McCaul K G, Nevill T J, Barnett M J, Toze C L, Currie C J, Sutherland H J, Conneally E A, Shepherd J D, Nantel S H, Hogge D E, Klingemann H G
Division of Hematology, Vancouver General Hospital and the University of British Columbia, Canada.
J Hematother Stem Cell Res. 2000 Jun;9(3):367-74. doi: 10.1089/15258160050079470.
Acute graft-versus-host disease (A-GVHD) is a life-threatening complication of allogeneic stem cell transplantation (SCT), and primary therapy consists of high-dose corticosteroids. Patients who fail to respond adequately to corticosteroids require salvage treatment, with anti-T cell antibodies being the most commonly utilized group of agents. We report our institution's experience treating steroid-resistant GVHD in 36 adult patients (median age 39 years, range 24-55) with a rabbit antithymocyte globulin product (thymoglobulin). Eleven patients had undergone sibling SCT (10 histocompatible, 1 one-antigen mismatched) and 25 patients had received unrelated donor bone marrow (17 matched, 8 one-antigen mismatched); 32 patients (89%) had grade III or IV A-GVHD. Thymoglobulin was administered in two different regimens; group 1 patients (n = 13) received 2.5 mg/kg/day x 4-6 consecutive days with maintenance of all other immunosuppressives. Group 2 patients (n = 21) were given the same dose of thymoglobulin on days 1, 3, 5, and 7 with discontinuation of cyclosporine for 14 days, during which the corticosteroid dose was held at 2-3 mg/kg/day. Two patients had severe adverse reactions to thymoglobulin (hypoxemia and hypotension) and could not complete treatment, however, in the other patients, aside from transient leukopenia (25%) and and hepatic dysfunction (25%), the antibody preparation was well tolerated. Of the 34 evaluable patients, 13 patients had a complete response (38%) and 7 patients (21%) had a partial response, for an overall response rate of 59%. Response rate was higher in group 1 patients (77%) compared to group 2 patients (48%), (p = 0.15); skin GVHD was more responsive (96% of patients) than gut GVHD (46% of patients) or hepatic GHVD (36% of patients). Opportunistic infections were a significant complication, with 11 patients developing systemic fungal infections and 9 patients serious viral infections; there were seven episodes of bacteremia following thymoglobulin treatment and one fatal protozoal infection. There were 9 patients (25%) who developed post-SCT lymphoproliferative disorder (PTLD) and 4 patients who had a relapse of underlying primary malignancy; none of these patients survived. Of the 36 patients entered on the study, only 2 patients (6%) survive, at 15+ and 34+ months post-unrelated donor SCT. Although thymoglobulin is associated with an impressive response rate when administered for advanced steroid-resistant GVHD, long-term survival is uncommon, even in responders, primarily due to the high risk of developing either an opportunistic infection or a PTLD.
急性移植物抗宿主病（A-GVHD）是异基因干细胞移植（SCT）的一种危及生命的并发症，主要治疗方法是大剂量使用皮质类固醇。对皮质类固醇治疗反应不佳的患者需要挽救治疗，抗T细胞抗体是最常用的一类药物。我们报告了我们机构使用兔抗胸腺细胞球蛋白产品（即胸腺球蛋白）治疗36例成年类固醇抵抗性GVHD患者（中位年龄39岁，范围24 - 55岁）的经验。11例患者接受了同胞供体SCT（10例组织相容性匹配，1例单抗原不匹配），25例患者接受了无关供体骨髓移植（17例匹配，8例单抗原不匹配）；32例患者（89%）患有III级或IV级A-GVHD。胸腺球蛋白采用两种不同的给药方案；第1组患者（n = 13）连续4 - 6天每天接受2.5 mg/kg，同时维持所有其他免疫抑制剂。第2组患者（n = 21）在第1、3、5和7天给予相同剂量的胸腺球蛋白，并停用环孢素14天，在此期间皮质类固醇剂量维持在2 - 3 mg/kg/天。2例患者对胸腺球蛋白有严重不良反应（低氧血症和低血压），无法完成治疗，然而，在其他患者中，除了短暂性白细胞减少（25%）和肝功能障碍（25%）外，该抗体制剂耐受性良好。在34例可评估患者中，13例患者完全缓解（38%），7例患者部分缓解（21%），总缓解率为59%。第1组患者的缓解率（77%）高于第2组患者（48%），（p = 0.15）；皮肤GVHD的反应性更高（96%的患者），高于肠道GVHD（46%的患者）或肝脏GVHD（36%的患者）。机会性感染是一个重要的并发症，11例患者发生系统性真菌感染，9例患者发生严重病毒感染；胸腺球蛋白治疗后有7例菌血症发作，1例致命的原生动物感染。有9例患者（25%）发生了移植后淋巴细胞增殖性疾病（PTLD），4例患者潜在的原发性恶性肿瘤复发；这些患者均无存活。在纳入该研究的36例患者中，仅2例患者（6%）存活，分别在无关供体SCT后15 +个月和34 +个月。尽管胸腺球蛋白用于治疗晚期类固醇抵抗性GVHD时缓解率令人印象深刻，但长期存活并不常见，即使是缓解的患者，主要是由于发生机会性感染或PTLD的风险很高。
