Bu/Cy预处理异基因造血干细胞移植病人肝静脉闭塞病的预防

目的 研究Bu/Cy预处理异基因造血干细胞移植（Allo-HSCT）病人肝静脉闭塞病（VOD）的发生。方法 10例Bu/Cy预处理的Allo-HSCT病人，MTX/CsA预防急性移植物抗宿主病。阿波莫斯10ml和前列素E1（PGE1）10μg静脉输注（-7d至＋28d）预防VOD。结果 本组病人仅1例发生VOD；移植前后病人ALT和TBIL无差异（P〉0．05）。结果 前列素E1与阿波莫斯的联合应用可预防VOD的发生。     

Bu/Cy预处理异基因造血干细胞移植病人肝静脉闭塞病的预防

目的研究Bu/Cy预处理异基因造血干细胞移植(Allo-HSCT)病人肝静脉闭塞病(VOD)的发生.方法 10例Bu/Cy预处理的Allo-HSCT病人,MTX/CsA预防急性移植物抗宿主病,阿波莫斯10ml和前列素E1(PGE1)10μg静脉输注(-7d至+28d)预防VOD.结果本组病人仅1例发生VOD;移植前后病人ALT和TBIL无差异(p>0.05).结果前列素E1与阿波莫斯的联合应用可预防VOD的发生.     

造血干细胞移植在血液系统疾病的临床应用

本文阐述了关于造血干细胞的特点和造血干细胞移植的新观点。移植需要的造血干细胞不仅应包括造血干细胞、造血祖细胞,还应该包括间充质干细胞。造血干细胞来源呈现多样化局面,当没有配型相合的供者时,配型相合的非血缘志愿者、脐带血和配型不合的亲缘供者都可以作为常规供者。造血干细胞适应证、供者、移植方式、移植时机的选择以及移植合并症的处理都趋向个体化。造血干细胞移植技术日趋成熟,已经逐渐发展成为一个相对独立的学科领域。     

清肿瘤性异基因造血干细胞移植

标准的清髓性异基因造血干细胞移植(allo-HSCT)对于需代替治疗的造血与免疫系统的非恶性疾病,应当是合理或足够的;然而,对于恶性血液病患者,清除患者骨髓造血组织,成功重建异体正常造血与免疫系统,并不一定能完全治愈恶性血液病,因为白血病(干)细胞并非只限骨髓中存在,它可浸润骨髓之外的其他任何组织。临床实践证实,allo-HSCT后仍然有30%左右的患者疾病复发,特别是具有高危因素或难治复发患者复发率可高达40%～70%以上。这些复发的白血病细胞几乎全系源自患者移植前本身的白血病细胞,其中半数患者以髓外部位复发开始,有证据提示,清髓性移植并没有完全杀灭患者体内的白血病细胞,特别是那些对化放疗不敏感或栖居在髓外"庇护所"中的白血病干细胞,最终导致疾病复发。因此笔者提出并建立了一个清肿瘤性异体造血干细胞移植(TAHSCT)的概念,在临床上对其进行了初步的探讨。其内容贯穿于移植技术全过程的各个环节,但主要为应用个体化清肿瘤性预处理方案和加强移植后免疫治疗。     

HLA单倍体与全相合异基因造血干细胞移植治疗恶性血液病

背景：异基因造血干细胞移植是治疗恶性血液病的一种非常有效的方法。单倍体相合的造血干细胞移植扩大了移植的应用范围,是无HLA相合供者患者的一种重要选择。 目的：比较HLA单倍体相合与全相合异基因造血干细胞移植治疗恶性血液病的临床疗效。 方法：回顾性分析接受异基因造血干细胞移植79例恶性血液病患者的临床资料,其中HLA单倍体相合组26例、全相合组53例,对比两组受者移植物抗宿主病的发生率、复发率、2年生存率等。 结果与结论：78例受者获得完全、持久供者干细胞植入;1例受者在移植后28 d尚未植入,后因感染死亡。两组慢性移植物抗宿主病发生率、复发率和2年无病生存率差异无显著性意义(P > 0.05)。单倍体相合组急性移植物抗宿主病发生率高于全相合组(P < 0.05);2年总生存率低于全相合组(P < 0.05)。提示血缘HLA单倍体相合移植治疗恶性血液病的安全性及疗效接近于全相合移植,在缺乏HLA相合供者的情况下,行HLA单倍体相合造血干细胞移植治疗恶性血液病是切实可行的选择。     

