自体干细胞移植治疗AL淀粉样变性及新型诱导方案的研究
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摘要
本研究包括三部分内容：
1.合并肾脏受累的原发性系统性淀粉样变性患者临床预后特点及危险因素分析
2.自体外周血干细胞移植治疗原发性系统性淀粉样变性的疗效及安全性分析
3.硼替佐米合并地塞米松的诱导方案联合自体外周血干细胞移植治疗原发性系统性淀粉样变性的临床研究
研究一合并肾脏受累的原发性系统性淀粉样变性患者临床预后特点及危险因素分析
研究目的：阐明我国汉族人群合并肾脏受累的免疫球蛋白轻链性(AL)淀粉样变性患者的临床预后特点及其相关危险因素。
研究方法：回顾性分析2003年3月～2011年8月期间南京军区南京总医院全军肾脏病研究所诊断的AL淀粉样变性患者的临床预后特点,利用Kaplan-Meier法计算患者的累计生存率,并利用COX回归模型分析相关危险因素。
研究结果：共245名患者纳入本研究,其中男性153例(63.5%),中位年龄56岁,起病是主要表现为乏力及水肿,除肾脏受累外,最常见的受累器官是肠道(55.9%),其次为心脏(46.9%)。患者诊断前中位病程为7月,主要表现为大量蛋白尿,平均24小时尿蛋白定量为4.86±4.32g,其中57.96%的患者尿蛋白在3.5-10g/之间。平均肌酐水平为1.29±1.17mg/dl,尿酸氮水平为22.7±15.3mg/dl,但有25%患者诊断时合并肾功能不全。患者M蛋白主要为λIgG (36.06%)和λIgA (18.75%),有32.69%的患者M蛋白检测为阴性。平均随访时间20.5月,期间死亡111例,患者总体的中位生存时间33.6月(范围1-98月),1年、2年、3年和5年的生存率分别为68.3%、52.7%、47.8%和30.7%。亚组分析发现心脏受累、肝脏受累、低血压、肾功能不全患者生存时间缩短,而经过特殊治疗(化疗或干细胞移植)患者预后明显提高。COX单因素回归模型表明年龄、性别、心脏受累、肝脏受累、低血压、骨髓浆细胞比例都是患者预后危险因素,而接受特殊治疗则是预后保护因素,进一步的多因素分析表明诊断年龄、肝脏受累、心脏受累及骨髓浆细胞比例是患者预后的独立危险因素,而特殊治疗是患者预后独立保护因素。随访期间共有57例患者接受透析治疗,其中血透49例,腹透8例,40例透析患者死亡。肾脏的中位生存时间为45月(1-98月),1年、2年、3年及5年肾存活率分别为78.6%、69.6%、63.2%和36.9%。肾脏预后单因素分析表明诊断年龄、性别、肌酐、RBP、心脏受累、肝脏受累、低血压均为进展至终末期肾脏病(ESRD)的危险因素,多因素分析表明诊断时肌酐水平和低血压是进展至ESRD的独立危险因素。
研究结论：本研究表明合并肾脏受累的AL患者易合并肠道、心脏受累,此类患者长期预后较差,其中合并心脏受累、肝脏受累、低血压及肾功能不全者预后更差,而接受特殊治疗可明显提高患者生存率。诊断时肌酐水平高及低血压提示肾脏预后不良。
研究二自体外周血干细胞移植治疗原发性系统性淀粉样变性的疗效及安全性分析
研究目的：评价大剂量马法兰联合自体外周血干细胞移植(HDM/SCT)治疗原发性系统性(AL)淀粉样变性的初步疗效及安全性。
研究方法：从2010年7月至2012年1月共有33例AL淀粉样变性患者在我科接受自体造血干细胞移植(AHSCT)治疗,所有患者均经肾活检明确诊断。采用粒细胞集落刺激因子(G-CSF)动员采集干细胞,采集成功后8周内接受干细胞移植治疗,预处理方案为大剂量马法兰,根据患者危险分层采用100、140和200mg/m2三种剂量。受累器官及疗效判断采用第12届国际淀粉样变性研讨会制订的标准。
