94例自体外周造血干细胞移植治疗血液系统恶性疾病临床分析
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摘要
背景
造血干细胞移植为血液系统恶性疾病的治疗带来了革命性的转变。在近二十年间，随着重组粒细胞集落刺激因子的广泛应用和外周血细胞采集分选技术的完善，自体外周血造血干细胞移植已基本取代了自体骨髓移植在多种恶性血液系统疾病中得以广泛应用。自体外周造血干细胞也成为移植所需干细胞的主要来源。但自体移植前后尚存在诸多问题有待更多的经验积累，如影响动员和采集成败的因素，回输适宜的干细胞数目，移植相关并发症及死亡，移植中的高复发率，远期生存如何等。各中心报道结论不尽相同。
目的
探讨自体外周造血干细胞移植在血液系统恶性疾病中的治疗作用，包括动员的有效性、造血的重建、预处理的毒性和耐受性，以及移植后的转归和远期生存。
方法
回顾性分析了1996～2005年间在我院进行自体造血干细胞移植的94例血液系统恶性疾病患者，涉及的疾病包括急性白血病、霍奇金淋巴瘤和非霍奇金淋巴瘤以及多发性骨髓瘤等常见血液系统恶性疾病，收集临床资料，随访远期预后，用统计学软件加以分析。
结果
Auto-PBSCT多数患者经过化疗+G-CSF(5～10ug／kg．d)的动员后，连续采集1～3天可获得MNC(5.27±3.76)×10~8／kg，CD34+细胞(8.08±7.46)×10~6／kg。回输CD34~+细胞(4.61±4.13)×10~6／kg可有效重建造血，ANC恢复至500／ul以上中位时间为d+10，PLT恢复至20000／ul以上无需输注的中位时间为d+13，ANC和PLT恢复时间与回输的CD34~+细胞数呈负相关(r=-0.324和-0.338，p=0.002和0.002)，且不受G-CSF加用时间的限制。回输的CD34~+细胞≥2×10~6／kg时，ANC恢复时间和PLT恢复时间不再随回输的CD34~+细胞增多而进一步缩短(r=-0.176和-0.185，p=0.097和0.099)。
移植期间常见的不良事件有消化道症状、发热、口腔溃疡、出血倾向、肝功异常等，多可耐受。移植期间合并感染常见为革兰氏阴性杆菌感染，病毒和真菌亦可见；急性间质性肺炎、出血性膀胱炎和植入失败者少见。未发现肝小静脉阻塞者。
88.3％(83人)进行了随访，中位随访时间为17.5月，51.8％移植后病情稳定，44.6％复发，22.9％死亡，死因主要为原发病复发进展，复发主要集中在移植后1年内，占70.3％。回输了体外分选的CD34~+干细胞者占16.9％，未发现分选对复发有显著影响。
移植后1年的总生存率为85.6％，3年总生存为72.9％，5年为65.2％。根据原发病分组，则多发性骨髓瘤(MM)患者移植后中位生存期为40个月，其1年总生存率为90％，3年OS为67.5％；急性白血病(AL)患者移植后中位生存期为73个月，其1年的总生存率为85.7％，3年为65.3％，8年为43.6％；淋巴瘤患者(包括NHL和HL)移植后1年总生存率为84.6％，3年为78.6％，5年为71.4％，并可观察到平台期。未发现各组间有显著差异。
Auto-PBSCT后1年总的无病生存率(DFS)为62.2％，3年总DFS为51.6％，5年为38.8％。MM患者移植后中位无病生存时间为23个月，其1年DFS为63.6％，3年DFS为31.8％；AL患者移植后中位无病生存时间为43个月，1年DFS为63％，3年DFS为52.5％，5年为39.4％；淋巴瘤患者移植后中位无病生存时间为52个月，1年内的DFS为62.4％，3年DFS为52.9％，5年为45.3％。
移植后半年内的CD4~+细胞计数和NK细胞计数与转归相关，CD4~+细胞和NK细胞恢复较好者预后相对较好。预处理方案含有TBI对OS和DFS有不利影响。
结论
1．经过化疗+G-CSF可对血液系统恶性疾病患者进行有效动员，并从外周血采集出足量的造血干细胞用于自体造血干细胞移植以重建造血，Auto-PBSCT回输的CD34~+细胞在应≥2×10~6／kg，有利于快速重建造血；
2．移植期间相关并发症如消化道症状、发热、口腔溃疡、出血倾向、肝功异常等发生率较高但多可耐受。移植期间合并感染常见为革兰氏阴性杆菌感染，病毒和真菌亦可见，持续高热常规抗细菌治疗无效应考虑真菌、病毒感染或混合感染可能；
3．Auto-PBSCT后的中位生存期MM为40个月，AL为73个月，中位无病生存期MM为23个月；AL为43个月，淋巴瘤为52个月。1年时的总生存和无病生存各组分别为：MM 90％和63.6％，急性白血病85.7％和63％，淋巴瘤84.6％和62.4％。各组之间无显著差异。
4．移植后半年内的CD4~+细胞计数与转归相关，CD4~+细胞恢复较好者预后相对较好。预处理方案是否含有TBI未发现与转归相关；移植后半年内的NK细胞恢复较好者可能对预后和无病生存有有利影响。
5．复发与是否分选无明显相关，复发的根源可能主要是患者体内残留的肿瘤细胞。
6．移植后维持治疗未发现对防止复发有有利影响。
7．预处理含有TBI者预后不良。
Background
Hematopoietic stem cell transplantation changed revolutionarily the conventional chemo-radio therapeutic mode of hematologic malignancies. In the past two decades, with the wide-spread application of G-CSF and the improved techniques of harvesting and selecting of blood stem cells, autologous peripheral blood stem cell (PBSC) transplantation has substituted traditional autologous bone marrow stem cell transplantation. And PBSC has been widely used in the transplantation therapy of many hematologic malignancies as the main source of hematopoietic stem cells. Yet there are still many controversial questions about transplantation, such as factors affecting mobilization and harvesting, the appropriate numbers of stem cells to transplant, complications and death associated with transplantation, relapse rate and long term survival and so on. Since different centers report inconsistent results, we need accumulate more experience to find our own answer.
