Homozygosity for human leucocyte antigen-C ligands of KIR2DL1 is associated with increased risk of relapse after human leucocyte antigen-C-matched unrelated donor haematopoietic stem cell transplantation

Human leucocyte antigen (HLA)-C molecules regulate the function of natural killer cells and may be subdivided into two groups, C(1) and C(2), based on their specificity for inhibitory killer immunoglobulin-like receptors. We analysed the impact of the HLA-C genotype on outcome of HLA-C-matched unrelated donor haematopoietic stem cell transplantation (URD-HSCT) recipients. HLA-C(2) homozygous patients (n = 18) had lower probability of overall survival (P = 0.01) and disease-free survival (P = 0.02), resulting from increased relapse rate (P = 0.02) when compared with both HLA-C(1) homozygous (n = 43) and HLA-C(1),C(2) heterozygous (n = 50) subgroups. Patients lacking HLA-C(1) should, therefore, be considered at increased risk of relapse following HLA-C-matched URD-HSCT.     

Infections after CD34-selected or unmanipulated autologous hematopoietic stem cell transplantation

Immune reconstitution may be delayed after CD34-selected compared with unmanipulated autologous peripheral blood stem cell transplantation (PBSCT), resulting in a theoretically increased risk of infections. In a case-control matched study we compared the incidence of infection in 25 recipients of CD34-selected PBSC (CD34 group) and 75 recipients of unmanipulated PBSC (PBSC group) transplants. The population included 52 males and 48 females suffering from non-Hodgkin's lymphoma (n = 32), Hodgkin's disease (n = 8), multiple myeloma (n = 40) or breast cancer (n = 20). Neutrophil engraftment was comparable in the two groups. The actuarial incidence of infection was similar in the two groups (56% vs. 49% at day 30, and 70% vs. 64% at 1 yr respectively). The proportion of patients with 1, 2 or 3 infections, the number of infectious event per patient (1.32 vs. 1.04; NS), the number of infections before day 15 or 30, between days 31 and 100 or after day 100, the risk of varicella-zoster virus or cytomegalovirus infection or disease, or the use of antibiotic or antifungal therapy, were not increased in the CD34 compared with the PBSC group. The main agents responsible for infection were bacteria, particularly gram-positive cocci, in both groups. Bacteremia accounted for 33% of all infectious events in the CD34 group vs. 16% in the PBSC group (P < 0.05). Fungal infections were rare. In conclusion, our results do not support the notion that CD34-selection of the graft is associated with an increased rate of infection after autologous PBSC transplantation. The role of extended infection prophylaxis should be evaluated.     

单倍体移植治疗白血病疗效观察

目的探讨单倍体移植治疗白血病的疗效。方法在单倍体移植时采用阿糖胞苷（Ara-c）、马利兰（Bu）、环磷酰胺（CTX）、甲基环己亚硝脲（Me-CCNU）联合作为预处理方案,用CTX、重组人粒细胞集落刺激因子（rhG-CSF）、环孢素A（CSA）、麦考酚酸酯（MMF）、抗胸腺细胞球蛋白（ATG）、白细胞介素11（IL-11）及甲氨蝶呤（MTX）联合预防急性移植物抗宿主病（aGVHD）,治疗7例白血病;结果 7例患者完全植入,白细胞〉1.0×109/L中位时间为16.9 d,Ⅲ~Ⅳ度aGVHD发生率为14.3%,中位随访时间25.6个月,无复发,至今仍存活。结论单倍体移植治疗白血病时,用Ara-c、Bu、CTX、Me-CCNU联合作为预处理方案,用CTX、rhG-CSF、CSA、MMF、ATG、IL-11及MTX联合预防aGVHD是安全、有效的。     