研究结果：33例患者中男性19例,年龄35-65(中位年龄53)岁,病程1-18月(中位时间6月),所有患者均通过肾活检明确诊断,肾组织λ轻链沉积11例,K轻链沉积2例。受累器官1-3(中位2个)个(仅评价肾脏、心脏、肝脏及神经系统等重要器官),患者均有肾脏受累,20例(60.6%)患者心脏受累,2例(6.1%)肝脏受累,1例(3.0%)外周神经受累。所有患者均成功采集干细胞,采集过程中的主要并发症为低钙血症、低钟血症及血小板减低。采集CD34+细胞数2.0-12(中位4.5)×106/'kg。所有患者造血均重建,粒缺期3-7天(中位时间4天),中性粒细胞植入时间9-13天(中位时间9天),血小板植入时间10-21(中位时间13天)天。移植过程中分级>2级的主要并发症为恶心、呕吐(54.5%),黏膜炎(36.4%),腹泻(36.4%),粒缺期发热(39.4%),心脏毒性(24.2%)及急性肾损伤(27.3%)等,其他少见并发症有急性肝损伤、肝破裂出血、胸腔积液和败血症等。移植后100天内2例患者死亡,移植相关死亡率为6.1%。移植后中位随访10月,有24例(72.7%)患者取得了血液学反应,其中完全缓解14例(42.4%),部分缓解10例(30.3%)。20例(60.6%)患者取得了器官反应,其中6例为肾脏及心脏均有反应,1例患者肝脏与肾脏有反应,13例为肾脏反应。
研究结论：对于严格选择的AL淀粉样变性患者,AHSCT治疗是一种有效的治疗手段,有较高的血液学及器官反应率。虽然各种移植相关并发症发生率较高,但致死性并发症少见,AHSCT是治疗AL的安全有效的手段,其远期疗效有待进一步观察。
研究三硼替佐米合并地塞米松的诱导方案联合自体外周血干细胞移植治疗原发性系统性淀粉样变性的临床研究
研究目的：评价硼替佐米联合地塞米松诱导治疗联合自体外周血干细胞移植的疗效和安全性。
研究方法：2010年1月至2012年2月期间,共有33例患者行干细胞移植治疗,一组为硼替佐米合并地塞米松(BD)诱导治疗两疗程后行干细胞移植治疗(组1),一组直接行干细胞移植治疗(组2)。BD诱导治疗方案为硼替佐米1.3mg/m2,第1、4、8和11天用药,地塞米松40mg,第1-4天用药,21天一疗程。干细胞动员方法为单用粒细胞刺激因子,预处理方案为大剂量马法兰。评价所有患者的疗效和安全性。
研究结果：33例患者分为两组,诱导治疗组(组1)为16例,干细胞移植组17例(组2)。两组间的基线资料无明显差别,诊断到移植的时间也没有明显差别。两组间总体的血液学反应率比较,组1为93.8%,组2为52.9%,组1明显高于组2(HR=3.41,P=0.004),而且组1的完全缓解率更高(68.8%vs.17.6%, HR=4.95, P=0.016)。两组间肾脏反应率比较组1也明显高于组2(87.5vs.35.3%,HR=3.74,P=0.008)。组1的心脏反应率也较高,但两组比较无统计学差异。副作用方面,两组之间无明显差异,诱导组因硼替佐米引起的相关副作用并不影响患者的治疗过程。中位随访12月后,两组间的总体生存有明显差异,组1生存率更高(P=0.045)。
结论：初步研究结果表明BD方案的诱导治疗可以明显提高干细胞移植治疗的血液学和器官反应率,但远期疗效有待进一步观察。
PART ONE:Renal involvement in AL amyloidosis:the clinical and prognosis outcomes in a Chinese single center
Background:Renal is the most common affected organ in AL(immunoglobulin light chain) amyloidosis, but data on clinical picture and survival of patients with renal AL amyloidosis are usually limited, especially in Chinese patients.
Methods:The patients with biopsy-proven AL amyloidosis in Jinling hospital from March2003to August2011were studied, all patients had renal involvement. The clinical and laboratory information were collected from diagnosis to death or until the last available clinical control. The patients survival and renal outcomes were also analyzed, and the relationships between clinical parameters and were assessed.
