四种不同的同种异基因移植法治疗第一慢性期慢性粒细胞白血病患者嵌合现象和微小白血病残留的比较研究

最近,陆续出现了代替传统骨髓移植(BMT)和外周血千细胞移植(PBSCT)的新的治疗血液系统恶性肿瘤的异基因移植方法,其中之一是Slavin等报道的减量预处理后PBSCT,此种移植的特征为预处理过程对相关器官的毒性降低,从而使患者对移植的耐受性增强,同时亦为老年及有严重并发症的患者提供了异基因移植的机会。     

慢性粒细胞白血病的治疗现状及其进展

慢粒白血病(CML)历来沿用烷化剂(如马利兰)和放射治疗等姑息性措施直至80年代仍认为不能治愈.近10年来,由于异基因骨髓移植(allo-BMT)的开展使该病成为可以治愈的恶性血液系统疾患之一.现就慢粒白血病的治疗现况及其进展综述如下:1 异基因骨髓移植1.1 疗效从HLA相配的同胞供者进行allo-BMT的CML患者,其5年无白血病生存率(LFS)为60%～70%,移植相关的死亡率20%,复发15%.据国际和欧洲骨髓移植登记处(IBMTR 1426例和EBMT 1082例)长期随访的结果,接受allo-BMT的CML患者5年无事故生存(EFS)率达40%～45%.450例CML慢性期患者进行非去除T细胞的BMT,其5年EFS约50%.虽然相当数量的CML患者BMT后复发,但仍对生存期产生有利的影响.Arcese等分析130例CML慢性期接受allo-BMT后复发的患者其6年生存可能性为36%.29例进行第2次BMT的CML患者其预计4年生存率约28%.189例慢性早期CML移植的患者(从诊断起12个月之内)4年EFS率60%,生存率80%.     

联合克拉屈滨预处理方案在难治/复发性急性髓系白血病患者异基因造血干细胞移植中的疗效观察

目的:评价联合克拉屈滨预处理方案在异基因造血干细胞移植（allo-HSCT）治疗难治/复发性急性髓系白血病（AML）中的疗效。方法:收集并分析2017年4月至2019年10月在我院层流病房行联合克拉屈滨预处理方案并行异基因造血干细胞移植治疗的17例难治/复发性AML患者的临床资料。结果:17例患者均完成造血重建,粒细胞植入中位时间为12(9~20）d,血小板植入中位时间为11(9~30)d。预处理过程中,1例患者出现出血性膀胱炎。4例出现Ⅰ-Ⅱ级急性移植物抗宿主病（aGVHD),随访结束时,11例存活患者中有8例出现局限型慢性移植物抗宿主病（cGVHD)。5例患者于移植后复发,中位复发时间为4（2~19）月。1年总生存率为57.2％,1年无病生存率为55.2％。结论:联合克拉屈滨预处理方案近期疗效较好,在不增加预处理相关不良反应的前提下,可有效提高患者生存率,改善患者的预后。     

全身照射方法在白血病治疗中的应用现况

全身照射(total body irradiation,TBI)是放疗特殊照射方法之一.自1959年Thomas第1次用TBI预处理方案成功完成了第1例移植后,40多年来TBI因其独特作用已成为异基因和白体基因移植的重要常规治疗的一部分,用于配合化学治疗和骨髓移植或外周血干细胞移植治疗白血病和某些晚期已经全身转移的对放射较敏感的恶性肿瘤.     

