人类白细胞抗原不合或单倍体亲属供者造血干细胞移植

异基因造血干细胞移植(allo-HSCT)是重症血液病的主要根治性治疗方法。除人类白细胞抗原(HLA)相合的健康同胞为首选供者外,非血缘、脐带血和亲属HLA不合或单倍体造血干细胞都作为重要的干细胞来源进入了临床。美国的统计资料显示只有不超过40%的患者可以找到HLA相合的同胞供者。白人中找到非血缘HLA相合供者的机会约为75%,但在少数人种中这一几率低于50%。尽管如此,非血缘供者的查询过程耗时长,使得许多急性患者无法在最适宜的时机接受移植。脐带血来源的造血干细胞虽然可以立即得到,对供者不构成任何负担而且运输过程污染机会小,但…     

分次TBI预处理及不完全匹配相关供者富集CD34+的造血祖细胞移植可导致移植物迅速成活

HLA相合的造血祖细胞移植是对血液系统恶性肿瘤患者的一种潜在有效的治疗。但是仅有不到1/3的患者具有HLA相合的同胞供者。而部分HLA相合的骨髓移植由于移植失败及严重的移植物抗宿主病(GVHD)受到限制。本文报道了采用分次全身照射(TBI)预处理法及HLA不完全相合的供者去除T细胞(TCD)的造血祖细胞(HPC)移植结果。     

非清髓造血干细胞移植治疗再生障碍性贫血

目的:探讨非清髓性造血干细胞移植(NST)治疗再生障碍性贫血(再障)的方法及疗效。方法:采用非清髓预处理方案进行造血干细胞移植治疗再生障碍性贫血2例。1例为同胞间HLA配型6个位点完全相合的异基因外周血造血干细胞移植,另1例为同胞间HLA配型6个位点完全相合的脐血移植。预处理方案主要由抗胸腺细胞球蛋白(ATG)和环磷酰胺组成。用环孢素A和霉酚酸酯(MMF)预防移植物抗宿主病(GVHD)。结果:2例患者均获造血重建(分别为 5及 9d),2例均未发生GVHD。1例患者在治疗期间未出现感染表现,另1例患者出现CMV感染,给予更昔洛韦病情得以完全控制。2例分别无病生存8及17个月。结论:非清髓造血干细胞移植简便安全,并发症少,疗效好,为治疗再生障碍性贫血有效方法。     

HLA配型相合的造血干细胞移植治疗重型再生障碍性贫血的临床研究

目的 评价HLA配型相合的异基因造血干细胞移植(allo-HSCT)治疗重型再生障碍性贫血(SAA)的疗效.方法 2000年1月至2008年11月采用allo-HSCT治疗SAA患者20例,其中同胞相合移植17例,非血缘关系移植3例.预处理采用环磷酰胺(Cy)50 mg·kg~(-1)·d~(-1)4 d加抗淋巴细胞免疫球蛋白(ATG)2.5 mg·kg~(-1)·d~(-1)或20 mg·kg~(-1)·d~(-1) d.移植物抗宿主病(GVHD)的预防方案为经典的环孢素A(CsA)联合短程甲氨蝶呤(MTX)及霉酚酸酯(MMF).同胞供者采集经重组人粒细胞集落刺激因子(G-CSF)动员的骨髓及外周血干细胞,非血缘供者单纯采集外周血干细胞.结果 回输单个核细胞中位数为7.89(4.00-14.21)×10~(8)/kg,所有患者均获供者造血重建,粒细胞植活中位时间14(11～20)d;血小板植活中位时间12(8～108)d.但1例患者发生晚期排斥,行另一供者二次移植后植活.21例次移植后共发生6例次急性GVHD(I度3例,Ⅱ度皮肤3例),发生率16%.19例生存期>100 d的患者中有7例发生慢性GVHD,其中4例为局限型,3例为广泛型.截至2009年2月28 日,经过中位18(2.0～106.8)个月的随访,共有17例患者无病生存,总生存率为82.5%.结论 采用Cy+ATG的预处理方案对SAA患者进行HLA配型相合HSCT,植活率高,可以获得良好的疗效.     

