自体外周血干细胞移植治疗原发性淀粉样变性

原发性系统性淀粉样变性（primary systemic amyloidosis） 是由于单克隆免疫球蛋白轻链或轻链片段以异常淀粉样纤维结构的形式沉积在组织导致的全身性疾病,也称AL型（amyloid light chain）淀粉样变性,呈进行性发展,最后可死于重要器官功能衰竭,是最常见也是预后最差的淀粉样变性,平均存活12～15个月,若累及心脏则不足5个月[1].激素、化疗往往效果不明显并且有副作用.近年来,自体外周血干细胞移植 （autologous peripheral stem cell transplantation, APSCT）结合大剂量化疗已成为原发性系统性淀粉样变性的重要治疗手段[2,3].     

自体外周血造血干细胞移植联合硼替佐米治疗原发性系统性淀粉样变性

目的:观察自体外周血造血干细胞移植联合硼替佐米治疗原发性系统性淀粉样变性的疗效.方法:2例原发性系统性淀粉样变性患者行自体外周血造血干细胞移植,移植后接受2个疗程硼替佐米联合地塞米松治疗.结果:2例患者移植后顺利造血重建,血清单克隆免疫球蛋白λ型轻链转阴.结论:自体造血干细胞移植联合硼替佐米治疗原发性系统性淀粉样变性疗效肯定,通过调整药物剂量可提高患者耐受性,降低治疗风险.     

自体外周血造血干细胞移植治疗系统性红斑狼疮的初步观察

目的探讨自体外周血造血干细胞移植(APBSCT)治疗系统性红斑狼疮(SLE)的可行性及临床效果。方法对8例女性难治性SLE病人进行APBSCT。采集的干细胞的单个核细胞计数平均为1.6×108/kg[(0.07～2.6)×108/kg]。预处理方案为环磷酰胺(50mg·kg-1·d-1,-5～-2d)静脉滴注及兔抗人淋巴细胞免疫球蛋白(10mg·kg-1·d-1,-3～-1d)静脉滴注。从移植前后皮肤红斑的变化,尿的改变,SLE相关的免疫指标的变化,移植后造血重建情况,移植的并发症等方面进行评价。结果8例病人均获得成功植入,外周血白细胞总数>1.0×109/L的平均时间为9.5d,中性粒细胞计数>0.5×109/L的平均时间为10d,白细胞总数恢复正常的平均时间为14d,血小板计数>50×109/L的平均时间为30d,血红蛋白含量平均在移植后第28天升至100g/L。移植后SLE临床症状均消失,尿蛋白转阴,自身抗体大部分转阴。移植相关并发症中,均出现血清病样预处理反应,2例出现严重的低血压;4例有出血性膀胱炎;2例出现败血症;4例发生霉菌感染;2例发生间质性肺炎。随访时间2个月～2.5年。结论APBSCT治疗SLE有较好的近期疗效,但观察病例及时间有限,远期疗效还需更长时间的观察。对药物治疗难以奏效的SLE病例,该法不失为一种更佳的选择。     

自体外周血造血干细胞移植治疗系统性红斑狼疮的临床观察

目的 探讨自体外周血造血干细胞移植(APBSCT)治疗难治性系统性红斑狼疮(SLE)的临床疗效和安全性.方法 10例难治性SLE患者接受APBSCT治疗,应用环磷酰胺(CTX)2～4 g/m2和粒细胞集落刺激因子5～10 μg·kg-1·d-1行外周血造血干细胞动员;预处理包括CTX(50 mg·kg-1·-1,-6～-3 d)和抗胸腺细胞球蛋白(ATG,15～20 mg·kg-1·d-1,-2 d、-1 d、1 d、2 d).患者输注的CD34+细胞＞2×106/kg.评估治疗前后临床表现、SLE疾病活动指数(SLEDAI)和免疫指标的变化.结果 APBSCT后10例SLE患者的临床症状缓解,SLEDAI评分降低,均获得造血重建,中性粒细胞＞0.5×109/L的中位数时间为9.5 d,血小板＞20×109/L中位数时间是11 d;尿蛋白减少或消失,抗核抗体滴度减低或转阴,补体水平升高;移植相关的并发症有:2例败血症,2例巨细胞病毒感染,1例出现肾毒性,3例急性左心衰竭,3例心律失常,无移植相关死亡.结论 APBSCT能够改善SLE患者的疾病活动和免疫学指标,是一种有效的治疗难治性SLE的方法,但远期疗效需进一步观察.     

