造血干细胞移植治疗多发性硬化的研究进展

造血干细胞移植(hematopoietic stem cell transplantation,HSCT)治疗血液系统恶性疾病和某些实体肿瘤已获得了很好的疗效。近年来,很多实验及临床尝试用HSCT治疗自身免疫性疾病并获得成功,其理论基础:自身免疫性疾病是多克隆干细胞病,因此通过造血干细胞移植重建一个具有自身耐受的新免疫系统,从而治愈自身免疫性疾病成为可能。大量的动物实验及临床治疗已取得了可喜的进展,其中神经系统自身免疫病多发性硬化(multiple sclerosis,MS)的造血干细胞治疗是研究的热点之一,其治疗方法日渐成熟,成为难治性MS的治疗新选择。本文主要对造血干细胞(特别是自体外周血干细胞)移植治疗多发性硬化的研究进展作一综     

造血干细胞移植治疗多发性硬化

多发性硬化(ｍｕｌｔｉｐｌｅｓｃｌｅｒｏｓｉｓ,ＭＳ)是一种自身免疫性疾病,病因尚不完全清楚。研究证明,ＭＳ主要是由Ｔ细胞介导的中枢神经脱髓鞘病[1]。目前,常规治疗方法包括激素、免疫抑制剂、干扰素β、放射治疗等,仅能延长疾病的缓解期。近年来发现造血干细胞移植(ＨＳＣＴ)治疗血液病的同时所合并的自身免疫性疾病得到缓解[2,3]。本文对近年ＨＳＣＴ治疗ＭＳ进展作一综述。一、动物实验用豚鼠髓鞘碱性蛋白(ＭＢＰ)或含脂质蛋白(ＰＬＰ)片段及完全福氏佐剂免疫ＳＪＬ/Ｊ小鼠或Ｂｕｆｆａｌｏ大鼠可造成ＭＳ的动物模型[4,5],即实验性…     

自体外周血造血干细胞移植治疗进展型多发性硬化的临床研究

目的观察自体外周血造血干细胞移植(APBSCT)治疗进展型多发性硬化(PMS)的疗效及安全性。方法16例进展型多发性硬化患者接受APBSCT治疗,造血干细胞动员采用环磷酰胺/粒细胞集落刺激因子(CY/GCSF)方案,预处理采用环磷酰胺/全身放疗(CY/TBl)或卡氮芥、足叶乙甙、阿糖胞苷和马法兰(BEAM)方案。采用无进展生存率和无复发生存率进行疗效评估,并记录移植、随访期间的毒副作用。结果中位数随访时间24个月,无进展生存率为80%,无事件生存率为50%。常见的不良反应有恶心、呕吐、感染、脱发、一过性转氨酶升高、短暂性神经症状加重,2例患者于移植后4.5个月和15个月分别死于严重肺部感染和不明原因的进行性黄疸。结论APBSCT治疗可明显阻止PMS患者的病情进展,其长期疗效和安全性仍需进一步随访观察。     

自体外周造血干细胞移植治疗进展型多发性硬化的临床观察(附一例报告)

目的观察自体外周造血干细胞移植(auto-PBSCT)治疗进展型多发性硬化(PMS)的疗效及安全性。方法PMS 1例,以重组人粒细胞集落刺激因子(G-CSF)动员造血干细胞(HSC),血细胞分离仪分离外周血干细胞50 mL,按患者体重拟回输的CD34 细胞2.85×106个/kg于-80℃液氮冻存。在马利兰/环磷酰胺方案预处理后,经锁骨下静脉回输HSC,G-CSF协助造血恢复。移植后2、4、8、12周观察患者临床、体征、实验室及影像学指标。结果移植后患者临床症状及体征基本恢复,MRI显示病灶有所缩小。结论auto-PBSCT治疗PMS较为安全、有效。     

造血干细胞移植治疗多发性硬化新进展

近年来临床应用造血干细胞移植(HSCT)治疗多发性硬化取得了一定的疗效.初步研究显示,对大部分进展型MS患者,HSCT能阻止疾病进展.但临床上HSCT治疗MS仍存在较多问题,如HSCT治疗后复发、如何选择最佳治疗时机等.本文主要介绍HSCT治疗MS的方法学、疗效及副作用现状及探讨该疗法在适应症及方法学方面所存在的问题.     

