摘要
目的评估小剂量环磷酰胺替代甲氨蝶呤的急性移植物抗宿主病（aGVHD）预防新方案的疗效及安全性。方法选择2013年1月至2015年5月于四川省人民医院血液科接受异基因造血干细胞移植（allo—HSCT）的75例血液系统疾病患者为研究对象，其中43例患者接受亲缘全相合allo—HSCT，32例接受亲缘单倍体相合atlo—HSCT。按照研究对象接受aGVHD预防方案不同分为，研究组（n=32，接受小剂量环磷酰胺联合环孢素A、吗替麦考酚酯的aGVHD预防新方案），对照组（n=43，接受甲氨蝶呤联合环孢素A、吗替麦考酚酯的aGVHD预防经典方案）。对2组患者的性别构成比、年龄、不同疾病种类构成比、不同allo～HSCT类型构成比、移植后中性粒细胞及血小板植活时间、aGVHD及慢性移植物抗宿主病（cGVHD）发生率、移植相关性口腔黏膜炎及出血性膀胱炎（HC）发生率、复发率、总体生存（OS）率等指标进行回顾性分析，并进行统计学比较。本研究遵循的程序符合四川省人民医院人体试验委员会制定的伦理学标准，得到该委员会批准，征得患者知情同意，并签署知情同意书。结果①2组患者的性别构成比、年龄、不同疾病种类构成比、不同allo—HsCT类型构成比等一般临床资料分别比较，差异均无统计学意义（P〉0．05）。②全部患者接受allo—HSCT后均获得造血干细胞植入，均达到完全嵌合状态，并且获得造血重建。研究组患者中性粒细胞植活时间为（13．9±1．6）d，对照组患者为（14．6±1．2）d，二者相比，差异无统计学意义（t=0．559，P=0．606）；研究组患者血小板植活时间为（15．1±1．3）d，对照组患者为（17．2±1．4）d，二者相比，差异亦无统计学意义（t=1．512，P=0．374）。③2组中接受亲缘全相合allo-HSCT的患者，allo—HSCT后100d内Ⅰ～Ⅳ度aGVHD的累积发生率相比，差异无统计学意义（x^2=0．135，P=0．447）。其中，Ⅰ～Ⅱ度及Ⅲ～Ⅳ度aGVHD的发生率分别比较，差异均无统计学意义（x^2=0．157、0．254，P=0．776、1．328）。截至随访结束，2组中接受亲缘全相合allo—HSCT的患者局限型及广泛型cGVHD发生率分别比较，差异均无统计学意义（x^2=0．018、1．342，P=0．264、0．327）。2组中接受亲缘单倍体相合allo—HSCT的患者，allo—HSCT后100d内Ⅰ～Ⅳ度aGVHD的累积发生率相比，差异无统计学意义（x^2=1．316，P=0．283）；其中，Ⅰ～Ⅱ度及Ⅲ～Ⅳ度aGVHD的发生率分别比较，差异均无统计学意义（x^2=1．472、1．087，P=0．296、0．379）。截至随访结束，2组中接受亲缘单倍体相合allo—HSCT的患者局限型及广泛型cGVHD发生率分别比较，差异均无统计学意义（x^2=1．312、1．129，P=0．287、0．284）。④研究组患者接受allo—HSCT后，移植相关性口腔黏膜炎发生率为29．3％（9／32），低于对照组的75．6％（32／43），并且差异有统计学意义（x^2=7．26，P=0．008）。其中，研究组患者2～4级移植相关性口腔黏膜炎发生率仅为12．6％（4／32），而对照组患者为52．8％（23／43）。⑤2组患者接受allo—HScT后HC发生率相比，差异无统计学意义（x^2=0．596，P=0．142）。⑥截至随访结束，2组患者的复发率及OS率分别比较，差异均无统计学意义（x^2=1．317、0．115，P=0．281、0．734）。结论小剂量环磷酰胺替代甲氨蝶呤的aGVHD预防新方案，不仅具有与aGVHD预防经典方案相似的预防aGVHD作用，保证造血重建，并且可以显著减低移植相关性口腔黏膜炎的发生率，同时并未增高HC的发生率。allo—HSCT后小剂量环磷酰胺替代甲氨蝶呤的aGVHD预防新方案是否可以作为aGVHD预防经典方案的替代选择，则尚需多中心、大样本的随机对照试验进一步研究、证实。
Objective To evaluate efficacy and safety of a novel prevention regimen for acute graft versus host disease （aGVHD） with low-dose cyclophosphamide in place of methotrexate. Methods From January 2013 to May 2015, a total of 75 patients with hematological diseases underwent allogeneic hematopoietie stem cell transplantation （allo HSCT） in Department of Hematology, Sichuan Provincial People＇s Hospital were selected as study subjects. Among them, 43 patients received related matched allo-HSCT, 32 patients received haploidentical allo-HSCT. According to different regimens of aGVHD prevention, study subjects were divided into study group （n=32） who received a novel aGVHD prevention regimen with low-dose cyclophosphamide combined with cyclosporine A and mycophenolate mofetil, and control group （n=43） who received a classic aGVHD prevention regimen with methotrexate combined with cyclosporine A and mycophenolate mofetil. The constituent ratio of gender, age, constituent ratio of different diseases, constituent ratio of different allo-HSCT types, the time of neutrophil and platelet engraftment, incidences of aGVHD and chronic graft versus host disease （cGVHD）, incidences of oral mucositis associated with transplantation and hemorrhagic cystitis （HC）, recurrence rate, overall survival （OS） rate between two groups were analyzed retrospectively, and compared statistically. The study protocol was approved by the Ethical Review Board of Investigation in Human at Sichuan Provincial People＇s Hospital. Informed consents were obtained from all participants. Results （1） There were no significant differences in constituent ratio of gender, age, constituent ratio of different diseases and constituent ratio of different alIo-HSCT types between two groups （P〈0.05）. （2） All patients achieved hematopoietic stem cell engrafted, complete chimerism states after allo-HSCT, and obtained hematopoietic reconstitution. Time of neutrophils engraftment of patients in study group and control group were （13, 9 ±1. 