重型再生障碍性贫血的异基因造血干细胞移植北大核心CSCD

艾曲泊帕等TPO受体激动剂的加入,重型再生障碍性贫血的免疫抑制治疗疗效取得一定提高,因具有长期治愈的优势,造血干细胞移植、尤其是替代供者造血干细胞移植治疗的进展更为迅速。同胞相合供者造血干细胞移植一直是≤50岁再障患者首选的一线治疗,其适应证具有向51~60岁发展趋势;非血缘相合供者造血干细胞移植广泛应用于儿童重型再障之外,一线治疗成人重型再障的研究也显示出良好疗效和较少的移植物抗宿主病;亲缘单倍体供者造血干细胞移植一线治疗重型再障的临床研究不仅显示良好的生存率、无失败生存率,而且长期随访证实其良好的移植后生活质量。而且造血干细胞移植在难以控制活动性感染下重型再障患者的抢救以及非重型再障发展而来的重型再障治疗方面具有较好的可行性和有效性。     

非血缘造血干细胞移植现状与问题

异基因造血干细胞移植(Allo HSCT)是某些血液系统恶性疾病惟一有望治愈的手段,也是某些血液系统非恶性疾病的重要治疗手段。HLA相合同胞供者是Allo HSCT首选的供者来源,但是只有部分患者可以找到相合的同胞供者。因此,寻找合适的非血缘供者就变得十分重要。近年来,随着移植技术方案的成熟和支持治疗的进步,移植现状已获得明显的改善,非血缘供者造血干细胞移植疗效已达到了与同胞供者移植接近的水平。     

异基因造血干细胞移植治疗恶性血液病

目的：探讨异基因造血干细胞移植(Allo—HSCT)治疗恶性血液病的疗效、造血重建、免疫重建及长期生存的情况。方法：血液系统恶性疾病患者12例，其中同胞HLA相合异基因骨髓移植(Allo-BMT)及外周血干细胞移植(Allo—PBSCT)7例；无亲缘关系HLA不全相合脐血移植(UCBT)5例。结果：11／12例受者获造血重建，UCBT患者造血重建速度较同胞PBSCT或BMT慢，1例UCBT移植后46d造血功能未重建，回输自体骨髓后恢复自体造血。11例Allo—HSCT受者免疫功能重建开始于移植后30d，死亡2例，均为移植后复发病例。结论：Allo—HSCT是目前治愈恶性血液病的最佳方法，对于无同胞HLA相合的供者，选择较高细胞数量、HLA1～2个位点不合的UCBT仍然安全有效。     

异基因造血干细胞移植治疗白血病20例临床观察

目的探讨不同类型异基因造血干细胞移植(allo-HSCT)治疗白血病的疗效、造血重建及存活情况。方法哈尔滨血液病肿瘤研究所2003年3月至2006年7月进行异基因造血干细胞移植的白血病患者20例,其中同胞间人类白细胞抗原(HLA)相合的异基因外周血造血干细胞移植(allo-PBSCT)12例,无亲缘关系HLA不全相合脐血移植(UCBT)4例,无关供者的异基因外周血干细胞移植(其中1例HLA-CW位点亚型不合)3例,无关供者骨髓移植1例(经过去除红细胞处理)。结果19/20受者获造血重建,UCBT患者造血重建速度较HLA相合的同胞allo-PBSCT慢,异基因造血干细胞移植后20例患者中发生急性移植物抗宿主病(aGVHD)7例,其中4例Ⅰ~Ⅱ度,3例Ⅲ~Ⅳ度。3例患者死于复发,3例死于移植物抗宿主病(GVHD),另15例至今仍无病存活,中位存活时间30(1~41)个月。结论allo-HSCT是目前治愈白血病的有效方法,对于无同胞HLA相合的供者,选择较高细胞数量,HLA1~2个位点不合的UCBT仍然有效、可行。     

