抗人T细胞猪免疫球蛋白联合重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白治疗异基因造血干细胞移植后Ⅲ/Ⅳ度急性移植物抗宿主病35例临床研究

Clinical study of anti-human T cell porcine immunoglobulin with recombinant human tumor necrosis factor-αreceptor II:IgG Fc in the treatment of 35 cases of grade III/IV acute graft-versus-host disease after allo-HSCT

目的评估抗人T细胞猪免疫球蛋白(P-ATG)联合重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白(益赛普)治疗Ⅲ/Ⅳ度急性移植物抗宿主病(aGVHD)的疗效及安全性。方法对接受P-ATG(5 mg·kg^-1·d^-1×3~5 d,序贯5 mg/kg隔日1次~每周2次)联合益赛普(25 mg每周2次,儿童剂量减半)方案治疗的35例异基因造血干细胞移植(allo-HSCT)后合并Ⅲ/Ⅳ度aGVHD患者进行回顾性分析。结果①35例Ⅲ/Ⅳ度aGVHD患者中,男21例,女14例,中位年龄10(3~54)岁。急性髓系白血病(AML)19例,急性淋巴细胞白血病(ALL)13例,重型再生障碍性贫血(SAA)、骨髓增生异常综合征(MDS)、混合表型急性白血病(MPAL)各1例。②治疗28 d疗效评估:完全缓解(CR)12例(34.3%),部分缓解(PR)18例(51.4%),总有效率为85.7%(30/35),Ⅲ度aGVHD组总有效率高于Ⅳ度aGVHD组[100%(19/19)对68.8%(11/16),P=0.004]。③治疗56 d疗效评估:CR 22例(62.9%),PR 5例(14.3%),总有效率为77.2%(27/35),Ⅲ度aGVHD组总有效率高于Ⅳ度aGVHD组[89.5%(17/19)对62.5%(10/16),P=0.009]。④不良反应:35例患者输注P-ATG过程中均为发生发热、寒战、皮疹等不良反应,亦无明显肝肾功能损害发生。巨细胞病毒、EB病毒再激活率分别为77.1%(27/35)、22.9%(8/35),细菌感染发生率为48.6%(17/35)。⑤中位随访时间为13(1~55)个月,移植后1、2年的总生存率分别为(68.1±8.0)%、(64.3±8.4)%,Ⅲ度aGVHD组移植后1年总生存率高于Ⅳ度aGVHD组[(84.2±8.4)%对(47.6±13.1)%,χ^2=3.38,P=0.05]。结论P-ATG联合重组人Ⅱ型肿瘤坏死因子受体-抗体融合蛋白治疗allo-HSCT后Ⅲ/Ⅳ度aGVHD有较好的疗效和安全性。

Objective To evaluate the efficacy and safety of anti-human T lymphocyte porcine immunoglobulin(P-ATG)with recombinant human tumor necrosis factor-αreceptorⅡ:IgG Fc fusion protein(rhTNFR∶Fc,Etanercept)on gradeⅢ/Ⅳacute graft-versus-host disease(aGVHD)after allogenic hematopoietic stem cell transplantation(allo-HSCT).Methods Thirty-five patients with GradeⅢ/ⅣaGVHD who received P-ATG with etanercept therapy after allo-HSCT were retrospectively analyzed.P-ATGs(5 mg·kg-1·d-1)were administrated for 3 to 5 days,and then 5mg/kg was sequentially administrated,QOD to BIW.Etanercepts were administrated 25 mg,twice a week(12.5 mg,BIW for pediatric patients).Results Among the 35 patients with gradeⅢ/ⅣaGVHD,21 were males and 14 females,with a median age of 10(3-54)years.A total of 19 cases of acute myeloid leukemia,13 of acute lymphoblastic leukemia,1 of severe aplastic anemia,1 of myelodysplastic syndrome,and 1 of mixed phenotypic acute leukemia were noted.The overall response(OR)rate of P-ATG with etanercept was 85.7%(30/35),with complete response(CR)and partial response(PR)rates of 34.3%(12/35)and 51.4%(18/35),respectively,on day 28.The OR rate of gradeⅢaGVHD group was higher than of grade IV aGVHD group[100%(19/19)vs.68.8%(11/16),P=0.004].On day 56,the OR rate became 77.2%(27/35),with CR and PR rates of 62.9%(22/35)and 14.3%(5/35),respectively.The OR rate of gradeⅢaGVHD group was also higher than of gradeⅣaGVHD group[89.5%(17/19)vs.62.5%(10/16),P=0.009].Thirty-five patients had no adverse effects such as fever,chills,and rash during the P-ATG infusion,and no obvious liver and kidney function damage was observed after treatment.The main treatment-related complication was infection.The reactivation rates of CMV and EBV were 77.1%(27/35)and 22.9%(8/35),respectively,and the bacterial infection rate was 48.6%(17/35).With a median follow-up time of 13(1-55)months after HSCT,the 1-year and 2-year OS rates were(68.1±8.0)%and(64.3±8.4)%,respectively.The 1-year OS rate of gradeⅢaGVHD group was superior to gradeⅣaGVHD group[(84.2±8.4)%vs.(47.6±13.1)%,χ^2=3.38,P=0.05].Conclusion This study demonstrated that P-ATG with etanercept was effective and safe in treating gradeⅢ-ⅣaGVHD after allo-HSCT.