外周血造血干细胞移植治疗恶性血液病53例

背景与目的:造血干细胞移植使恶性血液病的预后得到很大的改观,外周血造血干细胞移植(transplantation of peripheral blood stem cells,PBSCT)逐渐取代了骨髓移植(bone marrow transplantation,BMT)而成为造血干细胞移植的主要方式.本研究观察了自体或异基因外周血造血干细胞移植对53例恶性血液病患者的治疗效果.方法:53例恶性血液病患者于2003年7月～2006年5月在郑州大学第一附属医院血液科接受PBSCT治疗,中位年龄37岁.采用G-CSF或化疗联合G-CSF动员外周血干细胞.自体移植患者接受CD34 细胞的中位数为3.0×106/kg,异基因移植患者接受CD34 细胞的中位数为6.2×106/kg;自体移植采用MAC预处理方案,异基因移植采用改良的Bu/Cy预处理方案;移植物抗宿主病(graft versus host disease,GVHD)的预防采用MTX、环孢菌素A联合骁悉,1例1个点不合患者加用抗淋巴细胞球蛋白.结果:移植后中性粒细胞≥0.5×109/L、血小板≥20×109/L的天数在自体移植中分别为13天和19天,在异基因移植中分别为12天和15天;异基因移植中Ⅰ～Ⅲ度急性GVHD(aGVHD)的发生率为31.4%,慢性GVHD(cGVHD)的发生率为71.4%,复发率在自体移植和异基因移植患者中分别为38.9%和5.7%,700天无病生存率在自体移植和异基因移植患者中分别为57.9%和69.5%.结论:自体和异基因外周血造血干细胞移植均能很快地重建造血,是治疗恶性血液病的重要手段之一.     

外耳道及中耳恶性肿瘤的放射治疗(附68例临床病例分析)

本文收集我院1964年1月至1978年12月有病理证实的外耳道和中耳恶性肿瘤68例。 外耳道、中耳恶性肿瘤五年生存率为47.1％(32/68)十年生存率为(28％)(11/50)。 本文重点讨论外耳道及中耳恶性肿瘤的治疗方法、疗效和影响放射治疗疗效因素,治疗方式:单纯放射治疗、术后放疗二组五年生存率均为47.1％(16/34)。剂量:单纯放射治疗和术后放疗最适宜剂量似乎以5000—6000rads/4—6周为好,此处还讨论其它影响疗效因素。     

鼻咽癌局部复发分次立体定向放射治疗

目的　探讨分次立体定向放射治疗技术 ,在局部复发晚期鼻咽癌再程放疗中的应用。方法　 1997年 7月到 2 0 0 0年12月 ,采用分次立体定向放射治疗局部复发鼻咽癌 2 3例。所有病例均采用 6MVX线照射 ,设 1～ 3个中心 ,80 %剂量曲线将靶区完全包含。总剂量DT2 4～ 64Gy(中位剂量 5 2 .2Gy) ,单次剂量DT4～ 8Gy(中位剂量 6.4Gy)。 结果　局部复发鼻咽癌经分次立体定向放射治疗后 ,1年生存率为 78.3 % (18/2 3 )、2年生存率为 69.6% (16/2 3 )。 3 9.1% (9/2 3 )的患者随访期内死亡 ,其中死于局部复发 1例 ,死于远处转移 5例 ,鼻咽大出血 3例。结论　分次立体定向放射治疗用于局部复发鼻咽癌的治疗是安全有效的 ,但单次剂量和总剂量值得进一步研究。     

自体骨髓移植治疗急性髓性白血病

目的 :探讨急性髓性白血病患者自体骨髓移植前用 ACE方案预处理 (阿糖胞苷 +环磷酰胺 +鬼臼乙叉苷 )和全身照射 +ACE预处理的疗效。方法 :自体骨髓移植治疗 3例急性髓性白血病 ,1例采用 ACE方案预处理 ,2例用 TBI+ACE方案预处理。结果 :3例均移植成功 ,白细胞≥ 1.0×10 9/L 的时间分别为 +16天 ,+14天 ,+19天 ,血小板 >2 0× 10 9/L 的时间分别为 +17天、+19天、+19天。ACE方案预处理的并发症明显少于全身照射 +ACE预处理。结论 :单用 ACE预处理不影响自体骨髓移植疗效 ,且没有全身照射的毒副作用     

