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中华移植杂志(电子版) ›› 2022, Vol. 16 ›› Issue (04) : 224 -230. doi: 10.3877/cma.j.issn.1674-3903.2022.04.005

论著

不同预处理方案对重型再生障碍性贫血患者单倍体造血干细胞移植的疗效分析
赵爽1, 马梁明1, 朱秋娟1, 贡蓉1, 高志林1, 田卫伟1, 王涛1,†()   
  1. 1. 030032　太原，山西医科大学第三医院　（山西白求恩医院　山西医学科学院　同济山西医院）血液科
  • 收稿日期:2021-11-10 出版日期:2022-08-25
  • 通信作者: 王涛
  • 基金资助:
    山西省重点研发计划(201803D31144); 山西省回国留学人员科研资助项目(2017-126)

Effect of different conditioning regimens on haploid hematopoietic stem cell transplantation in patients with severe aplastic anemia

Shuang Zhao1, Liangming Ma1, Qiujuan Zhu1, Rong Gong1, Zhilin Gao1, Weiwei Tian1, Tao Wang1,†()   

  1. 1. Department of Hematology, the Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Taiyuan 030032, China
  • Received:2021-11-10 Published:2022-08-25
  • Corresponding author: Tao Wang
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引用本文：

赵爽, 马梁明, 朱秋娟, 贡蓉, 高志林, 田卫伟, 王涛. 不同预处理方案对重型再生障碍性贫血患者单倍体造血干细胞移植的疗效分析[J]. 中华移植杂志(电子版), 2022, 16(04): 224-230.

Shuang Zhao, Liangming Ma, Qiujuan Zhu, Rong Gong, Zhilin Gao, Weiwei Tian, Tao Wang. Effect of different conditioning regimens on haploid hematopoietic stem cell transplantation in patients with severe aplastic anemia[J]. Chinese Journal of Transplantation(Electronic Edition), 2022, 16(04): 224-230.

目的

分析氟达拉滨＋环磷酰胺＋抗胸腺细胞球蛋白(FC/ATG)预处理方案联合环孢素延迟口服方案对重型再生障碍性贫血(SAA)患者行单倍体造血干细胞移植(HSCT)的疗效与预后的影响。

方法

回顾性分析2011年12月至2021年9月在山西白求恩医院行单倍体HSCT治疗的106例SAA患者。对比FC/ATG与白消安＋环磷酰胺＋抗胸腺细胞球蛋白(Bucy/ATG)预处理方案、环孢素延迟口服与正常口服方案的疗效，评价指标包括预处理相关不良反应、造血重建、供受者干细胞嵌合情况、环孢素血药浓度监测和移植物抗宿主病(GVHD)发生率，并进行生存预后分析。正态分布计量资料采用成组t检验比较，非正态分布计量资料采用Mann-Whitney U检验比较；计数资料采用Fisher确切概率法比较；急性与慢性GVHD累积发病率应用Gray检验进行计算；采用Kaplan-Meier法计算总生存率，并用log-rank检验进行比较；用Cox比例风险模型分析SAA患者HSCT后发生急性GVHD的危险因素。P<0.05为差异有统计学意义。

结果

Bucy/ATG预处理组34例受者，FC/ATG预处理组72例受者；36例选择环孢素正常口服方案(消化道症状消失后口服)，62例选择环孢素延迟口服方案(维持静脉输注到＋50 d再改为口服)。两种预处理方案均获得中性粒细胞与血小板成功植入。Bucy/ATG组受者Ⅲ～Ⅳ度口腔溃疡和腹泻发生率(61.8%和44.1%)均高于FC/ATG组(16.7%和18.1%)，差异均有统计学意义(P均<0.05)。Bucy/ATG组和FC/ATG组受者预处理期间分别因合并重度感染导致死亡5(14.7%)、3例(4.2%)，病死率差异有统计学意义(P<0.05)。在＋30、＋40和＋50 d不同时间段时，环孢素正常口服组受者环孢素血药浓度均低于延迟口服组，差异均有统计学意义(t＝－4.322、－5.751和－9.773，P均<0.05)。环孢素正常口服组受者急性GVHD累积发病率(52.8%)和中重度慢性GVHD累积发病率(55.6%)均高于环孢素延迟口服组(24.2%和22.6%)，差异均有统计学意义(P均<0.05)。HLA配型不相合(RR＝0.476，95%可信区间：0.932～1.679，P<0.05)、环孢素正常口服方案(RR＝0.329，95%可信区间：1.331～1.843，P<0.05)是发生急性GVHD的危险因素。随访至2021年9月，106例受者中位随访时间为37.6个月(11～93个月)，共死亡21例。Bucy/ATG组和FC/ATG组受者HSCT后2年生存率分别为66.3%、87.9%，差异有统计学意义(χ2＝7.355，P<0.05)。

