Beneficial Role of Low-Dose Antithymocyte Globulin in Unrelated Stem Cell Transplantation for Adult Patients with Acquired Severe Aplastic Anemia: Reduction of Graft-versus-Host Disease and Improvement of Graft-versus-Host Disease-Free, Failure-Free Survival Rate
Beneficial Role of Low-Dose Antithymocyte Globulin in Unrelated Stem Cell Transplantation for Adult Patients with Acquired Severe Aplastic Anemia: Reduction of Graft-versus-Host Disease and Improvement of Graft-versus-Host Disease-Free, Failure-Free Survival Rate
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DOI：
10.1016/j.bbmt.2017.05.026
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发表时间：
2017-09-01
影响因子：
4.3
通讯作者：
Lee, Jong Wook
中科院分区：
文献类型：
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作者：
Park, Sung-Soo;Kwak, Dae Hun;Lee, Jong Wook
无血缘关系供者(URD)的干细胞移植(SCT)通常被认为是免疫抑制治疗失败且没有匹配同胞供者的重型再生障碍性贫血(SAA)患者。为了减少URD SCT中移植物抗宿主病(GVHD)的发生率，已提出在预适应方案中引入抗胸腺细胞球蛋白(ATG)。尽管ATG在患有不同血液病的队列中显示出在减少移植物抗宿主病中的作用，但它在SAA中的作用仍不确定。本研究的目的是确定ATG在成人SAA患者URD SCT中的疗效和毒性。我们调查了2003至2014年间接受URD SCT的83名成年SAA患者。移植方案包括全身照射(总剂量800cGy)和环磷酰胺(总剂量100~120 mg/kg)，然后是他克莫司和短期甲氨蝶呤。我们将患者分为两组：第一组(n=25)，接受不含ATG的人类白细胞抗原相合的骨髓(8/8)；第二组(n=58)，接受来自不相合的供者或外周血的干细胞移植。此后，组2根据ATG的使用情况被细分为作为历史队列的组2A(无ATG，n=26)和组2B(有ATG，n=32)。2B组用兔胸腺球蛋白(Genzyme-Sanofi，法国里昂)，剂量2.5 mg/kg。所有患者的平均年龄为30岁(范围为17至59岁)。2B组GVHD发生率明显低于2A组，第100天急性GVHD II级至IV级的发生率(31.2%比61.5%，P=0.003)和3年慢性GVHD的发生率(21.9%比65.4%，P=0.002)。3组患者的总体存活率相似。然而，2B组的无移植物抗宿主病无衰竭存活率(GFFS)显著高于2A组(P=0.034)。一个多变量模型确定使用ATG作为影响II至IV级急性GVHD(风险比[HR]，2.902；95%可信区间[CI]，1.417至5.942；P=.004)、慢性GVHD(HR，3.005；95%CI，1.279至7.059；P=.012)和GFFS(HR，2.363；95%CI，1.162至4.805；P=.014)的独立因素。包括感染并发症在内的毒性反应在3组间无差异。总而言之，小剂量ATG(2.5 mg/kg)可以降低接受人类白细胞抗原不相合供者或外周血干细胞的SAA患者的急性和慢性GVHD的发生率，并改善患者的生活质量；重要的是，这些好处是在不增加毒性的情况下实现的。此外，ATG可考虑用于人类白细胞抗原相合的骨髓细胞的URD SCT。(C)2017年美国血液和骨髓移植学会。
Stem cell transplantation (SCT) from an unrelated donor (URD) is often considered in patients with severe aplastic anemia (SAA) whom immunosuppressive therapy failed and matched sibling donor is not available. To reduce the incidence of graft-versus-host disease (GVHD) in URD SCT, introducting antithymocyte globulin (ATG) into the conditioning regimen has been proposed. Although ATG was shown to play a role in reducing GVHD in a cohort with diverse hematologic diseases, its role in SAA remains uncertain. The aim of this study was to determine the efficacy and toxicity of ATG in URD SCT for adult patients with SAA. We investigated 83 adult patients with SAA who underwent URD SCT between 2003 and 2014. The transplantation strategy consisted of total body irradiation (total 800 cGy) and cyclophosphamide (total 100 mg/kg to 120 mg/kg), followed by tacrolimus and a short-term methotrexate. We divided patients into 2 groups: group 1 (n = 25), which received HLA-matched (8/8) bone marrow (BM) without ATG, and group 2 (n = 58), which received SCT from either an HLA-mismatched donor or peripheral blood (PB). Thereafter, group 2 was subdivided according to ATG use into group 2A (without ATG, n = 26), which served as a historical cohort, and group 2B (with ATG, n = 32). Rabbit ATG (Thymoglobulin; Genzyme-Sanofi, Lyon, France) was used in group 2B at a dose of 2.5 mg/kg. The median age of all patients was 30 years (range, 17 to 59 years). The incidence of GVHD was significantly lower in group 2B than group 2A, as demonstrated by the rate of grade II to IV acute GVHD at day 100 (31.2% versus 61.5%, P=.003) and the rate of chronic GVHD at 3 years (21.9% versus 65.4%, P=.002). The overall survival rates of the 3 groups were similar. However, GVHD-free, failure-free survival (GFFS) was significantly higher in group 2B than group 2A (P=.034). A multivariable model identified use of ATG as an independent factor affecting grades II to IV acute GVHD (hazard ratio [HR], 2.902; 95% confidence interval [CI], 1.417 to 5.942; P=.004), chronic GVHD (HR, 3.005; 95% CI, 1.279 to 7.059; P=.012), and GFFS (HR, 2.363; 95% CI, 1.162 to 4.805; P=.014). Toxicities, including infectious complications, were not different among the 3 groups. In conclusion, low-dose ATG (2.5 mg/kg) can reduce the incidence of acute and chronic GVHD and improve the quality of life in patients with SAA who receive stem cells from either an HLA-mismatched donor or PB; importantly, these benefits are achieved without increased toxicity. Furthermore, ATG can be considered in URD SCT from HLA-matched BM cells. (C) 2017 American Society for Blood and Marrow Transplantation.