单倍体造血干细胞移植治疗儿童重型β-地中海贫血

目的：目前仅有30％左右的重型β-地中海贫血患者能找到HLA全相合的同胞供者,使造血干细胞移植治疗该病受到限制。该研究通过探讨单倍体造血干细胞移植治疗儿童重型β-地中海贫血的疗效,希望能够拓展供者源。方法：采用单倍体脐血或骨髓对10例重型β-地中海贫血患儿进行11例次移植。使用以羟基脲、氟达拉滨、白消安、环磷酰胺、抗胸腺细胞球蛋白为基础的预处理方案。结果：6例患者获长期稳定植入并脱离红细胞输注;2例短暂植入后排斥,其中1例恢复地中海贫血状态,另1例在移植早期死亡;1例行2次移植均未植入并出现移植后再障;1例未植入,出现再障,1年后恢复地中海贫血状态。8例植入者均发生急性移植物抗宿主病,仅1例发展为皮肤局限性慢性移植物抗宿主病。随访57.1（2.5～85.1）月,总体生存率90%,无病生存率为60%。结论：单倍体造血干细胞移植治疗儿童重型β-地中海贫血能长期重建造血,在无HLA相合同胞供体时,可以作为造血干细胞移植治疗的一种选择。［中国当代儿科杂志,2009,11（7）：546-548］     

单倍体造血干细胞移植治疗儿童重型再生障碍性贫血的研究进展

对于缺乏人类白细胞抗原（human leukocyte antigen,HLA）全相合同胞供者并且对免疫抑制疗法反应不佳的重型再生障碍性贫血患儿来说,单倍体造血干细胞移植是一种推荐的替代治疗方法。但由于HLA不全相合,患儿体内可能存在供者HLA特异性抗体,导致移植物功能不良发生率较高。与HLA全相合移植相比,其预处理方案的选择也仍需探讨。该文对单倍体造血干细胞移植中供者HLA特异性抗体的检测和处理、预处理方案的选择、移植物功能不良的机制及处理进行综述。 引用格式:     

HLA不全相合无关供者或单倍体外周血干细胞移植治疗X连锁无丙种球蛋白血症

异基因造血干细胞移植是目前可治愈X连锁无丙种球蛋白血症（XLA）的唯一方法。该研究病例1为4岁男性患儿,行HLA不全相合无关供者外周血干细胞移植;病例2为儿童期起病的24岁男性患者,合并原发皮肤肢端CD8⁺T细胞淋巴瘤,行单倍体外周血干细胞移植。两者均采用减低毒性的清髓性预处理方案,并用后置环磷酰胺、兔抗人胸腺细胞免疫球蛋白、甲氨蝶呤和环孢素预防移植物抗宿主病（GVHD）。病例1+11?d（移植后为“+”）中性粒细胞及血小板均植入,+90?d供者嵌合下降,经供者淋巴细胞输注后于+150?d恢复。病例2移植后+20?d中性粒细胞植入,+87?d血小板植入,+30?d为完全供者嵌合。两患者的相关指标（IgG、IgM、IgA和外周血中CD19⁺B细胞比例）分别于移植后2个月内、1年余恢复正常。两患者均未发生急性GVHD,病例1供者淋巴细胞输注后出现局限性慢性皮肤GVHD,经治疗后好转。该研究首次报道采用HLA不全相合无关供者或单倍体外周血干细胞移植联合后置环磷酰胺方案,配合改进的预处理方案成功治疗2例XLA患者,为供者的选择提供了新的途径。     

幼年型粒单核细胞白血病单倍体相合造血干细胞移植1例

目的探讨单倍体相合造血干细胞移植治疗幼年型粒单核细胞白血病(JMML)的可行性。方法 1岁6个月JMML患儿,行单倍体相合造血干细胞移植。采用Bu/Cy+Flu+ALG方案预处理及CSA+MMF+MTX方案预防移植物抗宿主病(GVHD)。结果于移植+10 d粒系植入成功(1.2×109/L),移植+14 d血小板植入成功(260×109/L),造血初步恢复。移植+21 d查植入证据为100%嵌合。患儿移植后反复出现Ⅰ～Ⅱ度GVHD(皮肤型),给予免疫抑制剂治疗后好转。至今已生存14个月,未见复发。结论单倍体相合造血干细胞移植可能是治愈JMML的可行方法。     

