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Umbilical Cord Blood Transplantation: Current Scientific Understanding

NOTE:  This report, written in response to Resolution 504 (A-02), represents the medical/scientific literature and AMA policy on this subject as of June 2003.
Full Text

This report reviews the literature on umbilical cord blood transplantation (UCBT) and provides an update on the recent scientific developments in this field.  Based on the findings of this report, the Council on Scientific Affairs (CSA) also offers several recommendations for consideration.

Data Sources

  • Literature searches conducted in the MEDLINE database for English-language articles published between 1989 to 2003 using the search term “umbilical cord blood transplantation” yielded a combined total of 1280 references. One hundred and fifty-three articles directly relevant to the use of umbilical cord blood hematopoietic stem cells in transplantation published from 1995 to 2003 were selected for further review.Eighty additional references were culled from the bibliographies of these references.
  • Lexis/Nexis news databases were searched for current developments using the search term “cord blood transplantation.”
  • The World Wide Web was searched using the “Google” search engine with the search term “cord blood transplantation.” Relevant references were examined for accuracy and appropriateness.

Introduction

The use of hematopoietic cell transplantation following high-dose myeloablative chemoradiotherapy for the treatment of selected malignant and nonmalignant diseases is well accepted.1-11 The transplantation of hematopoietic stem cells (HSCs) has been used to cure diseases such as acute and chronic leukemia, primary immunodeficiency, aplastic and sickle cell anemia, and inherited metabolic and genetic disorders such as mucopolysaccharidoses and leukodystrophy.1-4,6-10 These HSCs are derived from 1 of 2 possible donors: the patient him/herself as in the case of an autologous transplant, or from another person, an allogeneic donor who may be related or unrelated to the recipient.1-10 Because the chances of finding a fully matched sibling are low, ranging from 25% to 30%,1-4 an unrelated donor (URD) is often used in allogeneic transplants. For patients without a well-matched sibling, the National Marrow Donor Program  and affiliated international registries have a database of more than 7.3 million volunteers who may be able to serve as a URD for stem cell transplantation.1,3,4,12 However, stem cell transplantation with URD grafts is frequently associated with severe graft-versus-host disease or graft rejection.1,4

There are 4 possible sources for the transplanted HSCs: (1) bone marrow; (2) fetal liver; (3) peripheral blood; and (4) umbilical cord blood.13   Fetal liver stem cell transplantation has demonstrated only transient engraftment and will not be considered in this report. Peripheral blood-derived HSCs, also not considered in this report, have harvesting risks similar to bone marrow but appear to have promise in patients with advanced-stage cancer.13 On the other hand, transplantation of HSCs derived from umbilical cord blood is characterized by ease of harvest with no risk to the donor, may permit successful transplantation of only partially matched HSCs, and thus has drawn increased interest from researchers as a viable alternative to bone marrow-derived HSCs for use in transplantation.

Human Leukocyte Antigen (HLA) Matching: For successful transfer of HSCs from a donor to a recipient, the transplanted cells and the recipient's body must recognize each other as “self.” Self-recognition is more likely to occur when there is a close match between the donor and the recipient, and this is determined by inherited surface markers, present on most cells of the body. These markers, known as human leukocyte antigens (HLAs), are encoded by a series of closely linked genes located on human chromosome 6. There are 2 distinct types of HLA genes existing in 6 pairs, the class I HLA A, B, C genes and the class II HLA DR, DQ, DP genes. One copy (or allele) of each pair is inherited from the father and one copy is inherited from the mother. HLA genes possess 2 characteristics that make them important in HSC transplantation, their high degree of polymorphism and the strong immune reactions that their products can evoke in other individuals. T-cells from one individual can react vigorously to mismatched HLA molecules on the surface of cells from another individual in what is known as an allogeneic reaction. In this circumstance, the immune system of the recipient will determine the graft to be foreign and reject it, or the graft itself will attack the recipient, resulting in graft-versus-host disease.

For purposes of matching HSC donors and recipients, 3 HLA pairs (for a total of 6 antigens) are tested, HLA-A, HLA-B, and HLA-DR. The National Marrow Donor Program requires a minimum 5 out of 6 antigen match between donors and recipients and in fact such partially matched transplants from adult volunteer marrow or blood stem cell donors are seldom performed.  Well matched (6 of 6 HLA antigen) donors are used most frequently.  Matching at HLA-C may also yield superior transplant outcomes, but has not been well studied in UCBT.14,15

Unrelated Donor (URD) Bone Marrow Transplantation (BMT): Brief Review

Challenges: Statistics from the National Marrow Donor Program show that less than 80% of Caucasians and only about 60% of African Americans have a suitably matched donor.16 On average, less than 50% of searches for URDs will yield a suitably matched bone marrow donor,17 and 4 months is the average time from formal search to transplant, if a suitable donor is found.18 The National Marrow Donor Program has stated that requests for an urgent search are generally accomplished in 4 to 6 weeks (J. Chell, personal communication, 2003).  For many patients with aggressive disease, who are relapsing or are suffering treatment-related toxicity, this time delay is unacceptable.4 Even when a potential donor is identified, the National Marrow Donor Program reports that 30% of identified matches are no longer available for reasons of donor attrition, such as geographical movement, loss of motivation, disqualification due to a change in medical status, death, or name change.1 Ultimately, less than 20% of people referred for a preliminary search through the National Marrow Donor Program actually proceed on to transplantation, although the patients’ clinical status and choice of alternative therapies also contribute to this low percentage.19 However, because of these limitations, UCBT is being studied as an alternative to BMT especially because of the potential to increase available graft sources for some recipients, such as those in need of urgent transplantation or minorities.

Engraftment Outcomes: Numerous studies have examined the engraftment of HSCs from both HLA-matched and HLA-mismatched unrelated bone marrow donors. These studies indicate that successful engraftment rates range from 84% to 99%, depending on the number of HLA matches and the type of disease being treated.20-27 The primary reason for graft failure is the level of mismatch at the HLA antigens. Thus, success is highest in treatment of leukemia using stem cells transplanted from sibling donors who match 6 out of the 6 HLA antigens.23 When 4 out of 6 HLA antigens match, which falls outside the National Marrow Donor Program’s acceptable criteria for transplantation, the engraftment rate drops to 84%. This is true for all conditions treated with BMT.1 Of particular importance is a match at the class I HLA determinant, HLA-C. In fact, more than a single mismatch at a class I antigen seems to increase graft failure significantly.14,15

Apart from HLA class I mismatch, other factors that have been implicated in decreased engraftment rates include: (1) depletion of T-cells from the graft20,28; (2) inherited metabolic disorders29; and (3) the disease being treated, with Fanconi anemia,30 aplastic anemia,31,32 and chronic myeloid leukemia33,34 demonstrating the lowest engraftment rates.

Graft Versus Host Disease (GVHD): An important toxicity accompanying the use of URD BMT is the risk of GVHD. Grades III and IV acute GVHD develop in 18% to 50% of recipients of HLA-matched, URD bone marrow transplants,20,34,35 while chronic GVHD occurs in 55% to 75% of these patients.34 As with engraftment, many studies now show that HLA mismatches are the primary risk factors for GVHD.36-41 In a large study of leukemia patients, occurrence of acute-grade II-IV GVHD varied from 29% in HLA-matched sibling donors, to as high as 63% in URD donors with a single mismatch.23 The extent of acute GVHD is also dependent on the disease being treated. In a study of pediatric patients with malignant and nonmalignant diagnoses, acute grade II-IV GVHD occurred in 83% of patients who received HSCs from donors that matched at 6 of 6 HLA antigens while 98% of recipients of HSCs that matched at 5 of 6 HLA antigens experienced grade II-IV GVHD.37 This study should be compared to the large National Donor Marrow Program study of all patients with malignant and nonmalignant diagnoses, in which 64% of recipients experienced grade II-IV GVDH.20 Age of the recipient also appears to have a role, albeit small, in the incidence of GVHD.1 The negative effects of GVHD may counter the positive benefits of the graft-versus-leukemia (GVL) effect associated with URD BMT.1 Graft-versus-leukemia occurs when immune cells present in the graft attack the leukemia cells in the recipient of the graft, and in patients with malignant disease may be beneficial.42,43 For certain diseases, such as chronic myelogenous leukemia, this GVL effect provides the critical and curative anti-leukemic component of the transplant.44

Chronic GVHD occurs in a significant number of HLA-matched recipients as well, ranging from 42% to 62%.23 Additionally, chronic GVHD occurs at levels as high as 73% in HLA-mismatched recipients.23,34 Severe chronic GVHD can result in mortality in greater than 50% of patients due to the compromise in immune function.45

