甲磺酸伊马替尼治疗异基因造血干细胞移植后复发的慢性粒细胞白血病五例临床观察

异基因造血干细胞移植（allo-HSCT）是目前惟一能治愈慢性粒细胞白血病（CML）的方法。白血病复发仍是导致移植失败的主要原因之一。在慢性期接受allo-HSCT患者的复发率较低（5％～20％），但在疾病加速期或急变期进行移植，复发率则明显升高（30％％～60％）。移植后复发的治疗主要包括供者淋巴细胞输注（DLI），IFNα和第二次移植。虽然DLI可诱导长期的分子学完全缓解（CR），已成为治疗allo-HSCT后复发CML患者的首选方法，但同时可引起移植物抗宿主病（GVHD），骨髓抑制，甚至死亡。     

第2次同一供者Allo-PBSCT治疗移植后复发急性白血病的可行性

目的探讨急性白血病移植后复发患者行非清髓性第2次同一供者异基因外周血干细胞移植（Allo-PB-SCT）的可行性。方法1例难治急性髓细胞白血病（M2b型）Allo-PBSCT后复发患者行非清髓性第2次同一供者Allo-PBSCT治疗,调整患者第1次移植前复发达到完全缓解的药物剂量作为本次移植的预处理方案,且为了加强移植物抗白血病效应,移植初未采用预防移植物抗宿主病治疗。结果移植后第12天时,患者粒细胞〉0．5×10^9／L,血小板第45天后基本稳定于〉20×10^9／L水平,移植后4个月内3次复查骨髓示骨髓完全缓解,移植后第43天做AML1／ETO融合基因检测为阴性。结论第1次移植后复发的难治性自血病患者行非清髓性第2次同一供者Allo-PBSCT治疗安全可行。     

髓系白血病异基因造血干细胞移植后髓外复发的危险因素分析

目的:探讨髓系白血病异基因造血干细胞移植(allo-HSCT)后髓外复发的危险因素及治疗策略。方法:回顾性分析2008年1月至2018年12月河南省肿瘤医院280例行allo-HSCT髓系白血病患者的临床资料,分析患者性别、原发病、移植前疾病状态、染色体、预处理方案、供者类型、移植前髓外浸润、移植物抗宿主病等指标。应用log-rank检验方法进行单因素分析,Cox比例风险模型进行多因素分析。结果:280例患者中髓外复发20例,复发率为7.14%(20/280),中位时间为移植后7.5(1~123)个月。髓外复发患者16例死亡,病死率80%(16/20)。单因素分析中,疾病类别、第2次完全缓解(CR2)/进展期、移植前髓外浸润、预处理不含全身放疗、染色体异常与髓外复发显著相关(P<0.05)。Cox回归显示,CR2/进展期(RR=3.468,95%CI 2.189~7.786)、染色体异常(RR=1.494,95%CI 1.020~2.189)、移植前髓外浸润(RR=8.627,95%CI 3.921~18.452)为髓外复发的独立危险因素。结论:髓系白血病allo-HSCT后髓外复发的预后较差,联合治疗可能延长患者的生存期,早期评估预防至关重要。     

造血干细胞移植后死亡原因分析

目的 探讨造血干细胞移植（HSCT）治疗难治性血液病后患者的常见死亡原因。方法 对我院采用HSCT治疗的117例患者临床资料进行回顾性分析。结果 移植后共死亡33例（28．2％），分别死于未成功植入2例，宿主排斥移植物反应（HGV）1例，肺部感染6例，急性移植物抗宿主病（GVHD）2例，复发22例。自体移植复发率为33．3％，明显高于异体移植的7．0％（P〈0．01）。结论 肿瘤复发和感染是HSCT后最常见的死亡原因。有条件的情况下，应尽量选择异基因HSCT。     