白消安在非亲缘异基因造血干细胞移植预处理中的应用

背景：口服白消安剂型胃肠道吸收不稳定,影响异基因造血干细胞疗效且毒性增加。静脉剂型白消安在国内最近几年用于临床,但在非亲缘异基因移植预处理中应用的相关报道甚少。 目的：探讨静脉剂型白消安在非亲缘异基因造血干细胞移植预处理中应用的疗效并观察其毒副作用。 方法：14例非亲缘异基因干细胞移植采用静脉剂型白消安联合环磷酰胺预处理方案,18例亲缘异基因干细胞移植采用口服白消安联合环磷酰胺预处理方案,观察两组造血重建、植入率等疗效指标及胃肠道反应、口腔黏膜炎、出血性膀胱炎、肝功能损害、移植物抗宿主病等相关毒性指标。 结果与结论：两组患者植入率均为100%。静脉剂型组肝脏毒性、口腔黏膜炎发生率明显低于口服剂型组(14% vs. 67%,7% vs. 55%),差异均有显著性意义(P < 0.01),而胃肠道反应、出血性膀胱炎、造血重建、急性移植物抗宿主病、局限性移植物抗宿主病等方面差异均无显著性意义(P > 0.05)。结果可见静脉剂型白消安应用于非亲缘异基因造血干细胞移植预处理可获得满意疗效,且毒副反应少。     

造血干细胞移植与自身免疫病

自身免疫与免疫耐受是当今免疫学研究的中心课题。随着免疫应答,免疫耐受机理被逐步揭示,自身免疫病的治疗越来越受到研究者及临床医生的关注。近年的研究表明造血干细胞的异常是导致自身免疫疾病的发生的根本原因,其中很多自身免疫病已在基因水平找到了相应的缺陷。本文拟从动物实验及临床治疗两方面对用造血干细胞移植治疗自身免疫病的研究与应用作一综述。     

造血干细胞移植的免疫问题

造血干细胞移植作为血液恶性疾病的治疗手段已越来越获公认,其重要原因之一就是造血干细胞移植融化疗与免疫治疗于一体。造血干细胞移植的临床快速发展,丰富了移植免疫理论,移植免疫的进展促进了造血干细胞移植的临床实践。造血干细胞移植的诸多问题,如GVHD、GVL、免疫耐受等均有其免疫的机制。为更好地理解、认识这些问题,本文将从免疫学的角度对这些现象作一分析。1 T细胞抗原识别和激活的分子基础在造血干细胞移植,由于受者在移植前接受了预处理的超大剂量放/化疗,受者免疫功能受到抑制,因此,更多的情况是发生供者对受者的…     

造血干细胞移植与自身免疫病

自身免疫与免疫耐受是当今免疫学研究的中心课题。随着免疫应答、免疫耐受机理被逐步揭示,自身免疫病的治疗越来越受到研究者及临床医生的关注。近年的研究表明造血干细胞的异常是导致自身免疫病的发生的根本原因,其中很多自身免疫病已在基因水平找到了相应的缺陷。本文拟从动物实验及临床治疗两方面对用造血干细胞移植治疗自身免疫病的研究与应用作一综述     

