Search

The development of hematopoietic stem cell transplantation (HSCT) programs can face significant challenges in most developing countries because such endeavors must compete with other government health care priorities, including the delivery of basic services. While this is may be a limiting factor, these countries should prioritize development of the needed expertise to offer state of the art treatments including transplantation, by providing financial, technological, legal, ethical and other needed support. This would prove beneficial in providing successful programs customized to the needs of their population, and potentially provide long-term cost-savings by circumventing the need for their citizens to seek care abroad. Costs of establishing HSCT program and the costs of the HSCT procedure itself can be substantial barriers in developing countries. Additionally, socioeconomic factors intrinsic to specific countries can influence access to HSCT, patient eligibility for HSCT and timely utilization of HSCT center capabilities. This report describes recommendations from the Worldwide Network for Blood and Marrow Transplantation (WBMT) for establishing HSCT programs with a specific focus on developing countries, and identifies challenges and opportunities for providing this specialized procedure in the resource constrained setting. Keywords: Bone marrow transplantation, Developing countries, Low income countries

Umbilical cord blood (UCB) emerged in the last 20 years as a valid alternative source of hematopoietic stem cell (HSC) in allogeneic transplantation setting, mainly in the absence of a fully human leucocyte antigen (HLA)-matched sibling. The probability of finding a matched unrelated donor through the registries varies from 20 to 70%, depending on the ethnicity of the patients. Therefore, patients in need may benefit of an HLA-mismatched hematopoietic stem cell transplantation from haploidentical donors or from UCB. One of the advantages of using UCB is the lower incidence of acute graft-versus-host-disease and allowance of greater HLA mismatch. Conversely, the low number of HSCs and lymphocytes and specific immunological features of T cells are associated with delayed engraftment and immune reconstitution and consequently, increased opportunistic infections. Nevertheless, retrospective studies showed similar results comparing UCB with other stem cell sources, both in pediatric and adult setting. The ability to use partially HLA-matched UCB units allows expanding the donor pool. Many UCB banks have strategies to increase their inventory including UCB grafts that have rare haplotypes. HLA and cell dose are very important factors associated with outcomes after umbilical cord blood transplantation (UCBT) that interact with each other. Increasing cell dose counterbalances the number of HLA disparities. Understanding those interactions, the role of HLA mismatches and other immunogenic factors, are important to allow clinicians to choose the best cord blood graft for patients. This review will describe the role of HLA in UCBT setting.

Le sang du cordon ombilical (SCO) est une source alternative de cellules souches hematopoietiques pour les patients porteurs de maladies hematologiques, en l’absence d’un donneur familial ou d’un donneur non apparente HLA identique. En comparaison avec d’autres sources de cellules souches, le SCO offre une logistique plus simple et une extension du nombre de donneurs potentiels avec la possibilite de faire des greffes HLA incompatibles. La possibilite de faire des greffes incompatibles de SCO avec des resultats comparables aux greffes de moelle identiques a permis d’etendre les indications a tous les patients, doublant ainsi le nombre de patients pouvant etre greffes, y compris ceux qui ont des groupes rares. Le choix judicieux d’une unite de SCO repose principalement sur la dose cellulaire (nombre total de cellules nucleees et de cellules CD34 positives [CD34+]) et les differences HLA. Il y une nette interaction entre ces deux parametres et les resultats de la greffe: la prise des neutrophiles et des plaquettes, la mortalite liee a la greffe, la maladie du greffon contre l’hote (GVHD) aigue et chronique, la rechute (pour les maladies malignes) et la survie. Comparees aux greffes de moelle osseuse, les greffes de SCO sont associees a une prise plus lente des neutrophiles et des plaquettes, une incidence de GVHD aigue et chronique (malgre des disparites HLA) reduite et une mortalite precoce liee a la greffe, une probabilite de rechute et une survie globale comparables, aussi bien pour les enfants que pour les adultes. Plus recemment, l’utilisation de deux unites de SCO, dite « double greffe », est en cours d’investigation dans le but d’ameliorer la probabilite de prise, surtout pour les adultes. Les analyses preliminaires indiquent que l’injection de deux unites de SCO est associee a un delai plus court pour la prise des neutrophiles et une probabilite de prise plus elevee quavec un seul SCO. L’utilisation de conditionnement a intensite reduite, dite greffe non myeloblative, est aussi une alternative avec des resultats encourageants, indiquee surtout pour les adultes plus âges ou porteurs de comorbidites.

The authors describe three cases of diffuse pulmonary calcification; two metastatic in children with acute transitory renal failure and the other dystrophic in a child with leukaemia. All three patients underwent haematopoietic stem cell transplantation (HSCT). Chest radiographs disclosed diffuse calcification within the lungs. The distribution of this calcification was bilateral but asymmetric. Diagnosis was made in two cases by high resolution computed tomography (HRCT) and in one case by HRCT and bone scan. Radiological characteristics, scintigraphic features, pathological mechanism and clinical outcome of such pulmonary calcification are discussed.

Invasive central nervous system aspergillosis is being seen with an increased frequency, particularly due to the increased number of immunosuppressed patients. The major cause of invasive central nervous system aspergillosis is bone marrow transplantation. In most cases, aspergillosis develops in the paranasal sinuses and in the lungs, and secondarily spreads to the brain. Imaging of cerebral aspergillosis may present different patterns depending on the lesion's age and the immunologic status of the patient. Lesions of the spinal cord are far less common but has been encountered in our series. In this article we review the clinical and radiologic features of aspergillosis affecting the central nervous system in patients who underwent bone marrow transplantation. Different CT and MR patterns are presented, including pertinent clinical and pathologic material. Significant morbidity and mortality can be associated with this fungal infection, and it is therefore incumbent upon the radiologist to identify intracranial aspergillosis as early as possible so that appropriate therapy can be administered.