Because of its negative effects, much effort has been made to reduce the incidence of GVHD in bone marrow transplant recipients. Since the primary reason for graft-versus-host reactions is due to donor T-cells in the graft HSCs, studies have examined the effects of T-cell-depleted donor grafts on GVHD in the recipient. T-cell depletion of the graft and younger recipient age lower the risk of GVHD.20,35 Significant improvement in the incidence and severity of GVHD has also been reported with T-cell-depleted grafts.46-50 However, T-cell-depletion can result in delayed immune reconstitution of the recipient or graft failure. Thus, it remains to be seen whether T-cell depletion of the donor graft or actual treatment of GVHD in the recipient is the better protocol for reducing GVHD in BMT recipients. A large trial comparing the 2 is currently under way.1

Immune Reconstitution: A primary indicator of the success of BMT is the extent of recovery of immune function by the recipient. Restoration of immune function is believed to occur in 2 steps. The first is the expansion of the mature T-cells that are present in the graft. The second phase involves the thymus-dependent development of nonantigen exposed T-cells that are probably derived from the infused HSCs.1,51 Thus, T-cell-depletion may negatively affect the success of immune reconstitution by deletion of early, mature T-cell function in the recipient. Importantly, occurrence of severe GVHD also impairs immune reconstitution.1,52,53

As already suggested, one benefit from the immune cells in the graft is the GVL effect. This effect, wherein the mature T-cells in the graft attack leukemia cells present in the recipient, is associated with a reduced risk of relapse after transplant.42,43,54 However, ultimately, the primary risk factors for relapse are associated with the type of disease (the most pronounced benefit is in leukemia) and the disease status at the time of transplant.

Survival and Event-free Survival Rates: Even when URD bone marrow is HLA-matched to the recipient, a substantial risk still exists for graft failure, GVHD, immune compromise, and decreased survival. When the graft is mismatched at 2 or more HLA antigens, the risk of morbidity and mortality increases substantially and most URD BMT is performed using well-matched (6 of 6 HLA antigens) donors.1,2,4,37,38,55-57 In general, it has been shown that overall survival rates increase, regardless of the type of disease or the type of malignancy, when the URD bone marrow transplant is performed early in the course of the disease, with the most promising results being achieved with HLA-A-, HLA-B-, and HLA-DRB1-matched URD bone marrow transplants for the treatment of early chronic myeloid leukemia.15,41,58

Ultimately, survival rates will improve as science provides more tools for the identification of unidentified transplant antigens that may be important in survival, graft failure, and GVHD. For example, it recently has been suggested that “ancestral haplotypes” like HLA-C and HLA-DQB1 may play important roles in optimizing the transplantation process following matching of the standard 6 HLA antigens.15,59,60

Umbilical Cord Blood Transplantation (UCBT)

History: Due to the challenges associated with the use of bone marrow derived-HSCs for transplantation, umbilical cord blood (UCB) is now being advanced as another potential source of HSCs. The initial idea for using HSCs derived from UCB came from Edward Boyse in 1983,4 based on the observation that the numbers of granulocyte-macrophage progenitor cells within the neonatal circulation remains greater than or equal to the numbers found in adult bone marrow even several hours after birth.61,62 It was then demonstrated in murine models that near-term or neonatal blood contained sufficient HSCs for the reconstitution of lethally irradiated adult mice.63

The first related-donor, UCB-derived HSCs were transplanted into a child with Fanconi anemia in 1988 by Gluckman,64 and the first URD UCBT occurred in 1993.3 Since then more than 2000 patients across the world, primarily children, have received related or unrelated UCB transplants for a variety of malignant and nonmalignant hematological diseases, congenital immunodeficiencies, and solid tumors.3,65 UCB banks now exist worldwide, with more than 70,000 units available for consideration for transplantation.1 Significantly, unlike bone marrow-derived HSCs, where an average of almost 4 months is required to identify a potential donor, it takes only an average of 14 days for a potential UCB match to be identified.3

Advantages and Challenges: There are advantages to using UCB-derived HSCs over bone marrow-derived HSCs for stem cell transplantation.4 The Table (PDF, 63KB) summarizes the potential benefits and challenges of UCBT and resources where more information can be found. There is an abundant supply of UCB and the continued expansion in the number of cord blood banks will allow extensive libraries of HLA types to be established from UCB units. Thus, theoretically it should be possible to maintain adequate representation of all races and ethnicities, a significant challenge with bone marrow-derived cells. However, at the current time, the problem of recruitment of cord blood from minorities has not been solved and better strategies are needed to recruit these donors.66 On the other hand, tracking of donors, donor attrition, and possible development of medical conditions in donors are not potential problems. UCB is easily collected after delivery, without the cost, anxiety, hospitalization, and postoperative pain associated with harvesting bone marrow.  However, there are significant up-front costs with a UCB program. Costs are lower when the UCB HSCs are actually used.  It costs about $1000 to collect process, test, and store a unit of UCB (which may never be used) while it only costs $75 to test and enter an adult volunteer marrow donor into the registry (J. Chell, personal communication, 2003). Once banked, UBC is routinely typed for HLA antigens and for ABO blood groups and tested for infectious agents, and then immediately made available for use, usually within 14 days.67 Graft-versus-host-disease appears to be reduced when UCB HSCs are used, even with a higher level of HLA mismatch (this is discussed in greater detail below).

The primary challenge for UCBT is that the total nucleated cell dose is critical for engraftment and for the survival of patients receiving UCB-derived HSCs.4 Thus, even though UCB has a higher percentage of progenitor cells than adult bone marrow,4,61,68,69 the fixed cell content that is ultimately derived from UCB represents a major challenge to expanding UCBT to adults. In fact, UCB transplants tend to have a 1-log decrease in the number of nucleated cells infused as compared to bone marrow transplants.70-72 Despite this limitation, there has been encouraging success with engraftment and survival (discussed below). It has been suggested that 1.5-2.0 X 107 nucleated cells infused/kg represents the lowest limits at which successful transplantation can occur.3 Associated with lower doses of infused cells are delayed engraftment and poor immune reconstitution. Conversely, in URD marrow transplants, higher numbers of infused donor cells have been associated with shorter periods until engraftment.73 While no definitive data exist, it is likely that survival and relapse of underlying disease are negatively affected by transplantation using smaller graft cell doses. The sections below describe the different outcomes associated with UCBT. It is clear that the major research focus for UCBT will be exploring ways by which the existing cells in an UCB graft can be expanded prior to transplantation.

Some uncertainties associated with UCBT will be better understood as more data emerge.4 Thus, there is still uncertainty about the GVL activity, the extent of post-transplantation lymphoproliferative disorder (PTLD, associated with Epstein-Barr virus infection),74 and the long-term durability of a UCB graft. In the event these occur, or if there are complications during transplantation, the original source of the graft will not be available for donation of additional HSCs.

Engraftment: As with bone marrow transplants, several factors influence the engraftment of UCB transplants. However, the most important factor for successful engraftment of UCB-derived HSCs is the total number of nucleated cells infused in the graft. Results of many large-scale studies indicate that the consistent factor contributing to more rapid engraftment and quicker hematopoietic recovery is infusion of a large number of nucleated cells.9,75-79 Thus, in the Gluckman study, more rapid engraftment was correlated with infused nucleated cells doses of greater than 3.7 x 107/kg body weight.75 Neutrophil recovery was found in 78% and 87% of patients by day 60 and platelet recovery was demonstrated in 62% of patients receiving cells from related UCB donors and 39% of patients receiving cells from URDs at day 60. On the other hand, doses of less than 1.5 x 107 nucleated cells/kg or 1.7 x 105 CD34+ cells/kg showed significantly reduced speed to and likelihood of engraftment.75 CD34+ is the marker associated with hematopoietic progenitor cells.