Bone marrow transplantation for severe aplastic anemia in children

For young adults and children who have a bone marrow donor who is a genotypic or phenotypic sibling match, bone marrow transplantation is now the preferred treatment for severe aplastic anemia. For those who lack such a matched donor, use of matched unrelated donors and family member donors who are mismatched for a single HLA antigen have been successful and appear to be the treatment of choice. Patients lacking either of these alternatives should receive antilymphocyte globulin, either alone or combined with cyclosporine as a first step. Although the success rate of marrow transplants in our series using mismatched family donors is similar to that following treatment with antilymphocyte globulin, several caveats must be kept in mind. First, the results reported with use of alternative donors must be confirmed with study of larger numbers of patients and longer follow-up. Second, the preparative regimen given prior to bone marrow transplantation destroys the patient's residual bone marrow, whereas antilymphocyte globulin cyclosporine A and androgens do not. The sequence of immunosuppression followed by transplantation with alternative donor marrow should produce greater long-term hematopoietic improvement. Unfortunately, when marrow transplant follows one or more courses of immunosuppressive therapy, nonengraftment is then a problem because of sensitization to blood cell antigens. It should also be kept in mind that studies done in children, especially in those younger than 6 years old, show that these patients respond better to transplantation than to treatment regimens not including marrow transplantation. Therefore, for the child with severe aplastic anemia, every effort should be made to identify a suitable bone marrow donor. Finally, we need to determine the specific components of the conditioning regimen and the constitution of the donor marrow necessary for engraftment and to minimize potential long-term complications, and there should be only a tolerable degree of graft-versus-host disease. Many of the transplant-related problems that plagued us in the 1970s have still not been fully resolved, but many have shown improvement. As we enter the 1990s, increasing the pool of marrow donors for patients with severe aplastic anemia who lack an HLA-matched sibling will continue to be a top priority for research.     

Haploidentical stem cell transplantation as a salvage therapy for cord blood engraftment failure in a patient with Fanconi anemia

A 7‐year‐old male with Fanconi Anemia who developed primary graft failure following one antigen‐mismatched unrelated cord blood transplantation and a nonradiation‐based conditioning, underwent a second hematopoietic stem cell transplantation (HSCT) from his 2‐loci mismatched haploidentical father, using a nonradiation‐based regimen, 79 days after the first HSCT. A sustained hematological engraftment was achieved at 9 days post‐second HSCT. At 15 months post‐second HSCT; the patient demonstrated normal blood counts, sustained donor chimerism, and no evidence of GVHD. Haploidentical HSCTs as primary or secondary sources of stem cells, with appropriate T‐cell depletion, may be a readily available option in the absence of HLA‐matched related or unrelated donors. Pediatr Blood Cancer. 2010;55:580–582. © 2010 Wiley‐Liss, Inc.     

Successful reduced‐intensity conditioning hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria with aplastic anemia in two children

Paroxysmal nocturnal hemoglobinuria (PNH) is an extremely rare cause of bone marrow failure in children. We report two children who presented with pancytopenia, and were diagnosed with PNH with severe aplastic anemia. Both children underwent upfront, successful hematopoietic stem cell transplantation with reduced‐intensity conditioning. One patient had a syngeneic donor, and one patient had a 10/10 matched unrelated donor. Neither patient developed graft versus host disease, infections, or recurrent PNH. Reduced‐intensity conditioning hematopoietic stem cell transplantation is a reasonable therapy for PNH with marrow failure in children.     