HLA相合同胞供者异基因造血干细胞移植治疗慢性粒细胞白血病的疗效及预后因素分析

目的探讨HLA相合同胞供者异基因造血干细胞移植（allo-HSCT）治疗慢性粒细胞白血病（CML）的疗效及预后因素。方法35例CML患者,11例行HIA相合同胞供者异基因骨髓移植（allo-BMT）,24例行异基因外周血干细胞移植（allo-PBSCT）。全身照射（TBI）＋环磷酰胺（CY）方案预处理8例,白消安（BU）＋CY方案预处理27例。结果造血重建34例（97．1％）,3年无病生存率（DFS）为60．0％,5年累积生存率为57．1％。复发2例,移植相关死亡12例。并发症包括出血性膀胱炎（HC）5例,肝静脉闭塞病（HVOD）1例,急性移植物抗宿主病（GVHD）18例,慢性GVHD 17例。单因素分析显示,年龄≤30岁、慢性期移植、Ⅰ和Ⅱ度急性GVHD患者3年DFS分别高于年龄〉30岁、加速期移植及Ⅲ和Ⅳ度急性GVHD患者。多因素Cox回归分析结果表明,年龄、疾病状态、急性GVHD的严重程度是allo-HSCT患者长期生存的独立影响因素。结论年龄≤30岁、慢性期、轻度GVHD的CML患者行allo-HSCT治疗,可获得较高的长期生存率。     

化疗加后程加速超分割放射治疗食管癌的疗效分析

目的 :评价化疗加后程加速超分割放射治疗食管癌的疗效。方法 :118例食管癌患者 ,随机分为 2组 (化放组与单放组 ) ,每组 5 9例。放疗采用 6MVX线外照射 ,前 2 / 3疗程常规放射治疗 2Gy/次 ,共 4 0Gy ;后 1/ 3疗程改用加速超分割放射治疗 (2次 /天 ,1 35～ 1 4Gy/次 ) ,全疗程总剂量共 6 7～ 6 8Gy ,4 0分次 ,4 0～ 4 2天完成 ;化疗采用FP方案 (5 氟脲嘧啶和顺铂 )。结果 :化放组与单放组的 1、2年生存率分别为 86 4 %、6 9 5 %和 72 9%、5 0 8% (χ2 =3 95 ,4 2 8,P <0 0 5 ) ,其中 3、4年生存率分别为 4 9 2 %、4 2 4 %和 4 0 7%、33 9% (χ2 =0 86 ,0 89,P >0 0 5 )。结论 :化疗加后程加速超分割放射治疗食管癌能提高患者的近期生存率 ,并未增加毒性反应。     

Immediate toxicity during fractionated total body irradiation as conditioning for bone marrow transplantation.

BACKGROUND: Total body irradiation followed by bone marrow transplantation is well established as a part of the conditioning regimen in high dose therapy. The immediate tolerance of fractionated total body irradiation (FTBI) was investigated prospectively. METHODS: From January 1995 to December 1998 162 patients received a FTBI, 6x2 Gy on 3 consecutive days, lung dose 10 Gy, for allogeneic (n=112) or autologous (n=50) bone marrow transplantation. High dose chemotherapy (mostly Cyclophosphamide) was administered after the FTBI. A standardized supportive therapy was administered. The immediate toxicity of FTBI was evaluated prospectively prior to each radiation fraction using a defined questionnaire. RESULTS: Main symptoms distressing the patient during irradiation period were gastrointestinal symptoms like nausea and emesis. The prevalence of nausea per fraction increased to 26.1% after the 4th fraction, with a significant higher prevalence in children younger than 10 years at 1st and 2nd fractions. 42.6 and 22. 8%, respectively, of all patients complained of nausea and episodes of emesis, during FTBI. Mild xerostomia and parotiditis were observed in 29.9 and 7.1% of all patients. Further gastrointestinal side effects during FTBI were loss of appetite in 16.0%, indisposition in 25.3%, mild oesophagitis in 3.7% and diarrhoea in 3. 7% of the patients. During FTBI 41.4% of the patients developed a temporary skin irritation (mild erythema). Pruritus was registered in 3.7% of the patients. Headache was observed in 14.8% and Fatigue syndrome in 49.2% of women and 28.3% of men (P<0.005). CONCLUSION: FTBI is a well tolerated therapeutic regimen in high dose therapy. The 162 patients investigated revealed no severe immediate side effects.     