6） d and （14. 6± 1.2） d, respectively. There was no significant difference in time of neutrophils engraftment between two groups （t=0. 559, P〈0. 606）. Time of platelet engraftment of patients in study group and control group were （15.1±1.3） d and （17.2±1.4） d, respectively. There was no significant difference in time of platelet engraftment between two groups （t= 1. 512, P〈 0. 374）. （3） Among patients received related matched allo-HSCT, there was no significant difference in incidence of grade Ⅰ-Ⅳ aGVHD between two groups within 100 d after allo-HSCT （ x^2=0. 135, P = 0. 447）. And there were no significant differences in incidences of grade Ⅰ - Ⅱ and Ⅲ-Ⅳ aGVHD of patients received related matched allo-HSCT between two groups （ x^2=0. 157, 0. 254; P= 0. 776, 1. 328）. At end of the follow-up, there were no significant differences in incidences of localized and extensive cGVHD of patients received related matched allo-HSCT between two groups （x^2 =0. 018,1. 342;P=0. 264,0. 327）. Among patients received haploidentical allo- HSCT, there was no significant difference in incidence of grade Ⅰ -Ⅳ aGVHD between two groups within 100 d after allo-HSCT （cx^2= 1. 316,P〈0. 283）. And there were no significant differences in incidences of grade Ⅰ-Ⅱ and Ⅲ-Ⅳ aGVHD of patients received haploidentical allo-HSCT between two groups （ x^2= 1. 472,1. 087; P= 0. 296, 0. 379）. At end of the follow-up, there was no significant difference in the incidence of localized and extensive cGVHD of patients received haploidentical allo-HSCT between two groups （x^2 = 1. 312, 1. 129; P = 0. 287, 0. 284）. （4） The incidence of oral mucositis associated with transplantation in study group was 29.3% （9/32）, which was lower than that in control group （75.6%, 32/43）, and the difference was statistically significant （x^2 = 7. 26, P= 0. 008）. The incidence of oral mucositis was only 12.6% （4/32） in study group, and that was 52.80% （23/43） in control group. （5）There was no significant difference in incidence of HC between two groups after allo-HSCT （x^2 = 0. 596, P = 0. 142）. （6） There was no significant difference in recurrence rate and OS rate between two groups at the end of follow-up （x^2 =1. 317, 0. 115; P=0. 281, 0. 734）. Conclusions The novel aGVHD prevention regimen of low-doses cyclophosphamide in place of methotrexate not only has a prophylactic effect of aGVHD similar to that of classic aGVHD prevention regimen, ensures hematopoietic reconstitution, but also significantly reduces incidence of transplant-associated oral mucositis without increasing incidence of HC. Wether the novel aGVHD prevention regimen of low-dose cyclophosphamide in place of methotrexate after allo-HSCT can be used as an alternative to the classic aGVHD prevention regimen requires multicenter, large sample randomized controlled trials to further study and confirm.
出处
《国际输血及血液学杂志》
CAS
2017年第4期282-288,共7页
International Journal of Blood Transfusion and Hematology
基金
四川省卫生计生委基金项目（150225）
关键词
环磷酰胺
造血干细胞移植
移植物抗宿主病
Cyclophosphamide
Hematopoietic stem cell transplantation
Graft vs host disease