自体外周血干细胞移植治疗多发性硬化进展

部分多发性硬化(MS)患者用传统的免疫干预疗法不能控制病情,往往导致渐进性的神经功能损伤以至死亡。自体外周血干细胞移植(Autologous peripheral blood stem cell transplantation,APBSCT)近年来应用于此类MS患者,取得了较好的疗效。本文综述了目前APBSCT治疗MS的进展状况。     

自体造血干细胞移植治疗进展型多发性硬化的疗效评价

目的评价自体造血干细胞移植(AHSCT)治疗进展型多发性硬化(PMS)的疗效及安全性。方法选取2001年11月至2010年3月我院收治的82例PMS患者,行AHSCT治疗的41例为AHSCT组,行皮质醇激素治疗的41例PMS患者为激素治疗组。随访观察临床疗效,分析指标包括疾病无进展生存率(PFS)、神经功能残疾评分(EDSS)、总发作次数、平均年发作次数、生活质量评分(ADL)和MRI病灶变化情况、移植相关死亡率及毒副反应。结果 AHSCT组41例患者均完成了AHSCT,但3例失访,38例完成临床试验。其移植后EDSS评分、发作总次数、年均发作次数、病灶总容积及生活质量评分均较移植前下降(<0.05);5.2年PFS为78.9%。激素治疗组41例患者失访29例,随访12例患者治疗后EDSS评分、发作总次数及年均发作次数均较治疗前增加(P<0.05);2.8年PFS仅为8.3%。结论 PMS应用其他方法治疗效果欠佳时,采取自体造血干细胞移植,可有效降低EDSS评分、发作次数及病灶容积,提高生活质量。     

自体外周造血干细胞移植后对多发性硬化患者MRI强化病灶的影响

目的　评价自体外周造血干细胞移植术对进展型多发性硬化患者 MRI强化病灶的抑制作用、临床神经功能改善情况和毒副作用。方法　应用自体外周造血干细胞移植治疗进展型多发性硬化患者 10例 ,用惠尔血进行造血干细胞动员 ,预处理应用 BEAM方案 (卡氮芥、依托泊苷、阿糖胞苷、马法兰 ) ,移植前 1、2个月及移植后每间隔 3个月分别进行脑、脊髓的 MRI及强化扫描 ,同时评价扩充神经功能残疾量表 ( EDSS)。结果　中位随访时间 10个月 (范围 4～ 2 2月 )。移植后 1、3、6、9、12、15、18个月 MRI强化病灶数较移植前均明显减少 ,差异有显著意义 ( P<0 .0 1) ;移植后患者 EDSS评分较移植降低 ,差异有显著意义 ( P<0 .0 1)。造血干细胞动员、预处理和移植期间无 1例死亡 ,常见的副反应为发热感染等 ;2例患者在 3～ 6个月神经功能一过性加重 ,1例在 10个月后复发。结论　自体外周造血干细胞移植术对进展型多发性硬化患者 MRI强化病灶有明显的抑制作用 ,同时临床神经功能得到改善 ,无严重毒副作用 ,长期疗效仍需依据进一步观察随访的结果来决定     

自体外周血纯化CD34+细胞移植治疗进展型多发性硬化

目的 评价自体外周血纯化CD34+细胞移植治疗进展型多发性硬化(PMS)的安全性和疗效.方法 2002-09―2006-03期间15例PMS患者在首都医科大学宣武医院接受了自体外周血纯化CD34+细胞移植.单独使用粒细胞集落刺激因子(G-CSF)动员造血干细胞,全部回输采集物进行CD34+细胞纯化.预处理采用BEAM(卡氮芥、依托泊甙、阿糖胞苷、马法兰)方案.中位随访期为21(3～45)个月,移植前后应用扩充神经功能残疾量表(EDSS)、年平均发病次数进行疗效评价. 结果分选后中位CD34+细胞纯度为93.2 (78.6～97.7)%,中位回收率为67.0(22.4～79.8)%,相当于减少了4个对数级的T细胞.无移植相关死亡,造血重建时间与其自体外周造血干细胞移植(APBSCT)相当,未出现严重的毒性反应及并发症.患者移植后12个月EDSS评分(3.95±2.55)较移植前(5.64±0.71)降低(P＜0.05),年平均发病次数移植后(0.45±0.82)较移植前(1.31±0.71)减少(P＜0.05).移植后45个月疾病无活动者生存率为(47.01±17.87)%,EDSS评分无进展者(包括稳定和改善)生存率为(57.69±20.24)%. 结论自体外周血纯化CD34+细胞移植治疗PMS安全有效.     