PURPOSE To evaluate growth, thyroid function, puberty, cardiac function, and the incidence of cataracts in children who received allogeneic bone marrow transplantation (BMT) for acute myeloblastic leukemia (AML) in first complete remission (CR) after a preparation with or without total-body irradiation (TBI). PATIENTS AND METHODS Among 45 children studied, 26 received busulfan-cyclophosphamide (Bu-Cy) in preparation for transplantation and 19 received TBI. TBI was fractionated in nine cases and delivered as a single dose in 10. Four children in the Bu-Cy group and none in the TBI group had received prior cranial radiation. The mean follow-up duration after BMT was 5.9 years for the whole group. RESULTS The mean cumulative changes in height SD score (SDS) were -0.86 at 3 years and -1.56 at 5 years in the TBI group, whereas these changes were only -0.05 and -0.17 in the Bu-Cy group (P < .01 at 3 and 5 years). The 6-year probability of hypothyroidism was 9% +/- 8% in the Bu-Cy group and 43% +/- 15% after TBI (P < .02). Pubertal development after Bu-Cy was assessable in two girls and five boys: both girls had primary ovarian failure, whereas Leydig cell function appeared to be preserved in the five boys. One child who had received anthracycline when he was less than 1 year old developed cardiac dysfunction 4 years after Bu-Cy. The 6-year probability of cataracts was 70% +/- 13% in the TBI group and 0% after Bu-Cy. CONCLUSION The use of Bu-Cy represents an alternative transplant cytoreductive regimen for children with AML in first CR, which can reduce the risk of posttransplant growth impairment, thyroid dysfunction, Leydig cell damage, and the incidence of cataracts.

The PML (for 'ProMyelocytic Leukemia') gene product is a nuclear zinc finger protein, identified when the chromosomal translocation fusing this gene to the retinoic acid receptor was found in acute promyelocytic leukemia. Recently, a frequent occurrence of autoantibodies against the PML protein was detected in primary biliary cirrhosis (PBC) sera, suggesting that this protein could represent an autoantigenic trigger in PBC. Chronic GVHD features are close to those of PBC and in addition, antinuclear and antinucleolar antibodies are frequently detected in patients' sera. In order to determine if an abnormal expression of PML, followed by the development of anti-PML antibodies, can be implicated in chronic GVHD pathogenesis, we studied the expression of PML in the skin of seven patients with chronic GVHD as well as the presence of circulating anti-PML antibodies. PML was highly expressed by the lesional skin keratinocytes, but circulating antibodies were never detected. PML is induced by interferon (IFN) gamma. The expression of PML by GVHD epidermis is likely secondary to the IFN gamma produced by infiltrating lymphocytes. Since PML display growth suppressor properties, the role of this protein in tissue lesions is discussed.

Risk factors for the development of a new (secondary) malignancy after marrow transplantation are still incompletely defined. In the present study, we analyzed results in 700 patients with severe aplastic anemia treated with allogeneic marrow transplantation at the Fred Hutchinson Cancer Research Center in Seattle, WA, or at the Hopital St Louis in Paris, France. Twenty-three patients developed a malignancy 1.4 to 221 months (median, 91 months) after transplantation for a Kaplan-Meier estimate of 14% (95% confidence interval, 4% to 24%) at 20 years. Five cases were lymphoid malignancies (two acute lymphoblastic leukemias and three lymphoproliferative disorders) occurring 1.4 to 14.6 months (median, 3 months) posttransplant, and 18 were solid tumors (17 squamous cell and one mucoepidermoid carcinoma) presenting 30 to 221 months (median, 99 months) posttransplant. Thus, the hazard for lymphoid malignancies declined rapidly posttransplant, while the hazard for solid tumors increased progressively with time posttransplant. Risk factors for solid tumors identified in univariable analysis included the underlying diagnosis of Fanconi anemia (P = .0002), azathioprine therapy for chronic graft-versus-host disease (GVHD) (P < .0001), irradiation (total body or thoracoabdominal) as part of the conditioning regimen (P = .0002), chronic GVHD (P = .0099), acute GVHD (P = .0135), and male sex (P = .0499). In multivariable, stepwise proportional hazards models, azathioprine therapy (P < .0001) and the diagnosis of Fanconi anemia (P < .0001) were significant factors for all patients. Irradiation was a significant factor (P = .004) only if the time-dependent variable azathioprine was not included in the analysis. If only non-Fanconi patients were considered, azathioprine (P = .0043), age (P = .025), and irradiation (P = .042) were significant factors. Results in patients with Fanconi anemia and malignancies other than solid tumors were not subjected to an analysis because of the small number of events. It is of note, however, that no case of myeloproliferative disorder was observed. In summary, the highest risk of developing a solid tumor was associated with the diagnosis of Fanconi anemia. Better prevention of GVHD or omission of azathioprine as GVHD therapy (or both) may reduce the risk of late tumor development. Similarly, nonirradiation conditioning regimens may reduce the tumor risk, at least in patients without Fanconi anemia. Interactions between potential risk factors are complex, and further observation and additional analyses will be of interest.

Fanconi's anemia (FA), a disease characterized by malformations and progressive pancytopenia, can be successfully cured by allogeneic bone marrow transplantation. Due to the sensitivity of FA cells to alkylating agents, a modified conditioning regimen including low-dose cyclophosphamide (20 mg/kg) and 5 Gy thoracoabdominal irradiation has been used. We report here our experience with bone marrow transplantation in a series of 49 patients. In HLA-identical sibling transplants, the long-term survival was 75%. Results with matched unrelated transplants are limited by the small number of patients.

