与造血干细胞共移植的MSCs以及造血干细胞移植后给予的MSCs。
我们采用Cochrane预期的标准方法程序。由于参与者特征和干预措施的差异导致预期的临床异质性，我们对所有分析采用随机效应模型。
我们确定了12项已完成的RCTs（879名参与者）和13项正在进行的试验（计划纳入1532名参与者）。在12项已完成的试验中，10项比较了MSCs与无MSCs，2项比较了不同剂量的MSCs。1项试验针对重型地中海贫血患者，其余试验针对血液系统恶性肿瘤。7项试验给予MSCs预防GvHD，而5项试验给予MSCs治疗GvHD。在MSCs与无MSCs的比较中，细胞以10至10个细胞/kg的剂量给予，单次给药（6项试验）或在3天至4个月的时间内多次给药（4项试验）。剂量比较试验比较了2×10个细胞/kg与8×10个细胞/kg分两次输注，或1×10个细胞/kg与3×10个细胞/kg单次输注。7项预防性给予MSCs的试验的中位随访时间为10至60个月。在3项将MSCs作为aGvHD治疗的试验中，参与者随访了90或100天。在2项将MSCs作为cGvHD治疗的试验中，一项试验中MSCs组的平均随访时间为13.4个月，对照组为23.6个月，另一项试验中为56周。5项试验仅纳入成人，6项试验纳入成人和儿童，1项试验仅纳入儿童。在8项报告性别分布的试验中，女性百分比范围为20%至59%（中位数35.8%）。纳入研究的总体质量较低：随机化方法报告不佳，且多项纳入研究存在执行偏倚和报告偏倚的高风险。一项始于2008年的试验尚未发表，该试验进展情况不明，导致潜在的发表偏倚。因此，由于偏倚风险高以及总体参与者数量少导致的不精确性，所有结局的证据质量均为低或非常低，在某些情况下证据基于单一研究。我们发现，在预防性试验（HR 0.85，95%CI 0.50至1.42；参与者 = 301；研究 = 5；I = 34%；低质量证据）或治疗性试验（HR 1.12，95%CI 0.80至1.56；参与者 = 244；研究 = 1；极低质量证据）中，MSCs对全因死亡率风险可能几乎没有影响，与无MSCs相比，对恶性疾病复发风险也无差异（预防性试验：RR 1.08，95%CI 0.73至1.59；参与者 = 323；研究 = 6；I = 0%；低质量证据）。MSCs耐受性良好，未报告与输注相关的毒性或异位组织形成。没有研究报告与健康相关的生活质量。在预防性试验中，MSCs可能降低慢性GvHD的风险（RR 0.66，95%CI 0.49至0.89；参与者 = 283；研究 = 6；I = 0%；低质量证据）。这意味着在MSCs组中，每1000名患者中预计只有310名（95%CI 230至418）会发生慢性GvHD，而对照组为469名。然而，MSCs对aGvHD风险可能几乎没有影响（RR 0.86，95%CI 0.63至1.17；参与者 = 247；研究 = 6；I = 0%；低质量证据）。在GvHD治疗性试验中，我们非常不确定MSCs是否能改善aGvHD（RR 1.16，95%CI 0.79至1.70，参与者 = 260，研究 = 1；极低质量证据）或cGvHD（RR 5.00，95%CI 0.75至33.21，参与者 = 40，研究 = 1；极低质量证据）的完全缓解率。在2项比较不同剂量MSCs的试验中，我们未发现结局有任何差异的证据。
MSCs是一个研究活跃的领域，已开展或计划开展越来越多的试验。尽管有许多关于使用MSCs治疗急性GvHD取得阳性结果的报道，但迄今为止RCTs的证据并不支持它们是一种有效疗法的结论。有低质量证据表明MSCs可能降低cGvHD的风险。新的试验证据将纳入本综述的未来更新中，这可能会更好地确定MSCs在预防或治疗GvHD中的作用。
