Reduced-intensity allogeneic hematopoietic cell transplantation: Graft versus tumor effects with decreased toxicity

The potentially curative role of allogeneic hematopoietic cell transplantation (HCT) in neoplastic and non-neoplastic diseases is offset by the substantial risks of morbidity and mortality from complications of the intensive myeloablative and immunosuppressive preparative regimen. These regimen-related toxicities have restricted allogeneic HCT to young, otherwise healthy individuals without comorbid diseases. Pediatric patients undergoing conventional allogeneic HCT have lower procedure-related mortality but are at risk for non-fatal late effects of the high-dose pretransplant chemoradiotherapy, such as growth retardation, sterility and other endocrine dysfunction. Evaluation of reduced-intensity preparative regimens is the major focus of current clinical research in allogeneic HCT. Reduced-intensity HCT (RI-HCT) relies on the use of immunosuppressive but non-myeloablative agents that allow engraftment of donor cells, which provide adoptive allogeneic cellular immunotherapy and graft versus tumor (GVT) effects, with decreased regimen-related toxicities. Although the experience with RI-HCT in pediatric patients is very limited at this time, results in adults indicate that attenuated-dose preparative regimens allow older patients and those with organ dysfunction to undergo successful allogeneic HCT with acceptable morbidity and mortality. In adults, the potency of the allogeneic GVT effect varies among neoplastic diseases, with better results observed in patients with indolent hematological malignancies or renal cell carcinoma. The effectiveness of RI-HCT as treatment for children with hemoglobinopathies, chronic granulomatous disease and cellular immunodeficiencies is encouraging, and the role of reduced-intensity preparative regimens for allogeneic HCT in pediatric malignancies is under investigation.     

Allogeneic hematopoietic cell transplantation in chemotherapy‐induced aplasia in children with high‐risk acute myeloid leukemia or myelodysplasia

Relapse remains the most common cause of treatment failure after hematopoietic cell transplantation for acute myeloid leukemia. Inability to achieve hematologic complete remission has been a barrier to transplant for patients with refractory disease. We describe six children with refractory myeloid disease undergoing transplant in chemotherapy‐induced aplasia, as a strategy to facilitate curative therapy in refractory patients. Clofarabine‐ or high‐dose cytarabine‐based chemotherapy regimens were used to achieve marrow aplasia, followed by reduced‐intensity conditioning and allogeneic transplant before hematologic recovery. Long‐term disease control was achieved in five, with one transplant‐related mortality, suggesting the feasibility of this approach.     

History of pediatric stem cell transplantation

Abstract:  During the past 50 yr, intensive studies into the use of hematopoietic cell transplantation (HCT) for therapy of cancer and non-malignant hematologic diseases have changed this treatment modality from one that was thought to be plagued by insurmountable complications to one that is now standard therapy for some diseases. Continued research by transplant teams worldwide is likely to allow continued progress toward developing novel and improved treatment modalities and even wider application of the use of pluripotent hematopoietic stem cells in the treatment of human diseases.     

BIOLOGY AND CLINICAL UTILITY OF HEMATOPOIETIC STEM CELLS

Stem cell transplantation (SCT) was developed to treat patients with malignancies and fatal disorders of hematopoiesis. For patients with malignancies, SCT allows the use of higher doses of chemotherapy +/- radiation than recipients of conventional therapy. For patients with defects in hematopoietic cells, chemotherapy is necessary to prevent rejection of the donor stem cells. The infusion of normal hematopoietic stem cells following high-dose therapy minimizes the duration of pancytopenia and replaces defective stem cells with those from a normal donor. The first successful transplants used stem cells from HLA-matched donors. At that time, the use of stem cells from partially matched allogeneic donors was limited by the difficulty in preventing, diagnosing, and treating graft-versus-host disease (GvHD). The early success seen with leukemia and nonmalignant diseases led to the expansion of the indications for SCT and has transformed SCT from an experimental procedure performed by limited number of centers to an accepted part of the treatment of cancer. Today, successful SCTs are performed using autologous stem cells, stem cells from HLA matched, related donors; partially matched, related donors; unrelated donors, and from related and unrelated umbilical cord blood. The successes seen with these stem cell sources are the result of several advances in transplantation biology. We now have a better understanding of the relationship between residual host immunity and rejection and have used this information to develop more immunosuppressive preparative therapies capable of preventing rejection. We have a better understanding of the relationship between T cells and GvHD and have developed more effective methods to prevent and treat severe GvHD . We also have a better understanding of stem cell physiology that has resulted in our ability to quantitate hematopoietic progenitors and identify the cytokines important in inducing stem cell proliferation in vitro and in vivo. This paper reviews the recent advances in stem cell biology and how those advances impact on clinical stem cell transplantation.     