Fanconi anemia is a genetic disorder associated with diverse congenital abnormalities, progressive bone marrow failure, and increased risk of leukemia and other cancers. Affected persons often die before 30 years of age. Bone marrow transplantation is an effective treatment, but there are few data regarding factors associated with transplant outcome. We analyzed outcomes of HLA-identical sibling (N = 151) or alternative related or unrelated donor (N = 48) bone marrow transplants for Fanconi anemia performed between 1978 and 1994 and reported to the International Bone Marrow Transplant Registry. Fanconi anemia was documented by cytogenetic studies in all cases. Patient, disease, and treatment factors associated with survival were determined using Cox proportional hazards regression. Two-year probabilities (95% confidence interval) of survival were 66% (58% to 73%) after HLA-identical siblings transplants and 29% (18% to 43%) after alternative donor transplants. Younger patient age (P .0001), higher pretransplant platelet counts (P = .04), use of antithymocyte globulin (P = .005), and use of low-dose (15 to 25 mg/kg) cyclophosphamide plus limited field irradiation (P = .009) for pretransplant conditioning and cyclosporine for graft-versus-host disease prophylaxis (P = .002) were associated with increased survival. Bone marrow transplants are effective therapy for Fanconi anemia. The adverse impact of increasing age and lower pretransplant platelet count on transplant outcome favors earlier intervention, especially when there is an HLA-identical sibling donor.

Ionizing radiations have been reported as an in vitro apoptosis initiating stimulus in human lymphocytes. As the cytotoxicity of ionizing radiations and chemotherapeutic agents appears to be dependent on the efficacy of cell death induction, the manipulation of apoptosis initiation might be used as a means to supress some pathological process. In the present study the in vivo induction of gamma-ray mediated programmed cell death in humans is reported. The in vivo induction of apoptosis in peripheral blood lymphocytes (PBL) by ionizing radiations was investigated in 33 patients after each of two sessions (2 Gy and 4 Gy) of fractionated total body irradiation (FTBI) as part of their conditioning regimen before bone marrow transplantation. PBL committed to apoptosis were scored before irradiation (S1), 4 h (S2) and 24 h after 2 Gy (S3, 14-17 h after the second 2 Gy fraction). Nuclear morphology and chromatin-DNA were analysed by fluorescence microscopy immediately after blood sample withdrawal (I) and after 24 h in cell culture medium (II). When scored immediately after withdrawal, no circulating PBL with the apoptotic nuclear morphology were observed in S1 and S2 blood samples whereas S3 disclosed 21.9 +/- 11.7% of circulating lymphocytes with an apoptotic nuclear morphology. After 24 h in culture, S1 samples (before irradiation) generally contained less than 20% of apoptotic lymphocytes. A higher percentage of apoptotic cells was noted in some cases in relation with recent chemotherapy and possibly with pathology. After 24 h in culture, S2 and S3 samples contained 51.7 +/- 17.9% and 60.4 +/- 16.4% of apoptotic lymphocytes, respectively. These results confirm that ionizing radiations induce apoptosis in vivo in human lymphocytes and that the commitment to apoptosis can be determined after low doses (2 Gy) of therapeutic whole body irradiation. The results suggest that susceptibility to apoptosis induction by ionizing radiations could be related to previous therapy by cytotoxic drugs and possibly to the type of haematological malignancy.

Fanconi anaemia (FA) is an autosomal recessive disease featuring diverse clinical symptoms in addition to chromosomal instability and hypersensitivity to crosslinking agents. The much increased risk of FA patients developing leukaemia and squamous cell carcinomas makes FA an important model disease for cancer predisposition. Studies documenting the characteristics of FA cells and their response to environmental toxins have failed thus far to disclose the basic cellular process that is primarily disturbed in FA cells. Complementation analysis suggests that mutations in at least four different genes can cause FA (complementation groups FA-A to FA-D). The cDNA for FA-C has been cloned and found to encode a novel protein that localises to the cytoplasmic compartment of cells. Even though the protein's function is still unknown at present, research has now reached the point from where rapid progress to a detailed understanding of this syndrome may be foreseen.

Resume Nous avons mis au point une technique de PCR in situ pour les genes CD 34 et c-Kit dans des cellules mononucleees du sang peripherique humain. Apres depot et fixation des cellules sur des lames, afin de faciliter la penetration des reactifs necessaire a la PCR, une permeabilisation des membranes est effectuee par traitement a la proteinase K. La PCR terminee, une hybridation in situ est realisee en presence d'un oligonucleotide specifique marque a la digoxigenine. Ce marqueur ainsi lie au produit d'amplification est detecte par un anticorps antidigoxigenine marque par la phosphatase alcaline. L'addition des substrats de cette enzyme (le nitro-bleu tetrazolium [NBT] et le 5-bromo-4-chloro-3-indolyl phosphate [BCIP]) permet une revelation coloree en bleu-noir des cellulles dans lesquelles la PCR a ete realisee. Nous avons egalement montre que meme dans le cas de cellules fixees sur lame, un controle de la reaction d'amplification juste apres la PCR a ete effectue. En effet, la permeabilisation des membranes cellulaires provoque une diffusion du produit d'amplification vers l'exterieur de la cellule. En prelevant apres la PCR in situ le liquide reactionnel au-dessus des cellules, il est possible de visualiser par electrophorese en presence de bromure d'ethidium le produit d'amplification.