Results:245patients were studied.153patients were male, the median age at diagnosis was56years. The most common affect organs were intestinal tract (55.9%) and heart(46.7%) besides renal. Proteinuria was the major clinical feature of these patients,the mean24-hours proteinuria was4.86±4.32g,25%patients had renal insufficiency at diagnosis. The mean time of follow-up was20.5months(range1-98),111patients were dead, the median survival time of all patients was33.6months, the patients with heart involvement, hepatic involvement, hypotension and renal insufficiency had worse survival, and specific therapy can improve the survival. The1,2,3and5-year cumulative survival rate, calculated by Kaplan-Meier method, were68.3%、52.7%、47.8%and30.7%respectively. Multivariate COX analysis showed the age, hepatic involvement, cardic involvement, the rate of plasma cell in bone marrow can and specific therapy can significantly influence survival in these patients. The median time of renal survival was45months, the1,2,3and5-year renal survival rate were78.6%、69.6%、63.2%and36.9%respectively, Multivariate COX analysis showed the serum creatinine and hypotension were the important risk fators of renal failure.
Conclusion:Our results first demonstrated the clinical picture and survival of Chinese patients with renal AL amyloidosis. These patients were usually combined with intestinal tract and heart involvement, the survival of our cohort was poor, and the heart involvement, hepatic involvement, hypotension, renal insufficiency and specific therapy can significantly influence survival. The high serum creatinine level and hypotension at diagnosis implied the bad renal outcome.
PART TWO:The efficiency and safety of autologous stem cell transplantation for primary systemic amyloidosis
Objective:To evaluate the short time efficiency and safety of autologous hematopoietic stem cell transplantation(AHSCT) in primary systemic amyloidosis(AL).
Methodology:A total of13patients with biopsy-proven amyloidosis shown to be immunoglobulin light-chain type were enrolled on this study form July2010to Jan2011. The method of mobilization was granulocyte-colony-stimulating factor (G-CSF) alone. The patients received AHSCT in2-6weeks after collection. The condition regimen was high dose melphalan, the dose adjusted to100,140and200mg/m2according to patient stratification. The assessment of organ involvement and treatment response was according to the consensus opinion from the12th international symposium on amyloid and amyloidosis.
Results:There were8males and5females in our series, the age was from35to63years old (median54yr). the course of disease was from2to43months(median9m), the primary clinical symptoms of these patients was nephritic syndrome, The clonal light chain subtype, classified by immunohistochemical staining, was κ in2patients and λ in11patients. The involved organ number was1～3(2.0±0.58), Amyloid was seen clinically in the kidneys (100%), heart (76.9%), liver(15.4%), and peripheral nerves (7.7%).4patients were untreated before AHSCT, while others were received induction therapy. All patients were collected enough stem cells, the main complications of collections were hypocalcemia, hypopotassaemia and thrombocytopenia, the number of CD34+cells was2.0-8.36(4.02±2.01)×106/kg. all patients had successful engraftment, All patients achieved a granulocyte count of500/L between day9and day13(median9d), achieved an untransfused platelet count of20,000/L from day10to day21(13.69±2.56). The major complication of peri-transplantation period were nausea/vomiting(84.6%), mucositis(76.9%), fever(53.8%), arrhythmia(53.8%), acute renal injury(46.2%) and diarrhea(30.8%). The uncommon complication were acute liver injury, hepatic rupture, pleural effusion, sepsis and so on. One patients died of transplant-related hepatic rupture at the day21, the treatment related mortality was7.7%in day100. After follow up for4-10months,8patients achieved hematologic response,5had complete response and3had partial response.7patients achieved organ response,3cases had renal and heart response,4had renal response only.
Conclusion:The AHSCT was an efficiency and safety treatment for AL in selected patients, the hematologic and organ response rate was high. Though the complications of peri-transplantation were common, the fatal complications was rare. The long-term outcomes need future observation.
PART THREE:Induction chemotherapy with bortezomib and dexamethasone followed by autologous stem cell transplantation can improve both the hematologic and organ response rate for patients with AL amyloidosis
Purpose:The use of bortezomib alone and in combination with steroids has shown efficacy in primary systemic amyloidosis (AL amyloidosis), however, its role in combination with high-dose melphalan and autologous stem cell transplantation (HDM/SCT) is unknown. In this study, we evaluated bortezomib in combination with dexamethasone (BD) for induction chemotherapy prior to HDM/SCT.
Patients and Methods:We conducted a prospective study comparing induction therapy consisting of two BD cycles followed by HDM/SCT (Group1) with HDM/SCT alone (Group2) in the treatment of patients with naive AL amyloidosis. The efficacy and toxicity of each treatment was evaluated.