系统性红斑狼疮自体外周血干细胞移植后颅内出血一例

系统性红斑狼疮(SLE)系一种可累及人体多种器官和组织的自身免疫性疾病,神经系统损害的发生率可达50%～60%,其中以癫痫发作最多,精神症状、偏瘫、头痛等也较多见,但脑血管病变者较少.国内外尚未见SLE行自体外周血干细胞移植(APBSCT)后发生颅内出血的报道,现将近期经治的1例报告如下.     

非清髓性自体外周血造血干细胞移植治疗系统性红斑狼疮远期疗效分析

目的探讨非清髓性自体外周血造血干细胞移植(NAST)治疗系统性红斑狼疮(SLE)的远期疗效。方法总结中山大学附属第五医院2002年11月至2005年10月4例成功接受NAST的SLE患者移植后的随访情况。非清髓性预处理移植前1～2 d静脉滴注阿糖胞苷200 mg/(kg.d)及环磷酰胺40 mg/(kg.d)。评价患者移植前后的相关症状体征、远期并发症及免疫功能的变化。结果白细胞总数恢复正常的中位时间12 d,血小板>100×109/L的中位时间为10 d,血红蛋白>120 g/L的中位时间为22 d。随访中,NAST后4例患者临床症状和体症均消失,淋巴细胞亚群检测显示:CD4+及CD4+/CD8+均恢复正常。1例男性患者移植4年后妻子正常受孕并产下一健康女婴。3例女性均恢复正常工作与生活。结论 NAST造血重建快,远期疗效确切。SLE患者NAST治疗后生活质量较好。     

原发性系统性淀粉样变性的治疗进展

原发性系统性淀粉样变性 (primarysystemicamyloidosis)是淀粉样蛋白病的一种 ,为AL型 (amy loidlightchain) ,是单株浆细胞产生的单克隆免疫球蛋白轻链 (κ或λ)或轻链片段以淀粉样纤维素的形式沉积在组织 ,导致进行性器官功能不全为特征的全身性疾病 ,肾脏是最易受累的器官之一。活组织检查是诊断本病的金标准 (包括肾脏、腹壁脂肪、直肠粘膜等部位 )。早期肾小球系膜区呈无细胞性增宽 ,随着病情进展肾小球基底膜增厚、血管腔闭塞 ,形成无结构的淀粉样物质团块 ,病变早期单纯常规肾活检病理易误诊为系膜增生性肾小球肾炎、轻微病变或膜性…     

自体外周血干细胞移植治疗失代偿期肝硬化

目的评价自体外周血干细胞移植治疗失代偿期肝硬化的效果。方法选择42例住院治疗的失代偿期肝硬化患者,分为干细胞移植组20例和对照组22例,两组均予以相同的内科综合治疗,干细胞移植组加行经肝动脉自体外周血干细胞移植术,观察患者术后乏力、纳差、腹胀等主要症状的变化,检测移植术后4、8、12、24周肝功能、凝血功能等指标的变化,同期检测对照组的变化。结果两组患者在治疗后观察期间的主要症状乏力、纳差、腹胀均有改善。20例干细胞移植组患者手术均成功,无特殊不良反应及并发症。术后8、12、24周干细胞移植组患者肝功白蛋白均较术前明显回升(P0.05),与对照组比较差异有统计学意义(P0.05)。术后12周、24周细胞移植组凝血酶原活动度以及术后24周细胞移植组凝血酶原时间较术前明显改善(P0.05),但组间比较无统计学差异。术后12周、24周Child评分较术前及对照组明显改善,差异有统计学意义(P0.01)。结论经肝动脉自体外周血干细胞移植治疗失代偿期肝硬化是一种安全、有效的微创治疗方法,可在一定程度上改善患者的低蛋白血症及凝血功能。     