Objectives
To explore the therapeutic effects of ASCT in treating hematologic malignancies, and to investigate the efficacy of mobilization and harvesting of peripheral blood stem cells, reconstition of hematopoiesis, toxicity and tolerance of preparative regimens and clinical outcomes of auto-PBSCT.
Methods
During the 10 years between 1996 and 2005, 94 patients underwent auto-PBSCT who were diagnosed as hematologic malignancies including acute and chronic leukemia, iymphoma (Hodgkin's and non-Hodgkin's) and multiple myeloma. Their clinical information and follow-up conditions were collected, and retrospective statistics analysis methods were used to explore the regularity.
Results
For patients that underwent auto-PBSCT, most could be harvested enough stem cells after 1 mobilization which is comprised of chemotherapy and G-CSF. After consecutive harvesting for 1～3 days, (5.27±3.76)×10~8/kg MNC and (8.08+7.46)×10~6/kg CD34~+ could be obtained. (4.61±4.13)×10~6/kg CD34~+ were reinfused and reconstituted hemopoiesis effectively. The median time for ANC＞500/ul was at d+10, and the median time for PLT＞20000/ul free of transfusion was at d+13. Time for ANC and PLT recovery correlates negatively with the number of CD34~+ stem cells reinfused (r=-0.324 and -0.338, p=0.002 and 0.002). And this relation was not restricted by the time G-CSF was prescribed. But when more than 2×10~6/kg CD34~+ cells were reinfused, the speed of hemopoiesis recovery did not correlate with the number of CD34~+ cells reinfused any longer (r=-0.176 and -0.185, p=0.097 and 0.099).
Complications during transplantation included symptoms of digestive、fever、mucositis, bleeding inclination, hypohepatia and so on. They were tolerated well. Most of the pathogens responsible for infections were gram negative bacilli. Interstitial pneumonitis, hemorrhagic cystitis and graft failure were rare. No veno-occlusion disease occurred.
Totally 88.3% (n=83) patients received follow-up after transplantation. The median time of follow-up was 17.5 months. During follow-up, 51.8% maintained stable or CR, 44.6% relapsed, and 22.9% died. The main cause of death was the progression or relapses of original diseases. 70.3% of the relapses occurred in the 1st year after transplantation. 16.9% patients were transplanted with in vitro manipulated CD34~+ stem cells. But no significant effects were found on relapse.
The overall survival (OS) rate at 1st year was 85.6%, at 3rd year was 72.9%, and at 5th year was 65.2%. The median survival time for multiple myeloma (MM) was 40 months, and for acute leukemia (AL) 73 months. The OS rate for MM patients at 1st year was 90%, at 3rd year was 67.5%; The OS rate for AL patients at 1st year was 85.7%, at 3rd year was 65.3%, and at 8th year was 43.6%; For lymphoma patients the OS rate at 1st year was 84.6%, at 3rd year was 78.6%, at 5th year was 71.4%. No significant difference was found among the 3 groups.
The total disease free survival (DFS) at 1st year was 62.2%, at 3rd year was 51.6%, and at 5th year was 38.8%. The median disease-free survival time for MM was 23 months, for acute leukemia 43 months and for lymphoma 52 months. The DFS rate for MM patients at 1st year was 63.6%, at 3rd year was 31.8%; for AL patients the DFS rate at 1st year was 63%, at 3rd year was 52.5%, and at 5th year was 39.4%; For lymphoma patients at 1st year was 62.4%, at 3rd year was 52.9%, at 5th year was 45.3%. No significant difference was found among the three groups.
CD4~+ T cells number and NK cells number in 6 months after transplantation were correlated with clinical outcome with statistical significance. The higher numbers of CD4~+ cells or NK was, the better outcome would probably be. Whether TBI was included in preparative regimen correlate with clinical outcome also, Group of not including TBI seemed to have a better outcome.
Conclusion
1. Chemotherapy with G-CSF could effectively mobilize efficent peripheral blood stem cells in patients with heamotologic malignancy for auto-PBSCT. Time for ANC and PLT recovery correlated negatively with the number of CD34~+ cells transplanted. Suggest to transfuse at least 2×10~6/kg to accelerate reconstitution of hemopoiesis.
2. Complications during transplantation period included symptoms of digestive、fever、mucositis、bleeding inclination、hypohepatia and so on. But they were well tolerated. Pathogens of infections usually were gram negative bacilli. Virus and fungus infection also can occur and be worthy of paying attention to.
3. The median overall survival time after Auto-PBSCT for MM was 40 months, for AL was 73 months. The median DFS time for MM was 23 months, for AL was 43 months, and for lymphoma was 52 months. The OS and DFS rate for these 3 groups at 1st year separately were: MM 90% and 63.6%, AL 85.7% and 63%, lymphoma 84.6% and 62.4%. No significant difference was found among the three groups.
4. CD4~+ T cells numbers in 6 months following transplantation correlated with clinical outcome with statistical significance. The Higher numbers of CD4~+ cells were, the better outcomes would probably be. And a better recovery of NK cells after transplantation may have good effect on OS and DFS.