Results:Thirty-three patients were enrolled in this study, sixteen in Group1and seventeen in Group2. The patients presented with comparable disease severity and time from diagnosis to transplantation in the two treatment groups. The overall hematological response rates (ORR) were obtained for fifteen (93.8%) Group1and nine (52.9%) Group2patients (HR=3.41, P=0.004), and the complete hematological response rates were68.8%(11/15) for Group1and17.6%(3/17) for Group2(HR=4.95, P=0.016). Group1patients also achieved better renal response (87.5vs.35.3%, HR=3.74, P=0.008) and a better heart response (40vs.20%) without major adverse events related to BD therapy. After a median follow-up of twelve months (range:4-24months), overall survival was significantly higher in Group1(P=0.045).
Conclusions:Our preliminary data suggest that induction chemotherapy with BD can significantly improve both the hematologic and organ response rates in patients with AL amyloidosis who undergo the HDM/SCT procedure.
1.合并肾脏受累的原发性系统性淀粉样变性患者临床预后特点及危险因素分析
2.自体外周血干细胞移植治疗原发性系统性淀粉样变性的疗效及安全性分析
3.硼替佐米合并地塞米松的诱导方案联合自体外周血干细胞移植治疗原发性系统性淀粉样变性的临床研究
研究一合并肾脏受累的原发性系统性淀粉样变性患者临床预后特点及危险因素分析
研究目的：阐明我国汉族人群合并肾脏受累的免疫球蛋白轻链性(AL)淀粉样变性患者的临床预后特点及其相关危险因素。
研究方法：回顾性分析2003年3月～2011年8月期间南京军区南京总医院全军肾脏病研究所诊断的AL淀粉样变性患者的临床预后特点,利用Kaplan-Meier法计算患者的累计生存率,并利用COX回归模型分析相关危险因素。
研究结果：共245名患者纳入本研究,其中男性153例(63.5%),中位年龄56岁,起病是主要表现为乏力及水肿,除肾脏受累外,最常见的受累器官是肠道(55.9%),其次为心脏(46.9%)。患者诊断前中位病程为7月,主要表现为大量蛋白尿,平均24小时尿蛋白定量为4.86±4.32g,其中57.96%的患者尿蛋白在3.5-10g/之间。平均肌酐水平为1.29±1.17mg/dl,尿酸氮水平为22.7±15.3mg/dl,但有25%患者诊断时合并肾功能不全。患者M蛋白主要为λIgG (36.06%)和λIgA (18.75%),有32.69%的患者M蛋白检测为阴性。平均随访时间20.5月,期间死亡111例,患者总体的中位生存时间33.6月(范围1-98月),1年、2年、3年和5年的生存率分别为68.3%、52.7%、47.8%和30.7%。亚组分析发现心脏受累、肝脏受累、低血压、肾功能不全患者生存时间缩短,而经过特殊治疗(化疗或干细胞移植)患者预后明显提高。COX单因素回归模型表明年龄、性别、心脏受累、肝脏受累、低血压、骨髓浆细胞比例都是患者预后危险因素,而接受特殊治疗则是预后保护因素,进一步的多因素分析表明诊断年龄、肝脏受累、心脏受累及骨髓浆细胞比例是患者预后的独立危险因素,而特殊治疗是患者预后独立保护因素。随访期间共有57例患者接受透析治疗,其中血透49例,腹透8例,40例透析患者死亡。肾脏的中位生存时间为45月(1-98月),1年、2年、3年及5年肾存活率分别为78.6%、69.6%、63.2%和36.9%。肾脏预后单因素分析表明诊断年龄、性别、肌酐、RBP、心脏受累、肝脏受累、低血压均为进展至终末期肾脏病(ESRD)的危险因素,多因素分析表明诊断时肌酐水平和低血压是进展至ESRD的独立危险因素。