Aggressive Chemotherapy for Acute Leukemia Relapsed After Transplantation

Bone marrow transplantation procedure has emerged as an effective treatment for hematological malignancies. However, recurrence of leukemia is still the major cause of treatment failure. Subsequent treatment in this category of patients, generally considered incurable, has not been yet standardized. At our institution, 13 patients, 7 with acute non lymphoid leukemia (ANLL) and 6 with acute lymphoid leukemia (ALL), were treated at relapse after bone marrow transplantation either autologous or allogeneic (AuBMT 8, ABMT 4) performed in complete remission (CR). The interval between BMT and relapse was less than 9 months in 6 patients (2 ABMT and 4 AuBMT) and more than 9 months in 7 patients. Early relapsed patients showed no response to treatment and died at a median of 5.5 months (range 1-13) after relapse. Late relapse after BMT was characterized by a high percentage of response (5 CR and 1 PR), particularly after intensive chemotherapy and by a longer survival (median 14 months; range 2-36).

Chemotherapy after transplantation should be carefully evaluated in patients relapsed after BMT in order to select a population that can achieve long term disease free survival.     

Autologous bone marrow transplantation in pediatric cancer

Since May 1979, 47 patients with pediatric malignancy aged 1 to 18 years (median: 7) were treated with cryopreserved autologous bone marrow transplantation (ABMT) in the department of pediatrics, National Cancer Center Hospital. The malignancies were acute non-lymphocytic leukemia (n = 8), acute lymphocytic leukemia (n = 5), osteosarcoma (n = 7), neuroblastoma (n = 6), brain tumor (n = 5), rhabdomyosarcoma (n = 4), retinoblastoma (n = 3), Ewing's sarcoma (n = 3), non-Hodgkin's lymphoma (n = 2), malignant histiocytosis (n = 1), hepatoblastoma (n = 1), malignant melanoma (n = 1) and malignant neuroepithelioma (n = 1). Conditioning regimens for solid tumors were multi-agent high-dose chemotherapy, mainly consisted of cyclophosphamide (CY) 120 mg/kg or melphalan 180mg/m2 and that for hematological malignancies were CY with fractionated total body irradiation (12 Gy). In vitro purging by 4-hydroperoxycyclophosphamide was performed in 12 leukemia patients and 5 solid tumor patients. Of the 13 patients with acute leukemia, 1 died from relapse 1 year after the unpurged marrow transplantation and 1 relapsed in the testis. Remaining 11 patients are alive in continuous complete remission with a median follow up of 30 months (range, 2 to 65 months) after transplantation. The disease-free survival rate of them was 78%. Of the 34 patients with solid tumor, 21 patients died, their cause of death were relapse in 18 and each one of infection, graft failure and brain hemorrhage. Thirteen patients are alive without disease with a median follow up of 28 months (range, 2 to 107 months) posttransplant. The longest survivor is a brain tumor girl, and there are 5 other long survivors; 2 of them are osteosarcoma and each one of rhabdomyosarcoma, Ewing's sarcoma and malignant histiocytosis. The disease-free survival rate of total 34 solid tumor patients is 29%, but that of 17 patients who received ABMT in responsive and minimum tumor residue (MTR) period was 69%. These results suggest that autologous bone marrow transplantation is an effective and tolerable treatment for poor prognostic pediatric malignancies, especially for acute leukemia and such solid tumor as that in MTR state.     

Total body irradiation: techniques, dosimetry, and complications]

Total-body irradiation (TBI) has an established role in many preparative regimens used before bone marrow transplantation (BMT) in the treatment of hematological malignancies in children and adults. Better choice in TBI techniques and dosimetry have permitted better homogeneity of dose, and therefore a significant sparing of critical tissues. Advances in treatments over the past 20 years have greatly improved survival; therefore, the evaluation of early and late complications, with a sufficient follow-up, according to different conditioning regimens is important. In this article, we review and compare different TBI techniques and dosimetry, and their influence on the distribution and homogeneity of dose, and the possible relationship to the risk of complications. We also describe the acute and late effects of TBI in children and adults appearing in the first month post-BMT as veno-occlusive disease, interstitial pneumonitis, or after 3 months, i.e., endocrinal late effects and growth in children, cataracts, neurological and bone or other complications, secondary tumors and alteration in the quality of life. The responsibility of TBI in the increased rate of certain complications is difficult to assess from chemotherapy or allograft side effects (chronic graft vs. host disease) or from other associated medical treatments, such as long term steroid therapy.     