结论

FC/ATG预处理联合环孢素延迟口服方案可能是单倍体HSCT治疗SAA安全、有效的方案。

关键词: 重型再生障碍性贫血, 单倍体造血干细胞移植, 预处理, 环孢素
Objective

To analyze the efficacy and prognosis of FC/ATG pretreatment combined with cyclosporine delayed oral regimen for haploid stem cell transplantation (HSCT) in patients with severe aplastic anemia (SAA).

Methods

A total of 106 SAA patients who underwent HSCT in the Third Hospital of Shanxi Medical University from December 2011 to September 2021 were analyzed. The efficacy of FC/ATG and Bucy/ATG pretreatment regimens, delayed oral administration of cyclosporine and normal oral administration regimens were compared. The evaluation indicators included adverse reactions related to pretreatment, hematopoietic reconstitution, chimerism of donor and recipient stem cells, monitoring of cyclosporine plasma concentration, incidence of graft versus host disease (GVHD), and the survival and prognosis of patients were analysed. The measurement data with normal distribution were compared by group t test, and the measurement data with non-normal distribution were compared by Mann-Whitney U test. Enumeration data were compared by Fisher exact probability method. Gray test was used to calculate the cumulative incidence of acute and chronic GVHD. The overall survival rate was calculated by Kaplan-Meier method and compared by log-rank test. Cox proportional hazards model was used to analyze the risk factors of acute GVHD after HSCT in SAA patients. P< 0.05 was considered statistically significant.

Results

There were 34 patients in Bucy/ATG pretreatment group and 72 patients in FC/ATG pretreatment group; 36 patients chose the normal oral regimen of cyclosporine (after gastrointestinal symptoms disappeared), and 62 patients chose the delayed oral regimen of cyclosporine (maintained intravenous infusion for + 50 d and then changed to oral administration). Neutrophils and platelets were successfully implanted in both pretreatment schemes. The incidences of grades Ⅲ-Ⅳ oral ulcer and diarrhea in Bucy/ATG group (61.8% and 44.1%) were higher than those in FC/ATG group (16.7% and 18.1%), and the differences were statistically significant (all P<0.05). Severe infection caused 5 deaths (14.7%) in Bucy/ATG group and 3 deaths (4.2%) in FC/ATG group during pretreatment, and the difference in mortality was statistically significant (P<0.05). There were significant differences in the blood concentration of cyclosporine between the normal oral group and the delayed oral group at + 30 d, + 40 d and + 50 d, and the blood concentration of cyclosporine in the delayed oral group was more stable (t=-4.322, -5.751 and -9.773, all P<0.05). The cumulative incidence of acute GVHD (52.8%) and moderate to severe chronic GVHD (55.6%) in the cyclosporine normal oral regimen group were higher than those in the cyclosporine delayed oral regimen group (24.2% and 22.6%, all P<0.05). HLA mismatch (RR=0.476, 95%CI: 0.932-1.679, P<0.05) and cyclosporine normal oral regimen (RR=0.329, 95%CI: 1.331-1.843, P<0.05) were risk factors for acute GVHD. The median follow-up time of 106 recipients was 37.6 months (11-93 months), and a total of 21 patients died. The 2-year survival rates after HSCT in Bucy/ATG group and FC/ATG group were 66.3% and 87.9%, respectively (χ2=7.355, P<0.05).

Conclusion

FC/ATG pretreatment combined with cyclosporine delayed oral regimen may be a safe and effective regimen for HSCT in the treatment of SAA.