研究结论：本研究表明合并肾脏受累的AL患者易合并肠道、心脏受累,此类患者长期预后较差,其中合并心脏受累、肝脏受累、低血压及肾功能不全者预后更差,而接受特殊治疗可明显提高患者生存率。诊断时肌酐水平高及低血压提示肾脏预后不良。
研究二自体外周血干细胞移植治疗原发性系统性淀粉样变性的疗效及安全性分析
研究目的：评价大剂量马法兰联合自体外周血干细胞移植(HDM/SCT)治疗原发性系统性(AL)淀粉样变性的初步疗效及安全性。
研究方法：从2010年7月至2012年1月共有33例AL淀粉样变性患者在我科接受自体造血干细胞移植(AHSCT)治疗,所有患者均经肾活检明确诊断。采用粒细胞集落刺激因子(G-CSF)动员采集干细胞,采集成功后8周内接受干细胞移植治疗,预处理方案为大剂量马法兰,根据患者危险分层采用100、140和200mg/m2三种剂量。受累器官及疗效判断采用第12届国际淀粉样变性研讨会制订的标准。
研究结果：33例患者中男性19例,年龄35-65(中位年龄53)岁,病程1-18月(中位时间6月),所有患者均通过肾活检明确诊断,肾组织λ轻链沉积11例,K轻链沉积2例。受累器官1-3(中位2个)个(仅评价肾脏、心脏、肝脏及神经系统等重要器官),患者均有肾脏受累,20例(60.6%)患者心脏受累,2例(6.1%)肝脏受累,1例(3.0%)外周神经受累。所有患者均成功采集干细胞,采集过程中的主要并发症为低钙血症、低钟血症及血小板减低。采集CD34+细胞数2.0-12(中位4.5)×106/'kg。所有患者造血均重建,粒缺期3-7天(中位时间4天),中性粒细胞植入时间9-13天(中位时间9天),血小板植入时间10-21(中位时间13天)天。移植过程中分级>2级的主要并发症为恶心、呕吐(54.5%),黏膜炎(36.4%),腹泻(36.4%),粒缺期发热(39.4%),心脏毒性(24.2%)及急性肾损伤(27.3%)等,其他少见并发症有急性肝损伤、肝破裂出血、胸腔积液和败血症等。移植后100天内2例患者死亡,移植相关死亡率为6.1%。移植后中位随访10月,有24例(72.7%)患者取得了血液学反应,其中完全缓解14例(42.4%),部分缓解10例(30.3%)。20例(60.6%)患者取得了器官反应,其中6例为肾脏及心脏均有反应,1例患者肝脏与肾脏有反应,13例为肾脏反应。
研究结论：对于严格选择的AL淀粉样变性患者,AHSCT治疗是一种有效的治疗手段,有较高的血液学及器官反应率。虽然各种移植相关并发症发生率较高,但致死性并发症少见,AHSCT是治疗AL的安全有效的手段,其远期疗效有待进一步观察。
研究三硼替佐米合并地塞米松的诱导方案联合自体外周血干细胞移植治疗原发性系统性淀粉样变性的临床研究
研究目的：评价硼替佐米联合地塞米松诱导治疗联合自体外周血干细胞移植的疗效和安全性。
研究方法：2010年1月至2012年2月期间,共有33例患者行干细胞移植治疗,一组为硼替佐米合并地塞米松(BD)诱导治疗两疗程后行干细胞移植治疗(组1),一组直接行干细胞移植治疗(组2)。BD诱导治疗方案为硼替佐米1.3mg/m2,第1、4、8和11天用药,地塞米松40mg,第1-4天用药,21天一疗程。干细胞动员方法为单用粒细胞刺激因子,预处理方案为大剂量马法兰。评价所有患者的疗效和安全性。
研究结果：33例患者分为两组,诱导治疗组(组1)为16例,干细胞移植组17例(组2)。两组间的基线资料无明显差别,诊断到移植的时间也没有明显差别。两组间总体的血液学反应率比较,组1为93.8%,组2为52.9%,组1明显高于组2(HR=3.41,P=0.004),而且组1的完全缓解率更高(68.8%vs.17.6%, HR=4.95, P=0.016)。两组间肾脏反应率比较组1也明显高于组2(87.5vs.35.3%,HR=3.74,P=0.008)。组1的心脏反应率也较高,但两组比较无统计学差异。副作用方面,两组之间无明显差异,诱导组因硼替佐米引起的相关副作用并不影响患者的治疗过程。中位随访12月后,两组间的总体生存有明显差异,组1生存率更高(P=0.045)。
结论：初步研究结果表明BD方案的诱导治疗可以明显提高干细胞移植治疗的血液学和器官反应率,但远期疗效有待进一步观察。
PART ONE:Renal involvement in AL amyloidosis:the clinical and prognosis outcomes in a Chinese single center
Background:Renal is the most common affected organ in AL(immunoglobulin light chain) amyloidosis, but data on clinical picture and survival of patients with renal AL amyloidosis are usually limited, especially in Chinese patients.