Adult peripheral blood (PB) endothelial progenitor cells (EPC) are produced in the bone marrow and are able to integrate vascular structures in sites of neoangiogenesis. EPCs thus represent a potential therapeutic tool for ischaemic diseases. However, use of autologous EPCs in cell therapy is limited by their rarity in adult PB. Cord blood (CB) contains more EPCs than PB, and they are functional after expansion. They form primary colonies that give rise to secondary colonies, each yielding more than 10(7) cells after few passages. The number of endothelial cells obtained from one unit of CB is compatible with potential clinical application. EPC colonies can be securely produced, expanded and cryopreserved in close culture devices and endothelial cells produced in these conditions are functional as shown in different in vitro and in vivo assays. As CB EPC‐derived endothelial cells would be allogeneic to patients, it would be of interest to prepare them from ready‐existing CB banks. We show that not all frozen CB units from a CB bank are able to generate EPC colonies in culture, and when they do so, number of colonies is lower than that obtained with fresh CB units. However, endothelial cells derived from frozen CB have the same phenotypical and functional properties than those derived from fresh CB. This indicates that CB cryopreservation should be improved to preserve integrity of stem cells other than haematopoietic ones. Feasibility of using CB for clinical applications will be validated in porcine models of ischaemia.

This study analyses the growth and the growth hormone secretion of children given various conditioning protocols before bone marrow transplantation (BMT). Twenty nine children (14 boys, 15 girls) given BMT were classified according to their conditioning protocol: total body irradiation (TBI) given as a single exposure of 10 Grays (Gy, group I, 11 cases), or 8 Gy (group II, four cases), 12 Gy given as six fractionated doses (Group III, seven cases), or chemotherapy alone (group IV, seven cases). The arginine-insulin stimulated growth hormone peak, 2-7.5 years after BMT, was > 10 micrograms/l in all patients except four from group I (6.9-8.9 micrograms/l). A second growth hormone secretion evaluation was performed in 10 group I patients because of persistent low growth velocity despite a normal growth hormone peak. There were no significant changes in the mean (SEM) stimulated growth hormone peak (18.4 (2.2) v 20.1 (3.6) micrograms/l) at 3 (0.3) to 5.2 (0.6) years after BMT. The sleep growth hormone peaks and concentrations (n = 6) were normal. The mean cumulative height changes (SD) during the three years after BMT were: -1.4 (0.2) in group I, -0.1 (0.4) in group II, -0.4 (0.2) in group III, and 1.5 (0.5) in group IV; this was significant in groups I and IV. The final heights of two monozygotic twins (BMT donor and recipient) had differed by 17.5 cm, despite them both having normal growth hormone peaks and puberty. Eight patients, treated for congenital immune deficiency syndrome, were growth retarded at the time of BMT. Of these, only those conditioned by chemotherapy alone had significant catch up growth (2(0.6)SD) while those conditioned by a single Gy exposure did not (0(0.4)SD). It is concluded that the total radiation dose is critical for growth evolution, as is the fractionation schedule. For the TBI doses and the interval since BMT studied, there was no correlation between growth hormone peak and the height loss. The rapidity of decreased growth velocity after TBI and the comparison between the monozygotic twins suggest that radiation induced skeletal lesions are partly responsible for the decreased growth.

In a study concerning five CMV-infected bone-marrow-transplant recipients, five congenital CMV diseases and appropriate controls, presence of high levels of circulating interferon (IFN) was demonstrated exclusively during the course of CMV disease. This interferon was predominantly "immune" or gamma interferon (γ-IFN). These results suggest that during CMV disease the interferon compartment of the immune response is modified.

Bacterial infection is a common complication after allogeneic bone marrow transplantation. It is related to the toxic effects of the conditioning regimen on mucosal surfaces, to bone marrow aplasia an

Aplastic anemia is a rare disease in children that is most commonly idiopathic and less often a hereditary disorder. Hereditary bone marrow failure (BMF) syndromes, however, should be considered both in children and in adults before any attempt at treatment. Precise diagnosis is important because it will modify prognostic treatment options and the results of bone marrow transplantation. In this review, we will report recent results of treatment of Fanconi anemia and other hereditary BMF syndromes.

The first cord blood (CB) transplant was performed in 1988 in a patient with Fanconi anemia. The donor was his HLA-identical sister who was known by pre-natal diagnosis to be HLA identical and not affected by the Fanconi mutation. The CB was collected and cryopreserved at birth. The transplant was successful without GvHD and the patient is currently alive and free of disease more than 15 years after transplant, with full hematologic and immunologic donor reconstitution. At the time of the first transplant, little was known about the biologic properties of CB cells and it was thanks to the pioneering work of H. E. Broxmeyer and E. A. Boyse, who studied the progenitor cell content of CB, and of A. D. Auerbach, who realized the pre-natal diagnosis of Fanconi anemia, that this transplant was possible. Since this first transplant, many questions have been answered but others are still open for further research. For example: would a single CB unit contain enough stem cells to permanently engraft children and adults? Would maternal cell contamination in fetal blood engraft and give severe GvHD? What are the immunologic properties of CB cells? How does it interfere with GvHD, GvL and immune reconstitution? Is the immune immaturity of CB lymphocytes able to overcome the HLA barrier and authorize HLA-mismatched transplants? Is it possible to establish CB banks for unrelated and related transplants? What would be the criteria for collection, quality control and cryopreservation?

The purpose of this article is to present the imaging appearance of central nervous system effects of therapy that may occur in patients treated for hematological malignancies. Imaging in these patients relates to complications of high-dose therapy, bone marrow transplantation, infections occurring in immunocompromised patients, central nervous system dysfunction due to failure of other organ systems, or cerebral hemorrhages due to platelet refractoriness. Rapid and accurate diagnosis is essential but often difficult, as neurological manifestations are rarely disease specific. Neurological imaging, in combination with electrophysiological studies as well as blood and cerebrospinal fluid investigations, may be helpful for diagnosing most of these complications, as well as in differentiating between the manifestations of the underlying disease and complications of the treatment.