5. Selection of CD34+ stem cells in vitro may not affect relapse rate. Source of relapse probably is the residual tumor cells in patients' body.
6. Sustained treatment probably has no benefit to avoid relapse.
7. Including TBI in preparative regime seemed to have a worse outcome.
造血干细胞移植为血液系统恶性疾病的治疗带来了革命性的转变。在近二十年间，随着重组粒细胞集落刺激因子的广泛应用和外周血细胞采集分选技术的完善，自体外周血造血干细胞移植已基本取代了自体骨髓移植在多种恶性血液系统疾病中得以广泛应用。自体外周造血干细胞也成为移植所需干细胞的主要来源。但自体移植前后尚存在诸多问题有待更多的经验积累，如影响动员和采集成败的因素，回输适宜的干细胞数目，移植相关并发症及死亡，移植中的高复发率，远期生存如何等。各中心报道结论不尽相同。
目的
探讨自体外周造血干细胞移植在血液系统恶性疾病中的治疗作用，包括动员的有效性、造血的重建、预处理的毒性和耐受性，以及移植后的转归和远期生存。
方法
回顾性分析了1996～2005年间在我院进行自体造血干细胞移植的94例血液系统恶性疾病患者，涉及的疾病包括急性白血病、霍奇金淋巴瘤和非霍奇金淋巴瘤以及多发性骨髓瘤等常见血液系统恶性疾病，收集临床资料，随访远期预后，用统计学软件加以分析。
结果
Auto-PBSCT多数患者经过化疗+G-CSF(5～10ug／kg．d)的动员后，连续采集1～3天可获得MNC(5.27±3.76)×10~8／kg，CD34+细胞(8.08±7.46)×10~6／kg。回输CD34~+细胞(4.61±4.13)×10~6／kg可有效重建造血，ANC恢复至500／ul以上中位时间为d+10，PLT恢复至20000／ul以上无需输注的中位时间为d+13，ANC和PLT恢复时间与回输的CD34~+细胞数呈负相关(r=-0.324和-0.338，p=0.002和0.002)，且不受G-CSF加用时间的限制。回输的CD34~+细胞≥2×10~6／kg时，ANC恢复时间和PLT恢复时间不再随回输的CD34~+细胞增多而进一步缩短(r=-0.176和-0.185，p=0.097和0.099)。
移植期间常见的不良事件有消化道症状、发热、口腔溃疡、出血倾向、肝功异常等，多可耐受。移植期间合并感染常见为革兰氏阴性杆菌感染，病毒和真菌亦可见；急性间质性肺炎、出血性膀胱炎和植入失败者少见。未发现肝小静脉阻塞者。
88.3％(83人)进行了随访，中位随访时间为17.5月，51.8％移植后病情稳定，44.6％复发，22.9％死亡，死因主要为原发病复发进展，复发主要集中在移植后1年内，占70.3％。回输了体外分选的CD34~+干细胞者占16.9％，未发现分选对复发有显著影响。
移植后1年的总生存率为85.6％，3年总生存为72.9％，5年为65.2％。根据原发病分组，则多发性骨髓瘤(MM)患者移植后中位生存期为40个月，其1年总生存率为90％，3年OS为67.5％；急性白血病(AL)患者移植后中位生存期为73个月，其1年的总生存率为85.7％，3年为65.3％，8年为43.6％；淋巴瘤患者(包括NHL和HL)移植后1年总生存率为84.6％，3年为78.6％，5年为71.4％，并可观察到平台期。未发现各组间有显著差异。
Auto-PBSCT后1年总的无病生存率(DFS)为62.2％，3年总DFS为51.6％，5年为38.8％。MM患者移植后中位无病生存时间为23个月，其1年DFS为63.6％，3年DFS为31.8％；AL患者移植后中位无病生存时间为43个月，1年DFS为63％，3年DFS为52.5％，5年为39.4％；淋巴瘤患者移植后中位无病生存时间为52个月，1年内的DFS为62.4％，3年DFS为52.9％，5年为45.3％。
移植后半年内的CD4~+细胞计数和NK细胞计数与转归相关，CD4~+细胞和NK细胞恢复较好者预后相对较好。预处理方案含有TBI对OS和DFS有不利影响。
结论
1．经过化疗+G-CSF可对血液系统恶性疾病患者进行有效动员，并从外周血采集出足量的造血干细胞用于自体造血干细胞移植以重建造血，Auto-PBSCT回输的CD34~+细胞在应≥2×10~6／kg，有利于快速重建造血；
2．移植期间相关并发症如消化道症状、发热、口腔溃疡、出血倾向、肝功异常等发生率较高但多可耐受。移植期间合并感染常见为革兰氏阴性杆菌感染，病毒和真菌亦可见，持续高热常规抗细菌治疗无效应考虑真菌、病毒感染或混合感染可能；
3．Auto-PBSCT后的中位生存期MM为40个月，AL为73个月，中位无病生存期MM为23个月；AL为43个月，淋巴瘤为52个月。1年时的总生存和无病生存各组分别为：MM 90％和63.6％，急性白血病85.7％和63％，淋巴瘤84.6％和62.4％。各组之间无显著差异。
4．移植后半年内的CD4~+细胞计数与转归相关，CD4~+细胞恢复较好者预后相对较好。预处理方案是否含有TBI未发现与转归相关；移植后半年内的NK细胞恢复较好者可能对预后和无病生存有有利影响。
5．复发与是否分选无明显相关，复发的根源可能主要是患者体内残留的肿瘤细胞。
6．移植后维持治疗未发现对防止复发有有利影响。
7．预处理含有TBI者预后不良。
Background
Hematopoietic stem cell transplantation changed revolutionarily the conventional chemo-radio therapeutic mode of hematologic malignancies. In the past two decades, with the wide-spread application of G-CSF and the improved techniques of harvesting and selecting of blood stem cells, autologous peripheral blood stem cell (PBSC) transplantation has substituted traditional autologous bone marrow stem cell transplantation. And PBSC has been widely used in the transplantation therapy of many hematologic malignancies as the main source of hematopoietic stem cells. Yet there are still many controversial questions about transplantation, such as factors affecting mobilization and harvesting, the appropriate numbers of stem cells to transplant, complications and death associated with transplantation, relapse rate and long term survival and so on. Since different centers report inconsistent results, we need accumulate more experience to find our own answer.
