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  1. Expanding the role of umbilical cord blood transplantation. Brunstein CG, Setubal DC, Wagner JE. Br J Haematol. 2007;137:20-35.
    [Comment: Perhaps a more appropriate title for this article would be, “The expanding role of umbilical cord blood transplantation.”]

This article presents a detailed review of the state of the art and future directions with umbilical cord blood as a source of hematopoietic stem cells for transplantation in both children and adults. After an overview, the authors discuss hematopoietic recovery, GVHD, UCB transplantation for hematological malignancies, UCB transplantation for non-malignant diseases, double UCB transplantation after myeloablative therapy or after non-myeloablative therapy and future directions in umbilical cord blood transplantation. (The article should be read in its entirety - the following is a brief summary of some important points.)

Overview. Only about one-third of patients who need an allogeneic hematopoietic cell transplant (HSCT) will have a suitable related donor. Another third of patients will find a suitable unrelated donor (URD) among the 10 million donors registered worldwide. For the remaining third, particularly those of racial and ethnical minority decent, alternatives are needed. In addition, prolonged search times and the lack of availability of a significant percentage of donors listed in the registries have limited the potential benefits of URD HSCT. Approximately one-third of donors are not available at the time they are needed.

At the time of early reports of umbilical cord blood (UCB) transplants, there were a number of unanswered questions and obstacles regarding the reliability of UCB stem cells to provide long-term hematopoietic and immune reconstitution. Since then it has become clear that UCB is an effective and safe alternative source of HSC for transplantation in patients lacking a suitable related and unrelated donor, filling the gap for those patients who could potentially benefit from allogeneic HSCT. In addition, new research on UCB is now focused on the development of strategies to further improve upon engraftment, immune reconstitution, transplant-related mortality, risk of relapse and survival, It is anticipated that in the next 5 years, the use of UCB will expand not only as a useful source of HSC, but also as a source of potent immune effector cells or non-HSC populations.

Hematopoietic Recovery: Neutrophil and platelet recovery after UCBT has been shown to be delayed when compared with BMT. Median time to neutrophil recovery has ranged between 20 and 30 days in most series. Cell dose has long been known to significantly influence the rate and incidence of hematopoietic recovery after UCBT. Gluckman et al reported that patients who received a TNC median cell dose of ≥3.7 x 107/kg had a higher probability of neutrophil engraftment.

There is improved engraftment in recipients of 6 of 6 antigen-matched UCB grafts when compared to recipients of a 1- to 3- mismatched unit (with no difference in engraftment among those with 1- to 3-HLA mismatches).

Primary diagnosis has also been shown to influence engraftment. Patients who undergo UCBT for treatment of a malignant disease appear to have a higher probability of engraftment compared to patients with a non-malignant disease.

GVHD Immunological naivety of T-cell populations and the presence of cells capable of suppressing the alloreactive response (e.g., regulatory T cells and trophoblasts) are thought to be responsible for a reduced risk of GVHD, which is particularly striking in HLA-mismatched donor-recipient pairs.

Of particular interest are potential differences in the responsiveness of GVHD between HSC sources. Data indicate a superior proportion of patients achieving a complete and partial response to extensive chronic GVHD therapy and a lower non-relapse mortality for those patients undergoing chronic GVHD therapy for patients transplanted with UCB when compared with URD grafts. Whether this is true for acute A=GVHD is still unknown.

UCBT for hematological malignancies. It is becoming increasingly important to determine whether UCB is superior, equivalent or inferior to other HSC sources for specific diagnoses. Acute leukemia is the malignant diagnosis most frequently requiring allogeneic HSCT in children. There is less experience in adult patients with acute leukemia. (An extensive table summarizes data in numerous publications regarding UCBT for children and adults with acute leukemia.) Overall, UCB is a valuable HSC source alternative for patients with acute leukemia who need an allogeneic transplant but would be precluded from proceeding because of the lack of a suitable related or unrelated donor.

Several publications have reported outcomes in patients with CML, myelodysplastic syndrome and lymphoma.

