造血干细胞移植治疗儿童白血病若干问题

该文涉及各类儿童造血干细胞移植(HSCT),如骨髓移植(BMT)、外周血造血干细胞移植(PBSCT)和脐血移植(UCBT)治疗白血病的优缺点及HSCT在儿童白血病治疗中的地位。绝大多数儿童白血病可通过正规联合化疗根治,仅少数(约20%)高危、难治及复发的白血病是异基因HSCT的适应证,无适合的同胞供体时,可选择HLA全相合非血缘相关BMT或PBSCT,UD-UCBT更适合于儿童患者。     

Intrabone cord blood hematopoietic stem cell transplantation in a subset of very high-risk pediatric patients: a safety and feasibility pilot study

The main limit of umbilical cord blood hematopoietic stem cell transplantation is a more difficult engraftment related to the number of cells infused per kilogram of recipient body weight. This limit makes the cord blood a suboptimal source of hematopoietic stem cells for transplantation in case of difficult engraftment situations. Direct intrabone cord blood (CB) injection has been recently investigated as a solution to cell dose problem in the adults population, but there is a lack of data concerning this approach in pediatric patients. Here, we describe 5 pediatric patients undergoing intrabone cord blood transplantation (IBCBT) for different diseases characterized by a high risk of posttransplant graft failure. The conditioning regimen differed according to the disease, whereas the GvHD prophylaxis consisted of cyclosporine, mycophenolate, and ATG. The median numbers of total nucleated cells infused and CD34(+) cells were 3.3 × 10(7)/kg, 2 × 10(5)/kg. All the patients showed complete hematological recovery and complete donor engraftment. No patient had secondary graft failure, whereas 1 patient relapsed 6 months after IBCBT. No patient died of transplant-related complications. Our results show that IBCBT is safe and feasible in pediatrics as well, and suggest that IBCBT might be an attractive option to overcome some limits of umbilical cord blood hematopoietic stem cell transplantation.     

儿童第二次非血缘供者造血干细胞移植2例

目的探索非血缘造血干细胞移植后复发病例进行第二次移植的可行性。方法患幼年型慢性粒单细胞性白血病(JMML)及重型β-地中海贫血的两例患儿接受非血缘供者造血干细胞移植后分别于移植后的10个月和1个月后原疾病复发,前者给予福达华加环磷酰胺预处理后输注原供者干细胞,降低预防移植物抗宿主病强度;后者给予含TBI预处理,移植另一非血缘供者外周血干细胞。结果两例患者第二次移植后均获得稳定植入,JMML患者并发急慢性移植物抗宿主病,完全缓解至+24月;地中海贫血患者已完全脱离输血状态至+23月。结论对于非血缘造血干细胞移植后复发的患儿,第二次非血缘供者造血干细胞移植是可行的。     

Unrelated umbilical cord blood transplantation for an infant with beta-thalassemia major

BACKGROUND: beta-thalassemia major, one of the most prevalent hemoglobinopathies throughout the world, can be cured by allogeneic stem cell transplantation therapy. Many patients, however, lack a suitably matched related donor. Unrelated umbilical cord blood can be used as an alternative stem cell source for some of these patients. This report describes the successful transplantation of a 2-month-old infant with beta-thalassemia major using partially HLA-matched unrelated umbilical cord blood. METHODS: After cytoreduction with busulfan, cyclophosphamide, and antithymocyte globulin (ATG), the patient underwent transplantation at the age of 2 months with a 4/6 HLA matching umbilical cord blood unit from an unrelated donor. RESULTS: The patient engrafted promptly with 100% donor chimerism. His only major complication was an autoimmune hemolytic anemia that resolved 2 years after transplantation. He is currently surviving, event-free, 5 years after transplantation with normal growth and cognitive development and full donor chimerism without evidence of beta-thalassemia. CONCLUSIONS: Umbilical cord blood transplantation from related and unrelated donors should be considered for patients with beta-thalassemia major who lack traditional bone marrow donors. As most newborns undergo screening for hemoglobinopathies, those with disease could be transplanted early in life before experiencing the morbidity and mortality caused by transfusion therapy, alloimmunization, and iron overload, increasing the likelihood of successful transplantation therapy.     

Transplantation of a child with sickle cell anemia with an unrelated cord blood unit after reduced intensity conditioning

Sickle cell disease can be corrected by hematopoietic cell transplantation but success is limited by low availability of matched related/unrelated donors and comorbidities leading to the increased transplant-related morbidity/mortality. There is a need for expanded donor pools and reduced intensity regimens. We describe a case of a second unrelated cord blood transplant after a novel preparative regimen in a child with sickle cell disease related stroke and liver fibrosis. Hydroxyurea, rituximab, and alemtuzumab were followed by thiotepa and low dose total body irradiation before unrelated cord blood transplant. Rapid full donor chimerism and improved performance status was achieved and sustained over 2 years after transplant.     