异基因外周血干细胞移植治疗急性和慢性白血病52例临床观察

目的:评价异基因外周血干细胞移植(Allo-PBSCT)治疗血液肿瘤的疗效。方法:用Allo-PBSCT治疗血液肿瘤患者52例[急性淋巴细胞白血病(ALL)11例,急性髓系白血病(AML)12例,慢性粒细胞白血病(CML)29例]。预处理方案为含TBI(21例)与不含TBI的高剂量化疗方案(31例),采用环孢素加骁悉加甲氨喋呤(MTX)常规预防性控制移植物抗宿主病,非亲缘关系移植加用抗胸腺细胞球蛋白(ATG)。结果:52例患者移植后造血功能均重建,急性移植物抗宿主病(aGVHD)发生率23.1%,慢性移植物抗宿主病(cGVHD)发生率21.2%,其中局限型占15.4%;9例患者于移植后1～16月分别死于移植物抗宿主病、感染和疾病复发或进展,35例患者已PFS3～46个月,ALL-首次完全缓解(CR1)9例,无病存活(DFS)5例,带病生存2例,死亡2例,ALL-不缓解(NR)2例,死亡2例;AML-CR18例,DFS6例,带病生存2例,AML-CR24例,DFS2例,带病生存1例,死亡1例;CML(慢性期)22例,DFS19例,带病生存2例,死亡1例,CML(加速期)4例,DFS2例,带病生存1例,死亡1例,CML(急变期)3例,DFS1例,死亡2例。结论:异基因外周血干细胞移植是目前有可能治愈血液肿瘤的惟一方法。CML慢性期和急性白血病CR1后尽早选择异基因造血干细胞移植。     

异基因造血干细胞移植术后移植物抗宿主病的研究进展

造血干细胞移植（HSCT）特别是异基因造血干细胞移植（allo—HSCT）越来越多地用于治疗恶性血液系统疾病,而移植后出现的移植物抗宿主病（GVHD）是allo-HSCT的主要并发症和死亡原因之一。移植物抗宿主病按发生时间分为急性移植物抗宿主病（aGVHD）和慢性移植物抗宿主病（cGVHD）。     

多发性骨髓瘤的造血干细胞移植

近年来 ,临床开展了在大剂量强烈化疗或 (和 )放疗的基础上进行造血干细胞移植 ,并取得一定疗效。1　异基因造血干细细胞移植异基因造血干细胞移植的优点为移植物中无骨髓瘤细胞污染 ;在移植过程中出现移植物抗宿主病 (GVHD)的同时可发生移植物抗骨髓瘤细胞效应 (GVM) ,即利用移植物抗骨髓瘤细胞的特性 ,杀灭患者体内残留的骨髓瘤细胞 ,提高临床效果 ,减少复发 ,达到治愈。缺点为 :1由于多发性骨髓瘤患者多数年龄偏大 ,心、肺、肾功能不全 ,又缺乏 HL A相匹配的同胞供者 ,故移植机会较少 ;2危险性大 ,特别是移植物抗宿主病 (GVHD)发生…     

供者CD4＋CD25＋CD127-调节性T细胞与儿童异基因造血干细胞移植后急性移植物抗宿主病相关研究

目的：探讨供体移植物CD4＋CD25＋CDl27-调节性T细胞（_rreg细胞）表达水平对儿童异基因造血干细胞移植（allo—HSCT）后急性移植物抗宿主病（aGVHD）的影响。方法：采用流式细胞术检测供体淋巴细胞中CD4＋CD25＋CDl27-Treg细胞比例,回顾性分析83例allo—HSCT患儿移植物Treg细胞与移植后aGVHD．其中50例恶性疾病．33例良性疾病。结果：83例患儿allo．HSCT均获造血重建,其中51例发生O～Ⅰ度aGVHD,32例发生Ⅱ-Ⅳ度aGVHD。发生0～Ⅰ度aGVHD与Ⅱ-Ⅳ度aGVHD患儿移植物Treg细胞比例有统计学差异（3．0％-＋0．8％比2．5％±1．O％,P=0．030）。中位随访时间286（69～496）d,50例恶性疾病患儿中8例复发,复发与非复发患儿移植物Treg细胞无显著差异（3．2％±0．8％比2．8％±0．8％,P=0．549）。结论：高水平供体移植物Treg细胞有助于降低儿童all0．HSCT后aGVHD发生率,且未增加移植后复发风险;移植物Treg细胞表达量对预测aGVHD有一定意义。     