Objectives
To explore the therapeutic effects of ASCT in treating hematologic malignancies, and to investigate the efficacy of mobilization and harvesting of peripheral blood stem cells, reconstition of hematopoiesis, toxicity and tolerance of preparative regimens and clinical outcomes of auto-PBSCT.
Methods
During the 10 years between 1996 and 2005, 94 patients underwent auto-PBSCT who were diagnosed as hematologic malignancies including acute and chronic leukemia, iymphoma (Hodgkin's and non-Hodgkin's) and multiple myeloma. Their clinical information and follow-up conditions were collected, and retrospective statistics analysis methods were used to explore the regularity.
Results
For patients that underwent auto-PBSCT, most could be harvested enough stem cells after 1 mobilization which is comprised of chemotherapy and G-CSF. After consecutive harvesting for 1～3 days, (5.27±3.76)×10~8/kg MNC and (8.08+7.46)×10~6/kg CD34~+ could be obtained. (4.61±4.13)×10~6/kg CD34~+ were reinfused and reconstituted hemopoiesis effectively. The median time for ANC＞500/ul was at d+10, and the median time for PLT＞20000/ul free of transfusion was at d+13. Time for ANC and PLT recovery correlates negatively with the number of CD34~+ stem cells reinfused (r=-0.324 and -0.338, p=0.002 and 0.002). And this relation was not restricted by the time G-CSF was prescribed. But when more than 2×10~6/kg CD34~+ cells were reinfused, the speed of hemopoiesis recovery did not correlate with the number of CD34~+ cells reinfused any longer (r=-0.176 and -0.185, p=0.097 and 0.099).
Complications during transplantation included symptoms of digestive、fever、mucositis, bleeding inclination, hypohepatia and so on. They were tolerated well. Most of the pathogens responsible for infections were gram negative bacilli. Interstitial pneumonitis, hemorrhagic cystitis and graft failure were rare. No veno-occlusion disease occurred.
Totally 88.3% (n=83) patients received follow-up after transplantation. The median time of follow-up was 17.5 months. During follow-up, 51.8% maintained stable or CR, 44.6% relapsed, and 22.9% died. The main cause of death was the progression or relapses of original diseases. 70.3% of the relapses occurred in the 1st year after transplantation. 16.9% patients were transplanted with in vitro manipulated CD34~+ stem cells. But no significant effects were found on relapse.
The overall survival (OS) rate at 1st year was 85.6%, at 3rd year was 72.9%, and at 5th year was 65.2%. The median survival time for multiple myeloma (MM) was 40 months, and for acute leukemia (AL) 73 months. The OS rate for MM patients at 1st year was 90%, at 3rd year was 67.5%; The OS rate for AL patients at 1st year was 85.7%, at 3rd year was 65.3%, and at 8th year was 43.6%; For lymphoma patients the OS rate at 1st year was 84.6%, at 3rd year was 78.6%, at 5th year was 71.4%. No significant difference was found among the 3 groups.
The total disease free survival (DFS) at 1st year was 62.2%, at 3rd year was 51.6%, and at 5th year was 38.8%. The median disease-free survival time for MM was 23 months, for acute leukemia 43 months and for lymphoma 52 months. The DFS rate for MM patients at 1st year was 63.6%, at 3rd year was 31.8%; for AL patients the DFS rate at 1st year was 63%, at 3rd year was 52.5%, and at 5th year was 39.4%; For lymphoma patients at 1st year was 62.4%, at 3rd year was 52.9%, at 5th year was 45.3%. No significant difference was found among the three groups.
CD4~+ T cells number and NK cells number in 6 months after transplantation were correlated with clinical outcome with statistical significance. The higher numbers of CD4~+ cells or NK was, the better outcome would probably be. Whether TBI was included in preparative regimen correlate with clinical outcome also, Group of not including TBI seemed to have a better outcome.
Conclusion
1. Chemotherapy with G-CSF could effectively mobilize efficent peripheral blood stem cells in patients with heamotologic malignancy for auto-PBSCT. Time for ANC and PLT recovery correlated negatively with the number of CD34~+ cells transplanted. Suggest to transfuse at least 2×10~6/kg to accelerate reconstitution of hemopoiesis.
2. Complications during transplantation period included symptoms of digestive、fever、mucositis、bleeding inclination、hypohepatia and so on. But they were well tolerated. Pathogens of infections usually were gram negative bacilli. Virus and fungus infection also can occur and be worthy of paying attention to.
3. The median overall survival time after Auto-PBSCT for MM was 40 months, for AL was 73 months. The median DFS time for MM was 23 months, for AL was 43 months, and for lymphoma was 52 months. The OS and DFS rate for these 3 groups at 1st year separately were: MM 90% and 63.6%, AL 85.7% and 63%, lymphoma 84.6% and 62.4%. No significant difference was found among the three groups.