Preventing opportunistic infections in bone marrow transplant recipients

In 1996, a Center for Disease Control and Prevention (CDC)-sponsored working group began developing guidelines for preventing opportunistic infections (OIs) in bone marrow transplant (BMT) recipients. The purposes of the guidelines are to: a) summarize current data regarding the epidemiology of OIs in BMT recipients; b) produce an evidence-based statement of recommended strategies for preventing OIs in BMT recipients; c) decrease the incidence, morbidity, and mortality of OIs in BMT recipients; and d) define directions for future OI prevention research. Each recommendation is given two ratings: one indicating the strength of the recommendation, and another indicating the strength of evidence supporting the recommendation. The target audience for the guidelines includes transplant and infectious disease physicians and BMT unit and clinic staff. The BMT OI guidelines include sections on viral, bacterial, fungal, protozoal, and helminth infections, immunization, infection control, and blood and stem cell safety. The disease-specific sections address preventing exposure and disease among both adult and pediatric recipients of allogeneic and autologous BMTs. The immunization section addresses: a) immunization of BMT recipients, their household contacts, and health care workers; b) travel immunizations for BMT recipients; and c) passive immunization with immune globulin products. The infection control sections address room ventilation, isolation and barrier precautions, and prevention of nosocomial and other infections (e.g. infections acquired from visitors, plants, food, pets, construction sites, etc.). The blood safety section contains recommendations on preventing transmission of infections to BMT recipients from infected donated cells. After the guidelines are made available for public comment, they will be finalized and published in the Morbidity and Mortality Weekly Report and placed on the CDC web site ( Note Presented in part at the First World Congress of Transplant Infectious Disease, 1–4 April 1998, Orlando, Florida.
).     

Immune reconstitution after purified autologous and allogeneic blood stem cell transplantation compared with unmanipulated bone marrow transplantation in children

Immune reconstitution is critical for the long-term success of haematopoietic stem cell transplantation (HSCT). We prospectively analysed immune reconstitution parameters after transplantation of autologous (group 1; n = 10) and allogeneic (group 2; n = 12) highly purified CD34+ peripheral blood stem cells (PBSC) and unmanipulated allogeneic bone marrow (BM) (group 3; n = 9) in children. Median follow-up after HSCT was 56 (group 1), 61 (group 2), and 40.5 months (group 3). Median CD34-cell dose transplanted in the three groups was 9.4 x 10(6)/kg, 20.3 x 10(6)/kg, and 4.25 x 10(6)/kg recipient's body weight (BW) respectively. Complete haematopoietic engraftment was seen in all patients without any significant differences between the three groups. T-cell reconstitution at 6 months was significantly delayed in autologous peripheral blood stem cell transplantation (PBSCT) compared with allogeneic BM transplantation (P < 0.028) and allogeneic PBSCT (P < 0.034). At 3 months after transplantation numbers of CD56+/3- natural killer cells were higher in the allogeneic PBSC group (P < 0.01) compared with the BM group. The numbers of proven bacterial and viral infections were equally distributed between the three groups. In conclusion, recipients of allogeneic highly purified CD34+ PBSC or unmanipulated BM have higher lymphocyte subset counts at 6 months after transplantation than recipients of autologous CD34-selected PBSC. Infection rates and outcome, however, were not significantly different.     

Fever after peripheral blood stem cell infusion in haploidentical transplantation with post-transplant cyclophosphamide

Objective/backgroundNoninfection-related fever can occur after peripheral blood stem cell infusion in haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide. The objective of this study was to analyze the incidence of fever and characterize some clinical features of affected patients.MethodsA retrospective case-series study with 40 patients who received haploidentical hematopoietic stem cell transplantation was carried out.ResultsThirty-three patients (82.5%) developed fever; no baseline characteristic was associated with its development. Median time to fever onset was 25.5 h (range, 9.5–100 h) and median peak temperature was 39.0 °C (range, 38.1–40.5 °C). Not a single patient developed hemodynamic or respiratory compromise that required admission to the intensive care unit. Fever was not explained by infection in any case. Ninety-one percent of the febrile episodes resolved within 96 h of cyclophosphamide administration. No significant difference in overall survival, event-free survival, or graft versus host disease-free/relapse-free survival was found in the group of febrile individuals after peripheral blood stem cell infusion.ConclusionFever after peripheral blood stem cell infusion in this clinical setting was common; it usually subsides with cyclophosphamide administration. The development of fever was not associated with an adverse prognosis.     