Allogeneic bone marrow transplantation in leukemia

This paper describes European experience of bone marrow transplantation for hematological malignancies. From 1979 until December 1986 2224 transplants were reported to the European registry. The results clearly show that the leukemia-free survival is highest when the transplant is performed in the first complete remission of acute leukemia or in the first chronic phase of chronic myeloid leukemia. Under these conditions 50% of the patients can be expected to be alive and well at 8 years after the transplantation. Other factors influencing leukemia-free survival are age, donor-recipient sex combination, and prevention of graft-versus-host disease with cyclosporine.     

造血干细胞移植治疗恶性血液病临床研究

 目的 探讨造血干细胞移植（HSCT）治疗恶性血液病的临床疗效及并发症的防治。方法51例急慢性白血病、恶性淋巴瘤、多发性骨髓瘤患者中,36例选择自体造血干细胞移植（auto-HSCT）,15例接受异基因造血干细胞移植（allo-HSCT）,包括HLA不全相合3例及非血缘关系移植4例,混合移植2例;预处理自体移植主要选用CBV,BEAC方案,异基因移植采用BU／CY2及改良的BU／CY方案;移植物抗宿主病（GVHD）的预防采用CsA+MTX或CsA+MTX＋MMF方案。结果 51例患者中49例获得造血重建,在auto-HSCT和allo-HSCT后WBC≥1.0×109／L的中位时间分别为13 d和17 d,血小板≥20×109／L的中位时间分别为21和25 d;40 ％出现aGVHD,26.7 ％出现cGVHD;3.9 %出现HVOD;出血性膀胱炎发生率5.9 ％;CMV感染发生率33.3 ％;62.7 ％出现黏膜炎;54.9 ％出现不同部位的感染;移植相关死亡率3.5 %,随访3～95个月,移植后复发11例,其中auto-HSCT 9例,allo-HSCT 2例。结论 HSCT是目前治疗恶性血液病的最佳方法,但移植期间需要进一步探索如何减少其相关并发症,以提高血液肿瘤的治愈率及延长患者的无病生存时间。     

Allogeneic peripheral blood stem cell and bone marrow transplantation for hematologic malignancies: meta-analysis of randomized controlled trials

Peripheral blood stem cells have emerged as an alternative to bone marrow for allogeneic transplantation. To elucidate the advantages and disadvantages of research evidence related to the effects of allogeneic peripheral blood stem cells transplantation (PBSCT) and bone marrow transplantation (BMT) for hematological malignancies, we conducted a systematic review of the literature of randomized controlled trials comparing PBSCT to BMT. We systematically searched Cochrane Library, MEDLINE, EMBASE and CNKI up to May 2011. Two reviewers independently identified the eligible studies and assessed the methodological quality of included trials. The relevant data were extracted and analysed using RevMan 5.1. Ten trials totaling 1224 patients have been assessed. Pooled comparisons of studies of PBSCT and BMT found that the overall survival in PBSCT group was non-significantly different from that in BMT group [RR 0.92, 95% CI (0.80-1.07)]. The disease-free survival and relapse rate in PBSCT group were significantly different from that in BMT group [RR 0.67, 95% CI (0.52-0.86) and RR 0.51, 95% CI (0.34-0.76), respectively]. The number of days to reach the absolute neutrophil and platelet count were shorter with PBSCT. The rates of acute and chronic graft-versus-host disease (GVHD) in PBSCT group were significantly higher than that in the BMT group. The mortality in PBSCT group was non-significantly different from that in BMT group. We concluded that PBSCT was associated with a similar overall survival and mortality, improved disease-free survival and a decrease in relapse, faster engraftment, more GVHD when compared with BMT in transplantation for hematologic malignancies.     

