供者CMV和EBV血清学状态对异基因造血干细胞移植患者临床预后的影响

Effect of serological status of donor CMV and EBV on clinical prognosis in patients with allogeneic hematopoietic stem cell transplantation

目的:研究供者CMV与EBV血清学状态对异基因造血干细胞移植(allo-HSCT)后患者的CMV与EBV激活、临床特征及预后的影响。方法:纳入2017年9月-2020年9月我院215例allo-HSCT患者及相应的供者,统计供、受者移植前CMV与EBV血清学状态,并持续监测移植后患者CMV和EBV DNA拷贝数至移植后至少6个月,采用χ^(2)检验和Kaplan-Meier法及Cox回归模型分析CMV及EBV病毒血症的发生情况及临床随访资料。结果:移植后CMV D+/R+组和D-/R+组、D+/R-组和D-/R-组患者的CMV病毒血症的中位发生时间、CMV最高病毒拷贝数的中位数、CMV与EBV共激活率、CMV激活率、CMV病毒持续阳性率、移植后急性移植物抗宿主病(aGVHD)、慢性移植物抗宿主病(cGVHD)、移植后淋巴增殖性疾病(PTLD)、CMV肺炎发生率、2年总生存(OS)率、非复发死亡率(NRM)比较,差异均无统计学意义。移植后CMV D-/R+组CMV病毒反复激活率、出血性膀胱炎发生率明显高于D+/R+组(P=0.042、0.026)。单因素和多因素分析均提示对于CMV血清学阳性受者,供者CMV血清学阴性是CMV病毒反复激活、出血性膀胱炎的独立危险因素(P<0.05)。移植后EBV D+/R+组和D-/R+组、D+/R-组和D-/R-组患者的EBV病毒血症的中位发作时间、EBV激活率、CMV与EBV共激活率、EBV反复激活率、cGVHD、PTLD、CMV肺炎发生率、2年OS率比较,差异均无统计学意义。移植后EBV D+/R+组患者的aGVHD发生率明显高于D-/R+组,D+/R-组患者的aGVHD发生率明显高于D-/R-组(P=0.001、0.001);D+/R+组患者移植后2年NRM明显高于D-/R+组,D+/R-组患者移植后2年NRM明显高于D-/R-组(P=0.004、0.033)。单因素和多因素分析均提示不论受者移植前EBV血清学状态如何,供者EBV血清学阳性是aGVHD和NRM的独立危险因素(P<0.05)。结论:CMV-供者移植使CMV+受者CMV反复激活率、出血性膀胱炎发生率升高,接受CMV-供者移植可能会对CMV+受者临床预后产生不利影响。不论受者移植前EBV血清学状态如何,与供者EBV+组比较,供者EBV-组患者的aGVHD发生率和2年NRM低,移植患者可能受益于EBV血清学阴性供者。

Objective: To investigate whether the serologic status of CMV and EBV in donors affects CMV and EBV activation, clinical features and prognosis in patients after allogeneic hematopoietic stem cell transplantation(allo-HSCT). Methods: A total of 215 patients underwent allo-HSCT and corresponding donors from September 2017 to September 2020 in our hospital were included. The serological status of CMV and EBV of donors and recipients was counted, and the number of CMV and EBV DNA copies of patients after transplantation was continuously monitored for at least 6 months, and the incidence of CMV and EBV viremia and clinical follow-up data were analyzed by χ^(2) test, Kaplan-Meier method and Cox regression model. Results: In patients with CMV D+/R+ and D-/R+, D+/R-and D-/R-group after transplantation, there was no significant difference in median incidence time of CMV viremia, median number of highest viral copies of CMV, co-activation rate of CMV and EBV, CMV activation rate, persistent positive rate of CMV virus, incidence of acute graft-versus-host disease(aGVHD) after transplantation, chronic graft-versus-host disease(cGVHD), lymphoproliferative disorders(PTLD) after transplantation, CMV pneumonia, 2-year survival(OS) rate, non-relapsed death mortality(NRM). The CMV virus re-activation rate and the incidence of hemorrhagic cystitis in D-/R+ group were significantly higher than those in D+/R+ group(P=0.042, 0.026). Both univariate and multivariate analysis suggested that CMV negative donors was an independent risk factor for recurrent CMV activation and hemorrhagic cystitis in CMV seropositivity recipients(P<0.05). There was no significant difference in median onset time of EBV viremia, EBV activation rate, co-activation rate of CMV and EBV, recurrent EBV activation rate, cGVHD, CMV pneumonia, PTLD incidence, and 2-year OS rate in patients with EBV D+/R+ and D-/R+, D+/R-and D-/R-group after transplantation. The incidence of aGVHD was significantly higher in D+/R+ group than that in D-/R+ group, and the incidence of aGVHD in D+/R-group was significantly higher than that in D-/R-group(P=0.001, 0.001). The 2-year NRM after transplantation in D+/R+ group was significantly higher than that in D-/R+ group, and the 2-year NRM after transplantation in D+/R-group was significantly higher than that in D-/R-group(P=0.004, 0.033). Both univariate and multivariate analysis suggested that seropositive donors of EBV was an independent risk factor for aGVHD and NRM, regardless of recipients’ s serological status before transplantation(P<0.05). Conclusion: CMV-donor transplantation increases the rate of CMV recurrent activation, and the incidence of hemorrhagic cystitis, and receiving CMV-donor transplantation may adversely affect the clinical prognosis of CMV+ recipients. Regardless of the recipient’s serological status before transplantation, patients in the donor EBV-group have a low incidence of aGVHD and 2-year NRM compared to the donor EBV+ group, and transplant patients may benefit from an EBV-negative donor.