Rubinstein et al showed that increasing the numbers of nucleated cells infused in the graft was correlated with progressively shorter times to myeloid recovery, with doses greater than 2.5 x 107/kg showing similar results.76 Neutrophil recovery was demonstrated in 81% of patients by day 42 post-transplant and platelet recovery was shown in 85% of patients by day 180. Other studies have also demonstrated that doses below 1.5 x 107/kg infused are associated with dramatically poorer outcomes,7,80 and as a result, 1.5 x 107/kg is suggested as the minimal dose that should be infused in a UCB transplant.1,7

Other factors associated with successful engraftment, although not consistently reported in all studies, include HLA identity, younger age at transplantation, absence of infection after transplantation, absence of GVHD, and the type of disease being treated, with the best success reported with chronic myeloid leukemia and aplastic anemia.75 With respect to HLA identity, when HLA antigens are matched, the median time to successful engraftment as measured by neutrophil recovery was 23 days. However, when there were one or more HLA mismatches, the median time to neutrophil recovery increased to 28 days.75,76 Interestingly, the number of mismatches (1 versus 2 or more) did not result in any significant differences with respect to the engraftment properties of the graft.81

Graft-Versus-Host-Disease: As T-cells are the primary mediators of GVHD, it is predicted that UCB HSCs will pose a lesser risk of GVHD than bone marrow HSCs. This is because the number of T-cells in a UCB graft (8 x 106 CD3+ cells infused/kg recipient body weight) is far lower than the number (30-40 x 106/kg) infused with a bone marrow graft.4 Indeed, the incidence of GVHD associated with UCBT is significantly lower than that reported in BMT. This is made all the more impressive by the fact that many URD UCB transplants were performed with grafts mismatched by as many as 2 HLA antigens.1

However, to eliminate GVHD, the infused dose of T-cells must be lower than 0.1 x 106cells/kg; thus, there are probably other factors involved in the reduction of GVHD in UCBT. It has been suggested that the lower concentration of CD8+ T-cells may play a role, or that the relative immaturity of the T-cells found in UCB cells may lead to tolerance rather than alloactivation following repeated exposure to alloantigens.4 Finally, the unique, less pro-inflammatory cytokine profile secreted by UCB cells following activation has also been suggested to play a role in the reduced GVHD rate in UCB transplants.4

As with bone marrow transplants, HLA-mismatch is another potential risk factor for GVHD in UCB HSCs recipients, although unlike marrow transplants, the connection is less clear.1,4 Thus, while many studies report no impact of HLA-antigen mismatches on the incidence of acute or chronic GVHD,12,75,77,82 some studies suggest that the reason is that the impact of HLA-mismatch is only observable with related-donor UCB transplants, and is not seen with URD UCB transplants.75,82 In fact, in both related and unrelated UCBT, as well as in HLA-matched and HLA-unmatched grafts, the incidence and severity of acute and chronic GVHD is significantly less than for recipients of bone marrow transplants.1,4 Further, a large study performed by Rubinstein indicates that HLA-mismatch results in significantly higher rates of acute GVHD but has no impact on chronic GVHD.76 Interestingly, it appears that the age of the recipient does not affect the incidence of severe GVHD in UCB transplants, with adults receiving HLA-mismatch showing rates of severe GVHD similar to pediatric recipients.12

Based on these studies, in URD UCBT, despite HLA mismatching at 2 or more HLA antigens, the combined incidence of grade II-IV acute GVHD is reported to range from 35% to 40%, while the incidence of grade III-IV GVHD ranged from 11% to 22% and the incidence of chronic GVHD ranged from 0% to 25%.9,75-77 This demonstrates that, at least in children, UCB HSCs are definitively associated with reduced incidence of GVHD in transplanted patients.

Immune Reconstitution: Transplantation of HSCs generally occurs after ablative total body irradiation, and thus it is obvious that immune system reconstitution must be a primary goal of the transplant. Absent adequate immune reconstitution, the body is left vulnerable to post-transplantation infections that significantly increase morbidity and mortality. Because UCB grafts intrinsically have a lower T-cell count, with many of these T-cells being antigen-naïve, it has been proposed that UCB grafts would be less effective at immune reconstitution.

However, studies of immune reconstitution following UCBT are few in number and are hampered by variables affecting immune recovery. These variables include the dose of UCB HSCs that was infused, the conditioning regimen that these cells may have undergone, any GVHD prophylaxis that may have occurred, the degree of HLA mismatch, and the actual development of acute GVHD. However, an examination of the studies that exist suggests that immune reconstitution following UCBT, as measured by natural killer (NK) cell numbers and B- and CD4+ T-cell recovery, is similar to that obtained after BMT.83-86  Detailed analyses of early and late infections after UCB grafting have not been reported.

Disease Relapse and Graft-Versus-Leukemia Activity: One beneficial aspect of the presence of immune cells in the graft is that while they contribute to GVHD, they can also mediate a GVL effect that can help reduce the rate of future relapse.1,4,87 However, since UCB grafts have lesser numbers of existing T-cells and these cells tend to be antigen-naïve, it is believed that UCB transplants will also have a weaker GVL effect.1,88 This remains to be seen, although it is clear that GVHD is less severe in recipients of UCB transplants and that the development of GVHD is inversely correlated to the risk of disease relapse.43,89-91 However, the relationship between GVHD and the GVL effect remains to be elucidated.87 Finally, several major studies have demonstrated that UCB grafts are no different from bone marrow grafts in long-term, disease-free survival rates, suggesting that regardless of the cause, relapse rates are not much different between patients receiving either treatment.9,79,92

Current data indicate that for UCB transplants the biology and status of the disease at the time of transplantation are important factors in the relapse rate. One study conducted in one institution suggests that age and malignancy risk group are 2 factors implicated in increased relapse.77 A study with the Eurocord bank shows that with acute leukemia, the status of the disease at the time of transplant was most important.82 In this study, the 2-year incidence of relapse and the likelihood of 2-year survival without disease relapse in the high-risk groups were 75% and 7%. In the low-risk groups, these same percentages were 31% and 40%. This indicates that when the disease status is favorable at the time of transplant there is about a 2-fold reduction in incidence of relapse and a 4-fold increase in the number of patients surviving 2 years without a relapse.

Survival Rates: Many studies have looked at the survival rates following UCBT. These studies indicate that the most important criterion for survival is the dose of UCB HSCs infused with the graft. As with engraftment, it is postulated that cell doses less than 1.5 x 107 nucleated cells/kg result in significantly poorer survival outcomes, even though patients receiving low cell numbers may still be able to engraft.12,75,77 In fact, transplantation with doses below this cell number is generally no longer performed.

HLA mismatch likely plays another major role, although there is still uncertainty as to the extent of its impact.1 In studies by Locatelli et al, Gluckman et al, and Laughlin et al, HLA mismatches ranging from 1 to 3 antigens showed no association in overall survival rates in pediatric and adult patients following UCBT.12,75,82 However, larger trials conducted by Rubinstein and coworkers76 and Wagner and coworkers77 have suggested that with URD UCBT, HLA-mismatch is significantly associated with decreased survival rates.

Finally, there are data indicating that higher nucleated, specifically CD34+, cell doses can actually help compensate for HLA mismatches between graft and recipient.77 This is supported by a study from the New York Blood Center suggesting that if the nucleated cell dose is increased by about 3 x 107/kg, the negative effects of 1 HLA mismatch between graft and recipient can be overcome.1 However, more studies are needed to confirm this observation.

UCBT in the Adult Population: As indicated by the previous discussion, the factor hindering more widespread use of UCB transplants in adults is cell dose. Laughlin12 has published the first major adult UCBT series. In this study, the UCB grafts were primarily mismatched at 1 to 2 HLA antigens and the average dose of cells infused was 2.1 x 107 nucleated cell/kg. Significantly, 90% of patients demonstrated successful neutrophil engraftment at a median of 27 days, and the incidence of acute grade II-IV GVHD was 60%. Chronic GVHD occurred in 38% of patients. HLA mismatch did not significantly affect the rate of engraftment, GVHD, or survival. However, by 22 months, the probability of event-free survival was only 26%.

The high mortality rate in this study is likely related to the high-risk nature of the patient population. Despite this mortality rate, the importance of this study is that the engraftment statistics and the incidence of GVHD are acceptable for as many as 2 mismatched HLA antigens, and in fact compare favorably with results obtained with BMT. Thus, the use of UCB cells in adults demands research to increase the number of UCB HSCs that can be infused.

Intrinsic Properties of UCB: HSCs are the most developmentally primitive cells of the hematopoietic system and can give rise to a variety of primitive lineages that will develop into the mature cells of the hematopoietic system. The following progenitor cell lineages are derived from the hematopoietic stem cell: (1) the burst-forming unit-erythroid (BFU-E); (2) the colony-forming unit-granulocyte macrophage (CFU-GM); and (3) the CFU-megakaryocyte (CFU-Mk). It is clear that UCB-derived HSCs have both numerical and functional characteristics that are different from those derived from bone marrow.  In the absence of a definitive assay to measure the properties of a human long-term progenitor cell, surrogate assays have revealed unique properties of UCB HSCs that are not found in their bone marrow counterparts. UCB are more enriched for the primitive, committed progenitor cell lineages and for long-term culture-initiating cells than both bone marrow and peripheral blood sources.4,93-96 Thus, 7- to 10-day in vitro cultures of CD34+ UCB cells yield an increase in cell number that is several hundredfold better than bone marrow cells.97 Accordingly, compared to marrow-derived cells, UCB cells possess both a higher proliferative potential and a greater capacity to self-renew, which has been suggested to be due to longer telomere length in the UCB cells.98

Functionally, human UCB-derived cells appear to engraft immunodeficient mice better with fewer cell numbers than bone marrow- or peripheral blood-derived cells.2 In vitro, UCB HSCs also respond to the presence of exogenous cytokines via proliferation and expansion far better than bone marrow cells.2 This may explain why UCB cells engraft at lower cell doses than bone marrow-derived cells, although there is a longer delay to engraftment. Because the immune system of a neonate is functionally immature, it has been demonstrated that UCB grafts have reduced antigen- and mitogen-induced proliferative T-cell responses,99,100 potential tolerance induction,101,102 and reduced ability to mount an alloantigen-specific cytotoxic T-cell response.103 NK cell number and function remain intact,1 but lytic activity may be deficient,104 providing a possible explanation for the maintenance of GVL activity in UCB grafts.