Reduced intensity and non-myeloablative allogeneic stem cell transplantation in children and adolescents with malignant and non-malignant diseases

Allogeneic hematopoietic stem cell transplant (AlloSCT) from related or unrelated histocompatible donors has been well established as potentially curative therapy for children and adolescents with selected malignant and non-malignant diseases. In the malignant setting non-myeloablative (NMA)/reduced intensity (RI)-AlloSCT eradicates malignant cells through a graft versus malignancy effect provided by alloreactive donor T-lymphocytes and/or natural killer cells. In patients with non-malignant diseases NMA/RI AlloSCT provides enough immunosuppression to promote engraftment and correct underlying genetic defects. In children, myeloablative AlloSCT is not only associated with acute short-term toxicities but also long-term late complications such as growth retardation, infertility, and secondary malignancies. NMA/RI-AlloSCT in children may be associated with reduction in use of blood products, risk of infections, transplant-related mortality, and length of hospitalization. Despite the success of RI-AlloSCT in adults, large prospective and/or randomized multicenter studies are necessary in children and adolescent recipients to define the appropriate patient population, optimal conditioning regimens, cost-benefits, survival and differences in short-term and long-term effects compared to conventional myeloablative conditioning.     

Stem‐cell transplant preparative regimens

Abstract: Owing to the relatively high probability of recurrent disease in patients receiving hematopoietic stem‐cell transplantation (HSCT) for malignancies, further development of new preparative regimens is warranted. Based on the data presented, one can predict that it will continue to be difficult to identify HSCT regimens that are more effective. Incremental improvements are expected to be small, difficult to measure, and will require inclusion of very large numbers of patients. Controlled trials to evaluate the effectiveness of specific treatment regimens for specific groups of patients will require to be conducted only by centers with large numbers of patients, or co‐operative groups. Development of HSCT regimens with low mortality and a minimum of morbidity, without compromising efficacy, are needed. This may be accomplished through the use of agents to protect normal, non‐hematopoietic tissues from regimen‐related toxicity (RRT), further exploration, and expansion of applications of targeted radiolabeled antibody approaches and mixed chimerism approaches. The future holds much work, but great promise, in the development of new HSCT regimens.     

Intermittent oral trimethoprim/sulfamethoxazole on two non-consecutive days per week is effective as Pneumocystis jiroveci pneumonia prophylaxis in pediatric patients receiving chemotherapy or hematopoietic stem cell transplantation

Pneumocystis jiroveci pneumonia (PCP) is a serious complication in patients receiving chemotherapy or hematopoietic stem cell transplantation. Current recommendations for trimethoprim-sulfamethoxazole (TMP-SMZ) dosing as PCP prophylaxis in immunocompromised patients are based on either daily dosing or dosing three consecutive days per week. We report our experience of prophylaxis with TMP-SMZ twice daily on two non-consecutive days per week in 145 immunocompromised children with hematologic disorders, cancer, or metabolic disorders following chemotherapy or hematopoietic stem cell transplantation. There were no breakthrough cases of PCP. We therefore conclude our prophylaxis regimen is effective against PCP in immunocompromised children.     

儿童造血干细胞移植后巨细胞病毒感染的临床研究

目的了解儿童造血干细胞移植后巨细胞病毒的感染率和防治方法。方法对从2001年8月到2007年3月北京儿童医院血液病中心37例作造血干细胞移植的血液肿瘤及先天遗传性疾病患儿进行回顾性分析。结果31例可研究病例中,5例自体造血干细胞移植及5例同基因造血干细胞移植患儿无人类巨细胞病毒（HCMV）感染,21例异基因造血干细胞移植患儿,发生HCMV感染7例,感染率为33.3%,大剂量阿昔洛韦加丙种球蛋白预防及早期更昔洛韦加大剂量静脉丙种球蛋白治疗,仅1例发生巨细胞病毒相关性间质性肺炎（CMV-IP）,无1例发生巨细胞病毒感染相关死亡。结论巨细胞病毒感染是儿童造血干细胞移植术后的主要并发症,临床上进行定期监测、前瞻性预防、早期诊断和及时合理治疗,对降低移植术后巨细胞病毒感染和提高移植成功率至关重要。     