HLA半相合非清髓性造血干细胞与间充质干细胞共移植治疗重症再生障碍性贫血1例

目的:观察HLA半相合非清髓性造血干细胞与间充质干细胞(MSC)共移植治疗重症再生障碍性贫血(SAA)的疗效及安全性。方法:1例24岁男性SAA患者。应用非清髓性预处理方案,进行HLA半相合异基因外周血造血干细胞和MSC共移植。移植rhG-CSF动员的供者外周血单个核细胞9.22×108/kg,CD34 细胞8.56×106/kg,及体外扩增培养的供者骨髓MSC2.12×105/kg。结果:移植后 12d中性粒细胞数>0.5×109/L, 21d WBC4.5×109/L,Hb99g/L,PLT108×109/L。经HLA配型,红细胞亚型和VNTR检测,为供者型完全嵌合体。随访14个月,无急、慢性移植物抗宿主病(GVHD)发生。结论:HLA半相合非清髓性造血干细胞与MSC共移植治疗SAA是安全有效的方法。     

异基因造血干细胞移植治疗白血病76例临床观察

目的观察不同来源的异基因造血干细胞移植治疗白血病的疗效并探讨主要并发症的处理方案。方法对2001年9月至2007年3月第四军医大学西京医院血液科76例白血病患者行异基因造血干细胞移植治疗,其中慢性粒细胞白血病34例,急性髓性白血病24例,急性淋巴细胞白血病15例,T细胞淋巴瘤/白血病3例。人类白细胞抗原(HLA)全相合的同胞供者57例,1个HLA位点不合同胞供者3例,HLA单倍型半相合同胞供者7例,非血缘供者9例。预处理方案采用改良的马利兰联合环磷酰胺(BUCY)或改良的环磷酰胺联合全身放疗及阿糖胞苷或鬼臼乙叉甙(CyTBI Ara-c/VP-16)方案。采用标准的环孢素A(CsA)联合短期甲氨蝶呤(MTX)方案预防移植物抗宿主病(GVHD);无关供者移植加用抗人胸腺细胞球蛋白,单倍型半相合移植同时加用CD25单克隆抗体。结果96.1%(73/76)获得植入。24.7%(18/73)出现急性GVHD,32.9%(24/73)出现慢性GVHD;合并重症肝静脉闭塞病2例;并发纯红细胞性再生障碍性贫血5例。随访3~72个月,现存活56.6%(43/76),43.4%(33/76)在移植后1~36个月时死亡,19例死于白血病复发,14例死于移植相关并发症。结论多种来源的异基因造血干细胞移植是治疗白血病的有效方法,于慢性粒细胞白血病慢性期、急性白血病缓解期移植效果较好,移植前处于高危难治状态的病例复发率仍较高。     

Haematopoietic stem cell transplantation for patients with myelo-dysplastic syndromes and secondary acute myeloid leukaemias: a report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

Allogeneic stem cell transplantation from an HLA-identical sibling donor is a curative treatment option for a young patient with myelodysplastic syndrome, limited by age and lack of sibling donors. Alternative stem cell sources have been used more recently, such as unrelated donors, non-identical family members or autologous transplants. This analysis of 1378 transplants reported to the European Group for Blood and Marrow Transplantation (EBMT) addresses the outcome of the varying procedures according to the known risk factors. The estimated disease-free survival (DFS) and estimated relapse risk at 3 years were both 36% for 885 patients transplanted with stem cells from matched siblings. In the multivariate analysis, age and stage of disease had independent prognostic significance for DFS, survival and treatment-related mortality. Patients transplanted at an early stage of disease had a significantly lower risk of relapse than patients transplanted at more advanced stages. The estimated DFS at 3 years was 25% for the 198 patients with voluntary unrelated donors, 28% for the 91 patients with alternative family donors and 33% for the 126 patients autografted in first complete remission. The non-relapse mortality was 58% for patients with unrelated donors, 66% for patients with non-identical family donors and 25% for autografted patients. The relapse rate of 18% was relatively low for patients with non-identical family donors, 41% for patients with unrelated donors and 55% for patients treated with autologous stem cell transplantation. Both allogeneic and autologous stem cell transplantation have emerged as treatment options for patients with myelodysplastic syndromes. Transplantation with an HLA-identical sibling donor is the preferred treatment option. Patients without an HLA-identical sibling donor may be treated with either autologous stem cell transplantation or an alternative donor transplantation. Patients younger than 20 years may be treated with an unrelated donor transplantation. Patients older than 40 years, and probably also patients between 20 and 40 years, may benefit most from an autologous stem cell transplantation.     

