低剂量抗胸腺细胞球蛋白在供、受者年龄均≥40岁恶性血液病同胞相合外周血干细胞移植中的应用

Application of low-dose ATG for GVHD prophylaxis in patients undergoing PBSCT aged over forty years old

目的探讨在供、受者年龄均≥40岁同胞相合外周血干细胞移植（MSD—PBSCT）移植物抗宿主病（GVHD）预防方案中增加低剂量抗胸腺细胞球蛋白（ATG）的效果。方法回顾性分析2013年3月至2017年4月行MSD—PBSCT且供、受者年龄均≥40岁恶性血液病患者的临床资料。43例患者在常规急性GVHD预防方案（环孢素A或他克莫司联合短疗程甲氨蝶呤）中加入ATG1．5mg·kg^-1·d^-1×3d（ATG组），55例患者应用常规GVHD预防方案（对照组）。结果@ATG组中性粒细胞植入中位时间短于对照组[13（11～17）d对14（12～24）d，P=0．001]，血小板植入中位时间差异无统计学意义[14（11～43）d对15（11—42）d，P=0．071）]。②ATG组＋100d内急性GVHD累积发生率低于对照组[25．6％（95％CI13．7％～39-3％）对49．1％（95％C135．2％～61．6％），P=0．018]，Ⅱ～Ⅳ度急性GVHD、慢性GVHD发生率差异无统计学意义[18．6％（95％CI8．6％～31．5％）对23．6％（95％CI13．4％～35．6％），P=0．509；49．6％（95％CI31．6％～65.3％）对56．4％（95％C141．4％～69．0％），P=0．221]。@ATG组与对照组移植后1年巨细胞病毒血症累积发生率差异无统计学意义[21．1％（95％C110．3％～34．5％）对31．1％（95％C118．8％～44．2％），P=0．429]。④ATG组及对照组移植后2年累积复发率[24．0％（95％CI11．5％～38．9％）对24．0％（95％CI12．1％～38．2％），P=0．608]、非复发死亡率[10．2％（95％c，3．1％-22．1％）对21．6％（95％a9．4％～37．0％），P=0．411]及无病生存率[65．8％（95％a50．3％～81．3％）对54．4％（95％CI37．7％～71．1％），P=0．955]差异均无统计学意义，但ATG组移植后2年总生存率优于对照组[83．8％（95％C171．8％～90．0％）对58．0％（95％C142．2％～73．9％），P=0．019]。结论对于年龄较大的MSD—PBSCT患者，在常规GVHD预防方案基础上加入低剂量ATG可以显著降低移植后急性GVHD发生率、改善OS率，病毒感染发生率和复发率无明屁增加。

Objective To explore the effectiveness of a novel GVHD prophylaxis regimen containing low-dose anti-T lymphocyte globulin （ATG） in patients undergoing peripheral blood stem cell transplantation （PBSCT） from HLA-matched sibling donors （MSD） given both the patients and donors were aged over forty years old. Methods From March 2013 to April 2017, 98 patients with hematologic malignan- cies were enrolled in the study. Standard GVHD prophylaxis consisted of the administration of cyclosporine A/tacrolimus and a short course of methotrexate. In ATG group, 43 patients received low-dose rabbit ATG （Sanofi, 1.5 mg/kg per day for 3 consecutive days） before PBSCT. A retrospective matched-pair analysis was performed and 55 matched controls were available. The therapeutic process and clinical outcome were retrospectively analyzed. Results ①Neutrophil engraftment was achieved earlier in ATG group than the control one [ 13（11-17）d vs 14（12-24）d, P = 0.0011. The time to platelet engraftment was similar between the two groups [ 14（11-43）d vs 15（11-42）d, P = 0.0711. ②The cumulative incidence of aGVHD was significantly lower in ATG group [ 25.6% （95% CI 13.7%- 39.3%） vs 49.1% （95% C135.2%-61.6%）, P = 0.0181. The incidences of grade II- IV aGVHD [ 18.6% （95%CI 8.6%-31.5%） vs 23.6% （95%CI 13.4%-35.6%）, P = 0.509 ] and cGVHD [49.6% （95% CI 31.6%- 65.3%） vs 56.4% （95% CI 41.4%- 69.0%）, P = 0.221 ] were not significantly different between the two groups. ③The 1-year cumulative incidence of CMV viremia was similar between the two groups [ 21.1%（95%CI 10.3%-34.5%） vs 31.1% （95%CI 18.8%-44.2%）, P = 0.429 ]. ④The cumulative incidences of disease relapse [24.0%（95%CI 11.5%-38.9%） vs 24.0% （95% CI 12.1%-38.2%）, P = 0.608） , non-relapse mortality [ 10.2% （95% CI 3.1%-22.1%） vs 21.6% （95%CI 9.4%-37.0%）, P = 0.411 ] and DFS [65.8% （95%CI 50.3%-81.3%） vs 54.4% （95%CI 37.7%-71.1%）, P = 0.9551 were comparable between the two groups. 2-year overall survival （OS） was significantly better in ATG group than the control one [83.8% （95%CI 71.8%-90.0%） vs 58.0% （95%CI 42.2%-73.9%）, P= 0.0191. Conclusion The addition of low-dose ATG decreased the incidence of aGVHD and improved OS. The incidences of viral infections and disease relapse remained to be similar between the two groups. These results suggested that elderly patients undergoing MSD-PBSCT may benefit from this low-dose ATG containing GVHD prophylaxis regimen.