Allogeneic transplantation across the HLA barriers

In high-risk acute leukemia patients, a 10-fold increase in the dose of extensively T-cell-depleted hematopoietic stem cells ensures sustained full-donor engraftment of one-haplotype-mismatched transplants without graft-vs.-host disease. Since our first successful pilot study, which exploited the principle of a megadose stem cell transplant, our efforts have concentrated on developing new conditioning regimens, optimizing graft processing and improving the post-transplant immunologic recovery. The results so far achieved in more than 100 high-risk acute leukemia patients show that haploidentical transplantation is now a clinical reality. Because virtually all patients in need of a hematopoietic stem cell transplant have a full-haplotype-mismatched family donor, a T-cell-depleted mismatched transplant can be offered with curative intent, thus extending allogeneic transplantation procedures to virtually all candidates.     

Mesenchymal stem cells targeting the GVHD

Acute graft-versus-host disease(GVHD) occurs after allogeneic hematopoietic stem cell transplant and is a reaction of donor immune cells against host tissues.About 35%—50% of hematopoietic stem cell transplant(HSCT) recipients will develop acute GVHD.It is associated with considerable morbidity and mortality,particularly in patients who do not respond to primary therapy,which usually consists of glucocorticoids(steroids).Most of the available second-line and third-line treatments for steroid-refractory acut...     

Alloreactive killer cells: hindrance and help for haematopoietic transplants

Haematopoietic-cell transplantation is a treatment for leukaemia and lymphoma. To reduce the incidence of graft-versus-host disease (GVHD) caused by transplanted T cells, donors and recipients are HLA matched. For patients for whom a matched donor is not available, one option is transplantation from an HLA-mismatched relative who shares one HLA haplotype. This procedure is distinguished by the use of a stronger conditioning regimen for the patient and of a T-cell-depleted graft containing numerous stem cells. After transplantation, natural killer cells are prevalent, and they can include alloreactive cells that kill tumour cells and prevent GVHD. The alloreactions seem to be determined by the mismatched HLA class I ligands and their killer-cell immunoglobulin-like receptors.     

Invasive Fungal Infection in Haematopoietic Stem Cell Transplant Recipients: Epidemiology from the Transplant Physician’s Viewpoint

The practice of hematopoietic stem cell transplantation (HSCT) has undergone many changes that affect the likelihood that a given patient would develop an invasive fungal infection (IFI). The risks for IFI and the types of IFI that may occur are not continuous over the time course after transplantation. IFIs vary with the events that occur during the pre-engraftment neutropenic period, the early post-engraftment period until approximately day 100 post-transplant, and those in the late post-engraftment period after day 100. A number of well-recognized transplant recipient-, transplant procedure-, and transplant complication-related factors play a role in the likelihood of IFI. Important recipient-related factors include age, state of the underlying disease for which the HSCT is being done, and treatment-related history. Transplant procedure-related factors include the type of transplant (autologous or allogeneic), the use of and timing of anti-fungal prevention strategies including whether or not the transplant was conducted in a protected environment to minimize environmental exposure to mould conidia, the choice of conditioning (myeloablative or non-myeloablative), human leucocyte antigen-relatedness [autologous, matched related, mismatched related (including haploidentical pairings), unrelated (matched or mismatched)], stem cell source (bone marrow, peripheral, or cord blood), stem cell dosing, and stem cell product processing (red cell, plasma, or T-lymphocyte depletions, or CD34 selections). Transplant-related complications include duration of pre-engraftment period of neutropenia, graft failure or rejection, the degree of cytotoxic conditioning therapy-related intestinal mucosal damage, acute and chronic graft-versus-host disease (GvHD), the use of corticosteroids for the prevention or management of GvHD, the presence of cytomegalovirus infection and disease. The interaction of these factors over a given patient’s journey through HSCT conspires to promote or reduce the overall IFI risk and set the conditions for the development of any given IFI. The following discussion attempts to look at this from the perspective of the transplant physician struggling to account for these interactions and their attendant risks for IFI.     