非血缘脐血移植失败行二次单倍型造血干细胞移植成功治疗骨髓增生异常综合征1例并文献复习

目的：探讨非血缘脐血移植治疗骨髓增生异常综合征失败后立即行半相合型造血干细胞二次移植作为解救方法的可能性和安全性。方法：1例骨髓增生异常综合征难治性血细胞减少伴多系增生异常（MDS-RCMD）3年余患者,进行非血缘HLA不全相合双份脐血造血干细胞移植,移植后＋30dSTRPCR检测移植物未植入,立即予患者进行半相合造血干细胞干细胞移植以挽救患者生命。供者为患者母亲,采用“骨髓加外周血联合造血干细胞移植”,预处理方案采用“抗胸腺细胞球蛋白＋福达拉滨”。结果：二次移植物成功植入,形成完全供者来源的造血与免疫功能,二次移植后12dANC〉0．5&#215;10^5／L,＋15dPLT〉20&#215;10^9／L,无急慢性GVHD等并发症的发生,随访19月余,患者获得长期无病生存。结论：非血缘脐血移植失败后,50d内行半相合型造血干细胞移植治疗骨髓增生异常综合征是安全、有效的挽救治疗措施。     

供者外周血干细胞输注预防高危白血病单倍型移植后复发的临床研究

Objective To explore the preventative effect of donor peripheral blood stem cell (PBSC) infusion mobilized by granulocyte colony-stimulating factor (G-CSF) for the relapsing patients with leukemia after haplotype hematopoietic stem cell transplantation ( HSCT) , as well as its therapeutic effect and safety. Methods G-CSF was given at 5-10 μg · kg-1 · d-1 to donor and PBSCs were obtained on day 5 and frozen and allotted for storing. PBSC infusion was given to all the 20 patients on day 90 after HSCT,and the second treatment was given to 4 patients on day 30 after the first infusion. The occurrence of graftversus-host disease ( GVHD) , relapse rate of high risk leukemia and long-term survival were evaluat after PBSC infusion. Results A total of 19 patients had acute GVHD after PBSC infusion for a median of 25 (12-60) months, 4 of them were ≥ degree Ⅲ. The cumulative incidence rate was 22.9%, and all of them accepted PBSC infusion twice. Thirteen patients had assessable chronic GVHD, 10 of them were restricted,and no one died of it. Nine patients died of relapse of leukemia. The remaining 11 patients survived leukemia free, including 4 with chronic myelogenous leukemia, 4 with acute myeloid leukemia (AML) , 1 with lymphoma-leukemia and 2 with myelodysplastic syndrome-AML (MDS-AML). Kaplan-Meier analysis showed the disease free survival rate of 2-year was 52. 5%. Conclusion The prophylactic donor PBSC infusion mobilizing with G-CSF is effective, safe and feasible for the relapse of leukemia.     

供者外周血干细胞输注预防高危白血病单倍型移植后复发的临床研究

Objective To explore the preventative effect of donor peripheral blood stem cell (PBSC) infusion mobilized by granulocyte colony-stimulating factor (G-CSF) for the relapsing patients with leukemia after haplotype hematopoietic stem cell transplantation ( HSCT) , as well as its therapeutic effect and safety. Methods G-CSF was given at 5-10 μg · kg-1 · d-1 to donor and PBSCs were obtained on day 5 and frozen and allotted for storing. PBSC infusion was given to all the 20 patients on day 90 after HSCT,and the second treatment was given to 4 patients on day 30 after the first infusion. The occurrence of graftversus-host disease ( GVHD) , relapse rate of high risk leukemia and long-term survival were evaluat after PBSC infusion. Results A total of 19 patients had acute GVHD after PBSC infusion for a median of 25 (12-60) months, 4 of them were ≥ degree Ⅲ. The cumulative incidence rate was 22.9%, and all of them accepted PBSC infusion twice. Thirteen patients had assessable chronic GVHD, 10 of them were restricted,and no one died of it. Nine patients died of relapse of leukemia. The remaining 11 patients survived leukemia free, including 4 with chronic myelogenous leukemia, 4 with acute myeloid leukemia (AML) , 1 with lymphoma-leukemia and 2 with myelodysplastic syndrome-AML (MDS-AML). Kaplan-Meier analysis showed the disease free survival rate of 2-year was 52. 5%. Conclusion The prophylactic donor PBSC infusion mobilizing with G-CSF is effective, safe and feasible for the relapse of leukemia.     