UCBT for non-malignant diseases. Reports of UCBT for the treatment of hemoglobinopathies is quite encouraging, with high rats of engraftment and survival in patients with sickle cell disease and β-thalassemia.

Allogeneic transplantation has been successful in the treatment of patients with a number of metabolic diseases and immunodeficiency states.

Overall, data show that UCB is a valuable alternative source of HSC for the transplantation of children with non-malignant hematological disease and metabolic disorders.

Double UCBT. With experience in more than 200 double UCB transplants in both the myeloablative and non-myeloablative setting, it is clear that the use of two partially HLA-matched UCB units is both safe and efficacious, allowing nearly all adults (>90%) to be eligible for HSCT.

Although there were initial concerns regarding the possibility of cross-immunological rejection between the two immunologically functional UCB units from two HLA-mismatched donors, engraftment was consistently observed in practice. In fact, in a cohort of adult patients that had a significantly higher median weight, neutrophil engraftment was not only significantly better than adult recipients of a single unit but was not significantly different from that observed in children transplanted with UCB with a high cell dose.

Future directions in UCBT. As UCBT becomes incorporated in standard clinical practice, several challenges remain ahead. A report by the Institute of Medicine indicates that UCB has recently become the principal HSC source for use in transplantation in children. This fact combined with the growing interest in double UCBT in adults will increase the demand for UCB units, particularly those with large cell numbers. Passage of the stem Cell Act of 2005, which allocated nearly $80 million to augment the nation's UCB inventory, indicates interest by the U.S federal government, and will significantly assist in achieving the desired goal to make HSCT equally available to potential recipients of all ethnic and racial backgrounds.

Conclusions. Umbilical cord blood is an important source of HSC for use in allogeneic HSCT. In the pediatric setting, the data clearly establish UCB as a standard of care, now having surpassed the use of bone marrow and peripheral blood. While not yet main-stream in adults, the recent publication of results with the double UCB platform has remarkably changed the community's interest in UCB as a source of HSC for large recipients. Without question, UCB is being used more frequently, particularly for the thousands of patients who could potentially benefit from such therapy but cannot find an HLA-matched unrelated donor. It would appear that cell dose is no longer a limitation for most patients. This, in combination with recent innovations with less toxic non-myeloablative conditioning therapies, markedly broadens the applicability of allogeneic HSC to older patients that were previously managed only with palliative measures. This latter strategy should no longer be considered acceptable of those who are suitably fit, regardless of age.

  1. Umbilical cord blood transplantation for myeloid malignancies. Brunstein CG, Baker KS, Wagner JE. Curr Opin Hematol. 2007;14:162-9.

This article reviews the available data on the outcomes of pediatric and adult patients with AML, MDS and CML after UCBT. The literature shows that after UCBT the relapse rate, disease-free survival and overall survival of patients with myeloid malignancies is similar to other hematopoietic stem cell sources. Disease status at the time of transplantation is found in several studies to be a very important determinant of long-term outcome. Newer strategies such as double umbilical cord blood transplant and utilization of non-myeloablative conditioning regimens show promising results. (Detailed tables summarize much of the data in this manuscript.)

Pediatric UCBT for myeloid malignancies. A comparison of unrelated UCB to unmanipulated and T-cell-depleted marrow in 100 children with AML found similar relapse rates for UCB and unmanipulated marrow, both lower than the relapse rates seen for T-cell-depleted marrow. The 2-year survival was, however, poorer after UCBT as compared to unmanipulated marrow, likely due to a twice as high transplant-related mortality after UCBT (39% VS. 19%). Children with high-risk disease have a higher risk of relapse and poorer survival after UCBT.

Adult UCBT for myeloid malignancies. In adult UCBT, approximately 20-30% of allogeneic HSCTs are performed for AML. Two large registry-based reports included only adult patients with leukemias and compared UCB to URD marrow, both matched and mismatched. The first of these found UCB to be equivalent to HLA-mismatched marrow, but inferior to HLA-matched marrow. The second study found no significant difference in outcomes between recipients of UCB and URD marrow. An additional study compared UCB to URDS marrow for hematological malignancies and found that after UCBT there was a better disease-free survival. Another recent report compared UCB and related donor grafts (marrow and peripheral blood stem cells) for patients with hematologic malignancies and found no significant difference on 3-year disease-free survival.

