ABO血型不合异基因造血干细胞移植临床观察

目的：探讨ABO血型不合异基因造血干细胞移植治疗血液病的临床疗效和近远期并发症。方法：对15例包括恶性血液病5例(多发性骨髓瘤1例、急性白血病3例、慢性粒细胞白血病1例)、再生障碍性贫血一阵发性睡眠性血红蛋白尿2例、重型再生障碍性贫血8例，进行同胞供者外周血干细胞移植、外周血联合骨髓造血干细胞移植和无关供者脐血造血干细胞移植。观察植入效果、血型的转变、以及移植近远期并发症。结果：15例患者均恢复造血功能，13例植入混合性嵌合体(MC)、其中5例由MC转变为供者完全性嵌合体(CC)，8例长期保持MC状态，2例未植入。所有患者在输注移植物时出现轻微短暂的血红蛋白尿，无严重急性溶血和迟发性溶血发生，无急性移植物抗宿主病(aGVHD)，1例局部型慢性移植物抗宿主病(cGVHD)，1例广泛型cGVHD。在造血植入的患者，脐血移植4例保持MC状态、血型未转变，其余干细胞移植血型在1～2个月转变。结论：ABO血型不合异基因造血干细胞移植治疗血液病疗效肯定，对移植物和供受者体内凝集素的处理十分重要。     

HLA单倍相合造血干细胞移植治疗恶性血液病的临床研究

目的 探讨人类白细胞抗原(HLA)单倍相合造血干细胞移植(HSCT)治疗恶性血液病的疗效和主要并发症.方法 对2004年7月至2006年12月第三军医大学附属新桥医院收治的35例恶性血液病患者进行HLA单倍相合亲缘供者HSCT.采用延长、强化联合免疫抑制促进植入、抗胸腺细胞球蛋白(ATG)加强预防移植物抗宿主病(GVHD)、粒细胞集落刺激因子(G-CSF)动员的骨髓(BM)加外周血干细胞(PBSC)混合移植方案.结果 所有患者均重建供者造血.18例(51.4%)发生急性GVHD(aGVHD),其中Ⅰ度8例,Ⅱ度5例,Ⅲ度3例,Ⅳ度2例,Ⅱ～Ⅳ度aGVHD累积发生率为28.6%.12例(34.3%)发生慢性CVHD(cGVHD),均为局限性.23例患者存活,总存活率为65.7%,2年无病存活率(DFS)为62.9%.12例患者死亡,7例死于复发,5例死于移植相关合并症,其中肺部感染2例,Ⅳ度GVHD 2例,巨细胞病毒(CMV)感染1例.结论 随着预处理方案、GVHD预防方案及移植物成分的优化,HLA单倍相合造血干细胞移植的疗效明显改善,已成为治疗恶性血液病的重要方法.     

非血缘异基因造血干细胞移植治疗恶性血液病的临床研究

目的：分析总结非血缘关系异基因造血干细胞移植（URD-HSCT）治疗恶性血液病的疗效、造血重建、并发症以及长期生存情况。方法：采用非血缘关系HLA配型相合的外周血造血于细胞对24例恶性血液病患者进行了移植,预处理方案采用改良的BU／CY方案;移植物抗宿主病（GVHD）的预防采用CsA联合MMF、MTX并加用ATG;PGE1预防肝静脉闭塞症。结果：Ⅰ～Ⅳ度aGVHD发生率为37．50％,cGVHD的发生率为41．66％。24例患者均获造血重建;移植相关死亡率为12．5％;随访时间为2～38个月,16例生存,8例死亡。结论：URD-HSCT能提供更快的造血功能恢复,GVHD的发生率有所增加,而移植相关死亡率并无明显增加,是目前治愈恶性血液病的有效方法,相当部分患者可通过移植获治愈,但移植后疾病复发仍是影响患者长期生存的主要因素之一,防治移植后复发仍是需要解决的重要课题。     

异基因造血干细胞移植术后移植物抗宿主病的研究进展

造血干细胞移植（HSCT）特别是异基因造血干细胞移植（allo—HSCT）越来越多地用于治疗恶性血液系统疾病,而移植后出现的移植物抗宿主病（GVHD）是allo-HSCT的主要并发症和死亡原因之一。移植物抗宿主病按发生时间分为急性移植物抗宿主病（aGVHD）和慢性移植物抗宿主病（cGVHD）。     

非清髓性移植治疗高风险重型再生障碍性贫血(3例报告附文献复习)