减低剂量预处理方案在亲缘HLA单倍体相合造血干细胞移植中的应用

背景：近年来减低剂量预处理异基因造血干细胞移植已被证明是安全有效的治疗手段,在同胞全相合和无关供者中应用逐年增多,它特别适合老年人或年轻人合并器官功能障碍的患者,然而由于找到HLA配型相合供体的概率不高,使得同胞全相合和无关供者减低剂量预处理异基因造血干细胞移植开展受限,而HLA不相合/单倍体供体则可以迅速找到,但减低剂量预处理的单倍体造血干细胞移植应用的报道还较少,国内尚未见报道,因此对减低剂量预处理的单倍体造血干细胞移植的开展情况进行综述非常重要。 目的：综述减低剂量预处理在亲缘HLA单倍体造血干细胞移植中的应用现状。 方法：以“减低剂量预处理方案、非清髓性预处理方案、HLA单倍体相合、造血干细胞移植和No-nmyeloablative  conditioning,Reduced-intensity conditioning,HLA-haploidentical,Hematopoietic stem cell transplantation”为检索词,应用计算机检索1997至2014年万方数据库、CNKI和PubMed数据库、外文医学信息资源检索平台检索关于减低剂量预处理在亲缘HLA单倍体造血干细胞移植中应用的相关文献,根据纳入标准和排除标准,最终选取25篇文献进行分析,全部为英文。 结果与结论：减低剂量预处理异基因造血干细胞移植在HLA同胞全相合及无关供者中开展的较多且效果愈来愈好。减低剂量预处理的单倍体造血干细胞移植开展的较晚且报道较少,其植入、感染、移植相关死亡、移植物抗宿主病、长期无病生存率和总生存率等各个研究的结果差异较大,早期结果稍差,而近期总体情况有明显改善。目前看减低剂量预处理的单倍体造血干细胞移植是可行的,尤其对于找不到同胞相合及无关全相合供者的患者来说,HLA单倍体相合的血缘关系亲属成为最有潜力的干细胞来源。减低剂量预处理的单倍体造血干细胞移植保留较强的移植物抗白血病效应,且寻找供者容易,有足够的细胞后续治疗如供者淋巴细胞输注,同时通过发挥移植物抗白血病效应,可有效清除患者体内的肿瘤细胞,为处在疾病进展期或经历多次治疗失败的患者,尤其是老年患者、合并器官功能障碍及并发症患者,提供有效的挽救治疗手段。但由于开展的时间较短,今后在应用中该如何选择最佳方案、最佳时机以及减低移植物抗宿主病、移植相关死亡率及复发率等尚需进一步深入的研究。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：     

西达本胺在造血干细胞移植预处理方案中的研究进展

造血干细胞移植(hematopoietic stem cell transplantation,HSCT)是临床治疗恶性血液病的有效方式之一.预处理药物的选择与HSCT的成功及预后紧密相关.西达本胺属于组蛋白去乙酰化物酶抑制剂(histone deacetylase inhibitors,HDACi),可以靶向阻断HD...     

造血干细胞移植预处理对患者肝功能的影响

目的探讨造血干细胞移植预处理对患者肝功能的影响。方法用全自动生化仪对预处理前、后患者的肝功能项目进行检测。结果40例患者预处理前后的肝功能检测项目总蛋白(TP)、白蛋白(ALB)、球蛋白(GLO)、丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)、碱性磷酸酶(ALP)、γ-谷氨酰基转移酶(GGT)、总胆红素(TBIL)、直接胆红素(DBiL)、TBiL／DBiL和间接胆红素(IBiL)均值均有明显的差异，前3项浓度降低，余者升高；而A／G、AST／ALT、总胆汁酸fTBAl和麝香草酚浊度试验(TTT)无明显差异。结论预处理能导致患者肝功能异常，表明预处理后患者的肝细胞和／或胆管受损。     