Double UCBT. Current experience with myeloablative double UCBT (n=61), mostly in adults with hematologic malignancies, demonstrates an incidence of grade II-IV acute GVHD at 100 days of 57%, transplant-related mortality at 6 months of 18%, and probability of disease-free survival and overall survival at 2 years of 55 and 63%, respectively. A recent report on the outcomes of 96 patients with acute leukemia who received either single or double UCBT grafts showed that there was a 10-fold decrease in the risk of relapse for patients who receive double UCBTs in first or second complete remission. It has been reported that increased HLA mismatch is associated with lower risk of relapse suggesting that, since over 80% of double UCB recipients have at least one two-antigen HLA-mismatched unit, there is increased alloreactivity that may lead to reduced risk of relapse.

Nonmyeloablative UCBT. One report reviews the outcomes of 95 patients with advanced or high-risk hematologic diseases with a median age of 50 years, including one-third of patients with myeloid malignancies (AML, MDS, CML). Eighty percent of the patients received double UCB grafts. Remarkably, the 2-year progression-free survival was 38% and overall survival was 44%. Others have reported an overall survival of around 35%, and one small study that also utilized double UCB grafts reported a 1-year disease-free survival of 64%.

Conclusions. UCB has clearly become an alternative source of HSCs for patients with myeloid malignancies who require an allogeneic transplant, but who do not have a suitable sibling donor. The utilization of UCB as a source of unrelated HSCs for transplantation has grown rapidly over the last decade and according to a report by the Institute of Medicine, UCB is now the primary unrelated source of HSCs for transplantation in children.

  1. Who should get cord blood transplants? Barker JN. Biol Blood Marrow Transplant. 2007 Jan;13 Suppl 1:78-82 (From the 2007 Educational Supplement on Hemopoetic Cell Transplantation published as volume 13, number 1, supplement 1, January 2007).

The chief known benefits of unrelated donor UCB are rapid availability, with the absence of donor attrition, and, for a given degree of HLA match, a decreased incidence of GVHD.

The chief limitation of UCB is low cell dose. Multiple studies have demonstrated the devastating impact of low cell dose on engraftment, TRM and survival. The limitation of cell dose contributed to inferior hematopoietic recovery and increased TRM in adult single-unit UCBT recipients compared with 6/6 matched unrelated volunteer BM recipients reported by Laughlin et al. However, given that the disease-free survival after UCBT was comparable to that of HLA-mismatched BM recipients, this has introduced adult UCBT as a valid alternative to the use of HLA-mismatched volunteer donors. A similar comparison by Eurocord revealed comparable outcomes after unrelated donor BM transplantation and UCBT, and other series have shown considerably better outcomes after myeloablative single-unit UCBT.

In addition to cell dose, increasing data have demonstrated the critical importance of HLA match on UCBT outcome. Unpublished data suggest that a cell dose must be at least 2.5 x 107 nucleated cells (NCs)/kg in recipients of 5/6 units but recipients of 4/6 unity must receive a cell dose of at least 5 x 107 NCS/KG. This suggests that improved HLA match can compensate for low cell dose, or, conversely, that HLA mismatch must be compensated for by larger cell dose.

A recent report describes superior leukemia-free survival (LFS) after 6/6-matched UCBT and comparable LFS in 8/8 allele-matched BM and 5/6 matched or 4/6 matched UCB recipients. Notably, compared with 8/8 allele-matched BMT, TRM was comparable in matched and high cell doses (>3 x 107 NC/kg) 5/6 matched UCBT. Furthermore, although TRM was higher in recipients of low cell dose (<3 x 107 NC/kg) 5/6 and 4/6 (any cell dose) UCBT, relapse was lower in these patients accounting for the similarity in LFS compared with BM recipients. These results support the preference of HLA-matched or -mismatched UCB of adequate cell dose over BM in treating children with acute leukemia. Furthermore, if engraftment can be improved, as has been seen with more recent experience using fludarabine-based conditioning, for example, then the argument in favor of pediatric UCBT will be strengthened even further, due to the lower incidence of chronic GVHD and the likely consequent improvement in quality of life.

