中国组织工程研究

中国组织工程研究 ›› 2022, Vol. 26 ›› Issue (31): 5026-5031.doi: 10.12307/2022.775

• 造血干细胞 hematopoietic stem cells • 上一篇    下一篇

去除第11天甲氨蝶呤对单倍体造血干细胞移植患者发生急性移植物抗宿主病的影响

孔  黛，陈香丽，裴晓杭，牛晓娜，陈玉清，朱尊民，雷平冲，孙  恺，刘忠文   

  1. 河南省人民医院血液科，郑州大学人民医院，河南省郑州市   450002
  • 收稿日期:2021-12-19 接受日期:2022-01-06 出版日期:2022-11-08 发布日期:2022-04-24
  • 通讯作者: 刘忠文，博士，主任医师，河南省人民医院血液科，郑州大学人民医院，河南省郑州市 450002
  • 作者简介:孔黛，女，1987年生，河南省商丘市人，汉族，2012年郑州大学毕业，硕士，主治医师，主要从事恶性血液病诊治及造血干细胞移植。
  • 基金资助:
    河南省科技厅项目(112300410027)，项目负责人：刘忠文

Omission of day 11 methotrexate in regimen for the prophylaxis of graft-versus-host disease after haploid hematopoietic stem cell transplantation

Kong Dai, Chen Xiangli, Pei Xiaohang, Niu Xiaona, Chen Yuqing, Zhu Zunmin, Lei Pingchong, Sun Kai, Liu Zhongwen   

  1. Department of Hematology, Henan Provincial People’s Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450002, Henan Province, China
  • Received:2021-12-19 Accepted:2022-01-06 Online:2022-11-08 Published:2022-04-24
  • Contact: Liu Zhongwen, MD, Chief physician, Department of Hematology, Henan Provincial People’s Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450002, Henan Province, China
  • About author:Kong Dai, Master, Attending physician, Department of Hematology, Henan Provincial People’s Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450002, Henan Province, China
  • Supported by:
    Henan Science and Technology Department Project, No. 112300410027 (to LZW)

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摘要：

文题释义：
单倍体造血干细胞移植：将每一亲本的1条染色体一起遗传的HLA抗原称为HLA单倍型，父母与子女之间即互为单倍型相合供者。而同胞及旁系亲属之间进行HLA配型，有可追溯的相同HLA单倍型但又不是全相合的也互为单倍型供者。单倍型造血干细胞移植使得每位患者至少有1个单倍型供者，与非血缘供者相比，具有可随时获得供者来源移植物用于各种细胞治疗的优势。
移植物抗宿主病：是多系统疾病，指异基因造血干细胞移植患者在重建供者免疫的过程中，来源于供者的抗原特异性淋巴细胞(主要指T细胞)攻击受者脏器产生的临床病理综合征，可分为急性、慢性和重叠综合征。急性移植物抗宿主病主要表现为皮肤、肠道和肝脏3个器官的炎性反应，如经典的斑丘疹、腹部绞痛与腹泻、血清胆红素上升；慢性移植物抗宿主病临床表现多样，个体差异大，可累及全身任何1个或多个器官，通常有类似扁平苔藓或硬皮病的皮肤表现、黏膜萎缩/溃疡、胃肠道硬化、生殖道糜烂/溃疡等。