自体外周血干细胞移植与多发性硬化

多发性硬化（multiple sclerosis，MS）是以中枢神经系统白质脱髓鞘病变为特点的自身免疫性疾病，有反复发作的特点，部分患者病情呈进行性（PMS）加重。研究证明，MS主要是由T细胞介导的自身免疫性疾病。传统的疗法主要是以糖皮质激素、免疫抑制剂、干扰素B等方法行免疫干预，抑制炎性脱髓鞘病变，但都难以阻止病情的进展。大多数PMS患者5～10年内坐轮椅、卧床或死亡。近年来，临床上采用自体外周血干细胞移植（autologous peripheral blood stem cell transplantation，APBSCT）治疗常规疗法无效的MS，取得了一定的效果，因而MS患者APBSCT的疗效及进展也备受关注。     

自体外周血造血干细胞移植治疗恶性淋巴瘤

目的 :报告 7例恶性淋巴瘤在自体外周血造血干细胞移植 (APBSCT)支持下接受超大剂量放、化疗的治疗经验 ,评价所用外周血造血干细胞 (PBSC)动员方案的动员效果 ,预处理方案的疗效和耐受性 ,以及移植后造血重建情况。方法 :7例淋巴瘤患者中 ,1例霍奇金病 ,6例非霍奇金淋巴瘤。动员方案为MOEP/CMOP化疗联合rhG -CSF ,预处理采用经典的超大剂量环磷酰胺 (CTX)化疗联合全身放疗 (TBI)。结果 :APBSCT动员后获得到单个核细胞 4.2 (2 .7～ 6 .1)× 10 8/kg,回输单个核细胞 3.7(2 .5～ 5 .3)× 10 8/kg ,中性粒细胞计数恢复到 >0 .5× 10 9/L的时间和血小板 >5 0× 10 9/L的时间分别平均为第 11.6天和第 14.6天。毒副作用主要为消化道反应。结论 :APBSCT治疗恶性淋巴瘤效果肯定 ,采用MOEP/CMOP联合rhG -CSF动员以及经典CTX加TBI方案预处理 ,安全可靠 ,治疗效果良好。     

Prognostic factors for survival and response after high-dose therapy and autologous stem cell transplantation in systemic AL amyloidosis: a report on 21 patients

We retrospectively investigated the feasibility and the toxicity of autologous stem cell transpantation (ASCT) in 21 cases of systemic amyloidosis (AL). The conditioning regimens consisted of high-dose melphalan (HDM) alone ( n  = 18) or in combination with 12 Gy total body irradiation ( n  = 3). Toxic death rate was high: 9/21 patients (43%) died within the first month following ASCT, and 10/12 surviving patients achieved a response. With a median follow-up of 14 months, the OS and the EFS rates at 4 years were 57.1% (±10.8) and 29.9% (±14.5) respectively for the whole group. The major prognostic factor for both response and survival was the number of clinical manifestations at the time of ASCT, of the following five criteria, i.e. creatinine clearance <30 ml/min, nephrotic syndrome with urinary protein excretion > 3000 mg/24 h, congestive heart failure, neuropathy, or hepatomegaly associated with alkaline phosphatase level > 200 IU/l. For patients presenting with two or more clinical manifestations the 4-year OS and EFS were both 11.1% compared with 91.7% and 46.3% respectively in patients with fewer than two clinical manifestations at the time of ACST. We conclude that ASCT is feasible in AL in a subset of patients with fewer than two clinical manifestations at the time of ASCT. Given the severe extra-haematological toxicity, ASCT should not be considered in other cases.     