幼年粒单细胞白血病造血干细胞移植疗效初探

目的探讨造血干细胞移植治疗幼年粒单细胞白血病(JMML)的疗效。方法 5例JMML患儿接受无关供者脐血造血干细胞移植治疗。预处理均采用Bu/Cy+Mel+ATG方案:马利兰(0.8～1.0)mg/kg,每6小时1次共用16次(-8d～-5d);环磷酰胺60mg/(kg·d)用2d(-4～-3d);马法兰140mg/m2用1次(-2d):抗胸腺细胞球蛋白2.5mg/(kg·d)连用4d(-4～-1d)。GVHD预防采用CsA+MP±MMF。结果 5例成功植入,3例复发,1例复发后死于卡氏肺囊虫肺炎,1例死于CMV感染相关间质性肺炎,1例长期无病存活。结论 5例JMML移植初步治疗结果不满意,移植失败主要原因为白血病复发。为减少复发,今后需进一步改进移植方法 ,包括选择其他供体、改进GVHD预防方案。     

Donor cell-derived acute myeloid leukemia after second allogenic cord blood transplantation in a patient with Fanconi anemia

DCL following hematopoietic stem cell transplantation has been reported in approximately 5% of all leukemic relapses. There have been several reports on DCL, mainly AML after umbilical cord blood transplantation. In this case study, we present a young boy diagnosed with Fanconi anemia who underwent an umbilical cord blood transplantation. Because of the graft failure, he was retransplanted one month later, also with a cord blood transplant. Two years after the second transplant, he developed AML, where 100% of the cells were of female donor origin. The donor, a now 14-yr-old female, was recently reported healthy.     

Cord blood banking for potential future transplantation

In recent years, umbilical cord blood, which contains a rich source of hematopoietic stem and progenitor cells, has been used successfully as an alternative allogeneic donor source to treat a variety of pediatric genetic, hematologic, immunologic, and oncologic disorders. Because there is diminished risk of graft-versus-host disease after transplantation of cord stem cells using matched related donors, the use of less-than-completely matched HLA cord blood stem cells may incur less risk of graft-versus-host disease than mismatched cells from either a related or unrelated "walking" donor, although this remains to be proven. Gene-therapy research involving modification of autologous cord blood stem cells for the treatment of childhood genetic disorders, although experimental at the present time, may prove to be of value. These scientific advances have resulted in the establishment of not-for-profit and for-profit cord blood-banking programs for allogeneic and autologous cord blood transplantation. Many issues confront institutions that wish to establish or participate in such programs. Parents often seek information from their physicians about this new biotechnology option. This document is intended to provide information to guide physicians in responding to parents' questions about cord blood donation and banking and the types and quality of cord blood banks. Provided also are recommendations about appropriate ethical and operational standards, including informed consent policies, financial disclosures, and conflict-of-interest policies for physicians, institutions, and organizations that operate or have a relationship with cord blood-banking programs.     

Correction of chronic granulomatous disease after second unrelated-donor umbilical cord blood transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for chronic granulomatous disease (CGD), but many patients lack a suitably matched related donor. We report successful outcomes after mismatched, unrelated-donor umbilical cord blood transplantation (uUCBT) in two boys with X-linked CGD. Both patients experienced autologous recovery after first transplants, required second transplants to achieve durable donor engraftment, and are alive 27 and 15 months post-transplant. Both had invasive fungal disease and received granulocyte transfusions. In conclusion, uUCBT is effective in children with CGD, but immunosuppression in the conditioning regimen may need to be increased to decrease the risk of graft rejection.     