近 10年来 ,造血干细胞移植 (HSCT)治疗高风险重型再生障碍性贫血 (SAA)进展很大 ,但其失败的主要原因是移植物被排斥和GVHD。我们报告年龄大、病史长、经CSA和ALG治疗无效、长期输血、肝功能不良等移植高风险因素 3例SAA ,行非清髓性造血干细胞移植及移植后供者干细胞输注 (DSI)治疗 ,报道如下。1　病例和方法1.1　病例和供者资料　见表 1。例 1,10年病史 ,反复成分输血 ,予康力龙、CSA、强的松治疗 ,病情反复 ,近 1个月外周血象进一步下降。例 2 ,经过CSA及粒细胞集落刺激因子(G CSF ,Kirin公司产品 )治疗无效。例 3 ,抗淋…     

不同供者来源异基因造血干细胞移植治疗恶性血液病69例疗效和预后分析

目的评价和比较无关供者与同胞供者异基因造血干细胞移植治疗恶性血液病的临床疗效。方法回顾性分析东南大学附属中大医院血液科2006年4月至2011年12月进行异基因造血干细胞移植的69例恶性血液病患者的临床资料,根据造血干细胞(HSC)来源的不同,将患者分为无关供者(URD组)30例和同胞供者(RD组)39例。对两组患者移植后中性粒细胞和血小板的植入时间、细胞嵌合状态、移植物抗宿主病(GVHD)、感染的发生率以及复发和总生存(OS)率等长期随访结果进行分析。结果 69例达到完全稳定的供者植入,URD组和RD组中性粒细胞和血小板植活的中位时间分别为11 d、10 d和15 d、14 d(均P>0.05)。共33例发生急性GVHD,其中URD组发生I～Ⅱ度GVHD 12例(40.0%);7例(23.3%)发生Ⅲ～Ⅳ度GVHD;RD组12例(30.8%)发生Ⅰ～Ⅱ度GVHD,与URD组相比差异无统计学意义(P=0.455);2例(5.1%)发生Ⅲ～Ⅳ度GVHD,与URD组相比差异有统计学意义(P=0.035)。URD和RD组的5年OS率分别为56.7%和64.1%(P=0.621)。结论无关供者和同胞供者异基因造血干细胞移植均可成功治疗恶性血液病,疗效相似;但与RD比较,URD的Ⅲ～Ⅳ度aGVHD的累积发生率高、早期感染率较高、而复发率较低。     

NKT细胞在异基因造血干细胞移植中作用的临床初步研究

目的：初步观察NKT细胞在临床异基因造血干细胞移植（allo-HSCT）中的作用。方法：检测15例allo-HSCT患者移植物中NKT细胞含量,研究输注细胞数与移植物抗宿主病（GVHD）发生的关系。结果：15例患者均获造血重建,其中13例患者发生急性GVHD（aGVHD）,包括Ⅰ度8例,Ⅱ度1例,Ⅲ-Ⅳ度4例;8例患者发生慢性GVHD（cGVHD）,其中广泛型2例,局限型6例;7例患者同时出现aGVHD及cGVHD。aGVHD发生组和无aGVHD发生组NKT细胞输注数分别为2.16（0.43-8.82）×10^6/kg、7.71（0.3-15.12）×10^6/kg（P〉0.05）;0-Ⅰ度和Ⅱ-Ⅳ度aGVHD组NKT细胞输注数分别为2.33（0.3-15.12）×10^6/kg、1.99（0.43-8.82）×10^6/kg（P〉0.05）;cGVHD发生组和无cGVHD发生组输注NKT细胞数分别为2.07（0.3-3.05）×10^6/kg、2.99（0.43-15.12）×10^6/kg（P〉0.05）。结论：输注NKT细胞数不影响aGVHD发生、aGVHD严重程度及cGVHD发生。     

抗胸腺细胞球蛋白联合皮质激素治疗皮质激素耐药的急性移植物抗宿主病

异基因造血干细胞移植(allo—HSCT)是当前治愈恶性血液病的最主要方法，甚至是惟一的方法，急性移植物抗宿主病(aGVHD)是导致allo-HSCT后死亡的主要原因之一。本研究报道6例经大剂量甲泼尼龙(MP)治疗无效的aGVHD，采用抗胸腺细胞球蛋白(ATG)联合大剂量MP治疗取得理想疗效，现报告如下。     

