乙肝病毒感染供者来源异基因间充质干细胞联合非清髓性造血干细胞移植治疗骨髓增生异常综合征-难治性贫血一例

A case report of myelodysplastic syndrome treated with allogeneic transplantation of HLA-identical sibling using culture-expanded mesenchymal stem cells and hematopoietic stem cells originated from HBV infected donor

目的 进一步探讨骨髓增生异常综合征-难治性贫血（MDS-RA）患者采用异基因造血干细胞移植的安全性、有效性、可行性等;联合应用供者来源间充质干细胞（MSC）移植,进一步了解MSC在造血重建和免疫抑制方面的作用;探讨移植过程中供者来源乙肝的有效预防措施.方法 MDS-RA患者选用合适的预处理及移植物抗宿主病（GVHD）预防方案,移植前体外分离、培养、扩增供者来源MSC,供者经粒细胞集落刺激因子（G-CSF）动员后在回输当日采集外周血造血干细胞,造血干细胞回输前4 h先行回输MSC.供者来源乙肝处理：供者在移植前1个月开始抗病毒治疗;受者移植前2个月起予乙肝疫苗接种,移植前1周予高效价乙肝免疫球蛋白应用,移植1个月后起预防性抗病毒药物治疗,全程定期检测受者乙肝病毒表面抗原、e抗体、核心抗原、雅培乙肝表面抗体滴度等指标,根据乙肝表面抗体滴度及时补充高效价乙肝免疫球蛋白.结果 移植后＋10天患者造血重建,造血重建前未出现严重感染、出血等情况,无急慢性GVHD发生.移植后＋30天骨髓细胞学示：各系增生活跃,巨核细胞9个,血小板小簇可见;荧光原位杂交技术（FISH）检测性染色体：XY 47/300.移植后＋90天FISH检测：XY 7/300.移植后＋60天HBV-DNA外周血和骨髓标本均阴性,HBsAb阳性,HBsAh滴度持续大于100,＋60天时达800.患者继续随访中,血象正常,生活质量良好.结论 初步证实同胞来源异基因造血干细胞联合MSC移植救治MDS-RA方法可行且安全有效,临床有待更多病例积累.采用乙肝疫苗接种、高效价免疫球蛋白应用联合预防性抗病毒治疗的综合防治措施,有效预防受者感染供者来源乙肝,可供类似病例借鉴.

Objective To evaluate the safety, efficiency and feasibility of HLA-identical sibling using culture-expanded mesenchymal stem cells and hematopoietic stem cells in treatment for myelodysplastic syndrome （MDS）. Also to investigate for valid preventive measures to avoid the infection of HBV originated from donor. Methods A 46-years-old male patient with myelodysplastic syndrome-refractory anemia （MDSRA） got a cotransplantation of culture-expanded mensenchymal stem cells （MSC） and hematopoietic stem cells （HSCs） from HLA-identical sibling donor （his sister） who was infected by hepatitis B virus （HBV）. Some measures were applicated in order to avoid the recipient from getting a HBV infection. The antiviral therapy to the donor was began early at the time 1 month before transplant, and HBV vaccine inoculation was used 2 month before transplant. High titer of anti-hepatis B immunoglobulin was used 1 week before transplant and 1 month after transplant the use of prophylactic anti-hepatis B drug treatment was begun. A non-myeloablative preparative regimen included fludarabine monophosphate （Flu, 120 mg/m^2）, cyclophosphamide （Cy, 1200 mg/m^2） and antithymocyte globulin （ATG, 15 mg/kg） was given to him before culture-expanded mesenchymal stem cell and allogeneic peripheral blood stem cell from his HLA-matched sister. Results The regimen was well tolerated, and hemopoiesis was reconstituted on day 10 after transplant, idiochromosome detected by fluorescent in situ hybridization on day 30 showed XY 47/300 and on day 90 it was 7/300. No evidence of HBV infection was detected on day 60 after transplant. Conclusion The clinical course of this patient indicate that HLA-identical sibling culture-expanded mesenchymal stem cell transplantation combined with non-myeloablative stem cell transplantation can be an effective and safe approach in treatment of MDS.