自体造血干细胞移植治疗多发性硬化的长期临床疗效研究进展

自体造血干细胞移植(AHSCT)是治疗进展型多发性硬化(MS)的有效方法,相关研究已在世界范围内多个AHSCT中心开展.此文对AHSCT治疗MS前后病情变化及长期疗效进行综述.     

Autologous hematopoietic stem cell transplantation in progressive severe multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of central nervous system (CNS), which is disabling and majorly involves younger population. Various available treatments in forms of immunomodulation are not very effective; however, stem cell transplantation seems to be promising in recent literature. The current case report is a novel evidence for autologous hematopoietic stem cell transplantation (HSCT) in progressive MS. Case Summary: A 33 year old male with secondary progressive MS (SPMS), after being failed and/or intolerance to standard approved interferon (IFN) and mitoxantrone therapy, autologous HSCT was administered. At 2years of post-stem cell transplantation follow-up, he has remained stable with some improvement in functional status (Expanded Disability Status Scale (EDSS) reduced by 1.5), with no relapse, no treatment related complications, and no fresh magnetic resonance imaging (MRI) lesions. Conclusion: Autologous stem cell transplantation may be beneficial in progressive forms of MS, but needs to be tested in well-designed randomized trial.     

Guidelines for autologous blood and marrow stem cell transplantation in multiple sclerosis: a consensus report written on behalf of the European Group for Blood and Marrow Transplantation and the European Charcot Foundation

Recent reports suggest the possible beneficial effects of haemopoietic stem cell transplantation (HSCT) in autoimmune diseases such as multiple sclerosis (MS). The definition of the risk/benefit ratio for such a treatment is perceived as a major issue for the neurological community worldwide. The First Consensus Conference on Bone Marrow Transplantation in Patients with Multiple Sclerosis was held in Milan, Italy on 21 February 1998. Participants from 16 European, North American, and South American countries discussed the guidelines form performing HSCT in MS. This conference was organized in order to : (a) define criteria for patient selection; (b) define transplantation procedures to maximize efficacy of the treatment and minimize its toxicity; (c) standardize patient outcome evaluation; and (d) establish an international working group to evaluate the efficacy and safety of HSCT in MS and to study the immunological changes related to HSCT in MS patients. During the meeting in Milan agreement was reached on: (a) the preparation and distribution of a consensus report on HSCT in MS and (b) the design of an open trial for an initial assessment of the safety and efficacy of HSCT in MS. The consensus reached during the meeting and the design of the clinical trial are summarized in this contribution. Received: 14 May 1999, Received in revised form: 4 January 2000, Accepted: 19 January 2000     

Hematopoietic stem cell transplantation for multiple sclerosis. A retrospective multicenter study

Rationale Phase I/II studies of autologous hematopoietic stem cell transplantation (HSCT) for multiple sclerosis (MS) were initiated, based on results of experimental transplantation in animal models of multiple sclerosis and clinical observations in patients treated concomitantly for malignant disease. Patients Eighty-five patients with progressive MS were treated with autologous HSCT in 20 centers and reported to the autoimmune disease working party of the European Group for Blood and Marrow Transplantation (EBMT). 52 (61 %) were female, median age was 39 [20-58] years. The median interval from diagnosis to transplant was 7 [1-26] years. Patients suffered from severe disease with a median EDSS score of 6.5 [4.5-8.5]. Active disease prior to transplant was documented in 79 of 82 evaluable cases. Results The stem cell source was bone marrow in 6 and peripheral blood in 79, and stem cells were mobilized into peripheral blood using either cyclophosphamide combined with growth factors or growth factors alone. Three patients experienced transient neurological complications during the mobilization phase. The high dose regimen included combination chemotherapy, with or without anti-lymphocyte antibodies or, with or without, total body irradiation. The stem cell transplants were purged of lymphocytes in 52 patients. Median follow-up was 16 [3-59] months. There were 7 deaths, 5 due to toxicity and infectious complications, 2 with neurological deterioration. The risk of death of any cause at 3 years was 10 (±7)% (95 % confidence interval). Neurological deterioration during transplant was observed in 22 patients; this was transient in most but was associated with MS progression in 6 patients. Neurological improvement by ≥ 1 point in the EDSS score was seen in 18 (21 %) patients. Confirmed progression-free survival was 74 (±12)% at 3 years being 66 (±23)% in patients with primary progressive MS but higher in patients with secondary progressive or relapsing-remitting MS, 78 (±13)%; p = 0.59. The probability of confirmed disease progression was 20 (±11)%. MRI data were available in 78 patients before transplant showing disease activity (gadolinium enhancing, new or enlarging lesions) in 33 %. Posttransplant MRI showed activity at any time in 5/61 (8 %) evaluable cases. Conclusion Autologous HSCT suggest positive early results in the management of progressive MS and is feasible. These multicentre data suggest an association with significant mortality risks especially in some patient groups and are being utilised in the planning of future trials to reduce transplant related mortality. Received: 21 August 2001 Received in revised form: 4 February 2002 Accepted: 6 February 2002     