Defibrotide for the treatment of hepatic veno-occlusive disease in children

BACKGROUND: This retrospective report describes experience with defibrotide in children with hepatic veno-occlusive disease (HVOD) following hematopoietic progenitor cell transplant (HPCT) in a single institution. PROCEDURE: Children who had undergone HPCT between February 1999 and June 2001 and between July 2003 and September 2004 and who received defibrotide during their admission were identified. Demographic data and information regarding the clinical course of these patients were abstracted from their health records. RESULTS: Fourteen children (mean age: 9.3 years; range: 0.4-18.1) who underwent HPCT during the study period received defibrotide for the treatment of HVOD; nine were girls. Most patients underwent HPCT for hematologic malignancies (8/14) and received matched unrelated donor transplants (8/14). Conditioning regimens included cyclophosphamide with total body irradiation (5/14) and busulfan followed by cyclophosphamide (7/14). HVOD was diagnosed on transplant day -4 to +33 (median: +10.5); defibrotide was started on transplant day -4 to +40 (median: +12). The median initial defibrotide dose was 33 mg/kg/day (11-40 mg/kg/day); the median maximum defibrotide dose was 38.5 mg/kg/day (11-81 mg/kg/day). The median duration of defibrotide therapy was 16 days (4-37 days). Defibrotide was discontinued due to clinical improvement (9), death (3), drug unavailability (1), and neurological toxicity (1). Gastrointestinal hemorrhage was observed in two patients and intra-cranial hemorrhage was observed in one patient during defibrotide therapy. The survival rate to day +100 was 79%. CONCLUSIONS: Defibrotide appears to be an effective and relatively safe treatment for children with HVOD.     

Cord blood transplant: Current and future issues

Cord blood as the source of hematopoietic stem cells has several advantages over bone marrow cells for transplant purpose. It is readily available, and causes no physical harm or inconveniences to the donor in the processing of harvesting cells. Waiting time between initiating the search and the time to transplant from an unrelated donor is much shorter with cord blood than with unrelated donor bone marrow. The incidence of graft-versus-host diseases is much less. Because of these advantages, cord blood has been increasingly used as the source of stem cells. As of this writing, more than 200 cord blood transplants have been done in patients with hematological malignancies, solid tumors, hematological diseases, immunodeficiency syndromes, and metabolic diseases. One of the limitations inherent in the cord blood is its limited number of hematopoietic stem cells. Thus it has been primarily used for pediatric patients, though more recently, adult patients also have been transplanted with cord blood as people have become more experienced in harvesting cord blood thus yielding a large number of stem cells in a given specimen. Efforts have been made to amplify stem cellsin vitro following harvesting cord blood stem cells, so that adult recipients also would routinely benefit from this resource. Cord blood lymphocytes are functionally “naive”, do not generate vigorous mixed lymphocyte culture reactivities. The low incidence of graft-versus-host disease in the recipients of cord blood is due to this particular property. It is highly desirable that the world wide cord blood registry, similar to the international bone marrow registry would be instituted, but there are logistic, ethical and financial problems that need to be resolved. Cord blood is one of the best stem cell sources, and its application is quite wide.     

亲缘单倍体造血干细胞移植治疗22例儿童高危血液肿瘤的安全性及疗效分析

目的评估亲缘单倍体造血干细胞移植在儿童高危血液肿瘤治疗中的安全性及疗效。方法回顾性分析22例14岁及以下的高危恶性血液病患儿在接受亲缘单倍体造血干细胞移植后的并发症及疗效。结果全部患儿移植后造血干细胞植入成功。I～Ⅱ度急性移植物抗宿主病（GVHD）发生率为64％（14／22）,Ⅲ-Ⅳ度为14％（3／22）;慢性广泛型GVHD发生率为23％（5／22）;6例无GVHD发生。至随访期末,移植早期（〈100d）相关死亡率为O,总生存率为86％（19／22）,多因素分析提示移植后原发病的复发为影响总生存率的高危因素（P〈0．05）,移植后未出现复发或者复发倾向、出现复发或者复发倾向的两组患儿总生存率分别为94％和60％（P=0．017）。结论亲缘单倍体因造血干细胞移植在高危儿童血液肿瘤的治疗中是安全有效的,亲缘单倍体供者为合适的供者选择。     

Early Toxicity of Intensified Conditioning with Etoposide Combined with total Body Irradiation/Cyclophosphamide or Busulfan/Cyclophosphamide in Children Undergoing Autologous or Allogeneic Bone Marrow Transplantation