Hematopoietic stem cell transplantation for sickle cell disease: The changing landscape

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapy for sickle cell disease (SCD); however, its use is limited by lack of suitable human leukocyte antigen (HLA)-matched donors and decreased application in older patients with significant morbidity. Myeloablative, HLA-identical sibling transplantation in children with SCD offers excellent long-term survival, with overall and event-free survival rates of 95% and 92%, respectively. However, the risk of graft-versus-host-disease, infections, infertility, and other long-term transplant complications, further limits its widespread use. Recent approaches using reduced intensity conditioning (RIC) are associated with lower toxicity, allowing extension of this modality to children and adults with significant morbidity; however, these approaches are also associated with increased risk of graft failure. The optimal RIC regimen that strikes the optimal balance between maximizing the rate of stable engraftment while minimizing transplant-related morbidity and mortality is unknown. Alternative donor transplants, most prominently, partial HLA-mismatched related transplants (haploidentical), are being investigated with promising initial results. This review will discuss long-term results of HLA-matched sibling HSCT for SCD, and recent updates on HLA-matched unrelated donor and unrelated umbilical cord blood HSCT for SCD.     

Donor CMV serologic status and outcome of CMV-seropositive recipients after unrelated donor stem cell transplantation: an EBMT megafile analysis

Cytomegalovirus (CMV) has been a major cause of morbidity and mortality after allogeneic stem cell transplantation (SCT). The importance of the recipient's serologic status is paramount. However, the importance of the donor's serologic status in CMV-seropositive recipients is controversial. We analyzed the influence of the donor's CMV status in a large cohort of patients. A total of 7018 patients seropositive for CMV reported to the European Group for Blood and Marrow Transplantation (EBMT) were included; 5910 patients had undergone HLA-identical sibling SCT and 1108 patients had undergone unrelated donor SCT. Univariate and multivariate proportional hazards models were constructed for survival, event-free survival, transplant-related mortality, and relapse incidence. Patients receiving grafts from CMV-seropositive HLA-identical sibling donors had the same survival as patients grafted from seronegative donors (hazard ratio [HR], 1.04; P =.37; 95% confidence interval [CI], 0.95-1.14). However, unrelated donor stem cell (SC) transplant recipients receiving grafts from CMV-seropositive donors had an improved 5-year survival (35% versus 27%; HR = 0.8; P =.006), an improved event-free survival (30% versus 22%; HR = 0.8; P =.01), and a reduced transplant-related mortality (49% versus 62%; HR = 0.7; P <.001). There was no influence on the relapse incidence. The effects of donor CMV status remained in multivariate analyses. The effect of donor status was different among different disease categories. In patients with chronic myelogenous leukemia (CML), T-cell depletion abrogated the beneficial effect of donor status, suggesting that the effect is mediated through transfer of donor immunity. Our data suggest that donor CMV status influences outcome of unrelated SCT. For a CMV-seropositive patient, a seropositive donor might be preferable.     

Bone marrow transplantation for Fanconi anemia

Fanconi anemia is a genetic disorder associated with diverse congenital abnormalities, progressive bone marrow failure, and increased risk of leukemia and other cancers. Affected persons often die before 30 years of age. Bone marrow transplantation is an effective treatment, but there are few data regarding factors associated with transplant outcome. We analyzed outcomes of HLA-identical sibling (N = 151) or alternative related or unrelated donor (N = 48) bone marrow transplants for Fanconi anemia performed between 1978 and 1994 and reported to the International Bone Marrow Transplant Registry. Fanconi anemia was documented by cytogenetic studies in all cases. Patient, disease, and treatment factors associated with survival were determined using Cox proportional hazards regression. Two-year probabilities (95% confidence interval) of survival were 66% (58% to 73%) after HLA-identical siblings transplants and 29% (18% to 43%) after alternative donor transplants. Younger patient age (P .0001), higher pretransplant platelet counts (P = .04), use of antithymocyte globulin (P = .005), and use of low-dose (15 to 25 mg/kg) cyclophosphamide plus limited field irradiation (P = .009) for pretransplant conditioning and cyclosporine for graft-versus-host disease prophylaxis (P = .002) were associated with increased survival. Bone marrow transplants are effective therapy for Fanconi anemia. The adverse impact of increasing age and lower pretransplant platelet count on transplant outcome favors earlier intervention, especially when there is an HLA-identical sibling donor.     

