无关供者异基因造血干细胞移植治疗骨髓增生异常综合征9例患者临床分析

目的 探讨无关供者异基因造血干细胞移植（UD-HSCT）治疗骨髓增生异常综合征（MDS）的疗效和可行性。方法 MDS患者9例,其中男性6例,女性3例;年龄7 ～46岁,中位年龄30岁。其中难治性贫血（RA）1例,难治性血细胞减少伴有多系发育异常（RCMD）2例,难治性贫血伴有原始细胞过多-2（RAEB-2）5例,MDS进展为急性髓系白血病（MDS-AML）1例。接受UD-HSCT治疗的MDS患者中周血干细胞移植（PBSCT）8例,骨髓移植（BMT）1例。供受者HLA高分辨配型10/10位点相合4例、9/10位点相合4例、7/10位点相合1例。预处理方案为BU + CY + Flud + Ara-C + ATG 8例、BU + Mel + Flud + Ara-C + ATG 1例,移植物抗宿主病（GVHD）预防方案为FK506 + MTX + MMF 8例、CsA + MTX + MMF 1例。结果 9例患者均获得造血重建,中性粒细胞≥ 0.5 × 109/L和血小板≥20 × 109/L的中位时间分别为移植后15（11 ～ 20） d和23（8 ～ 32） d。6例患者发生急性GVHD（aGVHD）,其中Ⅰ度4例,Ⅱ度2例,5例患者发生局限型慢性GVHD（cGVHD）。中位随访20.3（6.4 ～ 50）个月,1例患者移植后14个月复发死亡,其余8例患者中位随访27.9（6.4 ～ 50）个月均无病存活,总体生存率（OS）及无病生存率（DFS）均为85.7 % ± 13.2 %。结论 UD-HSCT治疗MDS安全有效,在无同胞全合供者时,无关供者也可以作为此类患者有效治疗选择。     

造血干细胞移植治疗骨髓增生异常综合征20例疗效分析

目的评价造血干细胞移植（HSCT）治疗骨髓增生异常综合征（MDS）患者的疗效，探讨MDS患者接受HSCT治疗的适应证和时机。方法1993年11月～2007年4月对20例MDS及MDS转急性髓系白血病（AML）患者（男性12例,女性8例,中位年龄39岁）行HSCT治疗。其中18例接受同胞供者异基因外周血干细胞移植（allo—PBSCT）；1例为同基因骨髓移植（Svn—BMT）；1例为无关脐带血移植（CBT），＋25d时移植失败行自体骨髓移植。预处理主要采用修改的Bu／Cv方案。结果3年总生存率（SO）及3年无病生存率均为53.3％±12％；3年复发率（RR）10．8％±7％，移植相关死亡率（TRM）42．6％±12％。截止随访日期，存活11例，中位生存时间16．5（2.0～112）个月。结论HSCT是治疗MDS的有效方法,如有HLA匹配的同胞供者,HSCT可作为MDS患者的一线治疗。     

成人无关供者脐带血移植现状

成人无关供者脐血移植 (UD CBT)能对大多数患者提供长期稳定的造血重建 ,可短期内进行移植 ,且可增加找到供者的几率。未来成人UD CBT将着重于降低移植相关死亡率 ,采用合适的预处理方案、体外扩增或混合脐血输注及应用一些特殊药物可能是其主要解决手段。     

非清髓异基因造血干细胞移植治疗低增生性MDS1例并文献复习

目的探讨非清髓性异基因外周血造血干细胞移植治疗低增生性骨髓增生异常综合征（MDS）的疗效,观察其植入及并发症的发生情况。方法我院诊断为低增生性MDS患者1例,采用氟达拉滨＋阿糖胞苷＋环磷酰胺的非清髓预处理方案,环孢素A＋甲氨蝶呤＋骁悉预防移植物抗宿主病。结果 STR-PCR证实移植后30d及3个月骨髓植入为完全供者型,移植后3个月发生多发性脑梗塞,6个月出现面部皮疹及口腔溃疡,通过调整免疫抑制剂及输注间充质干细胞（5×10^7/次,2次）后症状明显好转。结论非清髓性异基因外周血造血干细胞移植治疗低增生性MDS获得较好的疗效。     