Hematopoietic stem cell transplantation for sickle cell disease: state of the science

Sickle cell disease (SCD) is an inherited disorder secondary to a point mutation at the sixth position of the beta chain of human hemoglobin resulting in the replacement of valine for glutamic acid. This recessive genetic abnormality precipitates the polymerization of the deoxygenated form of hemoglobin S inducing a major distortion of red blood cells (S‐RBC), which decreases S‐RBC deformability leading to chronic hemolysis and vaso‐occlusion. These processes can result in severe complications including chronic pain, end‐organ dysfunction, stroke, and early mortality. The only proven curative therapy for patients with SCD is myeloablative conditioning and allogeneic stem cell transplantation from HLA‐matched sibling donors. In this review, we discuss the most recent advances in allogeneic stem cell transplantation in patients with SCD including more novel approaches such as reduced toxicity conditioning and the use of alternative allogeneic donors, including matched unrelated donors (MUDs), unrelated cord blood donors (UCBT), and familial haploidentical (FHI) donors. The results to date are very encouraging regarding allogeneic stem cell transplantation for patients with SCD including high survival rates and enabling a greater number of patients suffering from this chronic and debilitating condition to receive curative allogeneic stem cell therapies. However, we still have several areas to investigate and barriers to overcome to successfully cure the majority of patients with severe SCD through allogeneic stem cell therapies.     

供者外周血干细胞输注预防高危白血病单倍型移植后复发的临床研究

Objective To explore the preventative effect of donor peripheral blood stem cell (PBSC) infusion mobilized by granulocyte colony-stimulating factor (G-CSF) for the relapsing patients with leukemia after haplotype hematopoietic stem cell transplantation ( HSCT) , as well as its therapeutic effect and safety. Methods G-CSF was given at 5-10 μg · kg-1 · d-1 to donor and PBSCs were obtained on day 5 and frozen and allotted for storing. PBSC infusion was given to all the 20 patients on day 90 after HSCT,and the second treatment was given to 4 patients on day 30 after the first infusion. The occurrence of graftversus-host disease ( GVHD) , relapse rate of high risk leukemia and long-term survival were evaluat after PBSC infusion. Results A total of 19 patients had acute GVHD after PBSC infusion for a median of 25 (12-60) months, 4 of them were ≥ degree Ⅲ. The cumulative incidence rate was 22.9%, and all of them accepted PBSC infusion twice. Thirteen patients had assessable chronic GVHD, 10 of them were restricted,and no one died of it. Nine patients died of relapse of leukemia. The remaining 11 patients survived leukemia free, including 4 with chronic myelogenous leukemia, 4 with acute myeloid leukemia (AML) , 1 with lymphoma-leukemia and 2 with myelodysplastic syndrome-AML (MDS-AML). Kaplan-Meier analysis showed the disease free survival rate of 2-year was 52. 5%. Conclusion The prophylactic donor PBSC infusion mobilizing with G-CSF is effective, safe and feasible for the relapse of leukemia.     

Comparison between antithymocyte globulin and alemtuzumab and the possible impact of KIR-ligand mismatch after dose-reduced conditioning and unrelated stem cell transplantation in patients with multiple myeloma