A Comparison of URD, BMT and UCBT

No prospective, side-by-side studies have been performed to compare the outcomes associated with UCBT with BMT. Three studies have examined the 2 techniques retrospectively, and the majority of the analyses below are derived from these 3 studies.9,79,92

Engraftment: Barker and co workers compared HLA-A, -B, and –DRB1 matched URD bone marrow transplants with UCBT mismatched at 0 to 3 HLA antigens. Patients receiving bone marrow transplants also received prophylaxis for GVHD. In this study, it was observed that the median time to engraftment as measured by neutrophil recovery was 29 days for those receiving URD UCB cells while the time to engraftment was 22 days for those receiving URD bone marrow cells.92 However, after 45 days, the overall myeloid engraftment rate was comparable for both treatments. If time to platelet engraftment is examined, no statistical difference can be discerned between the 2 therapies.

However, in another retrospective study, Rocha et al demonstrated a similar delay in the engraftment time for UCB transplants as measured by both neutrophil recovery and platelet engraftment.9 Thus, at day 60, neutrophil recovery had occurred in 96% of patients receiving unmanipulated BMT, while 80% of patients receiving UCB-derived cells had neutrophil recovery. Ninety percent of patients who received T-cell-depleted BMT had neutrophil recovery by day 60. In another earlier study with HLA identical siblings, these same workers showed that, by day 60, 98% of patients receiving BMT had neutrophil recovery while 89% of those receiving UCB cells had neutrophil recovery.79

Thus, it is clear that myeloid engraftment occurs more slowly and less frequently in recipients of UCB HSCs than in recipients of bone marrow HSCs. The principal reason for primary graft failure and delayed hematopoietic recovery is the limited cell dose. However, UCB grafts appear to also have limited alloreactivity, and while 80% to 90% engraftment rates may be lower than the percentages obtained with bone marrow transplants, these levels are acceptable, especially for patients without another reasonable treatment option. Thus, emphasis should be placed on methods to expand the number of UCB HSCs that can be infused into patients.

Graft-Versus-Host-Disease: As indicated above, patients receiving UCB transplants have significantly lower rates of GVHD than those receiving bone marrow transplants.24,105 In a study where outcomes of HLA-identical sibling UCBT were compared to HLA-identical sibling BMT, there was a significantly lower incidence of both acute and chronic GVHD in the UCB recipients.79 Thus, when patients are controlled for HLA identity, UCBT poses a lower risk of GVHD.

In comparing studies examining GVHD in URD bone marrow and UCB recipients, it was demonstrated that despite 1 to 2 antigen HLA mismatches in those receiving UCB cells, the risk of developing either acute or chronic GVHD was similar to, or even lower than, the risk in those receiving HLA-matched BMT.9,13,20,37,40,75,76,92,106 However, the reason for this lower risk of GVHD remains to be elucidated. There are suggestions that it may be related to the intrinsic properties of the UCB cells. For example, UCB lymphocytes are functionally and phenotypically more immature, comprising primarily naïve T-cells that have not been exposed to antigen.102,107,108 On the other hand, large numbers of mature, antigen-specific T-cells are infused in a bone marrow graft and these cells can initiate GVHD because of cross-reactivity of HLA antigens.108 However, these same T-cells are also involved in the GVL effect and are implicated in the repopulation of T-cells in the first year after a bone marrow transplant.109 This may thus also partially explain the delay in engraftment observed with UCB transplants.  Alternatively, data also implicate the lower number of T-cells infused with an UCB transplant as responsible for the reduced GVHD rates.80,110

Relapse and Graft-Versus-Leukemia Activity: In a study limited to pediatric acute leukemia patients,9 UCB graft recipients were compared to children receiving either bone marrow transplants or T-cell-depleted bone marrow transplants. While this is only a single study, the data suggest that: (1) those receiving UCB transplants and T-cell-depleted bone marrow transplants had a lower incidence of acute and chronic GVHD when compared to those receiving undepleted bone marrow grafts; and (2) the T-cell-depleted group, but not the group receiving UCB grafts, had a higher risk of disease relapse when compared to the undepleted bone marrow graft recipients. This is made more impressive by the fact that the group receiving UCB and undepleted bone marrow transplants had a higher proportion of advanced stage leukemia than the group receiving T-cell-depleted BMT.

In another study, Rocha and co-workers demonstrated that the 3-year survival in patients with malignant diagnoses receiving UCBT compared favorably with those receiving bone marrow-derived HSCs, suggesting that the risk of relapse in UCB recipients is no worse than in bone marrow recipients.79 Additionally, in a study of patients with either malignant or nonmalignant diagnoses who received either bone marrow or UCB grafts, Barker and coworkers reported better 2-year survival rates in those receiving UCB grafts.92

Despite the reduced GVHD activity in UCB grafts, there does not appear to be a higher rate of disease relapse in patients receiving these grafts. Observations that the recipient’s major histocompatibility (MHC) antigens induce tolerance in UCB donor cells better than they do in bone marrow-derived donor cells,101,102,108 and that GVL activity remains intact with UCB grafts, suggest that there is a cell population in UCB grafts that is compensating for the relative immaturity of the lymphocyte population in UCB grafts. Thus, the relative immaturity of the lymphocyte population in the UCB graft would be easily tolerized101 against the recipient MHC antigens, while the above postulated population of cells would serve to mediate the GVL effect and perhaps even assist in minimizing post-transplantation infection. It has been proposed that these are NK cells.107,111,112 Indeed, data exist to indicate that UCB grafts retain NK cell activity and that these cells can mediate a GVL effect in vitro.113-115 More recently, this hypothesis has been supported by data indicating that infusion of donor-derived alloreactive NK cells not only provides a GVL effect, but also reduces the risk of GVHD by targeting recipient antigen-presenting cells.116

Survival and Event-free Survival Rates: In terms of survival rates, results from studies indicate that at least with pediatric patients, the transplantation of UCB cells with limited HLA mismatch is an acceptable alternative to HLA-matched bone marrow transplants. Thus, one study comparing pediatric UCB recipients with at least one HLA mismatch to pediatric URD bone marrow recipients where 62% of patients demonstrated HLA identity found similar survival rates.117 When the mismatch in the UCB donor cells was increased to 2 HLA antigens, survival rates were reduced. In another pediatric leukemia study, children receiving UCB grafts mismatched at up to 2 HLA antigens, had a significantly earlier risk of death associated with the transplant, but this has not been reported by other investigators thus far.1 Early mortality associated with the transplantation can also be explained by the fact that the children receiving UCB cells were much sicker than those receiving bone marrow-derived cells. However, looking at overall survival rates between UCB transplants with up to 2 HLA antigen mismatchs and bone marrow transplants, it is clear that the 2 are quite comparable.9

Proposed Algorithm for Selecting an Unrelated Donor Graft

Two recent publications have proposed algorithms for the search process for URD HSCs for transplantation.1,3 The Figure (PDF, 73KB) presents both these algorithms as they were published.  The algorithms are similar and propose that a simultaneous search for a donor be conducted in both bone marrow and UCB registries. The source of HSCs to be selected should then be based on several factors; ie: (1) the urgency of the transplant; (2) the availability of an HLA-identical bone marrow donor; (3) the cell dose available for the UCB; and (4) the degree of HLA mismatch in the UCB units. There is a significant difference in time needed to identify a potential UCB match than to identify a potential bone marrow match. Thus, if urgent transplantation is needed, UCB may well be the best choice. Additionally, a UCB graft with 0 to 2 HLA antigens mismatched is may be preferred over a bone marrow graft that is mismatched at 1 HLA antigen, as long as the dose of cells infused is more than 1.5-2.0 x 107 nucleated cells.3 However, for satisfactory results, a dose of >3.0 X 107 cells/kg should be sought.  In disease conditions where HSC transplantation is associated with a high risk of graft rejection, or where need for the donor lymphocytes may arise after transplantation, then a bone marrow source may be the better option.1