Impact of donor type on outcome of bone marrow transplantation for Wiskott-Aldrich syndrome: collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program

Human leukocyte antigen (HLA)-identical sibling bone marrow transplantation is an effective treatment for Wiskott-Aldrich syndrome. However, most children with this disease lack such donors and many patients receive transplants from alternative donors. This study compared outcomes of HLA-identical sibling, other related donor, and unrelated donor transplantation for Wiskott-Aldrich syndrome. The outcome of 170 transplantations for Wiskott-Aldrich syndrome, from 1968 to 1996, reported to the International Bone Marrow Transplant Registry and/or National Marrow Donor Program were assessed. Fifty-five were from HLA-identical sibling donors, 48 from other relatives, and 67 from unrelated donors. Multivariate proportional hazards regression was used to compare outcome by donor type and identify other prognostic factors. Most transplant recipients were younger than 5 years (79%), had a pretransplantation performance score greater than or equal to 90% (63%), received pretransplantation preparative regimens without radiation (82%), and had non-T-cell-depleted grafts (77%). Eighty percent received their transplant after 1986. The 5-year probability of survival (95% confidence interval) for all subjects was 70% (63%-77%). Probabilities differed by donor type: 87% (74%-93%) with HLA-identical sibling donors, 52% (37%-65%) with other related donors, and 71% (58%-80%) with unrelated donors (P =.0006). Multivariate analysis indicated significantly lower survival using related donors other than HLA-identical siblings (P =.0004) or unrelated donors in boys older than 5 years (P =.0001), compared to HLA-identical sibling transplants. Boys receiving an unrelated donor transplant before age 5 had survivals similar to those receiving HLA-identical sibling transplants. The best transplantation outcomes in Wiskott-Aldrich syndrome are achieved with HLA-identical sibling donors. Equivalent survivals are possible with unrelated donors in young children.     

CD52 and CD45 monoclonal antibodies for reduced intensity hemopoietic stem cell transplantation from HLA matched and one antigen mismatched unrelated donors

Allogeneic hemopoietic stem cell transplantation (HSCT) is the only curative option for many patients with hematological malignancies. Since many of these patients lack HLA-identical sibling donors and are older or have comorbidity, a fully ablative HSCT is not feasible and an alternative approach is required. We studied 22 consecutive patients who could not have myeloablative conditioning because of comorbidity or age - 21/22 being over the age of 50 years (median 58 years range 20-70 years). A conditioning regimen consisting of fludarabine, total body radiation 450 cGy and alemtuzumab (CD52 mAb) was used for 15 patients. A second group of seven patients received CD45 monoclonal antibodies in addition. Unrelated donor stem cells were HLA matched (15 patients - 68%) or one locus mismatched (seven patients - 32%). In all, 16 patients had high-risk disease, including 12 with active malignancy at the time of transplant. With a median follow-up of 715 (216-1470) days, nonrelapse mortality, actuarial event-free and overall survival is 27, 45 and 45%, respectively. Hence the outcome of reduced intensity HSCT with lymphodepleting antibodies in older patients with intermediate/high-risk hematological malignancies appears comparable to that obtained with fully ablative transplantation in younger patients, even when these older recipients lack HLA-identical sibling donors.     

Should young children with sickle cell disease and an available human leukocyte antigen identical sibling donor be offered hematopoietic cell transplantation?

Availability of an HLA-identical sibling donor raises the question, “should young children with SCD, and an available HLA identical sibling donor be considered for hematopoietic cell transplantation (HCT) even before they manifest severe clinical presentations of sickle cell disease (SCD)?” The overall survival (OS) and event free survival (EFS) following HCT from an HLA identical sibling is excellent in young children, and worsen with increasing age at HCT. SCD related complications, organ dysfunction, quality of life, and risk for premature mortality all worsen with age. The ethical principles of non-maleficence, beneficence, autonomy and justice all support the consideration of this life, quality of life, and organ saving therapy at a young age.     

