第二次单倍体造血干细胞移植治疗首次移植失败再生障碍性贫血并发淋巴瘤1例

背景：急性重型再生障碍性贫血第一次异基因造血干细胞移植失败对患儿是严重致命的，若同时合并有继发性淋巴瘤等多种并发症，治疗就更为棘手，目前无成功方法可借鉴。 目的：探讨第二次HLA单倍体造血干细胞移植治疗首次移植失败且并发淋巴瘤的急性重型再生障碍性贫血患儿的有效性和安全性。方法：回顾性分析1例急性重型再障患儿的二次造血干细胞移植的临床资料：患儿男，3岁，2011年11月25日行第一次非血缘异基因外周血干细胞移植(供受者HLA为8/10相合，血型主要不合)，移植后粒细胞和血小板造血分别在11 d和14 d恢复，移植后30 d DNA移植植入鉴定和染色体检测均示移植成功植入，术后35 d出现皮肤Ⅰ度移植物抗宿主病，激素治疗后消失，术后54 d因出现自身免疫性溶血性贫血及纯红细胞再生障碍性贫血，给予大剂量丙种球蛋白冲击、激素及促红素等治疗好转，激素逐渐减量，EBV拷贝数逐渐升高，术后3个月患者出现发热、双侧颈部可触及数个肿大淋巴结，行B超引导下右侧颈部淋巴结穿刺活检，考虑移植后淋巴增殖性疾病，病理示：弥漫大B细胞淋巴瘤，治疗上减停免疫抑制剂，应用美罗华及CHOP方案化疗，淋巴结缩小，且EBV拷贝数下降，体温正常。移植术后5个月复查血象和骨髓象提示继发性植入失败，进而于2012年5月15日行第二次单倍体相合造血干细胞移植。供者为患儿的父亲，预处理方案为清髓性预处理方案：氟达拉滨+环磷酰胺+马利兰+米托蒽醌+抗CD52单克隆抗体。回输骨髓造血干细胞的同时输注脐带间充质干细胞。移植物抗宿主病预防：环孢素A+短程的甲氨喋呤+CD25单克隆抗体联合霉酚酸酯。回输的有核细胞分别为13.52×108/kg，CD34+细胞数为2.45×106/kg，无关供者脐带来源间充质干细胞的量为1×106/kg。随访时间为移植后24个月。结果与结论：移植后中性粒细胞达到0.5×109 L-1，血小板计数≥20×109 L-1分别为14 d和30 d；二次移植后1个月DNA指纹检测说明造血干细胞移植成功植入。预处理后肿大淋巴结逐渐缩小，但术后2个月因淋巴结有增大趋势，停用免疫抑制剂并局部放疗后淋巴结缩小且稳定至今，PET无明显代谢异常区，移植后每半年定期随访，目前正常生活及上学。结果说明：单倍体造血干细胞联合脐带间充质干细胞共移植是安全、高效的治疗第一次移植失败重型再生障碍性贫血的方法，患儿可以耐受预处理毒性，造血恢复较快，移植物抗宿主病可控，值得进一步临床研究。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；组织工程全文链接：

Second haploidentical hematopoietic stem cell transplantation for aplastic anemia complicated by lymphoma in one case undergoing a failed first transplantation

BACKGROUND: It is fatal for children with acute severe aplastic anemia undergoing failed first allogeneic. If there are secondary lymphoma and other complications, treatment is more difficult. Up to now, there is yet no feasible treatment. OBJECTIVE:To investigate the possibility and safety of second haploidentical hematopoietic stem cell transplantation because of the failure in the first unrelated blood transplantation and secondary lymphoma. METHODS: A 3-year-old boy with severe aplastic anemia underwent HLA 8/10 matched unrelated peripheral blood stem cell transplantation on November 25, 2011. There was a major ABO mismatch. The time of neutrophil exceeding 0.5×109/L and platelets recovery exceeding 20×109/L were 11 and 14 days, respectively after transplantation. Bone marrow aspiration showed normal while full donor engraftment was found by chromosomal analyses on day 30. Grade I graft-versus-host disease occurred after 35 days. Autoimmune hemolytic anemia and pure red cell aplasia were also diagnosed on day +54. He was given high-dose gamma globulin, erythropoietin and glucocorticoids, and autoimmune hemolytic anemia and pure red cell aplasia were controlled. Unfortunately, on day +90, the boy suffered from fever and superficial lymph nodes of the bilateral neck. B ultrasound-guided needle biopsy was done on the right cervical lymph nodes, and post transplant lymphoproliferative disorder was considered. Pathological examination showed diffuse large B-cell lymphoma. Managements for patients consisted of withdrawal of immunosuppressive treatment and application of rituximab plus chemotherapy. After treatment, the lymph node shrank, Epstein-Barr virus copy number was decreased, and the body temperature recovered. However, on day +150, blood routine examination and bone marrow aspiration showed transplant failure. Then, the boy received the second haploidentical stem cell transplantation on May 15, 2012. The donor was his father. A myloablative condition regimen was selected: high-dose fludarabine+cyclosphosphamide+ busulfan+mitoxantrone+anti-CD52 monoclonal antibody. Hematopoietic stem cells and mesenchymal stem cells were re-infused simultaneously. Prophylaxis strategy for graft-versus-host disease consisted of cyclosporine A +short-term methotrexate+CD25 monoclonal antibody combined with mycophenolate mofetil. Nucleated cells and CD34+ cells were re-infused at a dose of 13.52×108/kg and 2.45×106/kg, respectively. The follow-up time was 24 months after transplantation.RESULTS AND CONCLUSION: After second implantation, the time of neutrophil exceeding 0.5×109/L and platelets recovery exceeding 20×109/L was 14 and 30 days, respectively. DNA test showed full donor engraftment was found. The swollen lymph nodes shrank after pretreatment, but tended to be enlarged at 2 months after surgery. After withdrawal of immunosuppressor and local radiotherapy, the lymph node shrank stably. PET showed no obvious area with presence of metabolic abnormalities. Regular follow-up every 6 months after transplantation has showed that the body has normal life and goes to school. Results suggest that the co-transplantation of haploidentical hematopoietic stem cells and mesenchymal stem cells is safe and effective for treatment of severe aplastic anemia following the failure of first transplantation. Pretreatments can faster hematopoietic recovery and control graft-versus-host disease, which is worth further clinical research.