allo-HSCT后出血性膀胱炎的危险因素及脐带间充质干细胞早期输注的疗效分析

Risk factors of hemorrhagic cystitis after allo-HSCT and therapeutic effects of early transfusion of umbilical cord mesenchymal stem cells

目的探讨脐带间充质干细胞早期输注(即出现肉眼血尿)治疗异基因造血干细胞移植(allogeneic hematopoietic stem cell transplantation,allo-HSCT)后出血性膀胱炎(hemorrhagic cystitis,HC)的临床疗效及HC发生的危险因素。方法回顾性分析2016年1月至2021年7月于解放军联勤保障部队第九六〇医院血液科接受allo-HSCT治疗的300例受者的临床资料。根据HC发病情况,将全部受者分为发生HC组(89例)和未发生HC组(211例)。allo-HSCT后受者发生HC危险因素采用χ2检验进行单因素分析,P<0.05者纳入logistic回归分析法进行多因素分析。根据是否接受脐带间充质干细胞(umbilical cord mesenchymal stromal cell,UCMSC)输注,将51例HCⅡ~Ⅳ度的受者分为输注UCMSC组(24例)和未输注UCMSC组(27例),应用Mann-Whitney U检验对2组受者肉眼血尿及尿路刺激症状的持续时间进行统计学分析,评估UCMSC输注对于HC的临床疗效。结果①本研究300例受者中,有89例(29.67%)在allo-HSCT后发生HC。其中,Ⅰ度38例(42.70%),Ⅱ度36例(40.45%),Ⅲ度13例(14.61%),Ⅳ度2例(2.25%)。HC的中位发生时间为移植后29(21.5~35.0)d。②单因素分析结果显示:年龄≤30岁、单倍体移植、预处理应用抗胸腺细胞球蛋白(antithymocyte globulin,ATG)、急性移植物抗宿主病(acute graft versus host disease,aGVHD)、巨细胞病毒(cytomegalovirus,CMV)DNA阳性可显著增加HC发生风险(P值均<0.05)。多因素分析结果显示,aGVHD是发生HC的独立危险因素(OR=10.281,95%CI:1.606~65.831,P=0.014)。③89例发生HC受者中,Ⅰ度38例均完全缓解;Ⅱ~Ⅳ度51例中,有48例完全缓解,3例未缓解;51例中的24例在常规治疗基础上输注UCMSC(输注UCMSC组),肉眼血尿持续时间为12(9~17)d,较未输注UCMSC组的17(12.0~26.5)d短,差异有统计学意义(P=0.045)。输注UCMSC组尿路刺激症状持续时间为18(11~30)d,较未输注UCMSC组27(18.0~35.5)d短,差异亦有统计学意义(P=0.048)。结论输注UCMSC可以用于allo-HSCT后HC的治疗,能明显缩短患者病程。年龄≤30岁、单倍体移植、预处理应用ATG、aGVHD、CMV-DNA阳性可能增加allo-HSCT后HC的发生风险。aGVHD是allo-HSCT后受者发生HC的独立危险因素。

Objective To explore the clinical efficacy and risk factors of umbilical cord mesenchymal stem cells(UCMSCs)infusion at an early stage(i.e.gross hematuria)for hemorrhagic cystitis(HC)after allogeneic hematopoietic stem cell transplantation(allo-HSCT).Methods The relevant clinical data were retrospectively reviewed for 300 patients undergoing allo-HSCT from January 2016 to July 2021.According to the presence or absence of HC,they were assigned into two groups of HC(n=89)and non-HC(control,n=211).According to whether or not receiving an infusion of UCMSCs,51 patients of HC degreeⅡ-Ⅳwere divided into two groups of UCMSC infusion and non-infusion.The risk factors of HC after allo-HSCT were analyzed byχ2 test.Logistic regression was employed for multivariate analysis of P<0.05.Mann-Whitney U test was utilized for statistically analyzing the duration of gross hematuria and urinary tract irritation symptoms and evaluating the clinical efficacy of UCMSCs infusion for HC.Results Among them,89(29.67%)developed HC post-allo-HSCT.Clinical grades wereⅠ(n=38,42.70%),Ⅱ(n=36,40.45%),Ⅲ(n=13,14.61%)andⅣ(n=2,2.25%).The median occurrence time was 29(21.5-35.0)days post-allo-HSCT.In univariate analysis,age≤30 years,haploid transplantation,antithymocyte globulin(ATG),acute graft-versus-host disease(aGVHD),CMV-DNA positive pretreatment significantly boosted the risk of HC(P<0.05).In multivariate analysis,aGVHD was an independent risk factor for HC(OR=10.281,95%CI:1.606-65.813,P=0.014).Among 89 HC patients,38 gradeⅠpatients were complete remission(CR).Among 51 patients of gradeⅡ-ⅣHC,the outcomes were CR(n=48)and non-remission(NR)(n=3).And 24/51 of them received UCMSCs plus conventional treatment.The duration of gross hematuria was shorter in UCMSCs infusion group than that in UCMSCs non-infusion group[12(9-17)vs 17(12.0-26.5)day]and the difference was statistically significant(P=0.045).And the duration of urinary tract irritation symptoms was shorter in UCMSCs infusion group than that in UCMSCs non-infusion group[18(11-30)vs 27(18.0-35.5)days]and the difference was statistically significant(P=0.048).Conclusions Indicated for post-ALLO-HSCT HC,infusion of UCMSCs may significantly shorten the course of disease.Age≤30 years,haploid transplantation and preconditioning with positive ATG,aGVHD and CMV-DNA may boost the risks of HC post-allo-HSCT.And aGVHD is an independent risk factor for HC after allo-HSCT.