异基因造血干细胞移植治疗高龄恶性血液病的疗效分析

目的探讨异基因造血干细胞移植治疗年龄较大的白血病患者安全性和疗效。方法采用HSCT治疗10例45—63岁恶性血液病患者,HLA6／6位点相合8例,5／6位点相合2例。以清髓性方案预处理4例,减低强度方案预处理6例。HLA不全相合患者加用ATG。采用环孢素联合霉酚酸酯预防移植物抗宿主病（GVHD）。结果本组10例受者均获造血重建。中性粒细胞绝对计数≥0．5×10^9／L,血小板≥20×10^9／L的中位时间分别为移植后12（9～16）天和15（12～21）天。3例发生了急性GVHD（30％）,Ⅱ度以上2例。可评估的9例患者中2例出现了慢性GVHD（22％）。复发2例,死亡3例。可评估的2年无病生存率为70％。结论造血干细胞移植对于高龄白血病患者是一种有效、安全的根治疗法。     

HLA配型不合/单倍型造血干细胞移植供者淋巴细胞输注量与急性移植物抗宿主病的关系

急性移植物抗宿主病（aGVHD）是单倍型造血干细胞移植（HSCT）最常见的并发症之一。其发生率和病死率都较高，而且发病机制非常复杂。T细胞起着核心作用，移植物内T细胞过多可导致GVHD，而去除T细胞或T细胞亚群可以预防GVHD，但移植物被排斥和白血病／淋巴瘤的复发率增多。本研究检测59例HLA配型不合／单倍型HSCT供者淋巴细胞及T细胞亚群数，并分析其与受者aGVHD的关系。     

单倍体移植治疗白血病疗效观察

目的探讨单倍体移植治疗白血病的疗效。方法在单倍体移植时采用阿糖胞苷（Ara-c）、马利兰（Bu）、环磷酰胺（CTX）、甲基环己亚硝脲（Me-CCNU）联合作为预处理方案,用CTX、重组人粒细胞集落刺激因子（rhG-CSF）、环孢素A（CSA）、麦考酚酸酯（MMF）、抗胸腺细胞球蛋白（ATG）、白细胞介素11（IL-11）及甲氨蝶呤（MTX）联合预防急性移植物抗宿主病（aGVHD）,治疗7例白血病;结果 7例患者完全植入,白细胞〉1.0×109/L中位时间为16.9 d,Ⅲ~Ⅳ度aGVHD发生率为14.3%,中位随访时间25.6个月,无复发,至今仍存活。结论单倍体移植治疗白血病时,用Ara-c、Bu、CTX、Me-CCNU联合作为预处理方案,用CTX、rhG-CSF、CSA、MMF、ATG、IL-11及MTX联合预防aGVHD是安全、有效的。     

Cyclosporin A for the treatment of aplastic anemia refractory to antithymocyte globulin

Antithymocyte globulin (ATG) is an established form of therapy for severe aplastic anemia (SAA). However, in patients who do not respond to this treatment and who are not candidates for bone marrow transplantation few successful therapeutic alternatives exist. We report two such patients who have shown a therapeutic response to Cyclosporin A (CSA) (Sandimmune, Sandoz). Case 1, a 15 year old male, and Case 2, a 34 year old female, were diagnosed as having SAA in September 1984 and May 1984 respectively. Treatment with high dose Methylprednisolone (MPN) and ATG in Case 1 and MPN, ATG and Oxymetholone in Case 2 for ten days was ineffective in both cases. Case 1 developed anaphylaxis with both repeat ATG and ALG (antilymphoblast globulin), and Case 2 failed to respond to repeat ATG. Both required frequent packed cells and platelet transfusions. At five and six months respectively following completion of ATG therapy, CSA was started at 10 mg/kg/day in divided doses orally. Renal and liver functions and CSA blood levels were followed. Within six weeks both patients exhibited a hematologic response and were no longer transfusion dependent. On maintenance therapy of 4 mg/kg/day (Case 1) and four months after discontinuing CSA (Case 2) the hematologic values are as follows: hemoglobin 160 and 130 g/L, absolute granulocyte count 3100 and 1640 × 10⁹/L, and platelets 132 and 84 × 10⁹/L respectively. Side effects included hypertrichosis, gingival hyperplasia and mild reversible nephrotoxicity. CSA appears to represent an effective form of therapy for patients with SAA refractory to ATG.     

