抢先治疗减少异基因造血干细胞移植后早期巨细胞病毒疾病的临床研究  

Significant reduction of morbidity and mortality of early CMV disease after allogeneic hematopoietic cell transplantation by pre-emptive therapy with anti-viral drugs and CMV cytotoxic T lymphocytes

作　　者：卢岳[1] 吴彤[1] 曹星玉[1] 王静波[1] 孙媛[1] 赵艳丽[1] 达万明[1] 纪树荃[1] 童春容[2] 张隆基 陆道培[1] 

机构地区：[1]北京市道培医院移植科,北京100049 [2]北京市道培医院临床特检中心 [3]美国佛罗伦达大学细胞遗传与微生物实验室

出　　处：《临床血液学杂志》2011年第6期655-658,661,共5页Journal of Clinical Hematology

摘　　要：目的:采用联合抗病毒药物及巨细胞病毒(CMV)特异性T淋巴细胞(CMV-CTL)进行抢先抗病毒治疗,减少异基因造血干细胞移植后早期CMV疾病的发生率和病死率。方法:334例进行异基因造血干细胞移植的患者,其中同胞相合移植100例,非血缘移植88例,亲缘间半相同移植146例;移植后采用RQ-PCR方法每周检测1～2次检测血浆CMV-DNA,若>5×102拷贝数/ml为CMV血症。全部患者预处理阶段-9～-2d应用更昔洛韦预防CMV感染。抢先抗病毒治疗主要首先采用更昔洛韦(DHPG)或膦甲酸钠作为一线治疗,在一线治疗失败情况下部分患者采用联合抗病毒药物或者CMV-CTL过继细胞免疫进行挽救治疗。结果:移植后100d之内(+100d)334例患者中有231例发生CMV感染,总体累计发生率为69.10%,同胞相合移植的发生率最低33例(33.3%),明显低于非血缘移植78例(88.6%)和亲缘间半相同移植120例(82.1%)(P<0.05);在一线治疗失败的情况下,29.4%(68/231)的患者给予联合抗病毒药物治疗,12.1%(28/231)患者给予了CMV-CTL细胞治疗。93.9%(217/231)的患者经过抢先抗病毒治疗后转为阴性。CMV疾病的发生率为3.8%,病死率仅为1.7%。无论是单因素及多因素分析均表明,亲缘间半相同移植和非血缘移植,以及Ⅱ～Ⅳ急性移植物抗宿主病是CMV感染发生的高危因素。结论:allo-HSCT后通过RQ-PCR监测CMV血症并予联合抗病毒药物和CMV-CTL细胞进行抢先抗病毒治疗可以明显减少CMV疾病病死率,特别是对于接受亲缘间半相同/非血缘移植的高危患者。Objective：In present clinical study,morbidity and mortality of CMV disease after pre-emptive therapy with anti-viral drugs and CMV specific cytotoxic T lymphocytes（CMV-CTLs）in allo-HCT recipients were investigated.Method：From January 2007 to January 2009,334 patients who received allo-HCT were studied（matched sibling 100,unrelated 88,haploidentical 146）.Plasma CMV DNA was monitored 1 to 2 times weekly with real time quantitative polymerase chain reaction（RQ-PCR）.Ganciclovir was used for 8 days during conditioning.Either Ganciclovir or Foscarnet was used as front-line pre-emptive therapy when plasma CMV DNA turned to positive.Combination of Ganciclovir and Foscarnet or CMV-CTLs were administrated if the patients failed to front-line pre-emptive therapy.Result：Overall 100-day cumulative incidence of CMV viremia was 69.1%（231/334）with median time of day 33（range,day 11 to 79）.Much lower incidence of CMV viremia was found in matched sibling transplant（33.3%）compared with unrelated（88.6%）and haploidentical（82.1%）transplants（P0.01）.Total 29.4%（68/231）patients received combined anti-viral medicines and 12.1%（28/231）patients were managed with CMV-CTLs with median cell dose 1.87×105 /kg（range,2.4 103to 8.0×106/kg）.CMV DNA became negative in 93.9%（217/231）patients after pre-emptive therapy.Fourteen patients developed CMV disease（enteritis 12 cases,interstitial pneumonia 1 case,encephalitis 1 case）.Overall 100-day cumulative incidence of CMV disease was only 3.8%.Only 4 patients（1.7%）died of CMV disease（they are all enteritis）.Univariate and multivariate analysis showed that alternative donors and gradeⅡ~Ⅳ acute GVHD were the risk factors for CMV reactivation.Conclusion：Viremia which is determined by RQ-PCR guided pre-emptive therapy with anti-viral medicines and CMV-CTLs significant reduces morbidity and mortality of early CMV disease in allo-HCT patients,even in the setting from alternative donors.

关 键 词：异基因造血干细胞移植 巨细胞病毒 抢先治疗 

分 类 号：R617[医药卫生—外科学]