Autologous hemopoietic stem cell transplantation in the treatment of multiple sclerosis: rationale and clinical experience

Based on the encouraging results of transplantation in animals with experimental autoimmune encephalomyelitis (EAE), small-scale phase I/II trials of autologous hematopoietic stem cell transplantation (autoHSCT) were initiated in 1995 for the treatment of severe cases of multiple sclerosis (MS). More than 200 patients with treatment-resistant multiple sclerosis have been transplanted so far, mainly in Europe and the USA. The results of these studies appear promising in terms of impact on MRI disease parameters and, to a lesser extent, clinical stabilization or even improvement. Despite concerns raised by the morbidity and mortality noted in the initial pilot studies, a controlled, randomized, phase III trial of autoHSCT against the best currently available treatment, i.e., mitoxantrone, seems justified and is under way.     

Short-term intensive cyclophosphamide treatment in progressive multiple sclerosis

14 patients with chronic progressive multiple sclerosis, selected in a preliminary uncontrolled trial, were given a short course of intensive cyclophosphamide therapy, which was discontinued when the leukocyte count fell to 3000 cu.mm. 5 patients dropped out because of severe side effects. At 1 year follow-up were neurologically unchanged since admission to the trial; 4 remained stable at 2 years. The lack of clinical improvement, the high frequency of side effects and the proven oncogenicity of cyclophosphamide led us to discontinue the trial.

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Sommario 14 pazienti con SM definita e con forma cronica severamente progressiva sono stati trattati con un ciclo a breve termine e ad alto dosaggio di ciclofosfamide (400 mg/die), associata a cortisone (100 mg/die). L'immunosoppressione è stata considerata efficace quando è stata raggiunta una leucopenia di 3.000/mmc e a quel momento il farmaco è stato interrotto. 5 pazienti non hanno terminato il trattamento per la comparsa di gravi effetti collaterali. Dopo 1 anno di follow-up tutti i pazienti erano stazionari rispetto all'ingresso; 4 pazienti hanno terminato il secondo anno di follow-up e in essi la malattia si è mantenuta in fase di stabilizzazione. Nonostante questo, l'assenza di miglioramenti clinici, l'alta frequenza di effetti collaterali, la dimostrata oncogenicità della ciclofosfamide non ci incoraggia a continuare la sperimentazione.

     

POEMS syndrome: relapse after successful autologous peripheral blood stem cell transplantation

We report a patient with POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes) treated with high dose chemotherapy and auto-Peripheral Blood Stem Cell Transplantation (auto-PBSCT) who had a very good response with complete clinical remission. Seven years later, she relapsed and a new sclerotic bone lesion was found. To our knowledge, this is the first POEMS syndrome relapse after successful auto-PBSCT.     

Primary and secondary progressive multiple sclerosis

The progressive phase of multiple sclerosis (MS) is the one most often associated with irreversible accumulation of disability. An important question remains about the place of primary progressive MS (PP-MS): does it form an integral part of the disease spectrum, or is it maybe a distinct entity? This question could apparently be very theoretical, but it is not, as patients with PP-MS remain orphans when regarding disease-modifying treatments. Thus, they are usually excluded from therapeutic trials. A clue to this question could be the comparison between the different MS subtypes with a progressive phase. We discuss here the clinical similarities and differences between secondary and primary progressive MS.