二次异基因造血干细胞移植治疗移植后复发患者的疗效和安全性

目的 探讨应用二次异基因造血干细胞移植治疗移植后复发患者的疗效和安全性.方法 回顾性分析1999年10月-2010年3月在北京大学血液病研究所接受二次造血干细胞移植作为挽救治疗的25例移植后复发患者的资料.除1例移植前未达缓解状态的患者外,其余24例患者在第1次移植后的中位8.8(1～55)个月出现复发,经过中位3(0.3～20)个月的治疗,接受了二次移植.2次移植中位间隔10.6(0.6～59.0)个月.结果 25例患者预处理方案主要为含全身放疗(TBI)或改良的BUCY(马利兰+环磷酰胺)方案.全部患者达到白细胞植活标准,并生存超过30 d,有3例患者发生肝窦阻塞综合征,放射性皮炎以及急性心肌梗死等严重预处理相关毒性,但经治疗后均恢复.截至2011年1月,经过中位9.1(2.0～131.1)个月的随访,8例患者生存,总的生存率为30.9%.12例患者复发,复发率55.7%,复发中位时间是二次移植后的4.4(1.0～8.5)个月.7例患者因移植相关合并症死亡,非复发病死率35.1%.单因素分析发现患者二次移植时是否缓解与生存期有显著关联(P=0.009).结论 适度降低强度的预处理方案可以使二次异基因造血干细胞移植安全地应用于移植后复发的患者,保证移植物的植入,非复发病死率亦在可接受范围内.     

二次异基因造血干细胞移植治疗移植后复发患者的疗效和安全性

目的 探讨应用二次异基因造血干细胞移植治疗移植后复发患者的疗效和安全性.方法 回顾性分析1999年10月-2010年3月在北京大学血液病研究所接受二次造血干细胞移植作为挽救治疗的25例移植后复发患者的资料.除1例移植前未达缓解状态的患者外,其余24例患者在第1次移植后的中位8.8(1～55)个月出现复发,经过中位3(0.3～20)个月的治疗,接受了二次移植.2次移植中位间隔10.6(0.6～59.0)个月.结果 25例患者预处理方案主要为含全身放疗(TBI)或改良的BUCY(马利兰+环磷酰胺)方案.全部患者达到白细胞植活标准,并生存超过30 d,有3例患者发生肝窦阻塞综合征,放射性皮炎以及急性心肌梗死等严重预处理相关毒性,但经治疗后均恢复.截至2011年1月,经过中位9.1(2.0～131.1)个月的随访,8例患者生存,总的生存率为30.9%.12例患者复发,复发率55.7%,复发中位时间是二次移植后的4.4(1.0～8.5)个月.7例患者因移植相关合并症死亡,非复发病死率35.1%.单因素分析发现患者二次移植时是否缓解与生存期有显著关联(P=0.009).结论 适度降低强度的预处理方案可以使二次异基因造血干细胞移植安全地应用于移植后复发的患者,保证移植物的植入,非复发病死率亦在可接受范围内.     

二次异基因造血干细胞移植治疗移植后复发患者的疗效和安全性

目的 探讨应用二次异基因造血干细胞移植治疗移植后复发患者的疗效和安全性.方法 回顾性分析1999年10月-2010年3月在北京大学血液病研究所接受二次造血干细胞移植作为挽救治疗的25例移植后复发患者的资料.除1例移植前未达缓解状态的患者外,其余24例患者在第1次移植后的中位8.8(1～55)个月出现复发,经过中位3(0.3～20)个月的治疗,接受了二次移植.2次移植中位间隔10.6(0.6～59.0)个月.结果 25例患者预处理方案主要为含全身放疗(TBI)或改良的BUCY(马利兰+环磷酰胺)方案.全部患者达到白细胞植活标准,并生存超过30 d,有3例患者发生肝窦阻塞综合征,放射性皮炎以及急性心肌梗死等严重预处理相关毒性,但经治疗后均恢复.截至2011年1月,经过中位9.1(2.0～131.1)个月的随访,8例患者生存,总的生存率为30.9%.12例患者复发,复发率55.7%,复发中位时间是二次移植后的4.4(1.0～8.5)个月.7例患者因移植相关合并症死亡,非复发病死率35.1%.单因素分析发现患者二次移植时是否缓解与生存期有显著关联(P=0.009).结论 适度降低强度的预处理方案可以使二次异基因造血干细胞移植安全地应用于移植后复发的患者,保证移植物的植入,非复发病死率亦在可接受范围内.     