4. CD4~+ T cells numbers in 6 months following transplantation correlated with clinical outcome with statistical significance. The Higher numbers of CD4~+ cells were, the better outcomes would probably be. And a better recovery of NK cells after transplantation may have good effect on OS and DFS.
5. Selection of CD34+ stem cells in vitro may not affect relapse rate. Source of relapse probably is the residual tumor cells in patients' body.
6. Sustained treatment probably has no benefit to avoid relapse.
7. Including TBI in preparative regime seemed to have a worse outcome.
引文
1.M. Korbling, D. Przepiorka, Y.O. Huh, et al. Allogeneic Blood Stem Cell transplantation for Refractory Leukemia and Lymphoma: Potential Advantage of Blood Over Marrow Allografts. Blood, Vol 85, No 6 (March 15), 1995: pp 1659-1665.
2. H.D. Ottinger, D.W. Beelen, B. Scheulen, et al. Improved Immune Reconstitution After Allotransplantation of Peripheral Blood Stem Cells Instead of Bone Marrow. Blood, Vol 88, No 7 (October 1). 1996: pp 2775-2779.
3.Lee J, Lee MH, Park KW et al. Influential factors for the collection of peripheral blood stem cells and engraftment in acute myeloid leukemia patients in first complete remission. Int J Hematol. 2005 Apr;81(3):258-63.
4.Villalon L, Odriozola J, Larana JG et al. Autologous peripheral blood progenitor cell transplantation with <2 x 10(6) CD34 (+)/kg: an analysis of variables concerning mobilisation and engraftment. Hematol J. 2000; 1(6):374-81.
5. Schouten HC, Qian W, Kvaloy, et al. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP trial. J Clin Oncol 2003,21:3918-27.
6. Gondo H, Harada M, Miyamoto T, Autologous peripheral blood stem cell transplantation for acute myelogenous leukemia. Bone Marrow Transplant. 1997 Nov; 20(10):821-6.
7. Nademanee A, Forman SJ, Role of hematopoietic stem cell transplantation for advanced-stage diffuse large cell B-cell lymphoma. Semin Hematol. 2006 Oct; 43(4): 240-250.
8. Mundt AJ, Williams SF, Hallahan D. High dose chemotherapy and stem cell rescue for aggressive non-Hodgkin's lymphoma: pattern of failure and implications for involved-field radiotherapy. Int J Radiat Oncol Biol Phys.
9.N.C. Gorin. Autologous stem cell transplantation in hematological malignancies. Springer Semin Immun. 2004 26:3-30.
10. Kim H, Sohn HJ, Kim SE. et al. Lymphocyte recovery as a positive predictor of prolonged survival after autologous peripheral blood stem cell transplantation in T-cell non-Hodgkin's lymphoma. Bone Marrow Transplant. 2004 Jul; 34(1):43-9.
11. Yeh SP, Chiu CF, Lo WJ, et al. Low infectious morbidity in patients with heavily pretreated hematological malignancies receiving autologous peripheral blood stem cell transplantation without antimicrobial prophylaxis. Ann Hematol. 2003 Jan; 82(1):24-9.
1.Philip T, Guglielmin C, Hagenbeeb A, et al; Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. New Engl J Med. 1995, 333:1540-5.
2.Blay J, Gomez F, Sebban C, et al. The international prognostic index correlates to survival in patients with aggressive lymphoma in relapse: analysis of the PRAMA trial. Parma Group. Blood 1998, 92:3562-8.
3.Milpied N, Deconinck E, Gaillard F, et al. Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 2004, 350: 1287-95.
4.Martelli M, Gherlinzoni F, De Renzo A, et al. Early autologous stem cell transplantation vesus conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin's lymphoma: an Italian muticenter randomized trial. J Clin Oncol 2003; 21: 1255-62.
5.Gianni AM, Bregni M, Siena S, et al. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOPB in aggressive B-cell lymphoma. N Engl Med 1997, 336:1290.
6.Hauoun C, Lepage E, Gisselbreche C, et al. Suvival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin's lymphoma: final analysis of the prospective LNH87-2 protocol. J Clin Oncol 2000; 18: 3025-30.
7. Santini G, Salvagno L, Leoni P et al. VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group. J Clin Oncol 1998; 16:2796-2802.
8.Schouten HC, Qian W, Kvaloy, et al. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP trial. J Clin Oncol 2003, 21:3918-27.
9.N.C. Gorin. Autologous stem cell transplantation in hematological malignancies. Springer Semin Immun. 2004 26:3-30.
10.Yuen AR, Rosenberg SA, Hoppe RT, et al. Comparison between conventional salvage therapy and high-dose therapy with autografting for recurrent or refractory Hodgkin's disease. Blood 1997,89:814-22.
11.Schmitz N, Sextro M, Pfistner B, et al. High-dose therapy (HDT) followed by hematopoietic stem cell transplantation (HSCT) for relapsed chemosensitive Hodgkin's disease (HD): final results of a randomized GHSG and EBMT trial (HD-R1). Proc Annu Meet Am Soc Clin Oncol. 1999; 18:2a.
12.Bradley SJ, Pearce R,Taghipour G, et al. First remission autologous bone marrow transplantation for Hodgkin's disease: preliminary EBMT data. Leuk Lymphoma. 1995;15(suppl 1):51-53.
13.Carella AM, Prencipe E, Pungolino E, et al. Twelve years experience with highdose therapy and autologous stem cell transplantation for high-risk Hodgkin's disease patients in first remission after MOPP/ABVD chemotherapy. Leuk Lymphoma. 1996;21:63-70.