地西他滨联合造血干细胞移植治疗骨髓增生异常综合征转化急性白血病

背景：由骨髓增生异常综合征转化的急性白血病为难治白血病,临床疗效差,缓解率低,生存期短,因此探索新的有效治疗方法极为重要。 目的：观察地西他滨联合造血干细胞移植治疗骨髓增生异常综合征转化急性白血病的临床疗效及并发症。 方法：骨髓增生异常综合征转化的急性髓细胞白血病患者1例,先后予2个疗程地西他滨及异基因造血干细胞移植,观察临床疗效、地西他滨的毒副作用及移植相关并发症。 结果与结论：经2个疗程地西他滨治疗后,达到完全缓解,主要不良反应为骨髓抑制并发感染,该患者再接受异基因造血干细胞移植后获得无病生存213 d,移植过程中出现急性移植物抗宿主病及肺部感染。结果提示地西他滨联合造血干细胞移植治疗骨髓增生异常综合征转化急性白血病获得良好效果,毒副作用及相关并发症可控制,为临床上骨髓增生异常综合征转化急性白血病的治疗提供了新方法。     

骨髓增生异常综合征治疗的新进展

骨髓增生异常综合症(MDS)是造血干细胞异常，导致无效造血和外周血细胞减少的一种综合症，多见于老年人，欧美MDS发病率为4／10万，是急性髓性白细胞(AML)的两倍，在大于70岁的老年人可达20／10万。我国由于寿命的延长，有增长的趋势。     

异基因造血干细胞移植后骨髓免疫微环境重建研究

GVHD 和GVL 是影响异基因造血干细胞移植术成败的关键因素。骨髓不仅是造血器官,更是免疫器官,骨髓中的免疫微环境关乎移植后造血重建、免疫功能重建、移植后白血病复发。本文将从骨髓微环境的病理生理特点、异基因造血干细胞移植后免疫功能重建、骨髓免疫微环境与移植后造血恢复及移植后白血病复发等角度,综述近年来关于异基因造血干细胞移植后骨髓免疫微环境重建与造血重建和白血病复发相关研究情况。     

非亲缘供者异基因造血干细胞移植治疗恶性血液病15例

背景：异基因造血干细胞移植是治愈恶性血液病的主要方法,但中国多为单子女家庭,因此探索非亲缘供者异基因造血干细胞移植的治疗效果及并发症防治具有重要的意义。 目的：观察非亲缘供者异基因造血干细胞移植治疗15例恶性血液病的疗效和相关并发症。 方法：15例恶性血液病患者接受非血缘关系异基因造血干细胞移植治疗。所有患者均采用经典或改良的马利兰联合环磷酰胺预处理方案。4例采用环孢素A+短程甲氨蝶呤+麦考酚吗乙酯预防移植物抗宿主病,另11例患者同时加用抗胸腺细胞球蛋白。输注供者有核细胞中位数为6.3×108/kg,CD34+细胞中位数为3.1×106/kg。 结果与结论：除1例移植后早期死亡不能评估外,其余14例经检测均证实植活。发生急性移植物抗宿主病Ⅰ度5例,Ⅱ、Ⅲ、Ⅳ度各1例;慢性局限性移植物抗宿主病8例。发生肺部真菌感染5例,巨细胞病毒病毒血症3例,带状疱疹病毒感染2例,出血性膀胱炎6例。15例患者中目前无病存活10例,生存期为5个月~11年。结果提示非血缘关系异基因造血干细胞移植是安全且可行的,治疗恶性血液病疗效良好,降低移植相关并发症已成为非血缘关系异基因造血干细胞移植需解决的首要问题。     

骨髓间充质干细胞在骨髓增生异常综合征中的研究进展

骨髓增生异常综合征(MDS)是以无效造血并伴有向急性髓系白血病(AML)转化的风险为特点的异质性造血系统的恶性肿瘤。骨髓间充质干细胞(MSCs)的功能异常在疾病的进展和转化中发挥了重要的作用。与正常MSCs相比,MDS患者的MSCs在遗传学、表观遗传学、分化和功能等方面均存在差异,而且骨髓活检中MSCs密度增加是MDS的不良预后因素,其支持正常造血的能力下降,有利于克隆细胞生存并向AML转化。对MDS发病机制关键特点加深认识有助于推进产生新的治疗方式。     

HLA匹配同胞供者和半倍体供者异基因造血干细胞移植治疗多次输血的重型再生障碍性贫血

目的 研究HLA匹配同胞供者和半倍体供者异基因造血干细胞移植(allo-HSCT)治疗多次输血的重型再生障碍性贫血(SAA)患者的疗效。方法 回顾性分析11例多次输血的SAA患者移植疗效与并发症发生率。11例患者中8例接受HLA匹配同胞供者HSCT，3例接受半倍体(母亲)HSCT。供、受者之间HLAA，B，DR抗原全相合者7例，1个位点不相合者3例，3个位点不相合者1例。结果 所有11例患者移植后均获得造血重建，其中3例患者发生Ⅰ-Ⅱ度急性移植物抗宿主病(aGVHD)，2例发生慢性局限型GVHD，2例发生移植物排斥，1例死亡，1例因自身造血功能恢复而生存；1例患者移植后5个月死于间质性肺炎。中位随访13个月(3～71个月)，9例患者生存(包括3例半倍体供者植入HSCT)，其中8例患者供体细胞持久植入。结论 HLA匹配同胞供者和半倍体供者allo-HSCT是治疗SAA的一种有效方法。     