Successful reduced intensity allogeneic stem cell transplantation for systemic AL amyloidosis

No established treatments for systemic AL amyloidosis have been determined, and only four reports have described allogeneic stem cell transplantation for this disease. We report the case of a patient with orthostatic hypotension, diarrhea, nephrotic syndrome, and cardiac amyloidosis due to systemic AL amyloidosis. Reduced intensity allogeneic stem cell transplantation (RIST) was performed using a conditioning regimen comprising fludarabine 125 mg/m2 and melphalan 90 mg/m2. Hematologically complete remission and symptomatic improvement were obtained without severe transplantation-related complications. RIST may thus offer a useful treatment strategy for systemic AL amyloidosis complicated by cardiac amyloidosis.     

AL amyloidosis treated with induction chemotherapy with VAD followed by high dose melphalan and autologous stem cell transplantation

Abstract

High dose melphalan (HDM) followed by reinfusion of autologous blood stem cells (ASCT) has been applied in AL amyloidosis. Vincristine, doxorubicin, and dexamethasone (VAD) rapidly decrease light chain production in multiple myeloma.

In a Phase I/II study of VAD followed by HDM and ASCT in AL amyloidosis, toxicity, feasibility, and response to this regimen were evaluated. Over a 5-year period 38 patients with AL amyloidosis were seen of which 12 out of 18 eligible patients participated in the study.

VAD induced a distinct clonal response in 50% (6/12) of the patients, but without clinical improvement. In 11 patients HDM and ASCT was applied. Six months after ASCT 78% (7/9) of the surviving patients showed partial clonal response and none responded completely. Clinical condition evidently improved in 67% (6/9) of survivors, whereby clinical response, clinical response, performance score, and SAP scintigraphs were concordant. Therefore a complete clonal response is not a prerequisite for clinical improvement.

With median follow-up after ASCT of 25 months, 75% of the study group patients were alive. Mortality was strongly depending on the number of organs involved. Patients treated with HDM and ASCT had better survival than those not eligible (P < 0.0005).     

Reduced intensity allogeneic stem cell transplantation for systemic primary amyloidosis refractory to high-dose melphalan

Complete elimination of the plasma cell dyscrasia is a rational therapeutic goal, as intercepting supply of precursor protein is a necessary condition for a major regression of amyloid deposits. High-dose melphalan with autologous stem cell transplantation has shown the ability to induce complete hematological response (HR) along with recovery of organ dysfunction. However, the rate of HR with this treatment rarely exceeds 40%. We describe here the first known case of successful reduced intensity allogeneic stem cell transplantation (RIST) for a patient with primary amyloidosis complicated with nephrotic syndrome but without cardiac disease, who had obtained only partial HR by high-dose melphalan with autologous stem cell transplantation. RIST may be feasible and be capable of achieving complete HR along with recovery from nephrotic syndrome with acceptable toxicity.     

Early intensification and autologous stem cell transplantation in patients with systemic AL amyloidosis: a single-centre experience

Primary systemic amyloidosis (AL amyloidosis) continues to have a very poor prognosis. Most therapeutic strategies remain unsatisfactory. Conventional chemotherapy is known to offer at best only moderate efficacy. Several studies have yielded higher complete response rates after high-dose chemotherapy and autologous stem cell transplantation (ASCT) in addition to improving outcomes in a subgroup of patients. However, the superiority of an intensive approach in AL amyloidosis has not been confirmed in a randomised trial. The precise role of ASCT remains unclear. We report our experience in 16 patients diagnosed with AL amyloidosis and treated in a multidisciplinary approach with high-dose melphalan and ASCT. Median age was 59 (39–71) years. The kidneys were predominantly affected in 75% of cases; two or more organs were affected in 38%. Median time from diagnosis to transplantation was 2 (1–4) months. Three patients (19%) developed acute renal failure and required transient dialysis. Transplant-related mortality was 6% after 100 days. Haematological complete response (CR) was obtained in nine (56%) and organ response in six (38%) patients. Nine out of 12 patients (75%) with kidney involvement exhibited a sustained clinical benefit at 12 months. Half of all the patients (n = 8) were alive after a median follow-up of 33 months, including two in continuous CR. This suggests that high-dose chemotherapy and ASCT are still valid treatment options in AL amyloidosis and that a significant number of patients with renal involvement might benefit from this approach.     