T细胞调控与异基因造血干细胞移植

异基因造血干细胞移植（allo-HSCT）是目前治愈造血系统恶性肿瘤的唯一有效手段。近年来allo—HSCT技术发展迅速．移植成功率及患者长期生存率都有很大改善,但急性移植物抗宿主病（aGVHD）及移植后复发仍是allo-HSCT后患者死亡的最主要原因。有效控制GVHD及充分发挥移植物抗白血病（GVL）效应可大大改善移植相关病死率及移植后长期生存率。T细胞,包括辅助性T（Th）细胞、     

供者淋巴细胞输注对恶性血液病异基因造血干细胞移植后复发的治疗作用

异基因造血干细胞移植(Allo HSCT)已成为治疗恶性血液病的主要方法之一,但移植后恶性血液病的复发降低了患者的长期生存率。目前Allo HSCT后复发的治疗包括停用免疫抑制剂、供者淋巴细胞输注(DLI)、二次移植、化疗、细胞因子治疗等方法,而DLI是其中疗效较为显著,毒性相对较小,作用比较肯定的方法,并且已作为非清髓造血干细胞移植(NST)后续治疗的组成部分[1],甚至在自体移植中也使用DLI[2]。本文就DLI对Allo HSCT后恶性血液病复发治疗的相关问题作一综述。DLI诱发移植物抗白血病(GVL)效应的机制在HSCT后发生移植物抗宿主宿(…     

Significance of additional high-dose cytarabine in combination with cyclophosphamide plus total body irradiation regimen for allogeneic stem cell transplantation

The combination of cyclophosphamide (CY) and total body irradiation (TBI) has been used as a standard conditioning regimen for allogeneic transplantation. Several studies showed an advantage of adding high-dose cytarabine (HDCA) to this regimen. To clarify the significance of additional HDCA, we conducted a retrospective multicenter study and compared the clinical results of these two regimens. From June 1985 to March 2003, 219 patients with hematological malignancies underwent allogeneic transplantation after conditioning with CY+TBI 12Gy (n=73) or CA+CY+TBI 12Gy (n=146). Engraftment, overall survival, transplant-related mortality (TRM), relapse rate and incidence of graft-versus-host disease (GVHD) were compared according to risks and donors. Addition of HDCA had no impact on the relapse rate in all subgroups, and it was associated with lower TRM among standard-risk patients after related transplantation, and with higher TRM and worse survival among standard-risk patients after unrelated transplantation. The incidence of acute GVHD was not significantly different between the two regimens, and HDCA resulted in a higher incidence of chronic GVHD among standard-risk patients after related transplantation. In summary, addition of HDCA is not beneficial for high-risk patients, and is not recommended for standard-risk patients receiving unrelated transplantation.     

The non-relapse mortality rate for patients with diffuse large B-cell lymphoma is greater than relapse mortality 8 years after autologous stem cell transplantation and is significantly higher than mortality rates of population controls

High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is the preferred treatment modality for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). To assess long-term outcomes of these patients, we retrospectively analysed data from 309 consecutive patients who underwent ASCT for DLBCL between 1994 and 2006. We found that non-relapse mortality (NRM) became the major cause of death beginning approximately 8 years after ASCT. The most common causes of NRM during the study period were respiratory failure (31%), infection (13%), cardiac toxicity (15%) and secondary malignancy (15%). The strongest predictor of relapse mortality (RM) was disease status at transplant: patients who were in second or greater complete or partial remission had a higher risk of RM than those in first complete or partial remission [hazard ratio (HR) 3·7, P<0·001], as did those who were relapsed or refractory (HR 4·9, P<0·001). We describe the longest reported follow-up of a large cohort of DLBCL patients uniformly-treated with ASCT. Although relapse was initially the more likely cause of death, NRM exceeded RM after 8 years. After ASCT, surviving patients have significantly increased risk mortality rates relative to the general population and this excess risk persists over time.     