Long-term engraftment of p18INK4C-deficient hematopoietic stem cells is enhanced in the sublethally-irradiated recipients

Hematopoietic stem cell transplantation (HSCT) has been widely used for the treatment of hematologi-cal malignancies and congenital deficiencies. In recent years, non-myeloablative and reduced-intensity condi-tioning regimens have significantly expanded t…     

Possible Role of Minor H Antigens in the Persistence of Donor Chimerism after Stem Cell Transplantation; Relevance for Sustained Leukemia Remission

Persistent complete donor chimerism is an important clinical indicator for remissions of hematological malignancies after HLA-matched allogeneic stem cell transplantation (SCT). However, the mechanisms mediating the persistence of complete donor chimerism are poorly understood. The frequent coincidence of complete donor chimerism with graft-versus-leukemia effects and graft-versus-host disease suggests that immune responses against minor histocompatibility antigens (mHags) are playing an important role in suppressing the host hematopoiesis after allogeneic SCT. Here, we investigated a possible relationship between donor immune responses against the hematopoiesis-restricted mHag HA-1 and the long-term kinetics of host hematopoietic chimerism in a cohort of 10 patients after allogeneic HLA-matched, HA-1 mismatched SCT. Functional HA-1 specific CTLs (HA-1 CTLs) were detectable in 6/10 patients lysing host-type hematopoietic cells in vitro. Presence of HA-1 CTLs in the peripheral blood coincided with low host hematopoiesis levels quantified by highly sensitive mHag specific PCR. Additionally, co-incubation of host type CD34⁺ cells with HA-1 CTLs isolated after allogeneic SCT prevented progenitor and cobblestone area forming cell growth in vitro and human hematopoietic engraftment in immunodeficient mice. Conversely, absence or loss of HA-1 CTLs mostly coincided with high host hematopoiesis levels and/or relapse. In summary, in this first study, presence of HA-1 CTLs paralleled low host hematopoiesis levels. This coincidence might be supported by the capacity of HA-1 CTLs isolated after allogeneic SCT to specifically eliminate host type hematopoietic stem/progenitor cells. Additional studies involving multiple mismatched mHags in more patients are required to confirm this novel characteristic of mHag CTLs as factor for the persistence of complete donor chimerism and leukemia remission after allogeneic SCT.     

Long-term engraftment of p18 INK4C-deficient hematopoietic stem cells is enhanced in the sublethally-irradiated recipients

Non-myeloablative regimens for host conditioning have been widely used in clinical hematopoietic stem cell transplantation due to their reduced toxicity on the recipients. But a milder conditioning regimen may require a higher engrafting ability of donor stem cells in competing with endogenous stem cells. Thus, new strategies for enhancing the competitiveness of donor stem cells in non-myeloablative recipients would have important implications for current clinical stem cell transplantation. It is known that the absence of p18 ^INK4C (p18) gene can enhance the self-renewal potential of hematopoietic stem cells (HSCs). We applied the approach of competitive bone marrow transplantation to evaluate the impact of p18 gene deletion on long-term engraftment of HSCs in sublethally irradiated hosts. We found that p18 ^−/− HSCs had a significant advantage over wild-type HSCs during long-term engraftment in the mouse recipients that received a sub-lethal irradiation (5-Gy). The engraftment efficiency of p18 ^−/− HSCs in the sub-lethally irradiated recipients was similar to that in the lethally irradiated (10-Gy) recipients. Our current study demonstrates that enhanced engraftment of donor HSCs in the absence of p18 does not strictly depend on the dose of irradiation used for host conditioning. Therefore, p18 might serve as a potential drug target for increasing the efficacy of stem cell transplant in the patients that are preconditioned with either a myeloablative or non-myeloablative regimen.     

Long-term engraftment of p18INK4C-deficient hematopoietic stem cells is enhanced in the sublethally-irradiated recipients

Non-myeloablative regimens for host conditioning have been widely used in clinical hematopoietic stem cell transplantation due to their reduced toxicity on the recipients. But a milder conditioning regimen may require a higher engrafting ability of donor stem cells in competing with endogenous stem cells. Thus, new strategies for enhancing the competitiveness of donor stem cells in non-myeloablative recipients would have important implications for current clinical stem cell transplantation. It is known that the absence of p18 ^INK4C (p18) gene can enhance the self-renewal potential of hematopoietic stem cells (HSCs). We applied the approach of competitive bone marrow transplantation to evaluate the impact of p18 gene deletion on long-term engraftment of HSCs in sublethally irradiated hosts. We found that p18 ^−/− HSCs had a significant advantage over wild-type HSCs during long-term engraftment in the mouse recipients that received a sub-lethal irradiation (5-Gy). The engraftment efficiency of p18 ^−/− HSCs in the sub-lethally irradiated recipients was similar to that in the lethally irradiated (10-Gy) recipients. Our current study demonstrates that enhanced engraftment of donor HSCs in the absence of p18 does not strictly depend on the dose of irradiation used for host conditioning. Therefore, p18 might serve as a potential drug target for increasing the efficacy of stem cell transplant in the patients that are preconditioned with either a myeloablative or non-myeloablative regimen.     