14.Sureda A, Mataix R, Hernandez- Navarro F, et al. Autologous stem cell transplantation for poor prognosis Hodgkin's disease in first complete remission: a retrospective study from the Spanish GEL-TAMO cooperative group. Bone Marrow Transplant. 1997;20:283-288.
15. Nademanee A, Molina A, Fung H, et al. High-dose chemo/radiotherapy and autologous bone marrow or stem cell transplantation for poor-risk advanced stage Hodgkin's disease during first partial or complete remission. Biol Blood Marrow Transplant. 1999;5:292-298.
16. Andre M, Henry-Amar M, Blaise D, et al. Treatment-related deaths and second cancer risk after autologous stem-cell transplantation for Hodgkin's disease. Blood. 1998; 92:1933-1940.
17.Donna E. Reece, MD. Evidence- based management of Hodgkin's disease: the role of autologous stem cell transplantation. Cancer Control May/June 2000, Vol. 7, No.3 266-75.
18.AttaI M, Harousseau JL, Stoppa AM, et al. A prospective randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335:1844-1845.
19.Harousseau JL, Shaughnessy J Jr, Richardson P. Multiple myeloma. Hematology Am Soc Hematol Educ Program. 2004: 237-56.
20.Attal M, Harousseau JL, Stoppa AM, et al. A prospective randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med,335-91.
21.Vesole DH, Barlogie B, Jagannath S, et al. High-dose therapy for refractory MM: improved prognosis with better supportive care and double transplants. Blood 1994, 84, 950.
22. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 2003, 349: 2495.
23.Fassas AB, Spencer T, Desikan R, et al. Cytotoxic chemotherapy following tandem autotransplants in multiple myeloma patients. Br J Haematol 2002, 119: 164.
24.Fassas AB, Spencer T, Swyer L, et al. Both hypodiploidy and deletion of chromosome 13 independently confer poor prognosis in multiple myeloma. Br J Haematol 2002, 118:1041.
25. Tosi P, Zamagni E, Cellini C, et al. Thalidomide alone or in combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma and renal failure. Eur J Haematol 2004, 73:98.
26. Zittoun RA, Mandelli F, Willemze R, et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med. 1995;332:217-223.
27. Harousseau JL, Cahn JY, Pignon B, et al. Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. Blood. 1997;90:2978-2986.
28. Burnett AK, Goldstone AH, Stevens RMF, et al. Randomised comparison of addition of autologous bone marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. Lancet. 1998;351:700-708.
29. Cassileth PA, Harrington DP, Appelbaum FR, et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med. 1998;339:1649-1656.
30. Slovak ML, Kopecky KJ, Cassileth PA. et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adults acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000, 96: 4075.
31.Linker, CA Ries, CA Damon, et al. Autologous stem cell transplantation for acute myeloid leukemia in first remission. Biol Blood Marrow Transplant 2000, 6:50.
32.Suciu S, Mandelli F, Witte T de, et al. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMRMA AML-10 trial. Blood 2003, 102: 1232.
33.Ringden O, Labopin M, Frassoni F, et al. Allogeneic bone marrow transplant or second auto-graft in patients with acute leukemia who relapse after an autograft. Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation(EBMT). Bone Marrow Transplantation. 1999, 24:389.
34.Gorin NC, Labopin M, Pichard P et al. Feasibility and recent improvement of autologous stem cell transplantation for acute myelocytic leukemia in patients over 60 years of age: importance of the source of stem cells. Br J haematol 2000, 110:887.
35. Meloni G, Proia A, Capria S, et al. Obesity and autologous stem cell transplantation in acute myeloid leukemia. Bone Marrow Transplat. 2001,28: 365.
36. Messina C, Valsecchi MG, Arico M, et al. Autologous bone marrow transplantation for treatment of isolated central nervous system relapse of childhood acute lymphoblastic leukemia. AIEOP/FONOP-TMO group. Associazione Italiana Emato-Oncologia Pediatrica. Bone Marrow Transplant. 1998,21:9.
37. Fiere D, Lepage E, Sebban C, et al. Adult acute lymphoblastic leukemia: a multicentric randomized trial testing bone marrow transplantation as postremission therapy. The French Group on Therapy for Adult Lymphoblastic leukemia. J Clin Oncol 1993,11:1990-2001.
38. Gorin NC, Aegerter P, Auvert B. Autologous bone marrow transplantation for acute leukemia in remission: an analysis of 1322 cases. Haematol Blood Transfus 1990,33: 660-666.
39.Simonsson B, Burnett AK, Prentice HG, et al. Autologous bone marrow transplantation with monoclonal antibody purged marrow for high risk acute lymphoblastic leukemia. Leukemia 1989,3: 631-636.
40.Doney K, Buckner CD, Fisher L, et al. Autologous bone marrow transplantation for acute lymphobalstic leukemia. Bone Marrow Transplant 1993, 12: 315-321.
41. Powles R, Sirohi B, Treleaven J, et al. The role of posttransplantation maintenance chemotherapy in improving the outcome of autotransplantation in adult acute lymphobalstic leukemia. Blood 2002,100:1641-1647.
42. Mizuta S, Ito Y, Kohno A, et al. Accurate quantitation of residual tumor burden at bone marrow harvest predicts timing of subsequent relapse in patients with common ALL treated by autologous bone marrow transplantation. Nagoya BMT Group. Bone Marrow Tranplant 1999,24:77-784.