异基因造血干细胞移植治疗成人费城染色体阳性急性淋巴细胞性白血病的疗效分析

目的：探讨异基因造血干细胞移植（allo—HSCT）治疗成人费城染色体阳性（Ph＋）的急性淋巴细胞白血病（ALL）的疗效。方法：回顾性分析经VDP（长春新碱、蒽环类、糖皮质激素）±C（环磷酰胺或异环磷酰胺）±L（左旋门冬酰胺酶或培门冬酶）方案诱导化学治疗（化疗）的12例Ph＋ALL患者。初始诱导缓解患者在等待移植期间进行巩固化疗．并加用伊马替尼（400-800mg／d）,与化疗同步或交替应用。初始诱导失败患者及巩固治疗期间复发患者应用Hyper-CVAD／LALA（大剂量环磷酰胺、长春新碱、多柔比星、地塞米松或米托蒽醌、阿糖胞苷）方案联合伊马替尼或达沙替尼进行再次诱导。所有患者缓解后经白消安联合环磷酰胺（Bu—Cv）或改良Bu—Cv方案预处理后进行allo—HSCT。部分患者干细胞回输后2～3个月始继续服用酪氨酸激酶抑制剂。结果：12例患者移植前均获得血液学缓解、7例获得分子学缓解。其中完全缓解（CR）1期9例、CR2期2例、初发难治性1例。移植前11例患者应用伊马替尼;移植后5例患者应用酪氨酸激酶抑制剂,其中4例应用伊马替尼、1例应用达沙替尼。中位随访时间12．7（3-54）个月,7例患者生存．3例患者死于疾病复发．2例患者死于治疗相关并发症。所有患者均植入,移植后2年总生存率66．7％±13．6％;2年累计复发率40．6％±16．0％;2年累计非复发病死率16．7％±10．8％。首次缓解（CRl）后移植治疗的2年总生存率70．0％±14．5％;2年累计复发率40．0％±18．2％;2年累计非复发病死率20．0％±12．6％。结论：酪氨酸激酶抑制剂可能会使更多患者获得缓解．从而有机会进行allo—HSCT。CR1的生存获益更大。allo—HSCT联合酪氨酸激酶抑制剂为Ph＋ALL患者有前景的治疗方案。     

肝移植术后中枢神经系统并发症的特点及危险因素分析

目的 探讨肝移植术后中枢神经系统并发症(CNSC)的种类、发生率、危险因素及预后.方法 回顾性分析159例原位肝移植(OLT)患者的临床资料,以术后发生CNSC者为Ⅰ组,无CNSC者为Ⅱ组,比较两组各项临床参数.结果 本组OLT术后CNSC发生率为20.1%(32/159).弥漫性脑病占75%(24/32),桥脑中央髓...     

Cytomegalovirus seropositivity adversely influences outcome after T-depleted unrelated donor transplant in patients with chronic myeloid leukaemia: the case for tailored graft-versus-host disease prophylaxis

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after haematopoietic stem cell transplantation from matched unrelated donors (MUD). The role of T-cell depletion (TCD) as a strategy to prevent GVHD is controversial because of the associated increased risk of leukaemic relapse, graft failure and delayed immune reconstitution. The demonstration that donor lymphocyte infusion (DLI) is effective salvage therapy if patients relapse after transplantation for chronic myeloid leukaemia (CML) prompted us to examine the proposal that TCD may be a form of GVHD prophylaxis particularly suited to this disease in patients undergoing MUD transplantation. We analysed the outcome of 106 consecutive patients with CML in first chronic phase who underwent MUD transplantation. Patients were conditioned with cyclophosphamide and total body irradiation (TBI), and received in vivo TCD, using CD52 monoclonal antibody, as GVHD prophylaxis. Donor lymphocytes were infused at the time of leukaemic relapse. The projected survival at 5 years for all patients was 52.6%. The probability of developing severe acute GVHD (grade 3 or 4) was 14.5%. The only significant predictor of overall survival in univariate and multivariate analysis was patient cytomegalovirus (CMV) serostatus: in CMV-negative patients survival at 5 years was 60% vs. 42% in CMV-positive patients (P = 0.006). The use of TCD was associated with an increased risk of relapse (62% probability at 5 years after transplant), but 80% of patients who received DLI achieved molecular remission that was durable in all but two cases. In vivo TCD, in conjunction with DLI at relapse, is a valuable GVHD prophylactic regimen in CMV-seronegative recipients of MUD allografts, but in CMV-seropositive patients this approach is associated with an increased non-relapse mortality. Consequently, GVHD prophylactic regimens in MUD transplantation should be tailored according to the patient and donor pretransplant characteristics.     