Advances in haplo-identical stem cell transplantation in adults with high-risk hematological malignancies

Allogeneic bone marrow transplant is a life-saving procedure for adults and children that have high-risk or relapsed hematological malignancies. Incremental advances in the procedure, as well as expanded sources of donor hematopoietic cell grafts have significantly improved overall rates of success. Yet, the outcomes for patients for whom suitable donors cannot be found remain a significant limitation. These patients may benefit from a hematopoietic cell transplant wherein a relative donor is fully haplotype mismatched. Previously this procedure was limited by graft rejection, lethal graft-versus-host disease, and increased treatmentrelated toxicity. Recent approaches in haplo-identical transplantation have demonstrated significantly improved outcomes. Based on years of incremental preclinical research into this unique form of bone marrow transplant, a range of approaches have now been studied in patients in relatively large phase Ⅱ trials that will be summarized in this review.     

Mouse models of graft-versus-host disease: advances and limitations

The limiting factor for successful hematopoietic stem cell transplantation (HSCT) is graft-versus-host disease (GvHD), a post-transplant disorder that results from immune-mediated attack of recipient tissue by donor T cells contained in the transplant. Mouse models of GvHD have provided important insights into the pathophysiology of this disease, which have helped to improve the success rate of HSCT in humans. The kinetics with which GvHD develops distinguishes acute from chronic GvHD, and it is clear from studies of mouse models of GvHD (and studies of human HSCT) that the pathophysiology of these two forms is also distinct. Mouse models also further the basic understanding of the immunological responses involved in GvHD pathology, such as antigen recognition and presentation, the involvement of the thymus and immune reconstitution after transplantation. In this Perspective, we provide an overview of currently available mouse models of acute and chronic GvHD, highlighting their benefits and limitations, and discuss research and clinical opportunities for the future.     

Autologous hematopoietic stem cell transplantation in chronic myeloid leukaemia with different clinical stages

For most chronic myeloid leukaemia patients the option of a potentially curative allogeneic stem cell transplantation is not available because of age or lack of donor. Alternative therapy with interferon-alpha appears to prolong survival but is probably not curative. The aim of the study is to analyse the clinical results of the first Hungarian autologous transplantations in CML. METHODS: Seven patients were treated with ICE-based regimen plus G-CSF with the aim of mobilising and collecting Ph-negative peripheral stem cells in the setting of autologous transplant program. Five patients had CML in first chronic phase and two in accelerated phase. All patients have been previously treated with interferon-alpha. RESULTS: Median value and ranges for harvested mononuclear cells, CD34(+) cells and CFU-GM were: 5.65x10(8)/kg (2.61-11.38), 1.48x10(6)/kg (0.216-3.5) and 3.43x10(4)/kg (0.243-11.6), respectively. Four out of seven autologous grafts have been transplanted. Busulfan conditioning was used in one case and TBI/Cy conditioning in three patients. All patients are alive and well post-transplant being on interferon-alpha therapy. CONCLUSIONS: Based on the clinical advantages of autologous transplantation including long-term chronic phase, achievement of second chronic phase and improved response to interferon-alpha therapy, the procedure can offer an alternative treatment in CML in lack of HLA-identical donor.     

Adoptive transfer of T cells transduced with a chimeric antigen receptor to treat relapsed or refractory acute leukemia: efficacy and feasibility of immunotherapy approaches

Treatment outcomes of acute leukemia(AL) have not improved over the past several decades and relapse rates remain high despite the availability of aggressive therapies. Conventional relapsed leukemia treatment includes second allogeneic hematopoietic stem cell transplantation(allo-HSCT) and donor lymphocyte infusion(DLI), which in most cases mediate, at best, a modest graft-versus-leukemia effect, although their clinical efficacy is still limited. Although allo-HSCT following myeloablative conditioning is a curative treatment option for younger patients with acute myeloid leukemia(AML) in a first complete remission(CR), allo-HSCT as a clinical treatment is usually limited because of treatment-related toxicity. The overall DLI remission rate is only 15%–42% and 2-year overall survival(OS) is approximately 15%–20%, with a high(40%–60%) incidence of DLI-related graft-versus-host disease(GVHD). Therefore, development of new, targeted treatment strategies for relapsed and refractory AL patients is ongoing. Adoptive transfer of T cells with genetically engineered chimeric antigen receptors(CARs) is an encouraging approach for treating hematological malignancies. These T cells are capable of selectively recognizing tumor-associated antigens and may overcome many limitations of conventional therapies, inducing remission in patients with chemotherapy-refractory or relapsed AL. In this review, we aimed to highlight the current understanding of this promising treatment modality, discussing its adverse effects and efficacy.     