Methods:The patients with biopsy-proven AL amyloidosis in Jinling hospital from March2003to August2011were studied, all patients had renal involvement. The clinical and laboratory information were collected from diagnosis to death or until the last available clinical control. The patients survival and renal outcomes were also analyzed, and the relationships between clinical parameters and were assessed.
Results:245patients were studied.153patients were male, the median age at diagnosis was56years. The most common affect organs were intestinal tract (55.9%) and heart(46.7%) besides renal. Proteinuria was the major clinical feature of these patients,the mean24-hours proteinuria was4.86±4.32g,25%patients had renal insufficiency at diagnosis. The mean time of follow-up was20.5months(range1-98),111patients were dead, the median survival time of all patients was33.6months, the patients with heart involvement, hepatic involvement, hypotension and renal insufficiency had worse survival, and specific therapy can improve the survival. The1,2,3and5-year cumulative survival rate, calculated by Kaplan-Meier method, were68.3%、52.7%、47.8%and30.7%respectively. Multivariate COX analysis showed the age, hepatic involvement, cardic involvement, the rate of plasma cell in bone marrow can and specific therapy can significantly influence survival in these patients. The median time of renal survival was45months, the1,2,3and5-year renal survival rate were78.6%、69.6%、63.2%and36.9%respectively, Multivariate COX analysis showed the serum creatinine and hypotension were the important risk fators of renal failure.
Conclusion:Our results first demonstrated the clinical picture and survival of Chinese patients with renal AL amyloidosis. These patients were usually combined with intestinal tract and heart involvement, the survival of our cohort was poor, and the heart involvement, hepatic involvement, hypotension, renal insufficiency and specific therapy can significantly influence survival. The high serum creatinine level and hypotension at diagnosis implied the bad renal outcome.
PART TWO:The efficiency and safety of autologous stem cell transplantation for primary systemic amyloidosis
Objective:To evaluate the short time efficiency and safety of autologous hematopoietic stem cell transplantation(AHSCT) in primary systemic amyloidosis(AL).
Methodology:A total of13patients with biopsy-proven amyloidosis shown to be immunoglobulin light-chain type were enrolled on this study form July2010to Jan2011. The method of mobilization was granulocyte-colony-stimulating factor (G-CSF) alone. The patients received AHSCT in2-6weeks after collection. The condition regimen was high dose melphalan, the dose adjusted to100,140and200mg/m2according to patient stratification. The assessment of organ involvement and treatment response was according to the consensus opinion from the12th international symposium on amyloid and amyloidosis.
Results:There were8males and5females in our series, the age was from35to63years old (median54yr). the course of disease was from2to43months(median9m), the primary clinical symptoms of these patients was nephritic syndrome, The clonal light chain subtype, classified by immunohistochemical staining, was κ in2patients and λ in11patients. The involved organ number was1～3(2.0±0.58), Amyloid was seen clinically in the kidneys (100%), heart (76.9%), liver(15.4%), and peripheral nerves (7.7%).4patients were untreated before AHSCT, while others were received induction therapy. All patients were collected enough stem cells, the main complications of collections were hypocalcemia, hypopotassaemia and thrombocytopenia, the number of CD34+cells was2.0-8.36(4.02±2.01)×106/kg. all patients had successful engraftment, All patients achieved a granulocyte count of500/L between day9and day13(median9d), achieved an untransfused platelet count of20,000/L from day10to day21(13.69±2.56). The major complication of peri-transplantation period were nausea/vomiting(84.6%), mucositis(76.9%), fever(53.8%), arrhythmia(53.8%), acute renal injury(46.2%) and diarrhea(30.8%). The uncommon complication were acute liver injury, hepatic rupture, pleural effusion, sepsis and so on. One patients died of transplant-related hepatic rupture at the day21, the treatment related mortality was7.7%in day100. After follow up for4-10months,8patients achieved hematologic response,5had complete response and3had partial response.7patients achieved organ response,3cases had renal and heart response,4had renal response only.
Conclusion:The AHSCT was an efficiency and safety treatment for AL in selected patients, the hematologic and organ response rate was high. Though the complications of peri-transplantation were common, the fatal complications was rare. The long-term outcomes need future observation.
