allo—HSCT并使用高剂量环磷酰胺诱导免疫耐受治疗重型再生障碍性贫血

Clinical analysis of allogeneic hematopoietic stem cell transplantation with high-dose cyclophosphamideinduced immune tolerance for severe aplastic anemia

目的探讨异基因造血干细胞移植（allo-HSCT）并使用高剂量环磷酰胺诱导免疫耐受治疗重型再生障碍性贫血（SAA）的效果和安全性。方法选择2012年8月至2014年8月接受HLA半相合albHsCT后应用高剂量环磷酰胺诱导免疫耐受的新方法治疗的20例SAA患者，其中男性12例，女性8例，平均年龄17．8岁（6～37岁），均为HLA半相合HSCT。移植前所有受者均接受过环孢素A治疗，11例接受过抗人淋巴细胞免疫球蛋白（ATG）强化免疫治疗；供者接受了粒细胞集落刺激因子动员，采用供者骨髓和外周血干细胞联合移植；改良的预处理方案为环磷酰胺、氟达拉滨、白消安，移植后3d使用环磷酰胺（50mg·kg-1·d-1）诱导免疫耐受，移植物抗宿主病（GVHD）的预防采用联合免疫抑制剂包括环孢素A、氨甲蝶呤、他克莫司等，观察移植后受者GVHD、存活等情况。结果17例受者造血重建，3例受者第二次移植后植入，中性粒细胞≥0．5×10^9／L及血小板≥20×10^9／L的平均时间分别为17．4d和21．3d，植入检测证实为100％完全供者造血，移植前后T淋巴细胞亚群计数水平显著增高。随访至2015年4月，中位随访时间17．7个月（6~32个月），因并发症死亡3例，其余17例受者仍无SAA复发存活，存活率为85％，最长存活时间达32个月。结论减低强度预处理的allo-HSCT并使用高剂量环磷酰胺诱导免疫耐受治疗SAA具有良好的疗效和安全性。

Objective The study was aimed to explore the efficacy and safety of allogeneic stem cell transplantation （allo-HSCT） with high-dose cyclophosphamide-induced immune tolerance in the treatment of severe aplastic anemia（SAA）. Method 20 cases with SAA received reducing the intensity conditioning allo-HSCT from 2012 August to 2014 August, it is a new method for post-transplantation with high-dose cyclophosphamide-induced immune tolerance, including 12 males and 8 females, the age ranged from 6 to 37 years old, and the average age of 17. 8 years old, all are HLA-mismatched transplantation and received CsA therapy, eleven of them received ATG intensive immune therapy. The donors accepted mobilization with cell colony stimulating factor from both peripheral blood and bone marrow. The improved Preconditioning regimen was reduced strength of fludarabine combined with Busulfex and cytarabine, cyclophosphamide. Cyclophosphamide （ 50mg/Kg/d ） induced immune tolerance on the ＋ 3 days after transplantation, combined immunosuppressive agents were used for graft-versus-host disease （GVHD） prophylaxis, including CsA, Amethopterin, tacrolimus, etc.. and observed toxicity,GVHD and disease-free survival in patients after transplantation. Result 17 cases of hematopoietic reconstitution and the other three cases implants after the second transplantion, the average time were 17. 4 d and 21.3 d respectively with neutrophils≥0. 5 × 109/L and platelets≥20 × 109/L. Implantation was confirmed by the evidence of 100% of donor hematopoiesis and T lymphocyte subsets counts increased significantly before and after the transplantation. Follow-up to 2015 April,With the median follow-up duration of 17. 7 months （6~32 months） ,3 cases died of complication and the other 17 patients remained disease-free survival, disease-free survival rate was 85 ~ and the longest disease-free survival time up to 32 months. Conclusion Reduced intensity allogeneic hematopoietic stem cell transplantation with high-dose cyclophosphamide-induced immune tolerance treatment is the safe and effective method for severe aplastic anemia.