Allogeneic hemopoietic stem cell transplantation (HSCT) for Wiskott-Aldrich syndrome: a report of the Spanish Working Party for Blood and Marrow Transplantation in Children (GETMON)

Allogeneic stem cell transplantation is the only curative treatment for Wiskott-Aldrich syndrome. The authors retrospectively analyzed the outcome with this procedure in 13 patients with severe Wiskott-Aldrich syndrome transplanted in 5 Spanish centers from 1989 to 2006. A patient was transplanted twice from the same donor due to a late engraftment failure. Age at transplant ranged from 7 to 192 months (median 30 months). There were 10 matched donors (3 related and 7 unrelated), 2 mismatched unrelated, and 1 haploidentical. Conditioning regimen consisted of busulfan and cyclophosphamide (BuCy) in 11 cases and fludarabine and melfalan (1) or BuCy (1). ATG was added in transplants from non-genetically matched donors. GvHD prophylaxis consisted of cyclosporine and methotrexate in most patients plus T-cell depletion in the haploidentical HSCT. Nine of the 13 transplanted patients are alive with complete clinical, immunologic, and hematologic recovery 8-204 months (median 101 months) after HSCT. Eight surviving patients had been transplanted from matched donors (3 related and 5 unrelated) and 1 from a haploidentical donor. Four patients died, 2 transplanted from matched donors (1 from acute GvHD and organ failure, 1 from a lymphoproliferative disorder after a second transplant), and 2 transplanted from mismatched unrelated donors (1 from acute GvHD and organ failure, 1 from graft failure and infection). Allogeneic hemopoietic stem cell transplantation must be utilized in all patients with severe Wisckott-Aldrich syndrome, using the most suitable graft variant for each patient.     

PEDIATRIC ONCOLOGY AND THE INTERNET

Allogeneic stem cell transplantation is the only curative treatment for Wiskott-Aldrich syndrome. The authors retrospectively analyzed the outcome with this procedure in 13 patients with severe Wiskott-Aldrich syndrome transplanted in 5 Spanish centers from 1989 to 2006. A patient was transplanted twice from the same donor due to a late engraftment failure. Age at transplant ranged from 7 to 192 months (median 30 months). There were 10 matched donors (3 related and 7 unrelated), 2 mismatched unrelated, and 1 haploidentical. Conditioning regimen consisted of busulfan and cyclophosphamide (BuCy) in 11 cases and fludarabine and melfalan (1) or BuCy (1). ATG was added in transplants from non-genetically matched donors. GvHD prophylaxis consisted of cyclosporine and methotrexate in most patients plus T-cell depletion in the haploidentical HSCT. Nine of the 13 transplanted patients are alive with complete clinical, immunologic, and hematologic recovery 8–204 months (median 101 months) after HSCT. Eight surviving patients had been transplanted from matched donors (3 related and 5 unrelated) and 1 from a haploidentical donor. Four patients died, 2 transplanted from matched donors (1 from acute GvHD and organ failure, 1 from a lymphoproliferative disorder after a second transplant), and 2 transplanted from mismatched unrelated donors (1 from acute GvHD and organ failure, 1 from graft failure and infection). Allogeneic hemopoietic stem cell transplantation must be utilized in all patients with severe Wisckott-Aldrich syndrome, using the most suitable graft variant for each patient.     

Hematopoietic stem cell transplantation with reduced toxicity conditioning regimen in mitochondrial neurogastrointestinal encephalopathy syndrome

Background

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder due to mutations in the TYMP gene. Clinical findings are characterized by neurologic manifestations and severe gastrointestinal dysfunction. The syndrome is usually fatal, the most effective treatment appears to be hematopoietic stem cell transplantation (HSCT).

Procedure

In this retrospective study, we evaluated HSCT that was performed using a reduced toxicity myeloablative conditioning regimen in patients with MNGIE at our center.

Results

A total of six allogeneic transplant procedures were performed in four patients. Three patients had fully matched donors, and one patient had a haploidentical donor. Treosulfan-based myeloablative conditioning regimen was applied in five of six transplants. Bone marrow was used as a stem cell source. One patient is being followed up in the 4th year of posttransplant with full chimeric and without graft versus host disease (GVHD). One patient died of acute stage IV gastrointestinal system GVHD. Two patients underwent second transplantation due to engraftment failure, one of which was the patient who had a haploidentical transplant.

Conclusions

Treosulfan-based regimen is well tolerated, although engraftment failure with this conditioning regimen can be a significant problem. We share our haploidentical transplant experience, which will be the first reported case in the literature.     