PART THREE:Induction chemotherapy with bortezomib and dexamethasone followed by autologous stem cell transplantation can improve both the hematologic and organ response rate for patients with AL amyloidosis
Purpose:The use of bortezomib alone and in combination with steroids has shown efficacy in primary systemic amyloidosis (AL amyloidosis), however, its role in combination with high-dose melphalan and autologous stem cell transplantation (HDM/SCT) is unknown. In this study, we evaluated bortezomib in combination with dexamethasone (BD) for induction chemotherapy prior to HDM/SCT.
Patients and Methods:We conducted a prospective study comparing induction therapy consisting of two BD cycles followed by HDM/SCT (Group1) with HDM/SCT alone (Group2) in the treatment of patients with naive AL amyloidosis. The efficacy and toxicity of each treatment was evaluated.
Results:Thirty-three patients were enrolled in this study, sixteen in Group1and seventeen in Group2. The patients presented with comparable disease severity and time from diagnosis to transplantation in the two treatment groups. The overall hematological response rates (ORR) were obtained for fifteen (93.8%) Group1and nine (52.9%) Group2patients (HR=3.41, P=0.004), and the complete hematological response rates were68.8%(11/15) for Group1and17.6%(3/17) for Group2(HR=4.95, P=0.016). Group1patients also achieved better renal response (87.5vs.35.3%, HR=3.74, P=0.008) and a better heart response (40vs.20%) without major adverse events related to BD therapy. After a median follow-up of twelve months (range:4-24months), overall survival was significantly higher in Group1(P=0.045).
Conclusions:Our preliminary data suggest that induction chemotherapy with BD can significantly improve both the hematologic and organ response rates in patients with AL amyloidosis who undergo the HDM/SCT procedure.
引文
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2 Kyle RA, Gertz MA. Primary systemic amyloidosis:clinical and laboratory features in 474 cases. Semin Hematol,1995,32(1):45-59.
3 Rajkumar SV, Gertz MA. Advances in the treatment of amyloidosis. N Engl J Med, 2007,356(23):2413-5.
4 Cohen AD, Comenzo RL. Systemic light-chain amyloidosis:advances in diagnosis, prognosis, and therapy. Hematology Am Soc Hematol Educ Program, 2010,2010:287-94.
5 翟勇平,宋萍,唐玉梅,等.自体外周血干细胞移植治疗原发性系统性淀粉样变性二例报告并文献复习.中华血液学杂志,2007,28(5)：346-348.
6 Gertz MA, Comenzo R, Falk RH, et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL):a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France,18-22 April 2004. Am J Hematol,2005,79(4):319-28.
7 Harousseau JL, Moreau P. Autologous hematopoietic stem-cell transplantation for multiple myeloma. N Engl J Med,2009,360(25):2645-54.
8 Comenzo RL, Gertz MA. Autologous stem cell transplantation for primary systemic amyloidosis. Blood,2002,99(12):4276-82.
9 Palladini G, Perfetti V, Obici L, et al. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood, 2004,103(8):2936-8.
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1 Merlini G, Bellotti V. Molecular mechanisms of amyloidosis. N Engl J Med, 2003,349(6):583-96.
2 Kyle RA, Gertz MA. Primary systemic amyloidosis:clinical and laboratory features in 474 cases. Semin Hematol,1995,32(1):45-59.
3 Rajkumar SV, Gertz MA. Advances in the treatment of amyloidosis. N Engl J Med, 2007,356(23):2413-5.
4 Cohen AD, Comenzo RL. Systemic light-chain amyloidosis:advances in diagnosis, prognosis, and therapy. Hematology Am Soc Hematol Educ Program, 2010,2010:287-94.
5 翟勇平,宋萍,唐玉梅,等.自体外周血干细胞移植治疗原发性系统性淀粉样变性二例报告并文献复习.中华血液学杂志,2007,28(5)：346-348.
6 Gertz MA, Comenzo R, Falk RH, et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL):a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France,18-22 April 2004. Am J Hematol,2005,79(4):319-28.
7 Harousseau JL, Moreau P. Autologous hematopoietic stem-cell transplantation for multiple myeloma. N Engl J Med,2009,360(25):2645-54.
8 Comenzo RL, Gertz MA. Autologous stem cell transplantation for primary systemic amyloidosis. Blood,2002,99(12):4276-82.