We compared antithymocyte globulin (ATG) with alemtuzumab in 73 patients with multiple myeloma, who underwent reduced conditioning with melphalan/fludarabine, followed by allogeneic stem cell transplantation from human leucocyte antigen-matched or -mismatched unrelated donors. The ATG group had more prior high-dose chemotherapies (P < 0.001), while bone marrow was used more as the stem cell source in the alemtuzumab group (P < 0.001). Alemtuzumab resulted in faster engraftment of leucocytes (P = 0.03) and platelets (P = 0.02) and in a lower incidence of acute graft versus host disease (GvHD) grades II-IV (24% vs. 47%, P = 0.06). More cytomegalovirus (CMV) seropositive patients in the alemtuzumab group experienced CMV reactivation (100% vs. 47%, P = 0.001). The cumulative incidence of treatment-related mortality at 2 years was 26% [95% confidence interval (CI) = 12-37%] for ATG vs. 28% (95% CI = 15-55%) for alemtuzumab, P = 0.7. There was no significant difference in the estimated 2-year overall and progression-free survival between ATG and alemtuzumab: 54% (95% CI: 39-75%) vs. 45% (95% CI: 28-73%) and 30% (95% CI: 16-55%) vs. 36% (95% CI: 20-62%) respectively. In multivariate analysis, treatment with alemtuzumab had a higher risk for relapse (hazard ratio: 2.37; P = 0.05) while killer immunoglobulin-like receptor (KIR)-ligand mismatch was protective for relapse (P < 0.0001). We conclude that alemtuzumab produced less acute GvHD, but higher probability of relapse. The data implicated a major role of KIR-ligand mismatched transplantation in multiple myeloma.     

The role of haploidentical stem cell transplantation in the management of children with haematological disorders

The broader application of stem cell transplantation (SCT) for paediatric diseases has been limited by a lack of human leucocyte antigen (HLA)-matched donors. Virtually all children, however have at least one haploidentical parent who could serve as a donor. Such a donor is immediately available and the considerable costs of additional HLA typing, registry and banking expenditures that are necessary to procure an unrelated donor, could be reduced. Recent technological advances appear to have overcome the historical problems of graft rejection and severe graft versus host disease in the haploidentical setting, and in the latest studies the overall survival for children undergoing haploidentical SCT for leukaemia is now comparable with that following unrelated donor bone marrow or cord blood transplantation. Post-transplant infectious complications and leukaemia relapse remain the most important barriers yet to overcome, and new directions in the use of adoptive cellular immunity appear to be promising in this respect. Haploidentical SCT is now a viable option for those children who do not have an HLA compatible sibling or fully matched unrelated donor. The relative merits of a haploidentical family donor versus mismatched unrelated bone marrow or cord blood donation needs to be assessed in prospective, randomized clinical trials.     

HLA单倍体与全相合外周血干细胞移植后免疫功能重建与并发症的比较

目的 初探HLA单倍体相合与全相合异基因外周血干细胞移植(allo-PBSCT)后两组患者细胞免疫功能差异及其与主要并发症的关系.方法 选择2004年6月一2007年12月在新疆医科大学第一附属医院接受allo-PBSCT的67例患者,其中33例接受全相合,34例接受单倍体相合移植.采用间接免疫荧光法前瞻性检测移植前、后1、3、6、12及18个月两组患者的淋巴细胞亚群,同时检测100例正常对照.统计分析两组患者移植后免疫功能的重建情况及其与主要并发症的关系.结果 (1)67例患者与正常对照组比较,移植后1个月CD_3~+、CD_4~+、CD_4~+/CD_8~+、3个月CD_4~+、CD_4~+/CD_8~+及6个月CD_4~+均低于正常对照组,移植后3个月及6个月CD_4~+高于正常对照组.(2)单倍体与全相合患者移植后免疫功能比较差异无统计学意义(P>0.05).(3)单倍体移植重症感染与未感染患者免疫功能比较差异无统计学意义(P>O.05).(4)发生慢性移植物抗宿主病(cGVHD)与未发生cGVHD的两组患者间免疫功能比较差异均无统计学意义(P>0.05).(5)8例复发患者与未复发患者免疫功能差异无统计学意义(P>0.05).结论 应用含抗胸腺淋巴细胞球蛋白多种免疫抑制剂进行非体外去T细胞的PBSC单倍体移植,与常规方案进行HLA相合的PBSC移植相比,两组患者移植后的免疫功能重建总体无明显差异,移植后两组患者的重度感染率、白血病复发率及移植相关病死率差异也无统计学意义,提示单倍体移植方案是安全有效的.