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

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。

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

ObjectiveTo 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). MethodsA 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. ResultsThere 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). ConclusionFC/ATG pretreatment combined with cyclosporine delayed oral regimen may be a safe and effective regimen for HSCT in the treatment of SAA.