Reduced‐toxicity alternate‐donor stem cell transplantation with posttransplant cyclophosphamide for primary immunodeficiency disorders

We describe here the outcomes of reduced‐toxicity alternate‐donor stem cell transplant (SCT) with posttransplant cyclophosphamide (PTCy) for primary immunodeficiency disorders (PIDs) in eight children (haploidentical—seven and matched unrelated donor—one). The conditioning was with serotherapy (alemtuzumab‐3/rabbit‐anti‐thymoglobulin‐5); fludarabine, cyclophosphamide, and total body irradiation‐5 (additional thiotepa‐3); fludarabine and treosulfan‐2; and fludarabine and busulfan‐1. All received PTCy 50 mg/kg on days 3 and 4 as graft versus host disease prophylaxis along with tacrolimus and mycophenolate. Mean CD34 dose was 13.8 × 10⁶/kg. Two children died because of PIDs. Acute graft versus host disease up to grades I and II was seen in three children. All six survivors are fully donor and disease free at median follow‐up of 753 days. Alternate donor SCT with PTCy is feasible in PID and has good outcomes.     

Bearbeitung und Transplantation hämatopoetischer Stammzellen

Background

New graft manipulation procedures make it possible to obtain highly purified hematopoietic stem cells from healthy donors.

Patients and Methods

A total of 116 children with leukemias, lymphomas, and nonmalignant diseases received purified (97%) peripheral stem cells from matched unrelated donors or mismatched related (haploidentical) donors.

Results

Acute and chronic GVHD were vastly minimized and a high overall rate of engraftment was achieved. Event-free survival at 5 years was 46% after haploidentical transplantation for children with ALL in remission who otherwise lacked a matched donor. Moreover, excellent results were observed in patients with nonmalignant diseases.

Conclusions

Graft manipulation results in well-characterized transplants with minimal risk of GVHD and makes a donor available for each patient by recruiting the parents. Thus, alternative donors should be strongly considered in all patients who need a stem cell transplantation but lack an identical donor.     

Successful second transplantation with non‐myeloablative conditioning using haploidentical donors for young patients after graft failure following double umbilical cord cell transplantation

Liu H, Wang X, Geng L, Tang B, Tong J, Yao W, Wang Z, Sun Z. Successful second transplantation with non‐myeloablative conditioning using haploidentical donors for young patients after graft failure following double umbilical cord cell transplantation.
Pediatr Transplantation 2010: 14:465–470. © 2009 John Wiley & Sons A/S. Abstract: GF is a common and life‐threatening complication of UCBT. Here, we report that successful second transplantation of five patients using G‐CSF‐mobilized maternal stem cells with non‐myeloablative conditioning after GF following double UCBT. The median interval between the two transplants were 38 days. The first transplantation was administered after myeloablative conditioning for hematologic malignancies (n = 3), and rabbit ATG in combination with cyclophosphamide for SAA (n = 2). The second conditioning consisted of Flu and ATG‐based non‐myeloablative regimen. All five patients acquired quick and sustained engraftment after the second transplant. Treatment‐related toxicity was minimal. Three patients developed acute GVHD (>grade II = 1). Three patients developed chronic GVHD (limited = 1, extensive = 2). Severe infectious episodes were significant but manageable. With a median follow‐up of 713 days (592–1127), all patients have currently had an event‐free survival. These results indicate that a second transplant with non‐myeloablative conditioning using mother as the donor for young patient after GF is feasible.     

Allogeneic hematopoietic stem cell transplantation for nonmalignant hematologic disorders using chemotherapy-only cytoreductive regimens and T-cell-depleted grafts from human leukocyte antigen–matched or –mismatched donors

Nonmalignant hematologic disorders (NMHD) of childhood comprise a variety of disorders, including acquired severe aplastic anemia and inherited marrow failure syndromes. Patients with high-risk NMHD without matched related donors fare poorly with allogeneic hematopoietic alternative donor stem cell transplantation (allo-HSCT) and are at high risk for developing graft-versus-host disease following unmodified grafts. The authors retrospectively analyzed data on 18 patients affected by NMHD, lacking a human leukocyte antigen (HLA)-identical sibling donor, who underwent an alternative donor allo-HSCT at their institution between April 2005 and May 2013. Fifty percent of the patients had received prior immunosuppressive therapy, 72% had a history of infections, and 56% were transfusion dependent at the time of transplant. Cytoreduction included a combination of 3 of 5 agents: fludarabine, melphalan, thiotepa, busulfan, and cyclophosphamide. Grafts were T-cell depleted. All evaluable patients engrafted. Five died of transplant complications. The cumulative incidence of graft-versus-host disease was 6%. No patient had recurrence of disease. Five-year overall survival was 77%. Age at transplant <6 years was strongly associated with better survival. Based on these results, transplant with chemotherapy-only cytoreductive regimens and T-cell-depleted stem cell transplants could be recommended for patients with high-risk NMHD, especially at a younger age.     