Alloreactive donor lymphocytes (DLI) after allogeneic hematopoietic stem cell transplantation (HSCT): study of toxicity and efficacy

Adoptive immunotherapy represents a new therapeutic tool able to eradicate or to improve the course of various hematological malignancies and solid tumors. Alloreactive lymphocytes present within the hematopoietic transplant have been shown to be responsible for the occurrence of acute and chronic graft-versus-host-disease (GVHD). Retrospective analysis of survival curves after allogeneic bone marrow transplantation performed for leukemia have shown that GVHD was accompanied with lower relapse rates suggesting graft-versus leukemia (GVL) affect. T cell-depletion demonstrated the inverse balance existing between GVHD/GVL and relapse. Allogeneic bulk lymphocyte infusions were further used for successful treatment of relapse after transplantation in CML patients. However they were responsible for some cases of lethal acute GVHD and myelosuppressions in some patients. The concept of allogeneic transplantations after reduced intensity conditioning regimen (RICT) has recently emerged as a new strategy to treat cancer. This strategy exploited the immunological properties of the graft followed or not by donor lymphocyte infusions (DLI) while reducing the toxicity of the preparative regimen. Different means to perform RICT have been described, however the systematic use of DLI (bulk or escalating doses) after these transplantations remains controversial. Hereby, we report a summary of historical data that lead to the concept of adoptive immunotherapy and its applications.     

Allogeneic and autologous bone marrow transplantation for acute leukemia and malignant lymphoma: current status

The current status of autologous and allogeneic marrow transplantation for acute leukemias and malignant lymphoma is reviewed and compared to the current status of conventional chemotherapy. Based on the reviewed literature, it is concluded that marrow transplantation and conventional chemoradiotherapy are not mutually exclusive and that for most young patients with acute hematological malignancies the question is not if, but rather when to intervene with a marrow transplant treatment. Thus marrow transplantation and conventional chemoradiotherapy can work as complimentary units in the complex therapeutic approach needed to cure most patients with hematological malignancies.     

Dose-reduced conditioning and allogeneic hematopoietic stem cell transplantation from unrelated donors in 42 patients.

PURPOSE: A fludarabine-based "nonmyeloablative" preparative regimen was investigated in 42 patients with hematological malignancies receiving hematopoietic stem cell grafts from unrelated volunteer donors. EXPERIMENTAL DESIGN: Recipient conditioning consisted of fludarabine 30 mg/m(2) on days -6 to -2 and i.v. busulfan 3.3 mg/kg on days -6 to -5. Antithymocyte globuline was added at 2.5 mg/kg i.v. on days -5 to -2. The patients were grafted with bone marrow (n = 13) or peripheral blood stem cells either unmanipulated (n = 20) or CD34+ selected (n = 9). Graft-versus-host disease prophylaxis was performed with cyclosporine A (CsA, n = 12), CsA/methotrexate (n = 12), or CsA/mycophenolate mofetil (n = 18). RESULTS: With a median follow-up of 13 months (range, 5-26 months), the actuarial disease-free survival is 64% and 38% for patients with lymphoid malignancies and standard-risk leukemia compared with only 14% for patients with high-risk disease. The main cause of treatment failure was relapse of disease in high-risk patients (n = 14). An increased incidence of primary (n = 1) or secondary graft-failure (n = 8) was observed (21%). Chimerism analysis of CD56+/CD3--sorted natural killer (NK) cells, available in 10 patients, showed an impaired increase of donor NK cell chimerism between day 10 and 30 after transplantation in three of four patients with graft failure, whereas the percentage of donor NK cells surpassed 75% in all of the six patients with stable engraftment. CONCLUSIONS: Unrelated transplants after dose-reduced conditioning are associated with a higher risk of graft-failure. Pretransplant host immunosuppression has to be optimized to overcome resistance to grafts from unrelated donors after nonmyeloablative conditioning therapy.