Alternative donor hematopoietic stem cell transplantation: current concepts

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for many diseases such as hematological malignancies, bone marrow failure, immunodeficiency and other disorders. Unrelated donor and haploidentical family member are important alternative donors for the patients who need HSCT for otherwise incurable disease but without identical sibling donor. Since the first unrelated HSCT in 1974, the number and the clinical outcomes of unrelated transplant have been progressed significantly over time. More than 16 million adult unrelated donors have been registered worldwide. Near half of the donations from unrelated donors are international in recent years. HLA disparity between donor and recipient and disease status before transplant are key factors on survival after unrelated HSCT. In experienced centers, unrelated transplant has achieved comparable results with identical sibling HSCT. In addition, transplant from unrelated donor has advantage to cure some inherited disorders such as severe combined immunodeficiency disease, thalassaemia, Fanconi anemia, Familial Hemophagocytic Lymphohistiocytosis and so on. Haploidentical HSCT (haplo-HSCT) was initiated in 1981. The early results were poor mainly due to severe graft-versus-host disease (GVHD) and infections post-transplant. To reduce GVHD, T-cell depletion and mega dose CD34 + cells have been employed with certain success. Reduced intensity conditioning has further decreased early transplant-related mortality (TRM), but relapse rate is relatively high. Haplo-HSCT in our group with GIAC regimen has achieved comparable outcomes in terms of severe acute GVHD, chronic GVHD, relapse, TRM, disease-free survival (DFS), and overall survival (OS) with HLA-identical sibling transplant. New strategies have been applied in order to better manage complications post HSCT. As the third party cells, cord blood co-infusion has reduced severe acute GVHD and early TRM significantly. The majority of refractory cytomegalovirus, Epstein–Barr virus and aspergillus infections can be controlled with adoptive cellular therapy. Our clinical results from a large series of transplants have demonstrated that haplo-HSCT in sex-matched donor–recipient pair has survival advantage. Early disease stage before HSCT and high CD34 + cell infused but not age and HLA disparity have positive influence on DFS and OS. Therefore, it is better to consider haplo-HSCT for the patients who need urgent transplant to cure the diseases at earlier disease stage, when matched siblings or unrelated donors are not available. Among all haploidentical family members, sex-matched one should be the first choice as a donor for HSCT.     

造血干细胞移植治疗再生障碍性贫血的现状

文题释义：预处理：指在移植前对患者进行的放、化疗和免疫抑制治疗。再生障碍性贫血预处理的重点为免疫抑制,常采用非清髓和减低剂量预处理。 移植物抗宿主病：是异基因造血干细胞移植最常见的并发症,分为急性和慢性2种类型。目前认为移植物含有免疫活性细胞、供受者之间存在组织不相容性、受者不排斥植入的细胞是发生移植物抗宿主病3个必备条件。 背景：异基因造血干细胞移植治疗再生障碍性贫血的研究近年来取得很大的进步,但是移植后移植物抗宿主病、移植失败等仍是患者非复发死亡的主要原因,严重影响患者生存。 目的：总结异基因造血干细胞移植治疗再生障碍性贫血的现状及进展。 方法：中文检索词为“再生障碍性贫血,同胞全合异基因造血干细胞移植,无关供者造血干细胞移植,单倍体造血干细胞移植,脐血造血干细胞移植”,英文检索词为“aplastic anemia,matched sibling donor hematopoietic stem cell transplantation,unrelated donor hematopoietic stem cell transplantation,haploidentical hematopoietic stem cell transplantation,cord blood transplantation”,由第一作者检索1990年1月至2019年9月在PubMed、中国知网、万方、维普等数据库中发表的与造血干细胞移植治疗再生障碍性贫血相关的文献,最终选择55篇文献进行分析。 结果与结论：同胞全合异基因造血干细胞移植仍是目前首选的移植方式;对于无同胞全合供者的重型再生障碍性贫血患儿,一线治疗可以选择无关供者相合异基因造血干细胞移植;缺乏全合供者时,单倍体移植和脐血移植亦为不错的选择。 ORCID: 0000-0003-3931-8385(黄东平) 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     