背景：环孢素联合4次短程甲氨蝶呤方案仍是目前公认的、经典的预防急性移植物抗宿主病方案，以往研究显示在同胞全相合移植后第11天是否应用甲氨蝶呤对于急性移植物抗宿主病的发生率没有影响，但减少第11天甲氨蝶呤对单倍体造血干细胞移植患者急性移植物抗宿主病发生率的影响仍不清楚。
目的：探讨移植物抗宿主病预防方案中去除第11天甲氨蝶呤的应用对单倍体造血干细胞移植患者发生急性移植物抗宿主病的影响。
方法：回顾性分析 2017年1月至2019年12月接受单倍体造血干细胞移植治疗的 63例恶性血液病患者的临床资料，移植物抗宿主病预防方案为环孢素联合甲氨蝶呤15 mg/m2(第1天)，10 mg/m2(第3，6，11天)。在第11天时发生严重口腔黏膜炎(Ⅲ-Ⅳ级)的患者，取消第4次甲氨蝶呤应用，归为观察组，共19例；在第11天时发生轻度口腔黏膜炎(0-Ⅱ级)的患者，按标准方案继续第4次甲氨蝶呤应用，归为对照组，共44例。对两组植入情况、急性移植物抗宿主病发生率、总体生存率及复发率进行分析。
结果与结论：①中位随访时间 30(3-54)个月，两组患者中性粒细胞全部植活，中位植入时间分别为 12(9-29) d 和12(8-25) d，差异无显著性意义(P=0.682)；观察组1例血小板植入不良，对照组4例血小板植入不良，可分析数据两组中位植入时间分别为 12(9-18) d 和13(9-31) d，差异无显著性意义(P=0.71)；②急性移植物抗宿主病总体发生率为 44.4%，Ⅱ-Ⅳ度急性移植物抗宿主病为28.6%；观察组及对照组Ⅱ-Ⅳ度急性移植物抗宿主病发生率分别为31.5%，27.3%，差异无显著性意义(P=0.728)；③结果表明，对于单倍体造血干细胞移植，与标准甲氨蝶呤预防方案比较，去除第11天甲氨蝶呤的应用并不引起急性移植物抗宿主病发生率升高。

https://orcid.org/0000-0002-9345-7098 (孔黛) 

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

关键词: 恶性血液病, 甲氨蝶呤, 环孢素, 移植物抗宿主病, 口腔黏膜炎

Abstract: BACKGROUND: The regimen of cyclosporin combined with four times of short-range methotrexate is still recognized as the classic prevention regimen for acute graft-versus-host disease. Previous studies have shown that whether day 11 methotrexate is used in sibling transplantation has no effect on the incidence of acute graft-versus-host disease. However, the effect of reducing day 11 methotrexate on the incidence of acute graft-versus-host disease in haploid hematopoietic stem cell transplantation patients remains unclear. 
OBJECTIVE: To investigate the efficacy of the omission of day 11 methotrexate in the regimen for the prophylaxis of graft-versus-host disease in haploid hematopoietic stem cell transplantation.  
METHODS: The clinical data of 63 patients with malignant hematologic diseases who received haploid hematopoietic stem cell transplantation from January 2017 to December 2019 were retrospectively analyzed. The graft-versus-host disease prevention regimen was cyclosporine combined with methotrexate 15 mg/m2 on day 1, 10 mg/m2 on day 3, day 6 and day 11. In the observation group (n=19), oral mucositis was grade III-IV at day 11, and day 11 methotrexate was cancelled. In the control group (n=44), oral mucositis was grade 0-II at day 11, and day 11 methotrexate was applied. The implantation situation, incidence of acute graft-versus-host disease, overall survival rate, and recurrence rate of the two groups were analyzed.   
RESULTS AND CONCLUSION: (1) The median follow-up time was 30(3-54) months and all neutrophils were successfully implanted in both groups. The median implantation time was 12(9-29) days and 12(8-25) days, respectively, showing no significant difference (P=0.682). There was one patient with poor platelet implantation in the observation group, and four patients with poor platelet implantation in the control group. The median time of platelet implantation was 12(9-18) days and 13(9-31) days in the two groups, respectively, (P=0.71), showing no statistical difference. (2) The overall incidence of acute graft-versus-host disease was 44.4%, and grade II-IV acute graft-versus-host disease was 28.6%. The incidence of II-IV acute graft-versus-host disease in the observation group and control group was 31.5% and 27.3%, respectively, (P=0.728), and there was no statistical difference between the two groups. (3) The results showed that for haploid hematopoietic stem cell transplantation, the omission of day 11 methotrexate did not increase the incidence of acute graft-versus-host disease compared with the standard methotrexate regimen. 

Key words: hematological malignancy, methotrexate, cyclosporine, graft-versus-host disease, oral mucositis

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