Patients treated for hematological malignancies may develop central nervous system (CNS) complications at some point in the course of the disease. Some complications are caused by the underlying disease itself, while others are treatment-related. The latter include possible toxic side effects of irradiation and/or chemotherapy, infections caused by immunosuppression, thrombocytopenia, nutritional and metabolic stresses, and graft-versus-host disease (GVHD). As a result, CNS effects of therapy may be infectious, vascular, toxic, metabolic, or tumoral. Familiarity with these complications allows early recognition of most problems, and differentiation between CNS complications from the original disease and complications from the treatment. This is of clinical importance as — depending on the cause — patients may require additional or reinforced treatment, or withdrawal from therapy. This chapter presents a range of typical CT and MR imaging appearances of CNS therapeutic abnormalities seen in patients treated for hematological malignancies. Neurological imaging, in combination with electrophysiological studies as well as blood and cerebrospinal fluid investigations, may be helpful for diagnosing most of these complications, as well as in differentiating between the manifestations of the underlying disease and complications of the treatment. The main issues to keep in mind are that certain complications are most likely due to multiple underlying diseases, and that more than one complication can coexist.

Tresperimus, an analogue of 15-deoxyspergualine (15-DSG), has been found, in rodents, to induce a potent state of tolerance after organ and bone marrow allografts. In a previous study, we have reported that tresperimus at the optimal concentration of 0.5 microgram/ml supports the clonogenic potential of human cord blood CD34+ cells. Dose dependent inhibition of clonogenesis was also observed with complete reversibility following drug withdrawal. In this study, we tested the effect of 0.5 microgram tresperimus/ml on ex vivo expansion of primitive human cord blood CD34+CD38- cells. Our findings revealed that the total number of expanded cells was decreased in the presence of tresperimus. However, the multipotential and erythroid colonies were significantly increased in the presence of tresperimus compared with control cultures done without the test drug. Progenitor cell morphology was comparable in both test and control cultures. The telomerase activity was consistently lower in tresperimus-treated hematopoietic progenitors than in control cultures. These results suggest that tresperimus preserves primitive CD34+CD38- cells in a state of high potentiality while limiting the total number of their differentiated progeny. Bearing in mind that the test drug supports the clonogenic potential of CD34+ cells, the overall findings emphasize the importance of assessing the effect of tresperimus on in vivo long-term hematopoiesis which could predict the potential clinical use of tresperimus in the prevention of graft-versus-host disease in recipients of allogeneic bone marrow.

Contains fulltext : 186136.pdf (Publisher’s version ) (Closed access) The role of allogeneic bone marrow transplantation in lymphoma remains uncertain. We have analyzed 1185 allogeneic transplants for lymphoma reported to the EBMT registry between 1982 and 1998 and compared the results with those of 14687 autologous procedures performed over the same period. Patients receiving allogeneic transplants were subdivided according to histology: low-grade non-Hodgkin's lymphoma (NHL) 231 patients; intermediate-grade NHL 147 patients; high-grade NHL 255 patients; lymphoblastic NHL 314 patients; Burkitt's lymphoma 71 patients; and Hodgkin's disease 167 patients. These patients received allogeneic transplants as their first transplant procedure. Actuarial overall survival (OS) at 4 years from transplantation was: low-grade NHL 51.1%; intermediate-grade NHL 38.3%; high-grade NHL 41.2%; lymphoblastic lymphoma 42.0% years; Burkitt's lymphoma 37.1%; and Hodgkin's disease 24.7% years. These outcomes are relatively poor because of the high procedure-related mortality associated with these procedures, particularly in patients with Hodgkin's disease (51.7% actuarial procedure-related mortality at 4 years). Multivariate analysis showed that for all lymphomas apart from Hodgkin's disease, status at transplantation significantly affected outcome. A matched analysis was performed: for all categories of lymphoma, OS was better for autologous than for allogeneic transplantation. Relapse rate was better in the allogeneic group for low-, intermediate- and high-grade, and lymphoblastic NHL. It was equivalent for Burkitt's lymphoma and worse in the allogeneic group for Hodgkin's disease. Allogeneic transplantation appears to be superior to autologous procedures in terms of producing a lower relapse rate. The toxicity of allogeneic procedures must however be reduced before this translates into an improvement in OS.

Cord blood is an unlimited source of hematopoietic stem cells (HSCs) for allogeneic HSC transplant. Since the first human cord blood transplant performed 20 years ago, cord blood banks have been established worldwide for collection and cryopreservation of cord blood for allogeneic HSC transplant. More than 500 000 cord blood units are now available for international exchange of cord blood units. A global network of cord blood banks and transplant centers has been established for a common inventory and study of clinical outcomes. Results of unrelated allogeneic cord blood transplants in malignant and nonmalignant diseases, in adults and children, show that, compared with HLA-matched unrelated bone marrow transplant, cord blood has several advantages including prompt availability of the transplant, decrease of graft versus host disease and better long-term immune recovery resulting in a similar long-term survival. Several studies have shown that the number of cells is the most important factor for engraftment while some degree of HLA mismatches is acceptable. Progresses in this field are expected to facilitate engraftment including ex vivo expansion of stem cells, intra-bone injection of cord blood cells and double cord blood transplants.