Non-myeloablative stem cell transplantation and donor lymphocyte infusion for the treatment of cancer and life-threatening non-malignant disorders

Allogeneic bone marrow or blood stem call transplantation (BMT) represents an important therapeutic tool for the treatment of otherwise incurable malignant and non-malignant diseases. Until recently, autologous and allogeneic bone marrow and mobilized blood stem cell transplantations were used primarily to replace malignant, genetically abnormal or deficient immunohematopoietic compartments, and therefore highly toxic myeloablative regimens were considered to be mandatory for the effective eradication of all undesirable host-derived hematopoietic elements. Our preclinical and ongoing clinical studies have indicated that much more effective eradication of the host immunohematopoietic system cells can be achieved by adoptive allogeneic cell therapy with donor lymphocyte infusion following BMT. Thus, eradication of blood cancer cells, especially in patients with chronic myeloid leukemia and, less frequently, in patients with other hematologic malignancies, can frequently be accomplished despite the complete resistance of such tumor cells to maximally tolerated doses of chemoradiotherapy. Our cumulative experience has suggested that graft-vs.-leukemia (GVL) effects might be a useful tool for the eradication of otherwise resistant tumor cells of host origin. Based on the cumulative clinical experience and experimental data in animal models of human diseases, it appears that the induction of host-vs.-graft tolerance as an initial step may allow the durable engraftment of donor immunocompetent lymphocytes, which may be used for the induction of effective biologic warfare against host-type immunohematopoietic cells that need to be replaced, including malignant, genetically abnormal or self-reactive cells. Based on the aforementioned rationale, we speculated that the therapeutic benefit of BMT may be improved by using safer conditioning as part of the transplant procedure, with the goal being to induce host-vs.-graft tolerance to enable subsequent induction of GVL, possibly graft-vs.-tumor or even graft-vs.-autoimmunity effects, rather than attempting to eliminate host cells with hazardous myeloablative chemoradiotherapy. This hypothesis suggested that effective BMT procedures could be accomplished without lethal conditioning of the host, using new well-tolerated non-myeloablative regimens, thus possibly minimizing immediate and late side-effects related to the myeloablative procedures until recently considered to be mandatory for the conditioning of BMT recipients. Recent clinical data presented in this review suggest that effective BMT procedures may be accomplished with well-tolerated non-myeloablative stem cell transplantation (NST) regimens, with no major toxicity. Thus, new NST approaches may offer the feasibility of safer BMT procedures for a large spectrum of clinical indications in children and elderly individuals, without lower or upper age limits, while minimizing procedure-related toxicity and mortality. Taken together, our data suggest that high-dose chemotherapy and radiation therapy may be successfully replaced by a more effective biologic tool, alloreactive donor lymphocytes, thus setting the stage for innovative therapeutic procedures for safer and more effective treatment of patients in need of BMT.     

Factors affecting engraftment of allogeneic hematopoietic stem cells after reduced-intensity conditioning

Several factors influence the engraftment of allogeneic hematopoietic stem cells (HSC). Recently, there has been increased utilization of transplant-conditioning regimens that use reduced doses of chemotherapy and radiation that are considered to be non-myeloablative. These non-myeloablative (or reduced-intensity) allogeneic HSC transplants (RIST) decrease early post-transplant complications, but they are associated with higher incidences of mixed chimerism and graft rejection compared with transplantation after myeloablative condition-ing. RIST provides a unique opportunity to study allogeneic HSC engraftment. In particular, host immune status and stem cell graft composition have emerged as important factors affecting engraftment after RIST Based on these observations, it has been hypothesized that conditioning regimens and allograft composition can be tailored to an individual patients immune and disease status prior to transplant.     