Future Directions for Umbilical Cord Blood Transplantation

As data emerge on UCBT, delayed engraftment, not HLA identity, appears to be the primary barrier to more widespread use of UCBT. Thus, new approaches are needed to enhance the rate and degree of engraftment. While, clearly, the primary reason for delayed engraftment is the low cell dose in UCB grafts,118 it is also possible that the relative immaturity of the progenitor cells as determined by cell surface markers and proliferative responses to cytokines, or the lack of facilitating cells in the graft may also play roles.2,119

With respect to expanding the number of cells that can be infused, efforts are under way on several fronts. These include optimizing the UCB collection process, combining multiple units of closely matched, unrelated UCB cells, and ex vivo expansion.120-123 With respect to the combination of multiple units or unrelated but closely matched UCB HSCs, there was initial concern that immunologic rejection would occur. However, it has now been reported that mixed chimeras can be successfully created after the transplantation of UBC HSCs from 2 partially matched unrelated donors.120,124

Ex vivo expansion of UCB HSCs seeks to enhance specific cellular functions by culturing the cells in specific conditions.  One potential benefit is the ability to increase the number of cells infused in UCB grafts, but other applications include the expansion of specific cell types within the UCB graft to eliminate problems (such as post-transplantation neutropenia or thrombocytopenia); gene transfer technology; immunotherapy; and tumor purging.2 However, given the primary limitation of UCBT, significant effort is being placed into augmenting the HSC number in UCB grafts.

Nevertheless, several barriers need to be considered. First, the expansion of numbers of cells must not compromise their critical functions of self-renewal, multilineage differentiation capacity, and the ability to repopulate a myeloablated host. How the success of an ex vivo expansion is measured must be appropriate to the goal of the expansion. If increasing the dose of infusable cells is the objective, then the outcome of successful ex vivo expansion must be measured in terms of engraftment, differentiation potential, and longevity. However, the regulatory signals that govern how HSCs develop are still poorly understood and both intrinsic and extrinsic factors have critical roles. It is known that cellular contact with bone marrow stroma, and the cellular regulators that it produces, plays a role in the self-renewal of stem cells. Accordingly, culture conditions where cells are maintained in contact with bone marrow stroma have been able to support the maintenance and expansion of human progenitor cells.125,126 The use of stromal feeder cells derived from human sources has also been shown to support long-term repopulating cells.123,127 However, significant uncertainty still remains about whether such systems, either independently or as co-cultures, are truly needed for ex vivo expansion.

Recent research has therefore focused on the use of stroma-free culture systems containing specific choice and concentration of hematopoietic growth factors. What the optimum levels of these factors are remains to be established. Indeed, in animal models, these culture systems have had success in supporting limited expansion of cells that retain their capability to repopulate immunodeficient animals.107,128,129 However, a recent study demonstrated that while ex vivo expansion of a CD34+ population of UCB cells generates increased mature cells and progenitors capable of more rapid engraftment compared to unexpanded UCB cells, these expanded cells lack secondary and tertiary engrafting potential and therefore are not able to sustain the graft long term.122 Accordingly, these new data suggest that clinical protocols may need to use 2 separate populations of cells, an expanded UCB population to provide more rapid, but short-term, engraftment, and an unexpanded population to provide long-term engraftment.

Indeed, the use of separate populations of cells for engraftment has already been explored in a clinical feasibility study.121,130 In this study, 37 patients (25 adults and 12 children) received UCBT.130 However, before infusion, either 40% or 60% of each patient’s UCB graft was CD34-selected and then expanded ex vivo for 10 days in defined media with granulocyte-colony stimulating factor, stem cell factor, and thrombopoietin prior to infusion. The remaining cells (60% or 40%) were infused into the patients without further manipulation. Patients received a median of 0.99 x 107 total nucleated cells (expanded and unexpanded) per kg body weight. The median time to engraftment of neutrophils was 28 days and of platelets was 106 days. All patients that could be followed for longer than 28 days demonstrated neutrophil engraftment and at a median follow up of 30 months, 13 of 37 patients survived. Significantly, the majority of these patients received only a total of 0.99 x 107 cells/kg, a dose traditionally associated with poor engraftment, suggesting that the ex vivo expansion actually contributed to successful engraftment.

While preliminary, this study raises much hope for the future of UCBT; however, further research on the ex vivo expansion of UCB HSCs is needed.

Conclusions/Other Considerations

There are clear advantages to the use of UCBT and it is a viable alternative to BMT when appropriately considered for the individual patient. However, uncertainties remain about the use of UCB for transplantation and there is great need for additional scientific research in this exciting arena to improve options for its use.  Thus, there is a continued need to educate both physicians and their patients on the available options and limitations that are currently associated with UCBT.

The second resolve of Resolution 504 (I-02) specifically asks for legislation to promote the use of UCBT. However, this report focuses only on the scientific aspects and there remain ethical, economic, and social issues that need to be considered prior to the AMA endorsing such legislation.65,131,132  Examples of these issues include:

Should parents be advised to bank their own child’s UCB at birth for potential future autologous use or should the UCB be collected and centrally banked?

  • Should UCB be collected routinely without consent?
  • How should the issues of autonomy in making decisions about donation of cord blood be handled?
  • Should parents be informed if testing and screening of UCB reveals infection or genetic disease?
  • Who should be informed, if anyone, should nonpaternity be discovered during testing of UCB?
  • How should physicians and parents be advised on the existence of privately owned for-profit companies that bank UCB for a fee?

The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists have raised similar questions and have provided some guidance on these issues.131,132  Current AMA ethical opinion E-2.165 (AMA Policy Database) generally concludes that it is ethical to use UCB but does not address the specific issues raised above.  It is likely that in addition to more scientific research, some standardized guidance on these issues will need to be created before more universal support of, and advocacy for, UCBT can occur.

RECOMMENDATIONS (Adopted AMA Policy and Directives)

The following statements, recommended by the Council on Scientific Affairs, were adopted by the AMA House of Delegates as AMA policy and directives at the 2003 AMA Annual meeting:

  1. The AMA urges physicians to recognize that umbilical cord blood transplantation is a viable alternative to bone marrow transplantation in appropriately selected patients. (Policy)
  2.  The AMA encourages continued research into the scientific issues surrounding the use of umbilical cord blood-derived hematopoietic stem cells for transplantation, including the ex vivo expansion of umbilical cord blood-derived hematopoietic stem cells; the combination of multiple units of closely matched, unrelated umbilical cord blood cells for transplantation; and the improvement of umbilical cord blood cells collection techniques. (Directive)
  3. The AMA will work with appropriate organizations to educate physicians and the public about the potential benefits of, and limitations to, umbilical cord blood transplantation as an alternative to bone marrow transplantation. (Directive)
  4. The AMA encourages the development of national standardized guidance to address the ethical, economic, and social issues surrounding umbilical cord blood transplantation. (Policy) Back to top 