Total body irradiation–high-dose cytosine arabinoside and melphalan followed by allogeneic bone marrow transplantation from HLA-identical siblings in the treatment of children with acute lymphoblastic leukaemia after relapse while receiving chemotherapy: a Société Française de Greffe de Moelle study

We investigated the use of a new conditioning regimen followed by allogeneic bone marrow transplantation (BMT) for treating children with acute lymphoblastic leukaemia (ALL) after relapse within 6 months of the completion of therapy. One hundred and sixteen children with acute lymphoblastic leukaemia in second or subsequent complete remission (CR) underwent allogeneic bone marrow transplantation from HLA-identical siblings after a preparative regimen comprising total body irradiation (TBI), high-dose cytosine arabinoside and melphalan (TAM regimen). The Kaplan-Meier product-limit estimate (mean ± SE) of disease-free survival (DFS) at 7 years was 59.5 ± 9% (95% confidence interval). The estimated chance of relapse was 22.5 ± 15% with a median follow-up of 88.5 months (range 51–132). 26 patients (22.4%) died with no evidence of recurrent leukaemia, mainly from interstitial pneumonitis, veno-occlusive disease or acute graft-versus-host disease (GVHD). Three factors significantly affected DFS: acute GVHD, site of relapse and, for children in second remission after a marrow relapse, the disease status at the time of transplantation. The DFS were 59.02 ± 12.6%, 37.5 ± 19.8% and 77.4 ± 15% among patients in CR2 after a marrow relapse, in CR3 or in untreated partial marrow relapse, and in CR2 after an isolated CNS relapse, respectively. The lowest DFS was seen in children with acute GVHD grades 3–4. Two significant factors were associated with relapse: the marrow status at the time of transplantation and chronic GVHD. The relapse rate was lower among children in CR2 or with chronic GVHD. We conclude that transplantation after the TAM regimen is an effective therapy for this population with acceptable toxicity, particularly for children in second remission after a very early marrow relapse, or those with early isolated CNS involvement.     

Survival and late mortality among patients who survived disease-free for 2 years after stem cell transplantation

Most events that limit life expectancy after allogeneic haematopoietic stem cell transplantation (allo-HSCT) occur within the first 2 years; however, treatment outcomes in long-term survivors who survive for at least 2 years post-HSCT without relapse are yet to be elucidated. To explore the life expectancy trends and late complications and to assess the main mortality-related factors, we investigated the characteristics of patients who received allo-HSCT for haematological malignancies from 2007 to 2019 in our centre and survived in remission for 2 years. A cohort of 831 patients was enrolled; of these, 508 received grafts from haploidentical-related donors (61.1%). The estimated overall survival rate at 10 years was 91.9% (95% confidence interval [CI], 89.8–93.5), which was affected by prior grade III–IV acute graft-versus-host disease (GVHD) (hazard ratio [HR], 2.98; 95% CI, 1.47–6.03; p = 0.002) and severe chronic GVHD (HR, 3.60; 95% CI, 1.93–6.71; p < 0.001). The probability of late relapse and non-relapse mortality at 10 years was 8.7% (95% CI, 6.9–10.8) and 3.6% (95% CI, 2.5–5.1) respectively. The top cause of late mortality was relapsed (49.0%). Projected long-term survival in 2-year disease-free survivors following allo-HSCT was excellent. Strategies should be implemented to minimise the late death-specific hazards in recipients.     