非清髓性异基因造血干细胞移植预处理方案的毒性比较

背景：选择高效低毒的预处理方案是提高造血干细胞移植成功率的关键。氟达拉滨和抗胸腺细胞球蛋白,均属于强效免疫抑制剂,常用于非清髓性造血干细胞移植预处理中。 目的：对采用氟达拉滨或抗胸腺细胞球蛋白为基础的非清髓性异基因造血干细胞移植预处理方案患者,在预处理中及移植后早期毒性进行比较。 方法：32例血液系统恶性肿瘤患者中,按照非清髓性预处理方案中的免疫抑制剂分成两组即氟达拉滨组和抗胸腺细胞球蛋白组,预处理方案均为氟达拉滨或抗胸腺细胞球蛋白联合减低化疗强度的白消安/环磷酰胺,或者马法兰。抗胸腺细胞球蛋白组在形成混合性嵌合体后进行供者淋巴细胞输注。对两组患者预处理中出现的器官毒性进行统计学分析,毒性分级参照Bearman等制订的预处理相关毒性(RRT)分级标准。 结果与结论：两组无因预处理相关毒性而死亡。氟达拉滨组转氨酶发生率、腹泻发生率与和抗胸腺细胞球蛋白组比较差异均无显著性意义(P > 0.05);氟达拉滨组肝脏毒性发生率、黏膜炎发生率均显著低于抗胸腺细胞球蛋白组(P < 0.05);血液学毒性方面,氟达拉滨组白细胞达最低值、血小板≥50×109 L-1的时间、输注红细胞量、输注血小板的量均低于抗胸腺细胞球蛋白组(P < 0.05)。     

Allogenic stem cell transplantation after non-myeloablative conditioning regimen (mini-allogenic" stem cell transplantation)

Allogeneic stem cell transplantation is able to cure many hematologic malignancies, through, at least partially, a graft versus disease effect of the donor's immune system transfer. However, the toxicity of this technique limits its use to selected patients. The aim of non-myeloablative stem cell transplantation is to reduce the toxicity of the conditioning regimen while allowing the engrafement of donor's stem cells and the immunological antitumoral activity of the donor's immune system. Several reports have already demonstrated the validity of this concept. This new multi-step therapeutic strategy is complex, raises many questions and deserves further studies to be fully applicable to a greater number of patients.     

Randomized comparison of four-times-daily versus once-daily intravenous busulfan in conditioning therapy for hematopoietic cell transplantation.

Sixty patients were randomized to receive intravenous busulfan (iBU) either as 0.8 mg/kg, over 2 hours 4 times a day (BU4 arm) or 3.2 mg/kg, over 3 hours once a day (BU1 arm) in conditioning therapy for hematopoietic cell transplantation. The complete pharmacokinetic parameters for the first busulfan dose were obtained from all patients and were comparable between the 2 arms: for the BU4 and BU1 groups, elimination half-life (mean+/-SD) was 2.75+/-0.22 versus 2.83+/-0.21 hours, estimated daily AUC was 6058.0+/-1091.9 versus 6475.5+/-1099.4 microM.min per day, and clearance was 2.05+/-0.36 versus 1.91+/-0.31 mL/min/kg, respectively. Times to engraftment after transplantation were similar between the 2 arms. No significant differences were evident in the occurrence of acute graft-versus-host disease (aGVHD) and hepatic veno-occlusion disease (VOD). Moreover, other toxicities observed within 100 days after transplantation were not significantly different between the 2 arms. The cumulative incidence of nonrelapse mortality was 20.8% in BU4 arm and 13.3% in BU1 arm. In conclusion, our randomized study demonstrates that the pharmacokinetic profiles and posttransplant complications are similar for once-daily iBU and traditional 4-times-daily iBU.     