PURPOSE: Several studies show that allogeneic peripheral blood stem cells (PBSCs) engraft more rapidly than bone marrow (BM). However, the data are inconsistent with regard to acute and chronic graft-versus-host disease (GVHD), relapse, transplant-related mortality (TRM), and leukemia-free survival (LFS). PATIENTS AND METHODS: Between January 1994 and December 2000, 3,465 adult patients (older than 15 years of age) were reported to the European Group for Blood and Marrow Transplantation Registry from 224 centers. Among acute myeloid leukemia (AML) patients, 1,537 patients received BM and 757 patients received PBSC. In acute lymphoblastic leukemia (ALL) patients, the corresponding figures were 826 versus 345 patients who were analyzed for engraftment, GVHD, TRM, relapse, LFS, and survival. RESULTS: In multivariate analysis, the recovery of neutrophils and platelets was faster with PBSC than with BM (P < .0001). Chronic GVHD was associated with PBSC in patients with AML (relative risk [RR], 2.11; 95% confidence interval, 1.66 to 2.7; P < .0001) and ALL (RR, 1.56; 95% confidence interval, 1.09 to 2.27; P = .02). PBSC versus BM in patients with AML or ALL was not significantly associated with acute GVHD, TRM, relapse, survival, or LFS. In multivariate analysis of patients with AML, factors significantly associated with improved LFS included first remission at transplant (P < .0001), promyelocytic leukemia (M3) versus other French-American-British types (P < .0001), and donor age below median 37 years (P = .02). In patients with ALL, first remission (P < .0001) and methotrexate included in the immunosuppressive regimen (P = .001) were associated with improved LFS. CONCLUSION: Allogeneic PBSC results in faster neutrophil and platelet engraftment and a higher incidence of chronic GVHD than BM. However, acute GVHD, TRM, relapse, survival, and LFS were similar in patients receiving PBSCs versus BM.

Toxoplasmosis is a rare but severe complication of bone marrow transplantation. Here, we report three patients in whom toxoplasmic pneumonitis developed, leading to fatal acute respiratory distress syndrome (ARDS). All patients had positive pretransplantation tests for Toxoplasma gondii and were therefore at risk to develop toxoplasmosis reactivation. They all recovered from aplasia, but soon after they died from brutal and severe ARDS. The possible role of an immunopathologic response to T gondii in the lungs in triggering ARDS is discussed.Early screening of parasitemia using highly sensitive polymerase chain reaction methods in seropositive patients with unexplained fever may be needed.

To evaluate the long-term immune reconstitution after allogeneic haematopoietic stem cell transplantation (SCT), we prospectively screened standard immune parameters in a series of 105 patients, at a median time of 15 months after SCT. Analysing lymphoid phenotypes, in vitro immune functions and immunoglobulin levels, we found that, more than 1 year post SCT, cellular and humoral immunity was still altered in a significant number of patients. CD4+ T cells were200/microl in one third of patients, and the CD4/CD8 ratio was still reversed in 78% of patients. Almost all patients showed positive T-cell responses against mitogens, but antigen-specific proliferation assays identified 20% to 80% of non-responders. B-cell counts were reconstituted in 61% of the patients, but levels of total immunoglobulins were still low in 59%. In multivariate analyses, human leucocyte antigen (HLA) disparity between donor and recipient and chronic graft-versus-host disease were the leading causes affecting immune reconstitution. Interestingly, cytomegalovirus (CMV) infections were strongly associated with normal CD8+ T-cell counts. Studying the impact of impaired immune reconstitution on the rate of infections occurring in the 6 years following screening, we identified three parameters (low B-cell count, inverted CD4/CD8 ratio, and negative response to tetanus toxin) as significant risk factors for developing such late infections.

Immune recovery after cord blood transplantation (CBT) is of concern owing to the low number of lymphocytes transferred with the graft and their immaturity. Risk factors influencing lymphocyte subset reconstitution related to disease, patient, donor and transplant were studied in 63 children (16 years), given either related (n = 14) or unrelated (n = 49) CBT for malignant (n = 33) or non-malignant diseases (n = 30). Only children with sustained myeloid engraftment were analysed. Absolute numbers of T (CD3(+), CD4(+), CD8(+)), B and natural killer (NK) cells were reported 2--3, 6, 9, 12 and 12--24 months after CBT. Median patient age was 4.0 years (0--15) and median follow-up was 23 months (1.7--61.0). Twenty-six patients received human leucocyte antigen (HLA)-matched CBT and 37 received HLA-mismatched CBT. The median number of nucleated cells (NCs) collected/recipient weight was 6.1 x 10(7)/kg. In this selected population, the estimate 2 year survival was 85%. Lymphocyte reconstitution (defined as the median time to reach the normal value of age-matched healthy children) was 3, 6 and 8 months for NK, B and CD8(+) cells, while it was 11.7 months for both CD3(+) and CD4(+) lymphocytes. In the multivariate analysis, factors favouring T-cell recovery were: related donor (P = 0.002); higher NCs/kg (P = 0.005) and recipient cytomegalovirus (CMV)-positive serology (P = 0.04). Presence of acute graft-versus-host disease (GVHD) delayed T-cell recovery (P = 0.04). To summarize, in children with sustained myeloid engraftment the concern that lymphocyte recovery after CBT could be delayed does not appear to be substantiated by our results.

We tested the immunosuppressive effect of cord blood (CB) natural killer (NK) cells using highly purified CB NK cells in mixed lymphocyte cultures (MLC) containing autologous CB T cells as responders. Control cultures were done without NK cells. Our findings revealed that CB NK cells induced a dose-dependent inhibition of T lymphocyte proliferation as evidenced by decreased 3H-thymidine incorporation in MLC. The T cell alloproliferation was significantly decreased in the presence of an NK cell to responder cell ratio of 0.1, 0.2 or 0.4 compared with control cultures done without NK cells (p=0.02, 0.003 and 0.0002, respectively). T lymphocyte inhibition was also achieved using irradiated CB NK cells and still demonstrable on addition of disparate CB NK and T cells to the MLC. In agreement with previous reports, adult blood NK cells inhibited the alloreactive T cells in the MLC using adult T lymphocytes as responders. Compared to control cultures done without NK cells, statistically significant inhibition of 3H-thymidine incorporation in MLC was observed at a ratio of NK cells to responder cells ratio of 0.2 or 0.4 (p=0.02). To investigate the mechanism whereby CB NK cells can interfere with the development of alloreactive T cells in MLC, we measured the tumour necrosis factor-alpha (TNF-alpha) concentrations in MLC supernatants using NK cell-depleted or unseparated CB mononuclear cells (MNC) as responders. The results revealed significantly high levels of TNF-alpha in the absence of NK cells (p=0.007). We conclude that CB NK cells suppress alloreactive T lymphocytes as do their counterparts in adult blood. However, the high NK to T cell ratio in CB could contribute to a more marked suppressive potential compared to that in adult blood. The mechanism of NK-mediated inhibition is likely related to disruption of the TNF-alpha pathway of T-lymphocyte activation.