脐血造血细胞含量与白血病脐血移植疗效分析

目的分析4711份库存脐血造血细胞含量及探讨脐血造血细胞含量与白血病脐血移植疗效的关系。方法分析4711例库存脐血总有核细胞数(TNC)和CD34+细胞数分布情况,探讨不同的造血细胞输入量、供受者HLA不相合数、受者性别、年龄、体重和疾病类型间植入率和生存率的差异。结果 4711例库存脐血TNC和CD34+细胞中位数分别为1.14×109/kg和4.06×106/kg,按3.7×107/kg有效TNC输入量计算,93.2%脐血可供体重50 kg以下受者移植。89例白血病患者移植后植入75例,植入率为84.3%。中性粒细胞绝对值≥0.5×109/L、血小板≥20×109/L和≥50×109/L的时间分别为移植后17、34和46 d。75例植入病例中,长期无病存活47例,死亡26例,2例复发;急性移植物抗宿主病(GVHD)Ⅰ～Ⅱ度、Ⅲ～Ⅳ度和慢性GVHD发生率分别为54.7%、20.0%、9.3%。影响移植植入率的因素包括受者年龄、TNC和CD34+细胞输入量;影响生存率的因素包括受者年龄、体重和输入CD34+细胞数。结论在无法找到HLA全相合骨髓供者时,可选择脐血作为替代骨髓的造血干细胞来源治疗儿童与成人白血病,TNC和CD34+细胞数仍是选择脐血移植物的参考指标。     

Umbilical cord blood transplantation in Wiskott Aldrich syndrome

OBJECTIVE: To report the use of umbilical cord blood (UCB) stem cell transplantation in Wiskott Aldrich syndrome (WAS) when a matched sibling donor was unavailable. METHODS: Three children with WAS received unrelated umbilical cord blood stem cell transplantation after a preparative regimen for the treatment of combined immunodeficiency diseases. The patients ranged in age from 1.9 to 7.9 years. The cord blood units were 4/6 HLA antigen matches in 2 children and 5/6 in 1 child, with molecular HLA-DR match in all 3 children. RESULTS: The time for neutrophil engraftment (ANC >500/mm(3)) was 11 to 16 days, and the average time for platelet engraftment was 36 to 49 days. One patient had no evidence of GvHD, 1 patient grade I, and 1 patient grade II. No patient had chronic GvHD. The patient with grade II GvHD also had gut involvement. Immunologic reconstitution demonstrated that cord blood stem cell transplantation resulted in consistent and stable T-, B-, and NK-cell development. Functional B-cell antibody responses revealed that 2 of the patients in whom IVIG has been discontinued had low detectable antibody responses to tetanus and diphtheria toxoid immunizations at 18 to 24 months after transplantation. CONCLUSIONS: Unrelated umbilical donor cord blood is an alternative source of stem cells for transplantation in children with WAS when a suitable HLA-matched donor is not available. Benefits of UCB include rapid and reliable recovery of immune function, low risk of GvHD, and low viral transmission rate.     

Successful cord blood transplantation for sickle cell anemia from a sibling who is human leukocyte antigen-identical: implications for comprehensive care

We report the successful transplantation of umbilical cord blood stem cells from a sibling who is human leukocyte antigen-matched to a child with sickle cell anemia. Conditioning was with busulfan, cyclophosphamide, and antithymocyte globulin. Time to neutrophil count >500/microL was 23 days and to platelet count >50,000/microL was 49 days. Full donor engraftment was achieved without graft-versus-host disease. This case demonstrates the potential usefulness of harvesting cord blood from full siblings of patients with sickle cell disease. Routine collection of umbilical cord blood from siblings should be considered for patients with sickle cell disease, and may increase acceptance and use of transplantation by families.     

无关脐血移植治疗儿童噬血细胞综合征

目的探讨脐血移植对儿童噬血细胞综合征的治疗效果。方法一例16月龄确诊为噬血细胞综合征的幼儿,经HLH-2004推荐方案进行化疗及免疫治疗7个月后,病情未缓解,行HLA基因位点5/6相合无关脐血移植。预处理采用BU/CY+VP16方案:马利兰(BU)1mg/kg,第6h一次,用4d共16次(-8~-5d);足叶乙甙(VP16)30mg/kg,用1天(-4d);环磷酰胺(CY)60mg/kg,用2d(-3~-2d)。输入脐血有核细胞(NC)5·66×107/kg,CD3+4细胞1·21×105/kg。GVHD预防采用环胞菌素A(CsA)+骁悉(MMF)+抗胸腺细胞球蛋白(ATG)。移植后应用G-CSF加速造血重建。结果脐血造血干细胞未植入,自体造血恢复。移植治疗后,患儿病情逐渐好转。随访至移植后14个月,病情持续完全缓解。结论噬血细胞综合征经化疗和免疫治疗不能缓解者,应及时进行移植治疗;供体细胞植入失败的移植,也有可能暂时或长期缓解病情。     

Case report of unrelated cord blood transplantation for the treatment of recurrent refractory Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis with intestinal perforation and literature review北大核心CSCD