9 Palladini G, Perfetti V, Obici L, et al. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood, 2004,103(8):2936-8.
10 Kyle RA, Gertz MA, Greipp PR, et al. A trial of three regimens for primary amyloidosis:colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med,1997,336(17):1202-7.
11 Gertz MA, Lacy MQ, Dispenzieri A, et al. Transplantation for amyloidosis. Curr Opin Oncol,2007,19(2):136-41.
12 Schonland SO, Perz JB, Hundemer M, et al. Indications for high-dose chemotherapy with autologous stem cell support in patients with systemic amyloid light chain amyloidosis. Transplantation,2005,80(1 Suppl):S 160-3.
13 Barosi G, Boccadoro M, Cavo M, et al. Management of multiple myeloma and related-disorders:guidelines from the Italian Society of Hematology (SIE), Italian Society of Experimental Hematology (SIES) and Italian Group for Bone Marrow Transplantation (GITMO). Haematologica,2004,89(6):717-41.
14 Shah KB, Inoue Y, Mehra MR. Amyloidosis and the heart:a comprehensive review. Arch Intern Med,2006,166(17):1805-13.
15 Gertz MA, Lacy MQ, Dispenzieri A. Therapy for immunoglobulin light chain amyloidosis:the new and the old. Blood Rev,2004,18(1):17-37.
16 Dispenzieri A, Kyle RA, Lacy MQ, et al. Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation:a case-control study. Blood,2004,103(10):3960-3.
17 Gertz MA, Lacy MQ, Dispenzieri A, et al. Effect of hematologic response on outcome of patients undergoing transplantation for primary amyloidosis:importance of achieving a complete response. Haematologica,2007,92(10):1415-8.
18 Goodman HJ, Gillmore JD, Lachmann HJ, et al. Outcome of autologous stem cell transplantation for AL amyloidosis in the UK. Br J Haematol,2006,134(4):417-25.
19 Skinner M, Sanchorawala V, Seldin DC, et al. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis:an 8-year study. Ann Intern Med,2004,140(2):85-93.
20 Jaccard A, Moreau P, Leblond V, et al. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med,2007,357(11):1083-93.
21 Gertz MA, Lacy MQ, Dispenzieri A, et al. Stem cell transplantation for the management of primary systemic amyloidosis. Am J Med,2002,113(7):549-55.
22 Palladini G, Merlini G. Transplantation vs. conventional-dose therapy for amyloidosis. Curr Opin Oncol,2011,23(2):214-20.
23 Moreau P. Autologous stem cell transplantation for AL amyloidosis:a standard therapy. Leukemia,1999,13(12):1929-31.
24 Mollee PN, Wechalekar AD, Pereira DL, et al. Autologous stem cell transplantation in primary systemic amyloidosis:the impact of selection criteria on outcome. Bone Marrow Transplant,2004,33(3):271-7.
25 Tam M, Seldin DC, Forbes BM, et al. Spontaneous rupture of the liver in a patient with systemic AL amyloidosis undergoing treatment with high-dose melphalan and autologous stem cell transplantation:a case report with literature review. Amyloid, 2009,16(2):103-7.
26 Cohen AD, Zhou P, Chou J, et al. Risk-adapted autologous stem cell transplantation with adjuvant dexamethasone+/- thalidomide for systemic light-chain amyloidosis: results of a phase II trial. Br J Haematol,2007,139(2):224-33.
27 Gertz MA, Lacy MQ, Dispenzieri A, et al. Risk-adjusted manipulation of melphalan dose before stem cell transplantation in patients with amyloidosis is associated with a lower response rate. Bone Marrow Transplant,2004,34(12):1025-31.
28 Leung N, Slezak JM,Bergstralh EJ, et al. Acute renal insufficiency after high-dose melphalan in patients with primary systemic amyloidosis during stem cell transplantation. Am J Kidney Dis,2005,45(1):102-11.
29 Comenzo RL. How I treat amyloidosis. Blood,2009,114(15):3147-57.
30 Falk RH. Diagnosis and management of the cardiac amyloidoses. Circulation, 2005,112(13):2047-60.
31 Gertz MA, Merlini G, Treon SP. Amyloidosis and Waldenstrom's macroglobulinemia. Hematology Am Soc Hematol Educ Program,2004:257-82.
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