In recent years, high dose chemotherapy followed by bone marrow rescue has been established as a common treatment of hematologic and solid tumor malignancies. Despite unequivocal success, relapse after transplant remains a serious problem, being the main cause of treatment failure. In an attempt to reduce relapse rates, we intensified the conditioning regimens consisting of busulfan/cyclophosphamide versus fractionated total body irradiation (f-TBI)/ cyclophosphamide by the addition of high dose eloposide. Toxicity profiles of 25 pediatric patients with hematologic malignancies undergoing intensified conditioning did not differ significantly between the two groups, except for a higher incidence of veno-occlusive disease in busulfan-treated patients (3 of 13 patients) compared with the TBI group (0 of 12 patients). We observed no transplant-related mortality in neither group. Regimen-associated morbidity was moderate and reversible in all cases. Five patients died in each treatment arm, due to relapse of the underlying disease. We conclude that both regimens are feasible in marrow transplantation of pediatric patients. Open randomized trials are needed to assess the efficacy of intensified conditioning in terms of disease-free survival.     

复杂临床表现的幼年型粒单核细胞白血病1例

目的：总结一例幼年型粒单核细胞白血病（Juvenile myelomonocytic leukemia JMML）患儿临床资料,提高对JMML的疾病认识。方法：通过对1例复杂临床表现的JMML患儿的病例报道,并进行相关总结分析,文献复习。结果：患儿,男,2岁发病,以贫血、出血,肺部感染起病,合并1型神经纤维瘤病,并出现血型鉴定困难、溶血性贫血等表现。经抗感染,输血支持后出院, 1月后患儿死亡。复习文献表明：RAS/MAPK信号传导路径异常活化在JMML发病机制方面发挥关键作用, I型神经纤维瘤病等遗传性发育障碍性疾病患者伴发或继发JMML的风险显著增高。恶性血液病患者出现血型鉴定困难,多与骨髓干细胞恶性增值、引起红细胞表面血型抗原减弱或改变有关。结论：幼年型粒单核细胞白血病是一种发病率极低的儿童恶性血液病,是儿童时期的一种克隆性造血干细胞发育异常的疾病。临床表现多样,预后差,死亡率高,造血干细胞移植是大多数患儿治愈的唯一途径。     

Skin transplantation to monitor clinical donor-related tolerance in mixed hematopoietic chimerism

Mixed hematopoietic chimerism usually carries with it the tolerance to any other tissue from the same donor. Consequently, the establishment of a sustained chimerism may allow long-term acceptance of transplanted organs without immunosuppression. We report a girl with refractory severe aplastic anemia who developed low recipient level hematopoietic chimerism following transplantation of maternal highly purified CD34+ cells without prophylactic immunosuppression. Renal thrombotic microangiopathy led to chronic renal failure and she received skin allografts from her mother in view of a future kidney donation. The maternal skin grafts were accepted without immunosuppression and the hematopoietic chimerism remained stable. Skin transplantation may be a helpful and easily applicable tool to monitor donor-related tolerance in hematopoietic chimerism clinically. It should contribute to minimize the risks of subsequent solid organ transplantation from the same donor without immunosuppression.     

Milestones in the development of pediatric hematopoietic stem cell transplantation--50 years of progress

In the 1950s, the first infusions of hematopoietic stem cells were given as a form of treatment for childhood leukemia. This heralded the beginning of a field that has expanded to include the treatment of immune deficiencies, a variety of leukemias and solid tumors, and then genetic diseases. A number of milestones are highlighted, particularly in regard to the use of alternative sources of hematopoietic stem cells such as unrelated donors, peripheral blood stem cells and umbilical cord stem cells. In addition, newer techniques of using non-myeloablative preparative regimens helped to reduce the toxicity and long-term consequences of hematopoietic stem cell transplant. Many diseases now benefit from the replacement of the marrow stem cells and the provision of a new immune system and improved immune surveillance.     

Bone marrow transplantation and cord blood transplantation in children

OBJECTIVE: To review the indications, main steps and complications of bone marrow transplantation in children. SOURCES: Medline-based literature review. SUMMARY OF THE FINDINGS: We comment about the indications of autologous, allogeneic and syngeneic bone marrow transplantation, donor selections, harvest and infusion of the hematopoietic progenitor cells that will reconstitute the hematopoietic and immune systems. We describe the different conditioning regimens and the new sources of cells, such as cord blood. We also describe the most common events after the procedure, including infections, graft versus host disease, and cardiovascular, pulmonary, hepatic, genitourinary, and gastrointestinal complications. The late effects and their impact on quality of life are also discussed. CONCLUSIONS: Bone marrow transplantation does not confer an absolutely normal life span to all the patients; however, it represents the only chance of cure for children with certain neoplastic or immunological diseases. By knowing the steps of the procedure, pediatricians can be a source of information on bone marrow transplantation to the patients and their families.     

