无关供者HLA错配/单倍型相合非体外去除T细胞的造血干细胞移植:单中心中国经验

Related HLA-mismatched/haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion: observations of a single Chinese center.

作者信息

Huang Xiaojun, Liu Daihong

机构信息

Peking University Institute of Hematology, People's Hospital, Beijing, China.

出版信息

Clin Transpl. 2011:237-45.

DOI:
Abstract

The Institute of Hematology, Peking University, is the largest hematopoietic stem cell transplantation (HSCT) center in China. A total of 400 HSCTs performed in 2010 accounted for a quarter of all allogeneic HSCTs performed in China. The GIAC protocol, which uses HLA-mismatched/haploidentical blood or bone marrow transplantation without in vitro T-cell depletion, entails administration of granulocyte-colony stimulating factor (G-CSF) to all donors, intensified immunological suppression, and treatment with anti-human thymocyte immunoglobulin. The stem cell grafts are a combination of G-CSF-primed bone marrow cells and G-CSF-mobilized peripheral blood stem cells, which may be critical to the success of this protocol through the immune modulation of G-CSF. Using this protocol, more than 99% engraftment and complete donor chimerism were achieved in pediatric and adult patients with hematological malignancies. The incidence of graft-versus-host disease (GVHD) grades 3 and 4 was 13.4% and that of extensive chronic GVHD 22.6%. Comparable relapse rates were observed between patients who received unmanipulated haploidentical transplantation, and those who received HLA-identical or unrelated HSCT. Patients with confirmed minimal residual disease, (expression levels of Wilms' tumor suppressor gene 1 and flow cytometry) after HSCT received pre-emptive modified donor lymphocyte infusion to prevent relapse. Infection was the main cause of non-relapse death. Prospective studies are ongoing to investigate the mechanisms of immune reconstitution in order to refine the protocol. In 1964, a patient with severe aplastic anemia received a bone marrow infusion from her syngeneic, pregnant sister, and remained disease-free over a 40-year follow-up period. Following this success, there was a 20-year interruption in the transplantation program at our center. The hiatus ended in 1981 with the first allogeneic HSCT, which was used to treat a girl with acute lymphoblastic leukemia (ALL). In the mid-1990s, the facility performed allo-HSCTs from unrelated donors (URD) and umbilical cord blood (UCB). Then, in 2000, a patient with refractory acute leukemia received related haploidentical HSCT and achieved long-term survival without relapse over an 11-year followup period. Coincident with the rapid economic development experienced in China since 2000, the transplantation program at our Institute has been expanded to include broadened indications, multiple sources of stem cells and improved outcomes. The Institute is the largest HSCT center in China, now with 130 beds in four wards, 33 of which are laminar-flow rooms. Between 2007 and 2009, over 350 HSCTs were performed per year, rising to a total of 400 in 2010. Further, in 2010, 94% of these HSCTs were allogeneic transplants, accounting for a quarter of all allo-HSCTs performed in China. Of these, transplants from URD accounted for 6%-7%, those using UCB for less than 5%, those from identical siblings for 25%-30%, and those from the related haploidentical for 55%-65%. The most common indications for treatment with allo-HSCT are intermediate-to-high risk of acute leukemia or myelodysplastic syndrome, advanced chronic myeloid leukemia (CML), refractory lymphoma, or severe aplastic anemia.

摘要

北京大学血液病研究所是中国最大的造血干细胞移植(HSCT)中心。2010年共进行了400例HSCT,占中国所有异基因HSCT的四分之一。GIAC方案采用不进行体外T细胞去除的HLA不匹配/单倍型相合血液或骨髓移植,该方案要求对所有供者给予粒细胞集落刺激因子(G-CSF)、强化免疫抑制以及用人抗胸腺细胞免疫球蛋白进行治疗。干细胞移植物是G-CSF预处理的骨髓细胞和G-CSF动员的外周血干细胞的组合,通过G-CSF的免疫调节作用,这可能是该方案成功的关键。采用该方案,血液系统恶性肿瘤的儿童和成人患者实现了超过99%的植入率和完全供者嵌合。3/4级移植物抗宿主病(GVHD)的发生率为13.4%,广泛慢性GVHD的发生率为22.6%。接受未处理的单倍型相合移植的患者与接受HLA相合或无关HSCT的患者之间观察到相似的复发率。HSCT后确诊为微小残留病(威尔姆斯肿瘤抑制基因1的表达水平和流式细胞术)的患者接受了抢先性改良供者淋巴细胞输注以预防复发。感染是非复发死亡的主要原因。正在进行前瞻性研究以探讨免疫重建的机制,以便完善该方案。1964年,一名重型再生障碍性贫血患者接受了来自其同基因、怀孕妹妹的骨髓输注,在40年的随访期内一直无病生存。在此成功之后, 我们中心的移植项目中断了20年。1981年首例异基因HSCT用于治疗一名急性淋巴细胞白血病(ALL)女孩,中断结束。20世纪90年代中期,该机构开展了无关供者(URD)和脐带血(UCB)的异基因HSCT。然后,2000年,一名难治性急性白血病患者接受了相关单倍型相合HSCT,并在11年的随访期内实现了长期无复发生存。与中国自2000年以来经历的快速经济发展同步,我们研究所的移植项目不断扩大,包括扩大适应证、增加干细胞来源并改善治疗结果。该研究所是中国最大的HSCT中心,目前四个病房共有130张床位,其中33间是层流病房。2007年至2009年期间,每年进行超过350例HSCT,2010年增至400例。此外,2010年,这些HSCT中有94%是异基因移植,占中国所有异基因HSCT的四分之一。其中,来自URD的移植占6%-7%,使用UCB的移植占不到5%,来自同卵同胞的移植占25%-30%,来自相关单倍型相合的移植占55%-65%。异基因HSCT治疗最常见的适应证是急性白血病或骨髓增生异常综合征的中高危、晚期慢性髓性白血病(CML)、难治性淋巴瘤或重型再生障碍性贫血。

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