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References

  1. Grewal SS, Barker JN, Davies SM, Wagner JE. Unrelated donor hematopoietic cell transplantation: marrow or umbilical cord blood? Available at: http://www.bloodjournal.org/cgi/content/abstract/2002-08-2510v1. Accessed: 3-10-2003.
  2. Lewis ID. Clinical and experimental uses of umbilical cord blood.  Intern Med J. 2002;32:601-609.
  3. Barker JN, Wagner JE. Umbilical cord blood transplantation: current state of the art.  Curr Opin Oncol. 2002;14:160-164.
  4. Wadlow RC, Porter DL. Umbilical cord blood transplantation: where do we stand?  Biol Blood Marrow Transplant. 2002;8:637-647.
  5. Lasky LC, Lane TA, Miller JP, et al. In utero or ex utero cord blood collection: which is better?  Transfusion. 2002;42:1261-1267.
  6. Sanz MA, Sanz GF. Unrelated donor umbilical cord blood transplantation in adults.  Leukemia. 2002;16:1984-1991.
  7. Gluckman E. Hematopoietic stem-cell transplants using umbilical-cord blood.  N Engl J Med. 2001;344:1860-1861.
  8. Locatelli F, Rocha V, Reed W, et al. Related umbilical cord blood transplant in patients with Thalassemia and Sickle Cell Disease.  Blood. 2003;101:2137-2143.
  9. Rocha V, Cornish J, Sievers EL, et al. Comparison of outcomes of unrelated bone marrow and umbilical cord blood transplants in children with acute leukemia.  Blood. 2001;97:2962-2971.
  10. Gluckman E, Locatelli F. Umbilical cord blood transplants.  Curr Opin Hematol. 2000;7:353-357.
  11. Institute of Cellular Medicine. ICM Treatment. Available at: http://www.alshucb.org/. Accessed: 3-10-2003.
  12. Laughlin MJ, Barker J, Bambach B, et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors.  N Engl J Med. 2001;344:1815-1822.
  13. Korbling M, Anderlini P. Peripheral blood stem cell versus bone marrow allotransplantation: does the source of hematopoietic stem cells matter?  Blood. 2001;98:2900-2908.
  14. Petersdorf EW, Hansen JA, Martin PJ, et al. Major-histocompatibility-complex class I alleles and antigens in hematopoietic-cell transplantation.  N Engl J Med. 2001;345:1794-1800.
  15. Petersdorf EW, Longton GM, Anasetti C, et al. Association of HLA-C disparity with graft failure after marrow transplantation from unrelated donors.  Blood. 1997;89:1818-1823.
  16. National Marrow Donor Program. African American Facts & Figures. Available at: http://www.marrow.org/NMDP/aa_facts_figures.html. Accessed: 3-6-2003.
  17. Confer DL. The National Marrow Donor Program. Meeting the needs of the medically underserved.  Cancer. 2001;91:274-278.
  18. National Marrow Donor Program. Physician FAQs. Available at: http://www.marrow.org/FAQS/physician_faqs.html. Accessed: 3-6-2003.
  19. National Marrow Donor Program. General FAQs. Available at: http://www.marrow.org/FAQS/general_faqs.html. Accessed: 3-6-2003.
  20. Kernan NA, Bartsch G, Ash RC, et al. Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program.  N Engl J Med. 1993;328:593-602.
  21. Davies SM, Wagner JE, Weisdorf DJ, et al. Unrelated donor bone marrow transplantation for hematological malignancies-current status.  Leuk Lymphoma. 1996;23:221-226.
  22. Anasetti C. Transplantation of hematopoietic stem cells from alternate donors in acute myelogenous leukemia.  Leukemia. 2000;14:502-504.
  23. Szydlo R, Goldman JM, Klein JP, et al. Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings.  J Clin Oncol. 1997;15:1767-1777.
  24. Madrigal JA, Scott I, Arguello R, et al. Factors influencing the outcome of bone marrow transplants using unrelated donors.  Immunol Rev. 1997;157:153-166.
  25. Beatty PG, Boucher KM, Mori M, Milford EL. Probability of finding HLA-mismatched related or unrelated marrow or cord blood donors.  Hum Immunol. 2000;61:834-840.
  26. Ash RC, Horowitz MM, Gale RP, et al. Bone marrow transplantation from related donors other than HLA- identical siblings: effect of T cell depletion.  Bone Marrow Transplant. 1991;7:443-452.
  27. Ash RC, Casper JT, Chitambar CR, et al. Successful allogeneic transplantation of T-cell-depleted bone marrow from closely HLA-matched unrelated donors.  N Engl J Med. 1990;322:485-494.
  28. Trigg ME, Billing R, Sondel PM, et al. Clinical trial depleting T lymphocytes from donor marrow for matched and mismatched allogeneic bone marrow transplants.  Cancer Treat Rep. 1985;69:377-386.
  29. Peters C, Krivit W. Hematopoietic cell transplantation for mucopolysaccharidosis IIB (Hunter syndrome).  Bone Marrow Transplant. 2000;25:1097-1099.
  30. MacMillan ML, Auerbach AD, Davies SM, et al. Haematopoietic cell transplantation in patients with Fanconi anaemia using alternate donors: results of a total body irradiation dose escalation trial.  Br J Haematol. 2000;109:121-129.
  31. Storb R, Thomas ED, Weiden PL, et al. Aplastic anemia treated by allogeneic bone marrow transplantation: a report on 49 new cases from Seattle.  Blood. 1976;48:817-841.
  32. Storb R, Thomas ED, Buckner CD, et al. Allogeneic marrow grafting for treatment of aplastic anemia: a follow- up on long-term survivors.  Blood. 1976;48:485-490.
  33. Giralt S, Szydlo R, Goldman JM, et al. Effect of short-term interferon therapy on the outcome of subsequent HLA-identical sibling bone marrow transplantation for chronic myelogenous leukemia: an analysis from the international bone marrow transplant registry.  Blood. 2000;95:410-415.
  34. McGlave PB, Shu XO, Wen W, et al. Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years' experience of the national marrow donor program.  Blood. 2000;95:2219-2225.
  35. McGlave P, Bartsch G, Anasetti C, et al. Unrelated donor marrow transplantation therapy for chronic myelogenous leukemia: initial experience of the National Marrow Donor Program.  Blood. 1993;81:543-550.
  36. Petersdorf E, Anasetti C, Servida P, Martin P, Hansen J. Effect of HLA matching on outcome of related and unrelated donor transplantation therapy for chronic myelogenous leukemia.  Hematol Oncol Clin North Am. 1998;12:107-121.
  37. Balduzzi A, Gooley T, Anasetti C, et al. Unrelated donor marrow transplantation in children.  Blood. 1995;86:3247-3256.
  38. Beatty PG, Anasetti C, Hansen JA, et al. Marrow transplantation from unrelated donors for treatment of hematologic malignancies: effect of mismatching for one HLA locus.  Blood. 1993;81:249-253.
  39. Martin PJ, Petersdorf EW, Anasetti C, Hansen JA. HLA homozygosity and the risk of graft-versus-host disease.  Tissue Antigens. 1997;50:119-123.
  40. Anasetti C, Beatty PG, Storb R, et al. Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma.  Hum Immunol. 1990;29:79-91.
  41. Petersdorf EW, Longton GM, Anasetti C, et al. The significance of HLA-DRB1 matching on clinical outcome after HLA-A, B, DR identical unrelated donor marrow transplantation.  Blood. 1995;86:1606-1613.
  42. Weiden PL, Sullivan KM, Flournoy N, Storb R, Thomas ED. Antileukemic effect of chronic graft-versus-host disease: contribution to improved survival after allogeneic marrow transplantation.  N Engl J Med. 1981;304:1529-1533.
  43. Horowitz MM, Gale RP, Sondel PM, et al. Graft-versus-leukemia reactions after bone marrow transplantation.  Blood. 1990;75:555-562.
  44. Weisdorf DJ, Anasetti C, Antin JH, et al. Allogeneic bone marrow transplantation for chronic myelogenous leukemia: comparative analysis of unrelated versus matched sibling donor transplantation.  Blood. 2002;99:1971-1977.
  45. Atkinson K, Horowitz MM, Gale RP, et al. Risk factors for chronic graft-versus-host disease after HLA-identical sibling bone marrow transplantation.  Blood. 1990;75:2459-2464.
  46. Aversa F, Tabilio A, Velardi A, et al. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype.  N Engl J Med. 1998;339:1186-1193.
  47. Drobyski WR, Hessner MJ, Klein JP, et al. T-cell depletion plus salvage immunotherapy with donor leukocyte infusions as a strategy to treat chronic-phase chronic myelogenous leukemia patients undergoing HLA-identical sibling marrow transplantation.  Blood. 1999;94:434-441.
  48. Hale G, Zhang MJ, Bunjes D, et al. Improving the outcome of bone marrow transplantation by using CD52 monoclonal antibodies to prevent graft-versus-host disease and graft rejection.  Blood. 1998;92:4581-4590.
  49. Sehn LH, Alyea EP, Weller E, et al. Comparative outcomes of T-cell-depleted and non-T-cell-depleted allogeneic bone marrow transplantation for chronic myelogenous leukemia: impact of donor lymphocyte infusion.  J Clin Oncol. 1999;17:561-568.