We report three cases of typical aplastic anaemia (AA) associated with a Philadelphia chromosome. This translocation was detected at the time of diagnosis of AA (one patient) and when overt leukaemia was diagnosed (two patients: one chronic myeloid leukaemia and one acute lymphoblastic leukaemia) after AA therapy and recovery of blood counts. We discuss the literature arguments about considering some cases of AA as preleukaemic disorders and suggest that our cases illustrate the association of AA with a clonal malignant disorder. We conclude that cytogenetic analysis is necessary at diagnosis of AA or after recovery of blood counts.

Hemorrhagic cystitis (HC) is a common complication following allogeneic stem cell transplantation (SCT). In rare cases, it can be severe, inducing kidney failure and sepsis, and become life-threatening.We report three cases of severe HC in stem cell transplant recipients. Risk factors and the management of these patients were studied, as well as severe HC cases reported in the literature.All three patients received high-dose cyclophosphamide in addition to total body irradiation or busulfan in their preparative regimen. They underwent allogeneic SCT, one of them from unrelated cord blood. BK viruria was detected in two cases at the onset of hematuria. HC lasted for more than 3 months, resulting in urinary tract obstruction and sepsis. Ultimately, cystectomy was the last therapeutic procedure available to treat this life-threatening complication.We describe three patients, among a total of more than 1300 patients treated in our unit by allogeneic bone marrow transplantation, in whom HC was severe and long lasting enough to require cystectomy as a life-saving procedure.

Contains fulltext : 144689.pdf (Publisher’s version ) (Closed access) BACKGROUND: Systemic sclerosis (SSc, scleroderma) in either its diffuse or limited skin forms has a high mortality when vital organs are affected. No treatment has been shown to influence the outcome or significantly affect the skin score, though many forms of immunosuppression have been tried. Recent developments in haemopoietic stem cell transplantation (HSCT) have allowed the application of profound immunosuppression followed by HSCT, or rescue, to autoimmune diseases such as SSc. METHODS: Results for 41 patients included in continuing multicentre open phase I/II studies using HSCT in the treatment of poor prognosis SSc are reported. Thirty seven patients had a predominantly diffuse skin form of the disease and four the limited form, with some clinical overlap. Median age was 41 years with a 5:1 female to male ratio. The skin score was >50% of maximum in 20/33 (61%) patients, with some lung disease attributable to SSc in 28/37 (76%), the forced vital capacity being 25% after transplantation occurred in 20/29 (69%) evaluable patients, and deterioration in 2/29 (7%). Lung function did not change significantly after transplantation. One of five renal cases deteriorated but with no new occurrences of renal disease after HSCT, and the pulmonary hypertension did not progress in the evaluable cases. Disease progression was seen in 7/37 (19%) patients after HSCT with a median period of 67 (range 49-255) days. Eleven (27%) patients had died at census and seven (17%) deaths were considered to be related to the procedure (direct organ toxicity in four, haemorrhage in two, and infection/neutropenic fever in one). The cumulative probability of survival at one year was 73% (95% CI 58 to 88) by Kaplan-Meier analysis. CONCLUSION: Despite a higher procedure related mortality rate from HSCT in SSc compared with patients with breast cancer and non-Hodgkin's lymphoma, the marked impact on skin score, a surrogate marker of mortality, the trend towards stabilisation of lung involvement, and lack of other treatment alternatives justify further carefully designed studies. If future trials incorporate inclusion and exclusion criteria based on this preliminary experience, the predicted procedure related mortality should be around 10%.

In this retrospective multicentre study, we analysed the results of 82 consecutive second early allogeneic transplants for primary (n = 28) or secondary ([n = 54) graft failures performed between 1985 and 1997 in patients with acute leukaemia (n = 33), aplastic anaemia (n = 29) or chronic myeloid leukaemia (n = 20). HLA-matched siblings were used in 64 cases. The same donors were used for both transplants in 56 cases and the first transplant was T-cell depleted in 30 cases. The median age at transplant was 25 years and the median intertransplant time interval was 2 months. Estimates of the 3-year overall survival and day 100 transplant-related mortality were 30% and 53% respectively. A recipient age34 years at transplant, an intertransplant time intervalor = 80 d and a positive recipient cytomegalovirus serology were predictors of a better outcome. The use of cyclosporin A (CsA) after second transplant had a dramatic impact on outcome, the best results being observed with CsA alone. The day 40 probability of neutrophil recovery was 73%. The use of peripheral blood progenitor cells (PBPCs) was associated with a higher and faster neutrophil recovery. Other factors associated with neutrophil recovery were an intertransplant time intervalor = 80 d and a positive recipient cytomegalovirus serology. Therefore, second early allogeneic transplantation for graft failure is an effective treatment, especially if patients can receive CsA for graft-versus-host disease prevention and are retransplanted more than 80 d from first transplant.

Since it was shown that the number of haematopoietic stem cells contained in one sample of cord blood was sufficient for engrafting children and adults, cord blood banking has developed world wide. Cord blood banking has several advantages, including availability of this source of stem cells, low viral infection rate at birth, speed of the search and the possibility of collecting cord blood in ethnic groups under-represented in bone marrow donor registries. Other possible advantages which require further study, include a low risk of acute graft-versus-host disease, even with some degree of HLA mismatch. More than 700 cord blood transplants have been reported worldwide. The Eurocord Registry has analysed 250 cases. Briefly, analysis of the clinical results has shown that related cord blood transplants give better results than unrelated cord blood transplants. Factors associated with better survival in related and unrelated transplants were younger age, diagnosis with better results in inborn errors and children with acute leukaemia in first or second remission. High number of nucleated cells in the transplant and recipient negative cytomegalovirus serology were also favourable risk factors for survival.