Key words: Severe aplastic anemia, Haploid stem cell transplantation, Conditioning regimen, Cyclosporine
表1 Bucy/ATG组和FC/ATG组受者临床特征比较
临床特征 Bucy/ATG组(n＝34) FC/ATG组(n＝72) U/χ2值 P值
年龄[岁，M(Min，Max)] 39(13，56) 37(9，50) 26.639 >0.05
性别(例，男/女) 15/19 26/46 0.030 >0.05
确诊到移植时间[d，M(Min，Max)] 189(49，269) 192(59，490) 35.447 >0.05
前期行免疫抑制治疗无效[例(%)] 3(8.8%) 7(9.7%) 11.246 >0.05
ECOG评分[分，M(Min，Max)] 1(0，3) 1(0，3) 2.792 >0.05
PNH克隆[例(%)] 4(11.8%) 9(12.5%) 5.244 >0.05
供受者性别[例(%)]     3.561 >0.05
  男/男 12(35.3%) 21(29.2%)    
  男/女 9(26.5%) 17(23.6%)    
  女/男 3( 8.8%) 5( 6.9%)    
  女/女 10(29.4%) 29(40.3%)    
供受者ABO血型[例(%)]     1.933 >0.05
  相同 9(26.5%) 14(19.4%)    
  不相同 25(73.5%) 58(80.6%)    
供受者CMV血清学状态[例(%)]     9.017 >0.05
  阳性/阳性 2( 5.9%) 3( 4.2%)    
  阴性/阳性 6(14.6%) 4( 5.6%)    
  阴性/阴性 26(76.5%) 65(90.3%)    
单个核细胞计数[×108/kg，M(Min，Max)] 8.5(4.1，16.7) 9.2(5.3，18.0) 2.946 >0.05
CD34＋细胞计数[×106/kg，M(Min，Max)] 5.2(0.7, 8.4) 3.7(1.2，17.6) 3.623 >0.05
表2 Bucy/ATG组和FC/ATG组受者预处理相关不良反应[例(%)]
组别 例数 口腔溃疡 腹泻 肝功能异常 心功能损害 重度感染死亡
Ⅰ～Ⅱ度 Ⅲ～Ⅳ度 Ⅰ～Ⅱ度 Ⅲ～Ⅳ度 Ⅰ～Ⅱ度 Ⅲ～Ⅳ度 Ⅰ～Ⅱ度 Ⅲ～Ⅳ度
Bucy/ATG组 34 13(38.2) 21(61.8) 19(55.9) 15(44.1) 27(79.4) 7(20.6) 31(91.2) 3(8.8) 5(14.7)
FC/ATG组 72 60(83.3) 12(16.7) 59(81.9) 13(18.1) 53(73.6) 19(26.4) 70(97.2) 2(2.8) 3( 4.2)
检验值 － － － － － －
P值 － <0.05* <0.05* >0.05* >0.05* <0.05*
表3 环孢素正常口服组和延迟口服组受者环孢素血药浓度监测结果(μg/L)
组别 例数 单倍体造血干细胞移植后时间(d)
0～＋10 ＋11～＋20 ＋21～＋30 ＋31～＋40 ＋41～＋50
环孢素正常口服组 36 196±20 260±29 210±18 183±26 202±20
环孢素延迟口服组 62 210±24 300±29 386±23 390±17 400±16
t值 － －1.043 －0.367 －4.322 －5.751 －9.773
P值 － >0.05 >0.05 <0.05 <0.05 <0.05
表4 SAA患者HSCT后发生急性GVHD危险因素Cox比例风险模型分析(n＝98)
变量 回归系数 RR值 95%可信区间 P值
年龄(岁) －0.031 0.969 0.915～1.028 >0.05
性别        
  男性   1.000    
  女性 －0.011 0.989 0.350～2.795 >0.05
血型        
  相同   1.000    
  不相同 －0.063 0.476 0.241～2.157 >0.05
回输CD34＋细胞数量(×108/kg) －0.047 0.964 0.915～1.028 >0.05
回输CD3＋细胞数量(×108/kg) －0.051 1.909 0.350～2.795 >0.05
环孢素口服方案        
  延迟   1.000    
  正常 －1.634 0.329 1.331～1.843 <0.05
HLA配型        
  相合   1.000    
  不相合 －1.577 0.476 0.932～1.679 <0.05
图1 Bucy/ATG组与FC/ATG组受者生存曲线 注：Bucy/ATG.白消安＋环磷酰胺＋抗胸腺细胞球蛋白；FC/ATG.氟达拉滨＋环磷酰胺＋抗胸腺细胞球蛋白
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