Persistent Remission after Immunosuppressive Therapy of Hairy Cell Leukemia Mimicking Aplastic Anemia: Two Case Reports

Some patients with hairy cell leukemia (HCL) manifest pancytopenia and bone marrow hypoplasia without an apparent increase in atypical cells, so their disease resembles severe aplastic anemia at onset. We treated 2 HCL patients, who were initially diagnosed with aplastic anemia, with antithymocyte globulin (ATG) in combination with cyclosporine or antilymphocyte globulin (ALG). Both patients obtained partial remission in response to the immunosuppressive therapy and did not need transfusion treatment for more than 3 years. Sustained improvement of hematopoiesis in such B-cell malignancies after ATG/ ALG therapy suggests that the mechanisms underlying successful immunosuppressive therapy for aplastic anemia may involve B-cell suppression, inhibiting hematopoietic stem cells.     

Cyclophosphamide and other new agents for the treatment of severe aplastic anemia

Severe aplastic anemia (SAA) has a poor prognosis in the absence of treatment. Current accepted therapeutic strategies include allogeneic stem-cell transplantation and immunosuppression, both resulting in long-term survival in the majority of patients. Although human leukocyte antigen (HLA)-matched sibling stem-cell transplantation is highly effective, the 25% probability of finding a suitable sibling donor within a family renders this approach available to only a minority of patients. Transplantation using HLA-matched, unrelated donors carries a high risk of treatment failure along with considerable toxicity. While combined immunosuppression with both antithymocyte globulin (ATG) and cyclosporine A (CSA) produces hematologic improvement in most patients, relapse is common. Late evolution of aplastic anemia to other serious hematologic disorders, including paroxysmal nocturnal hemoglobinuria (PNH), myelodysplasia, and acute leukemia, is also a significant problem following treatment with ATG/CSA. Recently, results of immunosuppression in SAA with another potent immunosuppressive agent, cyclophosphamide, were reported in a small number of patients. The overall response rate was similar to that seen with ATG/CSA, but relapse and late clonal disease were not observed during a long period of follow-up. A larger randomized trial comparing sustained hematologic response rates to either conventional immunosuppression with ATG/CSA or high-dose cyclophosphamide and CSA is now underway; secondary end points include response duration, event-free survival, and overall survival. Additionally, a number of protocols designed to test the efficacy of alternative immunosuppressive or immunomodulatory agents are being developed.     

Intensive Immunosuppression Therapy for Aplastic Anemia Associated with Dyskeratosis Congenita: Report of a Case

Dyskeratosis congenita (DC) is a very rare inherited disorder characterized by skin pigmentation, nail dystrophy, and mucosal leukoplakia. It is also associated with a variety of noncutaneous abnormalities, such as fatal pulmonary complications, malignancy, and bone marrow failure.We report the case of a 32-year-old man with DC associated with severe aplastic anemia (SAA). The traditional treatment of DC-associated SAA is allogeneic hematopoietic stem cell transplantation (HSCT). However, in this case, an HLA-matched donor was not available. Therefore our patient was given intensive immunosuppressive therapy with antilymphocyte globulin (ALG) and cyclosporine A (CsA). The hemogram findings improved after the treatment, but the patient died of pulmonary complications after being in stable condition for 6 months. The results support the possible use of intensive immunosuppression with ALG and CsA for DC-associated SAA as an alternative treatment for patients who are not eligible for HSCT.     

Epstein-Barr virus reactivation in a patient treated with anti-thymocyte globulin for severe aplastic anemia

Epstein-Barr virus (EBV) infection and reactivation is an increasing complication in immune deficient patients, particularly after allogeneic hematopoietic stem cell transplantation (HSCT). Therapy with anti-thymocyte globulin (ATG) is associated with higher incidence of EBV-related disease in HSCT patients, but this risk is not documented in patients receiving ATG for severe aplastic anemia (SAA). We describe the case of a patient who developed an EBV infection, with the clinical features of an infectious mononucleosis, after immune suppression with cyclosporine and two courses of ATG for SAA.     