Improved outcome of patients older than 30 years receiving HLA-identical sibling hematopoietic stem cell transplantation for severe acquired aplastic anemia using fludarabine-based conditioning: a comparison with conventional conditioning regimen

Older age is a limitation for HLA-identical sibling hematopoietic stem cell transplantation (HSCT) as first-line therapy for severe acquired idiopathic aplastic anemia (SAA). Fludarabine (Flu)-based conditioning might improve outcome in older patients. We analyzed retrospectively 30 patients older than 30 years receiving such reduced-intensity conditioning HSCT according to recommendations of the European Group for Blood and Marrow Transplantation (EBMT) and compared their outcome to a control group receiving the standard regimen (cyclophosphamide+/−antithymocyte globulin) over the same study period (1998–2007). Patients conditioned with Flu had a higher probability of overall survival than the control group (p=0.04) when adjusting for recipient’s age. This might be related to a trend towards a reduced incidence of graft failure in patients receiving Flu (0% vs. 11%, p=0.09), while no difference was observed regarding graft-versus-host disease incidence. Flu-based conditioning regimen may reduce the negative impact of age in older patients with SAA receiving an HLA-identical sibling HSCT.     

Genomic tissue typing and optimal antithymocyte globuline dose using unrelated donors results in similar survival and relapse as HLA-identical siblings in haematopoietic stem-cell transplantation for leukaemia

Sixty-one leukaemia patients treated with haematopoietic stem cell transplantation (HSCT) from a genomic human leucocyte antigen (HLA)-A, -B and -DRbeta1 matched unrelated donor (MUD) were compared with 121 patients with an HLA-identical sibling donor. All patients received conventional conditioning. We selected all patients with unrelated donors who received optimal antithymocyte globuline (ATG) dose, 6 mg/kg. One hundred and seven patients received stem cells from peripheral blood and 75 patients received bone marrow (BM) cells. The incidences of acute graft-versus-host disease (GVHD) grades II-IV were 33.4% and 34.7% in the MUD and sibling group, respectively. After year 2001, the incidence of chronic GVHD was similar in the two groups (27.8% vs. 25.8%). There was no difference in overall survival (60% vs. 60%), transplant-related mortality (18.6% vs. 16.6%) and relapse (23% vs. 26.4%) between the two groups. Conclusion: Haematopoietic stem cell transplantation with unrelated donors results in similar GVHD, relapse and survival as compared to using sibling donors. Reasons for this may be improved tissue-typing techniques and supportive care and optimisation of the ATG dose.     

Successful hematopoietic stem cell transplantation for Fanconi anemia from an unaffected HLA-genotype-identical sibling selected using preimplantation genetic diagnosis

The only proven cure for Fanconi anemia (FA)-associated bone marrow failure is successful allogeneic hematopoietic stem cell transplantation (HSCT). However, HSCT with donors other than HLA-identical siblings is associated with high morbidity and poor survival. Therefore, we used preimplantation genetic diagnosis (PGD) to select an embryo produced by in vitro fertilization (IVF) that was unaffected by FA and was HLA-identical to the proband. The patient was a 6-year-old girl with FA and myelodysplasia previously treated with oxymetholone and prednisone. After her parents underwent 5 cycles of IVF with intrauterine transfer of 7 embryos over a span of 4 years, successful pregnancy ensued. Twenty-eight days after delivery, the patient underwent transplantation with her newborn sibling donor's HLA-identical umbilical cord blood hematopoietic stem cells (HSCs). Neutrophil recovery occurred on day 17 without subsequent acute or chronic graft-versus-host disease. Currently, 2.5 years after transplantation, the patient is well and hematopoiesis is normal. In summary, we have described the first successful transplantation, using IVF and PGD, of HSCs from a donor selected on the basis of specific, desirable disease and HLA characteristics. The medical, legal, and ethical issues involved with this approach are discussed.