目的探讨非血缘脐带血移植(UCBT)治疗儿童复发难治性EB病毒相关噬血细胞综合征(EBV-HLH)的临床经验及疗效。方法回顾性分析2015年9月郑州大学第一附属医院儿科诊治的1例复发难治性EBV-HLH合并肠穿孔,最终接受UCBT治愈患儿的临床资料,并进行文献复习。结果患儿,男,1岁6个月,因"发热15 d,皮疹9 d"为主诉入院,主要表现为高热,肝、脾、淋巴结大,快速进展的全血细胞减少、肝功能损害,骨髓涂片可见吞噬血细胞,2015年9月确诊为EBV-HLH,按国际组织细胞协会制定的HLH-2004方案化疗,维持期间2次复发,给予挽救性二线方案"培门冬酰胺酶、阿霉素脂质体、依托泊苷、甲泼尼龙"(L-DEP方案)化疗,化疗后评估噬血细胞综合征指标完全缓解,突发肠穿孔,紧急外科手术行小肠造瘘术,病情稳定后,给予"氟达拉滨+白消安+环磷酰胺"方案(Flu+BU+CY方案)预处理后行UCBT,全程静脉营养支持,移植后第13天中性粒细胞植入,第35天血小板植入,嵌合率为100%,植入成功;移植后第15天出现肝小静脉闭塞征,移植后第22天出现真菌性肺炎,移植后第26天出现皮肤移植物抗宿主病(GVHD)Ⅱ度,给予相应治疗好转;移植后第49天行二期肠造瘘关瘘术;现随访至移植后70个月,患儿一般状况良好,病情持续缓解,无慢性GVHD及其他合并症。结论异基因造血干细胞移植可能是治疗儿童复发难治性EBV-HLH的唯一有效手段;无合适同胞或非血缘供者时,非血缘脐带血干细胞可作为移植物来源;肠穿孔术后肠造瘘不是移植禁忌。     

造血干细胞移植治疗DOCK8基因突变致高IgE综合征2例病例报告

目的：评估异基因造血干细胞移植治疗DOCK8基因突变所致的高IgE综合征（HIES）患儿的治疗效果。方法：回顾性收集2例接受异基因造血干细胞移植治疗DOCK8基因突变所致的HIES患儿的临床特征、实验室检查、治疗和效果。结果：2例HIES患儿,例1男,移植时年龄7岁;例2女,移植时年龄9岁。例1采用同胞全相合外周血干细胞移植,例2采用非亲缘全相合脐血干细胞移植。均采用白消安联合氟达拉滨为基础的减低强度预处理方案,顺利植入并获得造血重建。中性粒细胞植入时间例1为移植后12 d,例2为移植后24 d;血小板植入时间例1为移植后13 d,例2为移植后35 d。移植后14 d嵌合检测提示为完全供者细胞嵌合。2例患儿移植期间肺部感染均有加重,经对症治疗好转。例1接受同胞供者移植,发生皮肤Ⅰ度急性移植物抗宿主反应,甲泼尼龙治疗后缓解。无其他移植相关并发症发生。2例移植后嗜酸性粒细胞及血清IgE水平均较移植前显著下降,例1和例2分别随访至移植后18和23个月,均无病生存。结论：DOCK8基因突变所致的HIES患儿可通过异基因造血干细胞移植治愈,宜采用减低强度预处理方案,同胞相合供者是最佳供者选择,非亲缘脐血干细胞移植也能取得良好疗效。     

HLA部分相合父母供髓骨髓移植二次治疗重型地中海贫血

目的探讨同胞脐血植入失败的重型β地中海贫血患者,应用HLA部分相合父母亲骨髓进行第二次移植的效果。方法两例分别应用同胞HLA2个位点不合和全相合脐血移植的重型β地中海贫血患者,首次移植后均发生植入失败,前者表现为重型再生障碍性贫血,后者自体造血恢复。分别于首次移植13、12个月后,应用HLA部分相合的父亲、母亲骨髓进行第二次移植,观察临床疗效。结果一例重型再生障碍性贫血患者,应用HLA4个位点相合的父亲骨髓进行第二次移植,再次发生植入失败;另一例自体恢复者,应用HLA5个位点相合的母亲骨髓进行第二次移植获成功植入,现已脱离输血20个月。结论在选择合适的移植时机和预处理方案的前提下,父母供髓的二次移植对植入失败的重型β地中海贫血可起到有效的治疗作用。     

Successful treatment of Wolman disease by unrelated umbilical cord blood transplantation

Wolman disease is a rapidly fatal lysosomal storage disease caused by the complete absence of lysosomal acid lipase activity. We report the cure of an infant with Wolman disease following transplantation of unrelated HLA-mismatched umbilical cord blood-derived stem cells. Umbilical cord blood was chosen as the stem-cell source because of its immediate availability and reduced tendency to cause graft-versus-host disease. The transplantation resulted in restoration of normal acid lipase levels before the onset of permanent end-organ damage. Four years after transplantation, the patient is thriving and has normal levels of acid lipase in peripheral blood cells. To our knowledge, this is the first report of a successful unrelated cord blood transplant in a patient with Wolman disease. Umbilical cord stem cells transplantation can restore acid lipase levels in Wolman disease, and if performed early, can cure the disease.     