非清髓异基因造血干细胞移植治疗恶性血液病临床分析

目的:观察非清髓异基因造血干细胞移植(NST)治疗恶性血液病的疗效及并发症的处理。方法:对33例恶性血液病患者施行NST并随访观察。预处理方案应用氟达拉滨30mg.m-2.d-1(-7～-2d),马利兰4mg.kg-1.d-1(-6～-5d),环磷酰胺350mg.m-2.d-1(-3～-2d),HLA不全相合者加用抗淋巴细胞球蛋白(ALG)750mg/d(-2～-1d)。移植物抗宿主病(GVHD)预防应用环孢素A(CsA)和骁悉(MMF)。应用美司那、大量水化、碱化尿液预防出血性膀胱炎。应用凯时(前列腺素E1)预防肝静脉闭塞病(VOD)。结果:全部患者均成功植入,造血重建速度快。中性粒细胞0.5×109/L的中位时间是+13(+10～+16)d,血小板20×109/L的中位时间是+12(+9～+25)d。3例患者在+100d左右出现间质性肺炎,血CMV-DNA阳性,应用更昔洛维抗病毒等治疗后均痊愈。17例患者发生急性移植物抗宿主病(aGVHD)(51.5%),Ⅰ度患者10例(30.3%),Ⅱ度患者5例(15.2%),Ⅲ度患者2例(6.06%)。有20例患者出现慢性移植物抗宿主病(cGVHD)(64.5%),其中局限型15例(48.4%),广泛型5例(16.1%)。有3例患者出现VOD(9.1%),5例患者出现出血性膀胱炎(15.2%),经积极治疗均有效控制。中位随访37(2.5～58.0)个月,现存活24例(72.7%),9例死亡(27.3%),5例疾病复发(15.2%)。9例死亡患者中7例死于GVHD,2例死于疾病复发。结论:NST植入可靠,造血重建快,复发率低,移植相关并发症感染、出血性膀胱炎、VOD发生率低,治疗安全、有效。但GVHD发生率较高,是导致死亡的主要原因。     

Reduced intensity conditioning and co-transplantation of unrelated peripheral stem cells combined with umbilical cord mesenchymal stem/stroma cells for young patients with refractory severe aplastic anemia

Five young patients with a long history of severe aplastic anemia (SAA) who had failed initial CSA treatment and lacked a HLA-matched sibling donor, underwent co-transplantation of unrelated donor peripheral blood stem cells (UD-PBSCs) and umbilical cord mesenchymal/stroma stem cells (UC-MSCs). After FLU + CTX + ATG ± 2GY TBI conditioning, all patients received UD-PBSCs and UC-MSCs. There were no side effects attributable to the infused MSCs, and no severe complications or infections were observed in any patient after transplantation. After transplantation, one patient experienced primary graft failure, the reason for which may be related to a long history (>17 years) of SAA. The other four patients achieved complete hematopoietic recovery and complete donor hematopoietic chimerism. We did not observe severe aGVHD or cGVHD. These data suggest that co-transplantation of UD-PBSCs and UC-MSCs is an acceptable alternative treatment for young patients with a long history of intensively treated SAA.     

重型再生障碍性贫血细胞免疫功能异常与强化免疫抑制治疗的关系

重型再生障碍性贫血（SAA）患者骨髓造血功能衰竭的发生、发展与细胞免疫紊乱,特别是T细胞数量、功能的 异常密切相关,因此免疫功能异常在SAA的发病机制中起着重要的作用。目前抗胸腺细胞球蛋白（ATG）或抗淋巴细 胞球蛋白（ALG）联合环胞霉素A（CsA）的强化免疫抑制治疗（IST）对改善SAA 预后有显著疗效。IST 能够使 60％～80％的SAA患者得到血液学恢复即是异常免疫反应损伤造血干细胞的最直接证据。然而,由其他非免疫因 素介导或造血干细胞极度耗竭所致的骨髓衰竭,IST就可能无效。因此,在IST前进行疾病评估和疗效预测具有重要 意义,其中细胞免疫功能异常对初治SAA进行IST的疗效具有重要意义。     

多克隆抗胸腺细胞球蛋白对白血病细胞增殖抑制及凋亡诱导作用

目的:探讨多克隆兔抗人胸腺细胞球蛋白(ATG)对白血病细胞的生长抑制以及诱导凋亡作用。方法:体外培养Jurkat、Raji、HL-60、NB4、K562、U937细胞株以及15例患者原代白血病细胞。用50、100、150、200、250μg/mL终浓度的ATG在不同时间分别作用于以上细胞,采用细胞计数试剂盒(CCK-8)比色法检测细胞增殖抑制率,应用流式细胞术测定细胞凋亡率。结果:ATG对Jurkat、Raji、HL-60细胞有明显的增殖抑制以及诱导凋亡作用,且高浓度ATG抑制作用更强。ATG对NB4、K562、U937细胞增殖抑制与诱导凋亡作用均不明显。15例初发白血病患者中7例的原代细胞经ATG作用后明显凋亡,凋亡率均>30%。结论:ATG具有广谱抗白血病作用,尤其是对淋巴细胞白血病作用较强,为其在异基因造血干细胞移植中的应用提供了实验依据。