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。     

抢先治疗减少异基因造血干细胞移植后早期巨细胞病毒疾病的临床研究

目的:采用联合抗病毒药物及巨细胞病毒(CMV)特异性T淋巴细胞(CMV-CTL)进行抢先抗病毒治疗,减少异基因造血干细胞移植后早期CMV疾病的发生率和病死率.方法:334例进行异基因造血干细胞移植的患者,其中同胞相合移植100例,非血缘移植88例,亲缘间半相同移植146例;移植后采用RQ-PCR方法每周检测1～2次检测...     

异基因造血干细胞移植术后供体型复发及文献复习

目的：提高对异基因造血干细胞移植术后供体型复发的认识水平，分析其发生原因。方法：回顾性分析2001年9月～2003年12月在我院行异基因造血f：细胞移植术后供者复发3例的移植前状态、治疗和预后。结果：3例患者移植后全部重建造血，DNA序列分析表明1个月内移植物植入．复发时嵌合体检查为完全供体型。结论：移植前未达完全缓解．或反复复发的白血病患者移植后易复发；STR-PCR结果显示．患者可在完全供者嵌合体状态下复发。     

自体造血干细胞移植后DC-CIK细胞预防急性白血病复发的效果探讨

目的 探讨白血病自体造血干细胞移植后应用树突状细胞-细胞因子诱导的杀伤细胞(DC-CIK细胞)预防急性白血病复发的临床疗效.方法 4例白血病自体造血干细胞移植后静注及腹股沟注射DC-CIK 细胞3次,观察疾病的复发情况以及DC-CIK细胞输注后的不良反应.结果 3例治疗后持续完全缓解(CR),CR期分别为32、36、45个月;1例急性非淋巴细胞白血病(M4)复发后进行异基因半相合造血干细胞移植,无病生存24个月.结论 DC-CIK细胞治疗可能协助清除微小残留病、预防复发,可作为白血病自体造血干细胞移植后预防复发的有效方法.     

异基因造血干细胞移植后供者淋巴细胞输注的优化策略

异基因造血干细胞移植(allo-HSCT)是可治愈多种血液系统恶性疾病的有效手段,而移植后疾病的复发一直是限制移植治疗效果的重要原因.     

造血干细胞移植后复发及其治疗

造血干细胞移植（HSCT）是恶性血液系统肿瘤惟一治愈方法。随着HSCT的进展，移植相关病死率明显降低，但移植后复发仍是影响预后的主要因素，且复发相关病死率高。     

单倍体与同胞相合异基因造血干细胞移植治疗恶性血液病疗效观察

目的:探讨单倍体与同胞相合异基因造血干细胞移植治疗恶性血液病疗效及影响预后的相关因素。方法:分析2013年6月—2019年12月于山西白求恩医院行异基因造血干细胞移植的82例恶性血液病患者的临床资料，急性髓系白血病51例，骨髓增生异常综合征11例，急性淋巴细胞白血病20例。同胞全相合异基因造血干细胞移植(MSD-HSCT)30例，单倍体异基因造血干细胞移植(Haplo-HSCT)52例。结果:82例患者中位随访时间为15个月，总植入率为87.8%,移植前疾病未缓解者MSD-HSCT组占26.7%(8/30),Haplo-HSCT组占15.4%(8/52),Haplo-HSCT组和MSD-HSCT组移植后2年总生存率(OS)分别为63.3%和65.4%,差异无统计学意义(P=0.771),其中Haplo-HSCT组患者Ⅰ～Ⅱ度急性移植物抗宿主病(aGVHD)发生率为73.1%(38/52),明显高于MSD-HSCT组的46.7%(14/30),差异有统计学意义(P=0.017),其余移植相关并发症包括植入失败率、Ⅲ～Ⅳ度aGVHD、外周血巨细胞病毒、EB病毒、出血性膀胱炎，2组比较均差异...     

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(400～800 mg/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-Cy)或改良Bu-Cy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、CR 2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(CR1)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.