CD4^＋CD25^＋Foxp3^＋调节性T细胞的体外扩增及其在移植物抗宿主病中的应用

同种异基因造血干细胞移植是急、慢性白血病及其他恶性血液病重要的治疗方法,但急慢性移植物抗宿主病（graft—versus-host disease,GVHD）作为异基因造血干细胞移植的主要并发症严重影响移植患者的存活率,阻碍移植的临床推广。很多研究发现,高表达Foxp3的CD4^＋CD25^＋调节性T细胞（regulatory T cells,Treg）不仅能控制急慢性GVHD的发生,而且不影响移植物抗白血病效应（graft-versusleukemia,GVL）,在急慢性GVHD发生发展及治疗方面有重要的作用。但Treg细胞在体内的数量很少,不能满足临床应用需求。目前应用外源的IL-2联合TCR、CD28信号通路共同刺激以及运用树突状细胞（dendritic cell,DC）刺激均能达到体外有效扩增Treg细胞的目的。这些扩增的Treg细胞在控制造血干细胞移植过程中急慢性GVHD的发生及防治自身免疫性疾病和移植排斥等方面具有明显作用,在疾病控制和临床应用中具有广阔前景。     

Escape of leukemia blasts from HLA-specific CTL pressure in a recipient of HLA one locus-mismatched bone marrow transplantation

A case of leukemia escape from an HLA-specific cytotoxic T lymphocyte (CTL) response in a recipient of bone marrow transplantation is presented. Only the expression of HLA-B51, which was a mismatched HLA locus in the graft-versus-host direction, was down-regulated in post-transplant leukemia blasts compared with that in pre-transplant blasts. All CTL clones, that were isolated from the recipient's blood when acute graft-versus-host disease developed, recognized the mismatched B(?)51:01 molecule in a peptide-dependent manner. The pre-transplant leukemia blasts were lysed by CTL clones, whereas the post-transplant leukemia blasts were not lysed by any CTL clones. The IFN-γ ELISPOT assay revealed that B(?)51:01-reactive T lymphocytes accounted for the majority of the total alloreactive T lymphocytes in the blood just before leukemia relapse. These data suggest that immune escape of leukemia blasts from CTL pressure toward a certain HLA molecule can lead to clinical relapse after bone marrow transplantation.     

Perspectives on establishing a public cord blood inventory in South Africa

The South African population is highly diverse, both ethnically and genetically. This diversity is particularly true for the African ancestry and various mixed ancestry population groups. These groups are under-represented in national and international bone marrow and peripheral blood donor registries, making it challenging to identify HLA-matched and mismatched unrelated donors when patients from these groups require allogeneic hematopoietic stem and progenitor cell transplantation. In most high-income countries, banked cord blood (CB) units provide an attractive source of hematopoietic progenitor cells for genetically diverse populations. SA does not have a public CB inventory, leaving many patients without access to this important treatment modality. Haploidentical transplantation provides an alternative. In recent years, the use of post-transplant cyclophosphamide has significantly reduced the incidence of graft-versus-host disease after haploidentical transplantation and has improved transplantation outcomes. However, it is difficult to identify suitable haploidentical donors in SA because of family disruption and a high prevalence of HIV. Here the authors provide a brief historical overview of the ethnic and genetic diversity of the country and region. The authors provide a southern African perspective on HLA diversity, consider the allogeneic hematopoietic stem and progenitor cell transplantation landscape and explore the need to establish a public CB bank (CBB) in SA. The health policy and regulatory frameworks that will impact on a CBB in the country SA are also explored. Finally, the authors discuss several matters we believe require attention when considering the establishment of a sustainable public CBB in the South African context.     

Antileukemia and antitumor effects of the graft-versus-host disease: a new immunovirological approach