Pulmonary function in long-term survivors of pediatric hematopoietic cell transplantation

BACKGROUND: The purpose of this study was to determine the prevalence of pulmonary dysfunction in pediatric hematopoietic cell transplant (HCT) survivors and to identify associated risk factors. PROCEDURE: In a cross-sectional study, patients surviving at least 5 years after pediatric HCT were requested to undergo pulmonary function testing (PFT). Risk factors for restrictive lung disease (RLD) and obstructive lung disease (OLD) were analyzed using multivariate analysis. RESULTS: Among 472 patients contacted, 260 (55%) participated and 215 were selected for analysis. These patients were transplanted at a median age of 8.3 (0.3-18.0) years; 175 for hematologic malignancies and 40 for non-malignant diseases. The preparative regimens for 133 patients included fractionated TBI (FTBI), 29 single-fraction TBI (SFTBI), and 53 non-TBI regimens. PFT was performed at a median of 10 (5.0-27.5) years after HCT. Forty percent of patients had either RLD or OLD (28% RLD, 9% OLD, 3% mixed RLD/OLD) and at least 15% had an isolated low-DLCO. Moderate-to-severe impairment was present in 45% of patients with RLD or OLD. In multivariate analysis, risk factors associated with RLD included transplant regimen, transplant diagnosis, scleroderma/contracture, and donor relation. Patients treated with SFTBI had the highest risk of RLD. Risk factors for OLD included chronic graft-versus-host disease, transplant regimen, and time after HCT. Patients surviving 20 or more years after HCT had the highest risk of OLD. CONCLUSIONS: Fifty-five percent of long-term pediatric HCT survivors had pulmonary dysfunction. These findings stress the need for long-term follow-up to detect pulmonary dysfunction.     

脐血造血干细胞移植研究进展

随着血液学和移植免疫学的快速发展,尤其是人类白细胞抗原(HLA)配型技术的不断发展,造血干细胞移植(hematopoietic stem cell transplantation,HSCT)技术逐渐成熟并广泛应用,成为治愈某些血液病的重要方法,并有望在今后的生物学治疗和基因治疗中发挥重要的作用.     

Expression of vascular endothelial growth factor receptor 3 and Tie1 tyrosine kinase receptor on acute leukemia cells

BACKGROUND: Recent data indicate a role for angiogenesis in hematologic malignancies. In addition to promoting new vessel growth in the bone marrow microenvironment, angiogenic factors are regulators of both hematopoietic and leukemic cells. Activation of vascular endothelial growth factor receptor 3 (VEGFR-3) and Tie1 tyrosine kinase receptor are known to promote leukemia cell survival. The details of this complex angiogenesis-related interaction are still uncertain. PROCEDURE: We studied bone marrow samples from 73 patients with acute lymphoblastic (ALL) or myelogenous (AML) leukemia by using immunological methods. RESULTS: Vascular endothelial growth factor receptor 3 expression was found in 15% of the samples, particularly in samples with pediatric lymphoblastic leukemias and monocytic AMLs. Tie1 protein expression was found in 11% of the samples, all of which were from adult AML patients. CONCLUSIONS: Our findings suggest that there are angiogenesis-related differences between pediatric and adult lymphoblastic leukemias as well as between lymphoid and myeloid leukemias.     

Effects of iron and vitamin B12 deficiencies on peripheral blood colony‐forming unit capacity

Iron and vitamin B12 deficiencies are two of the most common diseases in the childhood group. Deficiencies of iron and vitamin B12 affect many systems in the body. In this study, to discover the effects of iron and vitamin B12 deficiencies on the hematopoietic stem cells, we studied CFU assay from peripheral blood. One hundred and two children were included in our study and were evaluated in five categories: iron deficiency, iron deficiency anemia, vitamin B12 deficiency, iron and vitamin B12 deficiency, and controls. As a result of statistical analysis, no significant difference was detected between five groups in terms of CFU assays. The results of our study suggest that, in emergent situations, stem cell samples can be collected before treatment with B12 or iron which are common deficiencies in donors of hematopoietic stem cell transplantation. We conclude that we could reach more accurate results by designing a study which contains more patients and includes in vivo results.