  50. Martin PJ,  Rowley SD, Anasetti C, et al. A phase I-II clinical trial to evaluate removal of CD4 cells and partial depletion of CD8 cells from donor marrow for HLA-mismatched unrelated recipients.  Blood. 1999;94:2192-2199.
  51. Emerson SG, Gale RP. The regulation of hematopoiesis following bone marrow transplantation.  Int J Cell Cloning. 1987;5:432-449.
  52. Weisdorf D, Haake R, Blazar B, et al. Treatment of moderate/severe acute graft-versus-host disease after allogeneic bone marrow transplantation: an analysis of clinical risk features and outcome.  Blood. 1990;75:1024-1030.
  53. Gale RP, Bortin MM, van Bekkum DW, et al. Risk factors for acute graft-versus-host disease.  Br J Haematol. 1987;67:397-406.
  54. Weiden PL, Flournoy N, Thomas ED, et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts.   N Engl J Med. 1979;300:1068-1073.
  55. Davies SM, Ramsay NK, Haake RJ, et al. Comparison of engraftment in recipients of matched sibling of unrelated donor marrow allografts.  Bone Marrow Transplant. 1994;13:51-57.
  56. Anasetti C, Amos D, Beatty PG, et al. Effect of HLA compatibility on engraftment of bone marrow transplants in patients with leukemia or lymphoma.  N Engl J Med. 1989;320:197-204.
  57. Davies SM, Shu XO, Blazar BR, et al. Unrelated donor bone marrow transplantation: influence of HLA A and B incompatibility on outcome.  Blood. 1995;86:1636-1642.
  58. Petersdorf EW, Kollman C, Hurley CK, et al. Effect of HLA class II gene disparity on clinical outcome in unrelated donor hematopoietic cell transplantation for chronic myeloid leukemia: the US National Marrow Donor Program Experience.  Blood. 2001;98:2922-2929.
  59. Petersdorf EW, Longton GM, Anasetti C, et al. Definition of HLA-DQ as a transplantation antigen.  Proc Natl Acad Sci U S A. 1996;93:15358-15363.
  60. La Nasa G, Giardini C, Argiolu F, et al. Unrelated donor bone marrow transplantation for thalassemia: the effect of extended haplotypes.  Blood. 2002;99:4350-4356.
  61. Broxmeyer HE, Douglas GW, Hangoc G, et al. Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells.  Proc Natl Acad Sci U S A. 1989;86:3828-3832.
  62. Knudtzon S. In vitro growth of granulocytic colonies from circulating cells in human cord blood.  Blood. 1974;43:357-361.
  63. Broxmeyer HE, Kurtzberg J, Gluckman E, et al. Umbilical cord blood hematopoietic stem and repopulating cells in human clinical transplantation.  Blood Cells. 1991;17:313-329.
  64. Gluckman E, Broxmeyer HA, Auerbach AD, et al. Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling.  N Engl J Med. 1989;321:1174-1178.
  65. Burgio GR, Gluckman E, Locatelli F. Ethical reappraisal of 15 years of cord-blood transplantation.  Lancet. 2003;361:250-252.
  66. Ballen KK, Hicks J, Dharan B, et al. Racial and ethnic composition of volunteer cord blood donors: comparison with volunteer unrelated marrow donors.  Transfusion. 2002;42:1279-1284.
  67. Barker JN, Krepski TP, DeFor TE, et al. Searching for unrelated donor hematopoietic stem cells: availability and speed of umbilical cord blood versus bone marrow.  Biol Blood Marrow Transplant. 2002;8:257-260.
  68. Broxmeyer HE, Hangoc G, Cooper S. Clinical and biological aspects of human umbilical cord blood as a source of transplantable hematopoietic stem and progenitor cells.  Bone Marrow Transplant. 1992;9 Suppl 1:7-10.:7-10.
  69. Broxmeyer HE, Cooper S, Yoder M, Hangoc G. Human umbilical cord blood as a source of transplantable hematopoietic stem and progenitor cells.  Curr Top Microbiol Immunol. 1992;177:195-204.:195-204.
  70. Bender JG, Unverzagt K, Walker DE, et al. Phenotypic analysis and characterization of CD34+ cells from normal human bone marrow, cord blood, peripheral blood, and mobilized peripheral blood from patients undergoing autologous stem cell transplantation.  Clin Immunol Immunopathol. 1994;70:10-18.
  71. Mavroudis D, Read E, Cottler-Fox M, et al. CD34+ cell dose predicts survival, posttransplant morbidity, and rate of hematologic recovery after allogeneic marrow transplants for hematologic malignancies.  Blood. 1996;88:3223-3229.
  72. Sierra J, Storer B, Hansen JA, et al. Transplantation of marrow cells from unrelated donors for treatment of high-risk acute leukemia: the effect of leukemic burden, donor HLA- matching, and marrow cell dose.  Blood. 1997;89:4226-4235.
  73. Paulin T. Importance of bone marrow cell dose in bone marrow transplantation.  Clin Transplant. 1992;6:48-54.
  74. Barker JN,  Martin PL, Coad JE, et al. Low incidence of Epstein-Barr virus-associated posttransplantation lymphoproliferative disorders in 272 unrelated-donor umbilical cord blood transplant recipients.  Biol Blood Marrow Transplant. 2001;7:395-399.
  75. Gluckman E, Rocha V, Boyer-Chammard A, et al. Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group.  N Engl J Med. 1997;337:373-381.
  76. Rubinstein P, Carrier C, Scaradavou A, et al. Outcomes among 562 recipients of placental-blood transplants from unrelated donors.  N Engl J Med. 1998;339:1565-1577.
  77. Wagner JE, Barker JN, DeFor TE, et al. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival.  Blood. 2002;100:1611-1618.
  78. Ballen KK, Valinski H, Greiner D, et al. Variables to predict engraftment of umbilical cord blood into immunodeficient mice: usefulness of the non-obese diabetic--severe combined immunodeficient assay.  Br J Haematol. 2001;114:211-218.
  79. Rocha V, Wagner JE, Jr., Sobocinski KA, et al. Graft-versus-host disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources.  N Engl J Med. 2000;342:1846-1854.
  80. Gluckman E. Current status of umbilical cord blood hematopoietic stem cell transplantation.  Exp Hematol. 2000;28:1197-1205.
  81. Rubinstein P, Stevens CE. Placental blood for bone marrow replacement: the New York Blood Center's program and clinical results.  Baillieres Best Pract Res Clin Haematol. 2000;13:565-584.
  82. Locatelli F, Rocha V, Chastang C, et al. Factors associated with outcome after cord blood transplantation in children with acute leukemia. Eurocord-Cord Blood Transplant Group.  Blood. 1999;93:3662-3671.
  83. Moretta A, Maccario R, Fagioli F, et al. Analysis of immune reconstitution in children undergoing cord blood transplantation.  Exp Hematol. 2001;29:371-379.
  84. Talvensaari K, Clave E,  Douay C, et al. A broad T-cell repertoire diversity and an efficient thymic function indicate a favorable long-term immune reconstitution after cord blood stem cell transplantation.  Blood. 2002;99:1458-1464.
  85. Giraud P, Thuret I, Reviron D, et al. Immune reconstitution and outcome after unrelated cord blood transplantation: a single paediatric institution experience.  Bone Marrow Transplant. 2000;25:53-57.
  86. Comoli P, Locatelli F, Moretta A, et al. Human alloantigen-specific anergic cells induced by a combination of CTLA4-Ig and CsA maintain anti-leukemia and anti-viral cytotoxic responses.  Bone Marrow Transplant. 2001;27:1263-1273.
  87. Butturini A, Bortin MM, Gale RP. Graft-versus-leukemia following bone marrow transplantation.  Bone Marrow Transplant. 1987;2:233-242.
  88. Linch DC, Brent L. Marrow transplantation. Can cord blood be used?  Nature. 1989;340:676
  89. Weiden PL, Flournoy N, Sanders JE, Sullivan KM, Thomas ED. Antileukemic effect of graft-versus-host disease contributes to improved survival after allogeneic marrow transplantation.  Transplant Proc. 1981;13:248-251.
  90. Sullivan KM, Storb R, Buckner CD, et al. Graft-versus-host disease as adoptive immunotherapy in patients with advanced hematologic neoplasms.  N Engl J Med. 1989;320:828-834.
  91. Sullivan KM, Weiden PL, Storb R, et al. Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia.  Blood. 1989;73:1720-1728.
  92. Barker JN, Davies SM, DeFor T, et al. Survival after transplantation of unrelated donor umbilical cord blood is comparable to that of human leukocyte antigen-matched unrelated donor bone marrow: results of a matched-pair analysis.  Blood. 2001;97:2957-2961.
  93. Lu L, Xiao M, Shen RN, Grigsby S, Broxmeyer HE. Enrichment, characterization, and responsiveness of single primitive CD34 human umbilical cord blood hematopoietic progenitors with high proliferative and replating potential.  Blood. 1993;81:41-48.
  94. Hows JM, Bradley BA, Marsh JC, et al. Growth of human umbilical-cord blood in longterm haemopoietic cultures.  Lancet. 1992;340:73-76.