In leukemic mice, the native host's explicit and well-defined immune reactions to the leukemia virus (a strong exogenous antigen) and to leukemia cells (pretending in their native hosts to be protected "self" elements) are extinguished and replaced in GvHD (graft-versus-host disease) by those of the immunocompetent donor cells. In many cases, the GvHD-inducer donors display genetically encoded resistance to the leukemia virus. In human patients only antileukemia and anti-tumor cell immune reactions are mobilized; thus, patients are deprived of immune reactions to a strong exogenous antigen (the elusive human leukemia-sarcoma retroviruses). The innate and adaptive immune systems of mice have to sustain the immunosuppressive effects of leukemia-inducing retroviruses. Human patients due to the lack of leukemiainducing retroviral pathogens (if they exist, they have not as yet been discovered), escape such immunological downgrading. After studying leukemogenic retroviruses in murine and feline (and other mammalian) hosts, it is very difficult to dismiss retroviral etiology for human leukemias and sarcomas. Since no characterized and thus recognized leukemogenic-sarcomagenic retroviral agents are being isolated from the vast majority of human leukemias-sarcomas, the treatment for these conditions in mice and in human patients vastly differ. It is immunological and biological modalities (alpha interferons; vaccines; adoptive lymphocyte therapy) that dominate the treatment of murine leukemias, whereas combination chemotherapy remains the main remission-inducing agent in human leukemias-lymphomas and sarcomas (as humanized monoclonal antibodies and immunotoxins move in). Yet, in this apparently different backgrounds in Mus and Homo, GvHD, as a treatment modality, appears to work well in both hosts, by replacing the hosts' anti-leukemia and anti-tumor immune faculties with those of the donor. The clinical application of GvHD in the treatment of human leukemias-lymphomas and malignant solid tumors remains a force worthy of pursuit, refinement and strengthening. Graft engineering and modifications of the inner immunological environment of the recipient host by the activation or administration of tumor memory T cells, selected Treg cells and natural killer (NKT) cell classes and cytokines, and the improved pharmacotherapy of GvHD without reducing its antitumor efficacy, will raise the value of GvHD to the higher ranks of the effective antitumor immunotherapeutical measures. Clinical interventions of HCT/HSCT (hematopoietic cell/stem cell transplants) are now applicable to an extended spectrum of malignant diseases in human patients, being available to elderly patients, who receive non-myeloablative conditioning, are re-enforced by post-transplant donor lymphocyte (NK cell and immune T cell) infusions and post-transplant vaccinations, and the donor cells may derive from engineered grafts, or from cord blood with reduced GvHD, but increased GvL/GvT-inducing capabilities (graft-versus leukemia/tumor). Post-transplant T cell transfusions are possible only if selected leukemia antigen-specific T cell clones are available. In verbatim quotation: "Ultimately, advances in separation of GvT from GvHD will further enhance the potential of allogeneic HCT as a curative treatment for hematological malignancies" (Rezvani, A.R. and Storb, R.F., Journal of Autoimmunity 30:172-179, 2008 (see in the text)). It may be added: for cure, a combination of the GvL/T effects with new targeted therapeutic modalities, as elaborated on in this article, will be necessary.     

Acute Antibody-Mediated Rejection in Presence of MICA-DSA and Successful Renal Re-Transplant with Negative-MICA Virtual Crossmatch

The presence of donor-specific alloantibodies (DSAs) against the MICA antigen results in high risk for antibody-mediated rejection (AMR) of a transplanted kidney, especially in patients receiving a re-transplant. We describe the incidence of acute C4d+ AMR in a patient who had received a first kidney transplant with a zero HLA antigen mismatch. Retrospective analysis of post-transplant T and B cell crossmatches were negative, but a high level of MICA alloantibody was detected in sera collected both before and after transplant. The DSA against the first allograft mismatched MICA*018 was in the recipient. Flow cytometry and cytotoxicity tests with five samples of freshly isolated human umbilical vein endothelial cells demonstrated the alloantibody nature of patient’s MICA-DSA. Prior to the second transplant, a MICA virtual crossmatch and T and B cell crossmatches were used to identify a suitable donor. The patient received a second kidney transplant, and allograft was functioning well at one-year follow-up. Our study indicates that MICA virtual crossmatch is important in selection of a kidney donor if the recipient has been sensitized with MICA antigens.     

Results of unrelated umbilical cord blood hematopoietic stem cell transplantation

The number of umbilical cord blood transplants is increasing worldwide. The purpose of Eurocord is to evaluate the results and to compare the outcome of umbilical cord blood transplants with allogeneic bone marrow transplants. Data have been reported to Eurocord by multiple transplant centers. Close links have been established with the cord blood banks through Netcord. Bone marrow transplant data have been provided by transplant centers and also through the European Group for Blood and Marrow Transplantation (EBMT) and International Bone Marrow Transplant Registries (IBMTR). Eurocord has analyzed the outcome of unrelated umbilical cord blood transplants from 121 transplant centers and 29 countries. The results showed that survival with unrelated mismatched umbilical cord blood transplants was comparable to that with unrelated bone marrow transplants. Engraftment with cord blood was delayed, resulting in an increased incidence of early transplant complications. The incidence of acute and chronic graft-vs.-host disease was reduced with cord blood grafts even in human leukocyte antigen (HLA)-mismatched transplants and in adults. In patients with leukemia, the rate of relapse was similar to the rate of relapse after bone marrow transplant. The overall event-free survival with umbilical cord blood transplantation was not statistically different when compared to bone marrow transplants. This large registry study confirms the potential benefit of using umbilical cord blood hematopoietic stem cells for allogeneic transplants.