脐带血异基因造血干细胞移植后噬血细胞性淋巴组织细胞增生症1例临床分析

目的探讨异基因造血干细胞移植后噬血细胞性淋巴组织细胞增生症(HLH)的临床特征、诊断及治疗。方法回顾性分析1例急性髓系白血病非血缘相关脐带血造血干细胞移植(AML-URD-UCBT)患儿术后并发HLH的临床特点并复习相关文献。结果患儿移植术后第6天(+6 d,下同)出现皮肤、肝脏、肠道急性移植物抗宿主病(aGVHD),先后给予糖皮质激素、环孢素A(CsA)、赛尼哌、霉酚酸酯(MMF)、他克莫司(FK506)等免疫抑制治疗后,aGVHD症状好转,但+26 d后出现活动性巨细胞病毒(CMV)感染合并HLH,给予静脉注射用丙种球蛋白、无环鸟苷、更昔洛韦抗CMV治疗,输红细胞、血小板、血浆、纤维蛋白原等支持治疗,参照HLH-2004方案予依托泊苷、糖皮质激素及CsA治疗后,+61 d检测血CMV早期/晚期基质蛋白(CMV-PP65)转阴,+55、+63 d骨髓象未见噬血细胞,呈HLH完全缓解骨髓象,临床症状及血常规等实验室指标好转;+83 d检测血CMV-PP65及CMV脱氧核糖核酸(CMV-DNA)转阳,+86 d因严重肺部感染、肺出血、消化道出血及多器官功能衰竭而死亡。结论异基因造血干细胞移植后aGVHD及抗aGVHD的免疫抑制治疗,是引起移植后CMV感染相关HLH的危险因素;HLH-2004方案未考虑到异基因造血干细胞移植后HLH的特殊性,需进一步研究有针对性的治疗方案,以提高疗效。     

Use of two unrelated umbilical cord stem cell units in stem cell transplantation for Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome, an X-linked primary immunodeficiency can be cured by bone marrow transplantation. Umbilical cord haemopoietic stem cells are increasingly used as an alternative to bone marrow; advantages include ready availability, no risk to the donor, low rate of viral contamination, and low risk of graft versus host disease. Disadvantages include low stem cell dose for larger patients and lack of stem cells for boost infusions following the initial procedure. We report the case of a child with Wiskott-Aldrich syndrome who underwent cord blood stem cell transplantation with two separate cord blood units, 8 days apart.     

Successful engraftment without radiation after fludarabine-based regimen in Fanconi anemia patients undergoing genotypically identical donor hematopoietic cell transplantation

BACKGROUND: To potentially reduce late effects of malignancy, chronic graft-versus-host disease (GVHD), endocrinopathy, and infertility in patients with Fanconi anemia (FA) undergoing HLA-matched related donor hematopoietic cell transplantation (HCT), we developed a regimen using fludarabine (FLU), cyclophosphamide (CY), and anti-thymocyte globulin (ATG) followed by infusion of T-cell depleted (TCD) bone marrow (BM) or unmanipulated umbilical cord blood (UCB). GVHD prophylaxis consisted of cyclosporine and short course methylprednisolone. PROCEDURE: Between April 2000 and June 2003, 11 patients (10 aplastic anemia (AA), 1 myelodysplastic syndrome (MDS)) underwent HCT using this regimen. Stem cell sources were BM and UCB in eight and three patients, respectively. RESULTS: All patients demonstrated primary engraftment. Median days to neutrophil and platelet engraftment were 11 days (range 9-21) and 38 days (range 19-381), respectively. No patient developed GVHD after primary HCT. The patient with MDS relapsed with AML and a maternal donor recipient experienced secondary graft failure. For the nine FA patients with AA who underwent HLA-identical sibling donor HCT, the Kaplan-Meier estimates of overall survival and event-free survival (EFS) at 2 years are 100% and 82%, respectively, at a median follow-up of 2.9 years (range 1.9-4.8). CONCLUSIONS: In summary, a FLU-based, non-irradiation approach is effective for FA patients with AA undergoing HLA-identical sibling donor HCT.