  95. Lewis ID, Verfaillie CM. Multi-lineage expansion potential of primitive hematopoietic progenitors: superiority of umbilical cord blood compared to mobilized peripheral blood.  Exp Hematol. 2000;28:1087-1095.
  96. Traycoff CM, Abboud MR, Laver J, et al. Evaluation of the in vitro behavior of phenotypically defined populations of umbilical cord blood hematopoietic progenitor cells.  Exp Hematol. 1994;22:215-222.
  97. Lansdorp PM, Dragowska W, Mayani H. Ontogeny-related changes in proliferative potential of human hematopoietic cells.  J Exp Med. 1993;178:787-791.
  98. Vaziri H, Dragowska W, Allsopp RC, et al. Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age.  Proc Natl Acad Sci U S A. 1994;91:9857-9860.
  99. Cohen SB, Madrigal JA. Immunological and functional differences between cord and peripheral blood.  Bone Marrow Transplant. 1998;21 Suppl 3:S9-12.:S9-12.
  100. Macardle PJ, Wheatland L, Zola H. Analysis of the cord blood T lymphocyte response to superantigen.  Hum Immunol. 1999;60:127-139.
  101. Risdon G, Gaddy J, Horie M, Broxmeyer HE. Alloantigen priming induces a state of unresponsiveness in human umbilical cord blood T cells.  Proc Natl Acad Sci U S A. 1995;92:2413-2417.
  102. Takahashi N, Imanishi K, Nishida H, Uchiyama T. Evidence for immunologic immaturity of cord blood T cells. Cord blood T cells are susceptible to tolerance induction to in vitro stimulation with a superantigen.  J Immunol. 1995;155:5213-5219.
  103. Harris DT, LoCascio J, Besencon FJ. Analysis of the alloreactive capacity of human umbilical cord blood: implications for graft-versus-host disease.  Bone Marrow Transplant. 1994;14:545-553.
  104. Gaddy J, Risdon G, Broxmeyer HE. Cord blood natural killer cells are functionally and phenotypically immature but readily respond to interleukin-2 and interleukin-12.  J Interferon Cytokine Res. 1995;15:527-536.
  105. Madrigal JA, Cohen SB, Gluckman E, Charron DJ. Does cord blood transplantation result in lower graft-versus-host disease? It takes more than two to tango.  Hum Immunol. 1997;56:1-5.
  106. Kurtzberg J, Laughlin M, Graham ML, et al. Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients.  N Engl J Med. 1996;335:157-166.
  107. Harris DT, Schumacher MJ, LoCascio J, et al. Phenotypic and functional immaturity of human umbilical cord blood T lymphocytes.  Proc Natl Acad Sci U S A. 1992;89:10006-10010.
  108. Garderet L, Dulphy N,  Douay C, et al. The umbilical cord blood alphabeta T-cell repertoire: characteristics of a polyclonal and naive but completely formed repertoire.  Blood. 1998;91:340-346.
  109. Roux E, Helg C, Dumont-Girard F, et al. Analysis of T-cell repopulation after allogeneic bone marrow transplantation: significant differences between recipients of T-cell depleted and unmanipulated grafts.  Blood. 1996;87:3984-3992.
  110. Ho VT, Soiffer RJ. The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation.  Blood. 2001;98:3192-3204.
  111. Umemoto M, Azuma E, Hirayama M, et al. Two cytotoxic pathways of natural killer cells in human cord blood: implications in cord blood transplantation.  Br J Haematol. 1997;98:1037-1040.
  112. Han P, Hodge G, Story C, Xu X. Phenotypic analysis of functional T-lymphocyte subtypes and natural killer cells in human cord blood: relevance to umbilical cord blood transplantation.  Br J Haematol. 1995;89:733-740.
  113. Granberg C, Hirvonen T. Cell-mediated lympholysis by fetal and neonatal lymphocytes in sheep and man.  Cell Immunol. 1980;51:13-22.
  114. Moretta A, Locatelli F, Mingrat G, et al. Characterisation of CTL directed towards non-inherited maternal alloantigens in human cord blood.  Bone Marrow Transplant. 1999;24:1161-1166.
  115. Moretta A, Comoli P, Montagna D, et al. High frequency of Epstein-Barr virus (EBV) lymphoblastoid cell line-reactive lymphocytes in cord blood: evaluation of cytolytic activity and IL-2 production.  Clin Exp Immunol. 1997;107:312-320.
  116. Ruggeri L, Capanni M, Urbani E, et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants.  Science. 2002;295:2097-2100.
  117. Rubinstein P, Stevens CE. The New York Blood Center's Placental/Umbilical Cord Blood Program. Experience with a "new" source of hematopoietic stem cells for transplantation.  Ernst Schering Res Found Workshop. 2001;47-70.
  118. Niehues T, Rocha V, Filipovich AH, et al. Factors affecting lymphocyte subset reconstitution after either related or unrelated cord blood transplantation in children - a Eurocord analysis.  Br J Haematol. 2001;114:42-48.
  119. Migliaccio AR, Adamson JW, Stevens CE, et al. Cell dose and speed of engraftment in placental/umbilical cord blood transplantation: graft progenitor cell content is a better predictor than nucleated cell quantity.  Blood. 2000;96:2717-2722.
  120. Barker JN, Weisdorf DJ, Wagner JE. Creation of a double chimera after the transplantation of umbilical-cord blood from two partially matched unrelated donors.  N Engl J Med. 2001;344:1870-1871.
  121.   McNiece I, Kubegov D, Kerzic P, Shpall EJ, Gross S. Increased expansion and differentiation of cord blood products using a two-step expansion culture.  Exp Hematol. 2000;28:1181-1186.
  122.   McNiece IK, Almeida-Porada G, Shpall EJ, Zanjani E. Ex vivo expanded cord blood cells provide rapid engraftment in fetal sheep but lack long-term engrafting potential.  Exp Hematol. 2002;30:612-616.
  123. Lewis ID, Almeida-Porada G, Du J, et al. Umbilical cord blood cells capable of engrafting in primary, secondary, and tertiary xenogeneic hosts are preserved after ex vivo culture in a noncontact system.  Blood. 2001;97:3441-3449.
  124. Chen BJ, Cui X,  Chao NJ. Addition of a second, different allogeneic graft accelerates white cell and platelet engraftment after T-cell-depleted bone marrow transplantation.  Blood. 2002;99:2235-2240.
  125.   Itoh K, Tezuka H, Sakoda H, et al. Reproducible establishment of hemopoietic supportive stromal cell lines from murine bone marrow.  Exp Hematol. 1989;17:145-153.
  126. Sutherland HJ, Eaves CJ, Lansdorp PM, Thacker JD, Hogge DE. Differential regulation of primitive human hematopoietic cells in long- term cultures maintained on genetically engineered murine stromal cells.  Blood. 1991;78:666-672.
  127.   Brandt JE, Bartholomew AM, Fortman JD, et al. Ex vivo expansion of autologous bone marrow CD34+ cells with porcine microvascular endothelial cells results in a graft capable of rescuing lethally irradiated baboons.  Blood. 1999;94:106-113.
  128. Conneally E, Cashman J, Petzer A, Eaves C. Expansion in vitro of transplantable human cord blood stem cells demonstrated using a quantitative assay of their lympho-myeloid repopulating activity in nonobese diabetic-scid/scid mice.  Proc Natl Acad Sci U S A. 1997;94:9836-9841.
  129. Kobari L, Pflumio F, Giarratana M, et al. In vitro and in vivo evidence for the long-term multilineage (myeloid, B, NK, and T) reconstitution capacity of ex vivo expanded human CD34+ cord blood cells.  Exp Hematol. 2000;28:1470-1480.
  130.   Shpall EJ, Quinones R, Giller R, et al. Transplantation of ex vivo expanded cord blood.  Biol Blood Marrow Transplant. 2002;8:368-376.
  131. Cord blood banking for potential future transplantation: subject review. American Academy of Pediatrics. Work Group on Cord Blood Banking.  Pediatrics. 1999;104:116-118.
  132. ACOG committee opinion. Routine storage of umbilical cord blood for potential future transplantation. Number 183, April 1997. Committee on Obstetric Practice. American College of Obstetricians and Gynecologists.  Int J Gynaecol Obstet. 1997;58:257-259.

Resolution 504 (A-02)

Resolution 504 (A-02), introduced by the Resident and Fellow Section at the 2002 Annual Meeting and referred to the Board of Trustees, asks:

That the American Medical Association (AMA) work with Health Resources and Services Administration to increase the availability and access for expectant mothers to donate their cord blood to the National Marrow Donor Program within every state; and

That the AMA draft and promote model state and federal legislation to present the option to all expectant mothers of donating cord blood, along with technical assistance and resources for the institutions collecting the samples.

The Council on Scientific Affairs (CSA) agreed to examine the scientific aspects of umbilical cord blood stem cell transplantation so that Resolution 504 (A-02) could be properly evaluated. Back to top

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