Outcome of autologous stem cell transplantation for AL amyloidosis in the UK

High-dose chemotherapy with autologous stem cell transplantation (SCT) is widely used as a treatment for systemic AL amyloidosis, but its efficacy has not been proved and it has substantial toxicity in this setting. We report here the outcome of 92 patients evaluated at the UK National Amyloidosis Centre who underwent SCT for AL amyloidosis between 1994 and 2004 in various British centres. Median age was 53 years and median of two organs were affected by amyloidosis. All-cause day 100 mortality [treatment-related mortality (TRM)] was 23% for the entire cohort, although this was substantially greater for patients treated from 1994 to 1998 (15/47, 32%) than subsequently (6/45, 13%). Independent factors significantly associated with TRM on multivariate analysis were: number of affected organs, performance status, serum albumin and age. Response of the underlying clonal disease, defined by > or = 50% reduction in the aberrant serum-free light chain concentration, occurred in 83% of evaluable patients. Overall median survival was 5.3 years, and was 8.5 years among patients who survived beyond day 100. Despite recent refinements in patient selection, TRM remains substantial during SCT for systemic AL amyloidosis, and its place in the therapeutic armamentarium for this disease needs to be defined in randomised controlled clinical studies.     

Successful treatment of systemic amyloidosis with hepatic involvement and factor X deficiency by high dose melphalan chemotherapy and autologous stem cell reinfusion

Systemic amyloidosis with hepatic involvement is a rare disorder, which is characterized by the deposits of amyloid fibrils in the liver. The prognosis is poor and the median survival is 13 months. Bleeding problems resulting from coagulopathy frequently complicates systemic amyloidosis. We present two patients with a severe factor X deficiency and hepatomegaly as the presenting abnormalities of systemic amyloidosis. One of the patients was treated with high dose melphalan chemotherapy and autologous stem cell reinfusion, resulting in a normalization of the liver enzyme tests and the factor X level. The diagnosis and treatment of systemic amyloidosis with hepatic involvement and the management of the multifactorial coagulopathy in these cases is discussed.     

Infections after CD34-selected or unmanipulated autologous hematopoietic stem cell transplantation

Immune reconstitution may be delayed after CD34-selected compared with unmanipulated autologous peripheral blood stem cell transplantation (PBSCT), resulting in a theoretically increased risk of infections. In a case-control matched study we compared the incidence of infection in 25 recipients of CD34-selected PBSC (CD34 group) and 75 recipients of unmanipulated PBSC (PBSC group) transplants. The population included 52 males and 48 females suffering from non-Hodgkin's lymphoma (n = 32), Hodgkin's disease (n = 8), multiple myeloma (n = 40) or breast cancer (n = 20). Neutrophil engraftment was comparable in the two groups. The actuarial incidence of infection was similar in the two groups (56% vs. 49% at day 30, and 70% vs. 64% at 1 yr respectively). The proportion of patients with 1, 2 or 3 infections, the number of infectious event per patient (1.32 vs. 1.04; NS), the number of infections before day 15 or 30, between days 31 and 100 or after day 100, the risk of varicella-zoster virus or cytomegalovirus infection or disease, or the use of antibiotic or antifungal therapy, were not increased in the CD34 compared with the PBSC group. The main agents responsible for infection were bacteria, particularly gram-positive cocci, in both groups. Bacteremia accounted for 33% of all infectious events in the CD34 group vs. 16% in the PBSC group (P < 0.05). Fungal infections were rare. In conclusion, our results do not support the notion that CD34-selection of the graft is associated with an increased rate of infection after autologous PBSC transplantation. The role of extended infection prophylaxis should be evaluated.