Comparison of outcome following allogeneic bone marrow transplantation with cyclophosphamide-total body irradiation versus busulphan-cyclophosphamide conditioning regimens for acute myelogenous leukaemia in first remission

We evaluated transplant-related mortality (TRM), leukaemia relapse, leukaemia-free survival (LFS) and overall survival (OS) in patients receiving busulphan and cyclophosphamide (BuCy) or cyclophosphamide and total body irradiation (CyTBI) prior to allogeneic bone marrow transplantation (BMT) for acute myelogenous leukaemia (AML) in first remission. Outcomes of 381 human leucocyte antigen (HLA)-matched sibling transplants using BuCy were compared with 200 transplants using CyTBI performed between 1988 and 1996. The incidence of hepatic veno-occlusive disease was higher with BuCy (13%) than with CyTBI (6%) (P = 0.009). Risks of acute and chronic GVHD were similar. In multivariate analysis, relapse risk was higher in the BuCy group [relative risk (RR) = 1.72; 95% confidence interval (CI), 1.05-2.81; P = 0.031]. Eleven of 373 evaluable patients in the BuCy group had a central nervous system relapse in contrast to none of 194 evaluable patients in the CyTBI group (P = 0.016). There were no differences in TRM, LFS and OS. CyTBI conditioning may lower relapse risk but produces comparable TRM, LFS and OS to BuCy for HLA-matched sibling transplantation in first remission AML.     

Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies

Many patients who require allogeneic hematopoietic stem cell transplantation (allo-HSCT) lack a human leukocyte antigen (HLA)-matched donor. Here, we report a protocol for haploidentical allo-HSCT that combines granulocyte-colony stimulating factor primed bone marrow (G-BM) and peripheral blood stem cells (PBSC) without in vitro T-cell depletion (TCD). In this study, 171 patients, including 86 in high-risk group, underwent transplantation from haploidentical family donors. All patients achieved sustained, full donor chimerism. One hundred and eleven patients were alive in remission at a median of 682 (253-1502) days. The cumulative incidence of grade III-IV acute graft-versus-host disease (GVHD) was 23% and that of extensive chronic GVHD, 47%; these were not influenced by HLA disparity. Patients younger than 15 years had less grade III-IV acute GVHD than older patients (P=0.044). The 2-year probability of relapse was 12% for standard-risk disease and 39% for high-risk disease. The 2-year probability of leukemia-free survival (LFS) was 68% for standard-risk patients and 42% for high-risk patients (P=0.0009). Grade III-IV acute GVHD was associated with better LFS (P=0.0017). The results require confirmation and show that G-BM combined with PBSC from haploidentical family donors, without in vitro TCD, may be used as a good source of stem cells for allo-HSCT.     

Haematopoietic stem cell transplantation with non-myeloablative conditioning in the outpatient setting: results, complications and admission requirements in a single institution

Thirty patients with haematological malignancies received peripheral blood stem cells from human leucocyte antigen (HLA)-identical sibling donors after non-myeloablative conditioning with fludarabine and total body irradiation. Twenty-seven patients received the transplant as an outpatient procedure. All patients engrafted. The probability of acute graft-versus-host disease (GVHD) grades II-IV and extensive chronic GVHD was 57% and 80%, respectively. Patients alive on day +365 experienced a median of 44 d (range 4-151) of hospitalization during the first year. In the entire cohort, GVHD accounted for 22%, infections for 18%, thrombotic thrombocytopenic purpura (TTP) for 16% and engraftment syndrome for 14% of the time in hospital. The 1-year risk of TTP was 26%. Acute GVHD was a risk factor for the development of TTP (P = 0.008). With a median follow-up of 602 d, the 2-year estimates for overall survival, progression-free survival, non-relapse mortality and relapse related mortality were 68%, 43%, 22% and 13%, respectively. This transplantation regimen is feasible and induces long-term remissions in heavily pretreated patients. The procedure can be performed in the outpatient setting, but complications could result in a substantial number of admissions during the first year.