Maximally tolerated busulfan systemic exposure in combination with fludarabine as conditioning before allogeneic hematopoietic cell transplantation

Systemic exposure to high-dose busulfan has been correlated with efficacy and toxicity after hematopoietic cell transplantation for malignancy. We used the area under the concentration-time curve (AUC) to prospectively determine the maximally tolerated systemic exposure to i.v. busulfan when given once daily after fludarabine administered at 40 mg/m(2) for 4 days. Three target AUC levels were planned: 6,000, 7,500, and 9,000 μM-min. Included were patients 16 to 65 years old, with a hematologic malignancy, an HLA A, B, or C, DRB1 8/8 or 7/8 matched donor, Karnofsky performance status ≥70%, and adequate organ function. For level 1 patients, i.v. busulfan doses 1 and 2 were 170 mg/m(2)/day, then doses 3 and 4 were adjusted based on first-dose pharmacokinetic modeling to achieve an average daily AUC of 6,000 μM-min. Doses 1 and 2 for the subsequent cohorts were based on the level 1 data: 180 mg/m(2)/day for AUC 7,500 μM-min (level?2) and 220 mg/m(2)/day for AUC 9,000 μM-min (level 3), with pharmacokinetic targeting for doses 3 and 4. Pharmacokinetic analysis after the last dose showed that 88% of the patients had been exposed to a mean AUC within 10% of the target. Forty patients were treated at level 1, 29 patients at level 2, and three patients at level 3. DLT was veno-occlusive disease of the liver, which occurred in none of 40 patients (0%) at level 1, two of 29 patients (7%) at level 2, and three of three patients (100%) at level 3. Dermatitis (P < .01) and pulmonary toxicity (P = .01) were also increased at higher AUC levels. Level 2 (7,500 μM-min × 4 days) was the maximally tolerated AUC. Within the confines of the trial's small sample size, there was no suggestion that escalating busulfan AUC from 6,000 to 7,500 μM-min × 4 days increased nonrelapse mortality. Assessment of the higher busulfan AUC on relapse prevention requires trials in patients with a homogeneous risk of relapse.     

Pharmacokinetics of a test dose of intravenous busulfan guide dose modifications to achieve an optimal area under the curve of a single daily dose of intravenous busulfan in children undergoing a reduced-intensity conditioning regimen with hematopoietic stem cell transplantation.

We studied 30 pediatric patients with malignant (n = 16) or nonmalignant (n = 14) conditions. The preparative regimen consisted of fludarabine, intravenous (IV) busulfan (Bu) for 2 daily doses, and antithymocyte globulin before stem cell transplantation. A test dose of IV Bu (0.8 mg/kg), anticipated to target an area under the concentration-time curve (AUC) of 800 to 1200 micromol.min, was followed later by 2 daily doses adjusted according to the pharmacokinetics (PK) to target an AUC of 3200 to 4800 micromol.min. The median test dose AUC was 953 micromol.min (range, 439-1315 micromol.min). The median AUC of single daily doses was 3798 micromol.min (range, 1511-7254 micromol.min). PK-based dose modification was required in 20 patients: 12 were adjusted to a higher dose, and in 8 the dose was decreased. Nausea and vomiting were noted in 15 patients. No patient developed hepatic veno-occlusive disease or seizures. Full donor chimerism was attained in 20 patients (mean of 24.5 days), 3 achieved partial chimerism, 5 did not engraft, and in 2 it is too early to assess chimerism. Acute graft-versus-host disease developed in 11 patients, grades I to II developed in 10 patients, and grade III developed in 1. Four patients died of infection and 5 of progressive disease. Thus, PK of a test dose of IV Bu provided information to adjust subsequent daily doses of IV Bu: this resulted in a regimen that was feasible, safe, and convenient for administration to children.     

Intravenous immunoglobulin: appropriate indications and uses in hematopoietic stem cell transplantation.

