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

【作者】 赵丽丹；

【导师】 周道斌；

【作者基本信息】 中国协和医科大学 ， 血液内科学， 2006， 硕士

【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。更多还原

【Abstract】 BackgroundHematopoietic 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.ObjectivesTo 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.MethodsDuring 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.ResultsFor 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.Conclusion1. 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.更多还原