Domestic and foreign donor candidates result in differential probability of matching minor histocompatibility antigens – relevance of selection for hematopoietic stem cell transplantation

Mismatches between patient and donor at minor histocompatibility antigens (minor H antigens) account for most of the genetic component of histocompatibility problems in human leukocyte antigen (HLA)-matched hematopoietic stem cell transplantations (HSCTs). There are usually more genetic differences outside the matched HLA region between unrelated donors and patients than in transplantations between related individuals. Also, foreign unrelated donors may differ from domestic donors at several loci as allele frequencies vary between populations. To unravel differences in minor H antigen matching when using unrelated donors from various registries worldwide, we genotyped 10 minor H antigen loci for 143 consecutive Finnish patients and 424 unrelated donor candidates. We observed that probability of matching specific minor H antigens was different for domestic and foreign donor candidates. HA-2 and HA-3 minor H antigens were significantly more often mismatched with Finnish donor candidates ( P  = 0.0003 for HA-2 and P = 0.004 for HA-3), whereas ACC1 and ACC2 minor H antigens were significantly more often mismatched with foreign donor candidates ( P  = 0.04 for ACC1 and P  = 0.03 for ACC2). This observation is of clinical importance when specific minor H antigens are intended to match or mismatch in the future to minimize the risk for graft- vs -host disease or to maximize the graft- vs -malignancy effect in HLA-matched HSCT from an unrelated donor.     

Maximizing optimal hematopoietic stem cell donor selection from registries of unrelated adult volunteers

Today, more than 50 registries of HLA-typed potential adult hematopoietic stem cell donors have been established in 40 countries and include more than 7.5 million volunteers. HLA testing of new volunteers includes HLA-A, -B and often -DR typing at low to intermediate resolution. Searching patients are tested for these same loci, preferably at a higher level of resolution. Over 95,000 patient searches are received by registries annually resulting in approximately 4660 unrelated transplants. In 2001, nearly one-third of transplants involved a patient in one country receiving stem cells from a donor in another. The diversity of the HLA system complicates the search process, requiring sophisticated registry algorithms for matching, and expertise in allele and haplotype frequencies and associations to design search strategies. Within registries, HLA frequency data have been used to evaluate optimal registry size and composition.     

Polymorphisms in the TNFA gene promoter region show evidence of strong linkage disequilibrium with HLA and are associated with delayed neutrophil engraftment in unrelated donor hematopoietic stem cell transplantation

Sustained myeloid engraftment is an important determinant of outcome in hematopoietic stem cell transplantation (HSCT). Human tumor necrosis factor (TNF)-alpha is encoded by a gene, TNFA, located in the class III region of the major histocompatibility complex on chromosome 6, flanked by the human leukocyte antigen (HLA) class I and II regions. A number of polymorphisms in the promoter region of the TNFA gene have been associated with increased production of TNF-alphain vivo. Additionally, raised TNF-alpha levels have been reported to have a detrimental effect on the outcome in HSCT, in particular on early complications such as acute graft vs host disease, failure to engraft, and transplant-related mortality. There is evidence of linkage disequilibrium (LD) between TNFA promoter polymorphisms and extended HLA haplotypes. We have genotyped 73 cell lines and 189 donor/recipient pairs (undergoing HSCT) for their TNFA polymorphism, all of which had been well characterized with respect to their HLA genes. We found evidence of strong LD between HLA genes and TNFA; however, there was also evidence for recombination events having taken place, as we found that a number of transplant pairs who were matched for their HLA haplotypes were not matched for their TNFA alleles. We analyzed early outcomes in the transplant recipients and found a significant delay in engraftment in those pairs where both donor and recipients possessed an AG allele (associated with higher TNF-alpha levels). Our results suggest a functional effect of TNFA polymorphisms on myeloid engraftment in unrelated HSCT.     

Immunogenetics in stem cell donor registry work: The DKMS example (Part 1)

Currently, stem cell donor registries include more than 35 million potential donors worldwide to provide HLA‐matched stem cell products for patients in need of an unrelated donor transplant. DKMS is a leading stem cell donor registry with more than 9 million donors from Germany, Poland, the United States, the United Kingdom, India and Chile. DKMS donors have donated hematopoietic stem cells more than 80,000 times. Many aspects of donor registry work are closely related to topics from immunogenetics or population genetics. In this two‐part review article, we describe, analyse and discuss these areas of donor registry work by using the example of DKMS. Part 1 of the review gives a general overview on DKMS and includes typical donor registry activities with special focus on the HLA system: high‐throughput HLA typing of potential stem cell donors, HLA haplotype frequencies and resulting matching probabilities, and donor file optimization with regard to HLA diversity.