43. Thomas DA, kantarjian H, Smith TL, et al. Primary refractory and relapsed adult acute lymphoblastic leukemia: characteristics, treatment results, and prognosis with salvage therapy. Cancer 1999,86:1216-1230.
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4. Hannum Ch, Wilcox CJ, Arend WP et al. Nature, 1990, 343: 336-340.
5. Antin JH, Weisdorf D, Neuberg D et al. Blood, 2002, 100: 3479-3482.
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3.Lee J, Lee MH, Park KW et al. Influential factors for the collection of peripheral blood stem cells and engraftment in acute myeloid leukemia patients in first complete remission. Int J Hematol. 2005 Apr;81(3):258-63.
4.Villalon L, Odriozola J, Larana JG et al. Autologous peripheral blood progenitor cell transplantation with <2 x 10(6) CD34 (+)/kg: an analysis of variables concerning mobilisation and engraftment. Hematol J. 2000; 1(6):374-81.
5. Schouten HC, Qian W, Kvaloy, et al. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP trial. J Clin Oncol 2003,21:3918-27.
6. Gondo H, Harada M, Miyamoto T, Autologous peripheral blood stem cell transplantation for acute myelogenous leukemia. Bone Marrow Transplant. 1997 Nov; 20(10):821-6.
7. Nademanee A, Forman SJ, Role of hematopoietic stem cell transplantation for advanced-stage diffuse large cell B-cell lymphoma. Semin Hematol. 2006 Oct; 43(4): 240-250.
8. Mundt AJ, Williams SF, Hallahan D. High dose chemotherapy and stem cell rescue for aggressive non-Hodgkin's lymphoma: pattern of failure and implications for involved-field radiotherapy. Int J Radiat Oncol Biol Phys.
9.N.C. Gorin. Autologous stem cell transplantation in hematological malignancies. Springer Semin Immun. 2004 26:3-30.
10. Kim H, Sohn HJ, Kim SE. et al. Lymphocyte recovery as a positive predictor of prolonged survival after autologous peripheral blood stem cell transplantation in T-cell non-Hodgkin's lymphoma. Bone Marrow Transplant. 2004 Jul; 34(1):43-9.
11. Yeh SP, Chiu CF, Lo WJ, et al. Low infectious morbidity in patients with heavily pretreated hematological malignancies receiving autologous peripheral blood stem cell transplantation without antimicrobial prophylaxis. Ann Hematol. 2003 Jan; 82(1):24-9.
1.Philip T, Guglielmin C, Hagenbeeb A, et al; Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. New Engl J Med. 1995, 333:1540-5.
2.Blay J, Gomez F, Sebban C, et al. The international prognostic index correlates to survival in patients with aggressive lymphoma in relapse: analysis of the PRAMA trial. Parma Group. Blood 1998, 92:3562-8.
3.Milpied N, Deconinck E, Gaillard F, et al. Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 2004, 350: 1287-95.
4.Martelli M, Gherlinzoni F, De Renzo A, et al. Early autologous stem cell transplantation vesus conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin's lymphoma: an Italian muticenter randomized trial. J Clin Oncol 2003; 21: 1255-62.
5.Gianni AM, Bregni M, Siena S, et al. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOPB in aggressive B-cell lymphoma. N Engl Med 1997, 336:1290.
6.Hauoun C, Lepage E, Gisselbreche C, et al. Suvival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin's lymphoma: final analysis of the prospective LNH87-2 protocol. J Clin Oncol 2000; 18: 3025-30.
7. Santini G, Salvagno L, Leoni P et al. VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group. J Clin Oncol 1998; 16:2796-2802.
8.Schouten HC, Qian W, Kvaloy, et al. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP trial. J Clin Oncol 2003, 21:3918-27.
9.N.C. Gorin. Autologous stem cell transplantation in hematological malignancies. Springer Semin Immun. 2004 26:3-30.
10.Yuen AR, Rosenberg SA, Hoppe RT, et al. Comparison between conventional salvage therapy and high-dose therapy with autografting for recurrent or refractory Hodgkin's disease. Blood 1997,89:814-22.
11.Schmitz N, Sextro M, Pfistner B, et al. High-dose therapy (HDT) followed by hematopoietic stem cell transplantation (HSCT) for relapsed chemosensitive Hodgkin's disease (HD): final results of a randomized GHSG and EBMT trial (HD-R1). Proc Annu Meet Am Soc Clin Oncol. 1999; 18:2a.
12.Bradley SJ, Pearce R,Taghipour G, et al. First remission autologous bone marrow transplantation for Hodgkin's disease: preliminary EBMT data. Leuk Lymphoma. 1995;15(suppl 1):51-53.
13.Carella AM, Prencipe E, Pungolino E, et al. Twelve years experience with highdose therapy and autologous stem cell transplantation for high-risk Hodgkin's disease patients in first remission after MOPP/ABVD chemotherapy. Leuk Lymphoma. 1996;21:63-70.
14.Sureda A, Mataix R, Hernandez- Navarro F, et al. Autologous stem cell transplantation for poor prognosis Hodgkin's disease in first complete remission: a retrospective study from the Spanish GEL-TAMO cooperative group. Bone Marrow Transplant. 1997;20:283-288.
15. Nademanee A, Molina A, Fung H, et al. High-dose chemo/radiotherapy and autologous bone marrow or stem cell transplantation for poor-risk advanced stage Hodgkin's disease during first partial or complete remission. Biol Blood Marrow Transplant. 1999;5:292-298.
16. Andre M, Henry-Amar M, Blaise D, et al. Treatment-related deaths and second cancer risk after autologous stem-cell transplantation for Hodgkin's disease. Blood. 1998; 92:1933-1940.