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.     

Reduced intensity hematopoietic stem-cell transplantation across human leukocyte antigen barriers in a patient with congenital amegakaryocytic thrombocytopenia and monosomy 7

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited bone marrow failure syndrome that has the potential to progress to pancytopenia and acute myeloid leukemia. Hematopoietic stem-cell transplantation (HSCT) is presently the only curative treatment approach. We used a reduced intensity transplantation regimen in a CAMT patient with aplastic anemia and monosomy 7 who had no matched related donor. The patient had rapid and durable engraftment with minimal complications and is well 24 months post-transplantation. Thus, reduced intensity conditioning might be a feasible approach to stem-cell transplantation in patients with CAMT who do not have a related donor and who are at increased risk of toxicity from standard conditioning regimens.     

Diagnosis and treatment of aplastic anemia

Severe aplastic anemia is a rare disorder in childhood. Among various therapeutical strategies bone marrow transplantation (BMT) and immunosuppressive treatment with antithymocyte globulin (ATG) have proven to be most successful. Priority should be given to BMT over ATG treatment for patients with HLA-identical donors. Patients with Fanconi's anemia require a reduced conditioning program with cyclophosphamide and irradiation for BMT. Own experiences indicate that cooperative studies are highly needed to improve medical care for patients with severe aplastic anemia.     

ͬ��������Ѫ��ϸ����ֲ���ƶ�ͯѪҺ��4������

目的观察同基因外周血造血干细胞移植治疗儿童再生障碍性贫血、白血病的植入情况及疗效。方法北京儿童医院于2004-08—2004-12,对4例分别患有慢性粒细胞性白血病(慢性期)、急性非淋巴细胞白血病(M2)、急性再生障碍性贫血、急性淋巴细胞白血病(ph1+)的患儿进行正规方案治疗,3例白血病患儿获得首次缓解,4例患儿接受不同预处理方案,进行同基因外周血干细胞移植。所有供者均为患儿的同卵双胎同胞,并经重组人粒细胞集落刺激因子(rhG-CSF)动员。结果4例患儿接受干细胞(MNC)平均数量为10·08×108/kg。白细胞及血小板平均植入时间分别为10·7d及12·3d,无明显移植并发症。病例4随诊5个月后复发,放弃治疗2个月后死亡,余病例均存活,可正常生活,随诊时间均在16个月以上。结论同基因外周血干细胞移植可以作为治疗包括白血病在内的多种血液病的有效方法,但其远期效果还有待进一步评估。     

Comparison between bone marrow transplantation and antithymocyte globulin in treatment of young patients with severe aplastic anemia

Fifty-seven patients younger than 25 years with severe aplastic anemia underwent either bone marrow transplantation or antithymocyte globulin therapy (ATG) to ascertain which approach should be used in young patients. Thirty-five patients who had an HLA-identical sibling donor underwent bone marrow transplantation after conditioning with cyclophosphamide and low-dose total-body radiation. Twenty-two patients who did not have an HLA-identical donor received ATG. The 2-year actuarial survival of patients after transplant is 72% (95%, CI 64% to 80%), versus 45% (95%, CI 29% to 61%) in those given ATG therapy (P = 0.18). In those patients surviving 6 months after treatment, return of peripheral blood counts to normal values was more common in patients who received marrow transplant compared with those given ATG therapy (P less than 0.001). Furthermore, 24 of 26 transplant survivors had Karnofsky performance scores greater than 90%, compared with only five of 13 ATG survivors. These data suggest that bone marrow transplantation is the preferred therapy for severe aplastic anemia in young patients who have an HLA-identical sibling donor. ATG should be reversed for those young patients with severe aplastic anemia who do not have a histocompatible marrow donor.     

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.