Umbilical-cord blood as an alternative to bone marrow for hematopoietic stem-cell transplantation may lower the risk of graft-versus-host disease (GVHD).We studied the records of 113 recipients of cord blood from HLA-identical siblings from the period from 1990 through 1997 and compared them with the records of 2052 recipients of bone marrow from HLA-identical siblings during the same period. The study population consisted of children 15 years of age or younger. We compared the rates of GVHD, hematopoietic recovery, and survival using Cox proportional-hazards regression to adjust for potentially confounding factors.Recipients of cord blood were younger than recipients of bone marrow (median age, 5 years vs. 8 years; P0.001), weighed less (median weight, 17 kg vs. 26 kg; P0.001), and were less likely to have received methotrexate for prophylaxis against GVHD (28 percent vs. 65 percent, P0.001). Multivariate analysis demonstrated a lower risk of acute GVHD (relative risk, 0.41; P=0.001) and chronic GVHD (relative risk, 0.35; P=0.02) among recipients of cord-blood transplants. As compared with recovery after bone marrow transplantation, the likelihood of recovery of the neutrophil count and the platelet count was significantly lower in the first month after cord-blood transplantation (relative risk, 0.40 [P0.001], and relative risk, 0.20 [P0.001]), respectively. Mortality was similar in the two groups (relative risk of death in the recipients of cord blood, 1.15; P=0.43).Recipients of cord-blood transplants from HLA-identical siblings have a lower incidence of acute and chronic GVHD than recipients of bone marrow transplants from HLA-identical siblings.

Fanconi's anaemia is a severe refractory anaemia, associated with congenital malformations in approximately two-thirds of cases. Although these malformations may involve every organ system, suggestive dysmorphic features include growth retardation, radial ray deformities and urinary malformations. These malformations are not specific for Fanconi's anaemia, but should be recognized during pregnancy, or later in childhood, and suggest the possibility of inherited haematopoiesis disorders.

Major developments have occurred in the field of hematopoietic stem cell transplantation since the first successful transplants from HLA-identical siblings in the late 60's. The formally experimental procedure has become established therapy for a number of congenital or acquired disorders of the hematopoietic system and for chemotherapy-sensitive malignancies. Reduced transplant-related mortality has led to a widening of indications. The present review summarizes current issues and future prospects in allogeneic stem cell transplantation. These issues and prospects will include; stem cell sources, alternative donors, graft-versus-host disease, indications and long-term survival following allogeneic stem cell transplantation.

Since the demonstration that the number of hematopoietic stem cells contained in one cord blood was sufficient for engrafting children and adults, cord blood banking has developed worldwide. Cord blood banking for allogeneic unrelated and related transplants has several advantages including availability of this source of stem cells, low viral infection rate at birth, speed of search, and the possibility to collect cord blood in ethnic groups underrepresented in bone marrow donors registries. Another possible advantage includes the low risk of acute graft-versus-host disease (GVHD), even with some degree of HLA mismatch. Currently, more than 25 000 units are available for transplantation. To develop and evaluate cord blood transplant (CBT) results, the European Blood and Marrow Transplantation group (EBMT) has organized a concerted action, the Eurocord group. The objectives of Eurocord are to study the properties of hematopoietic progenitors and gene transfer in cord blood; to study the immune function of cord blood lymphocytes; to coordinate and facilitate the exchange of sera and cells from donor and recipients of cord blood transplants; to establish a European registry of patients treated by cord blood transplants; and to design protocols comparing cord blood transplants with alternative conventional blood and bone marrow hematopoietic stem cell transplants. Recently, Netcord, a nonprofit organization, was created for establishing criteria of qualification and accreditation of cord blood banks, and a network was set up between cord blood banks for facilitating donor search. The purpose is to ensure the quality of the cord blood units obtained for transplantation and to aid transplant centers in finding suitable units to increase the number of cord blood transplants (CBT) throughout the world. Briefly, recent analysis of the clinical results in 255 CBTs performed in 90 countries has shown that factors associated with better survival in related and unrelated transplants were younger age, diagnosis with better results in children with inborn errors, and acute leukemia in first and second remission. High numbers of nucleated cells in the transplant and recipient-negative CMV serology were also favorable risk factors for survival. The most important factor influencing engraftment was the number of cells infused.

Fanconi's anaemia (FA) is an autosomal recessive disorder characterized by progressive bone marrow failure that often evolves towards acute leukaemia. FA also belongs to a group of chromosome instability diseases. Because telomeres are directly involved in chromosomal stability and in cell proliferation capacity, we examined telomere metabolism in peripheral blood mononuclear cells (PBMC). Telomere length was significantly shorter in 54 FA patient samples, compared to 51 controls (P0.0001). In addition, mean telomere terminal restriction fragment lengths (TRF) in nine heterozygous patient samples did not differ from those of controls. In 14 samples from FA patients with severe aplastic anaemia (SFA), telomere length was significantly shorter than in 22 samples of age-matched FA patients with moderate haematological abnormalities (NSFA) (P0.001). However, no correlation was found between TRF length and the presence of bone marrow clonal abnormalities in 16 additional, separately analysed, patient samples. Sequential measurement of TRF in six FA patients showed an accelerated rate of telomere shortening. Accordingly, telomere shortening rate was inversely correlated with clinical status. Telomerase, the enzyme that counteracts telomere shortening, was 4.8-fold more active in 25 FA patients than in 15 age-matched healthy controls. A model for the FA disease process is proposed.