Intravenous immune globulin (IVIG) therapy has been prescribed in many different disease states. Hyperimmune products are also available. Recently, routine use for many indications has come under scrutiny secondary to high cost, limited supply, and unclear benefit. IVIG is U.S. Food and Drug Administration-approved for application in hematopoietic stem cell transplantation (HSCT), a very common indication for its use. In an attempt to clarify the most appropriate indications and doses in HSCT recipients, we conducted a MEDLINE search in which we reviewed all relevant articles from 1966 to the present. Search terms included bone marrow transplantation, intravenous immune globulin, hyperimmune globulin, GVHD, and cytomegalovirus (CMV). Also, the references of all pertinent studies and review articles were scanned for studies missed via MEDLINE. CMV prophylaxis/treatment and GVHD prophylaxis are the 2 indications with the most significant clinical support, but there are very few prospective, randomized, controlled trials reported. Furthermore, sample size usually was small, included heterogeneous patient populations, and employed different primary end points. Several reports support IVIG therapy in combination with ganciclovir for prevention and treatment of CMV infection, whereas others have shown ganciclovir monotherapy to be effective, blurring the benefit of IVIG administration. CMV IgG data are also imprecise and difficult to interpret. The role of IVIG therapy in prevention and treatment of GVHD also is vague. Only 1 randomized investigation showed a benefit in the prevention of acute GVHD, and no studies showed efficacy in chronic GVHD prophylaxis and therapy. Reports examining the utility of IVIG or CMV IgG in HSCT are hampered by marked variation in trial design and dosing and diverse patient characteristics. Although IVIG may be useful as a component of preemptive therapy and treatment of CMV disease, its contribution to the prevention of reactivation of CMV infection is dubious. Extended IVIG therapy during GVHD prevention may impair recovery of humoral immunity, and its role in prophylaxis and therapy of GVHD has not been clearly defined. Hospital monitoring programs may be a valuable way to detect areas of high use and allow for streamlining of prescribing.     

Intravenous versus oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality.

Hepatic venoocclusive disease (HVOD) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT) and is a well-recognized dose-limiting toxicity of oral busulfan (Bu)-based preparative regimens. The unpredictable absorption of oral Bu from the gastrointestinal (GI) tract and hepatic first-pass effects have led to the development of an intravenous Bu preparation (i.v. Bu). The purpose of this retrospective comparison was to evaluate the incidence rate of HVOD and the 100-day mortality rate in patients treated with a busulfan/cyclophosphamide (BuCy2) regimen in which either oral Bu or i.v. Bu was administered. Data from 2 similar groups of patients treated between March 1995 and December 1997 were analyzed. Thirty patients were treated with oral Bu (1 mg/kg x 16 doses) at City of Hope and 61 patients were treated with i.v. Bu (0.8 mg/kg x 16 doses) in a multicenter trial involving 7 sites. Bu was followed by Cy (60 mg/kg x 2 days) and a histocompatible-sibling-donor HSCT. In the i.v. Bu treatment group, 48% of the patients were classified as heavily pretreated (> or = 3 prior chemotherapy regimens, prior radiation, or prior HSCT) with 13% having had a prior HSCT and 75% having active disease at the time of transplantation. According to the same classification criteria, 33% of the patients in the oral-Bu treatment group were considered heavily pretreated, with 23% having had a prior HSCT and 80% having active disease at the time of transplantation. The incidence rates of clinically diagnosed HVOD were 5/61 (8%) and 10/30 (33%) after i.v. and oral Bu, respectively. HVOD-related mortality occurred in 2 (3.3%) of 61 i.v. and 6 (20%) of 30 oral Bu patients. The (standardized) Jones criteria for HVOD were met by 4.9% of i.v. and 20% of oral Bu patients. Univariate logistic regression analysis identified oral versus i.v. Bu (P = .001) and a diagnosis of myelodysplastic syndrome (P = .04) as statistically significant factors in the development of HVOD, with prior extensive treatment identified as marginally significant (P = .25). No other demographic parameter was found to be significant. After adjustment for prior treatment, multivariate analyses showed that the use of oral versus i.v. Bu was the strongest predictor for development of HVOD (odds ratio, 7.5; 95% confidence interval, 2.1-27.2; P = .002). This study showed that the incidence rate of HVOD is significantly lower (P = .002) and the 100-day survival rate significantly higher (P = .002) in patients treated with i.v. Bu than in patients treated with oral Bu when Bu is used as part of a BuCy2 preparative regimen for allogeneic HSCT.