17.Donna E. Reece, MD. Evidence- based management of Hodgkin's disease: the role of autologous stem cell transplantation. Cancer Control May/June 2000, Vol. 7, No.3 266-75.
18.AttaI M, Harousseau JL, Stoppa AM, et al. A prospective randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335:1844-1845.
19.Harousseau JL, Shaughnessy J Jr, Richardson P. Multiple myeloma. Hematology Am Soc Hematol Educ Program. 2004: 237-56.
20.Attal M, Harousseau JL, Stoppa AM, et al. A prospective randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. N Engl J Med,335-91.
21.Vesole DH, Barlogie B, Jagannath S, et al. High-dose therapy for refractory MM: improved prognosis with better supportive care and double transplants. Blood 1994, 84, 950.
22. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 2003, 349: 2495.
23.Fassas AB, Spencer T, Desikan R, et al. Cytotoxic chemotherapy following tandem autotransplants in multiple myeloma patients. Br J Haematol 2002, 119: 164.
24.Fassas AB, Spencer T, Swyer L, et al. Both hypodiploidy and deletion of chromosome 13 independently confer poor prognosis in multiple myeloma. Br J Haematol 2002, 118:1041.
25. Tosi P, Zamagni E, Cellini C, et al. Thalidomide alone or in combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma and renal failure. Eur J Haematol 2004, 73:98.
26. Zittoun RA, Mandelli F, Willemze R, et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med. 1995;332:217-223.
27. Harousseau JL, Cahn JY, Pignon B, et al. Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. Blood. 1997;90:2978-2986.
28. Burnett AK, Goldstone AH, Stevens RMF, et al. Randomised comparison of addition of autologous bone marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. Lancet. 1998;351:700-708.
29. Cassileth PA, Harrington DP, Appelbaum FR, et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med. 1998;339:1649-1656.
30. Slovak ML, Kopecky KJ, Cassileth PA. et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adults acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 2000, 96: 4075.
31.Linker, CA Ries, CA Damon, et al. Autologous stem cell transplantation for acute myeloid leukemia in first remission. Biol Blood Marrow Transplant 2000, 6:50.
32.Suciu S, Mandelli F, Witte T de, et al. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMRMA AML-10 trial. Blood 2003, 102: 1232.
33.Ringden O, Labopin M, Frassoni F, et al. Allogeneic bone marrow transplant or second auto-graft in patients with acute leukemia who relapse after an autograft. Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation(EBMT). Bone Marrow Transplantation. 1999, 24:389.
34.Gorin NC, Labopin M, Pichard P et al. Feasibility and recent improvement of autologous stem cell transplantation for acute myelocytic leukemia in patients over 60 years of age: importance of the source of stem cells. Br J haematol 2000, 110:887.
35. Meloni G, Proia A, Capria S, et al. Obesity and autologous stem cell transplantation in acute myeloid leukemia. Bone Marrow Transplat. 2001,28: 365.
36. Messina C, Valsecchi MG, Arico M, et al. Autologous bone marrow transplantation for treatment of isolated central nervous system relapse of childhood acute lymphoblastic leukemia. AIEOP/FONOP-TMO group. Associazione Italiana Emato-Oncologia Pediatrica. Bone Marrow Transplant. 1998,21:9.
37. Fiere D, Lepage E, Sebban C, et al. Adult acute lymphoblastic leukemia: a multicentric randomized trial testing bone marrow transplantation as postremission therapy. The French Group on Therapy for Adult Lymphoblastic leukemia. J Clin Oncol 1993,11:1990-2001.
38. Gorin NC, Aegerter P, Auvert B. Autologous bone marrow transplantation for acute leukemia in remission: an analysis of 1322 cases. Haematol Blood Transfus 1990,33: 660-666.
39.Simonsson B, Burnett AK, Prentice HG, et al. Autologous bone marrow transplantation with monoclonal antibody purged marrow for high risk acute lymphoblastic leukemia. Leukemia 1989,3: 631-636.
40.Doney K, Buckner CD, Fisher L, et al. Autologous bone marrow transplantation for acute lymphobalstic leukemia. Bone Marrow Transplant 1993, 12: 315-321.
41. Powles R, Sirohi B, Treleaven J, et al. The role of posttransplantation maintenance chemotherapy in improving the outcome of autotransplantation in adult acute lymphobalstic leukemia. Blood 2002,100:1641-1647.
42. Mizuta S, Ito Y, Kohno A, et al. Accurate quantitation of residual tumor burden at bone marrow harvest predicts timing of subsequent relapse in patients with common ALL treated by autologous bone marrow transplantation. Nagoya BMT Group. Bone Marrow Tranplant 1999,24:77-784.
43. Thomas DA, kantarjian H, Smith TL, et al. Primary refractory and relapsed adult acute lymphoblastic leukemia: characteristics, treatment results, and prognosis with salvage therapy. Cancer 1999,86:1216-1230.
1. James L. M. Ferrara,, Kenneth R. Cooke, Takanori Teshima. Int. Journal of Hemotology, 2003, 78: 181-187.
2. AbhyankarS, Gilliland DG, Ferrara JLM. Tansplantation, 1993, 56: 1518-1523.
3. Eisenberg SP, Evans RJ, Arend WP et al. Nature, 1990, 343: 341.
4. Hannum Ch, Wilcox CJ, Arend WP et al. Nature, 1990, 343: 336-340.
5. Antin JH, Weisdorf D, Neuberg D et al. Blood, 2002, 100: 3479-3482.
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