Novel strategies that are currently under investigation to improve UCBT outcome in adults include ex vivo expansion and the use of haploidentical HSCs to ameliorate the prolonged neutropenia associated with adult UCBT.

An alternative approach is to use double-unit grafts to augment graft cell dose. Published data indicate that double-unit UCBT can be performed safely in adults with improved engraftment and reduced TRM compared with single-unit historical controls. Of further interest is that preliminary data have suggested that double-unit UCBT may be associated with a reduced incidence of relapse.

In summary, UCBT is a valid alternative for any patient requiring unrelated donor transplantation without a suitably matched and readily available unrelated volunteer. At the author's institution, for patients <16 years with leukemia, emerging data indicate that the outcome is superior with matched UCB and comparable with 4-5/6 matched units, suggesting that UCB should take priority over BM, particularly if there is a 6/6 unit, or a 5/6 unit with a dose >3 x 107 NCs/kg. In adults, the priority of unrelated volunteer HSCs versus UCB will depend on the strategy for preventing GVHD using unrelated volunteer HSCs (particularly in the setting of mismatch) and on the strategy for augment the UCB graft cell dose. Transplant centers should be encouraged to have a written algorithm dictating the minimum criteria of cell dose and HLA match, as well as an approach to trading off dose and match, to guide search coordinators in unit selection.

  1. Comparative single-institute analysis of cord blood transplantation from unrelated donors with bone marrow or peripheral blood stem cell transplantation from related donors in adult patients with hematological malignancies after myeloablative conditioning regimen. Takahashi S, Ooi J, Tomonari A, Konuma T, Tsukada N, Oiwa-Monna M, Fukuno K, Uchiyama M, Takasugi K, Iseki T, Tojo A, Yamaguchi T, Asano S. Blood 2007; 109:1322-1330.

The authors studied the outcomes of 171 adults with hematological malignancies who received unrelated cord blood transplantation (CBT) as a primary unrelated stem cell source (n=100), or bone marrow transplantation (BMY) or peripheral blood stem cell transplantation (PBSCT) from unrelated donors (n=71, 55 BMT and 16 PBSCT). All patients received myeloablative regimens including 12 Gy TBI. The authors analyzed the hematological recovery, risks of GVHD, transplant-related mortality (TRM) and relapse, and disease-free survival (DFS).

Significant delays in engraftment occurred after CBT; however, overall engraftment rates were almost the same for both grafts. The cumulative incidences of grades III to IV aGVHD and extensive cGVHD among CBT recipients were significantly lower than those among BMT/PBSCT recipients. Multivariate analysis demonstrated no apparent differences in TRM (9% in CBT and 13% in BMT/PBSCT), relapse (17% in CBT and 26% in BMT/PLBSCT) and DFS (70% in CBT and 60% in BMT/PBSCT) between both groups.

The authors concluded that the data suggest that unrelated cord blood could be as safe and effective a stem cell source as related bone marrow or mobilized peripheral blood for adult patients when it is used as a primary unrelated stem cell source.

The authors speculated on the possible reasons for their favorable results in CBT. (1) One reason might be the availability of grafts containing sufficient numbers of cells --- only 7 patients received cord blood grafts containing <2 x 107 NC/kg among the 100 CBT recipients. (2) Secondly, Japanese patients might have some advantages in the setting of HLA-mismatched transplantation due to HLA or non-HLA immune genetics. Indeed, there is mounting evidence indicating that polymorphisms in non-HLA immune mediators and host defense genes, such as tumor necrosis factor, interleukin-10, or their receptor genes, could affect the severity of GVHD. (3) The preparative conditioning and GVHD prophylaxis regimens used in this study might also have been favorable factors. (4) The quick availability of cord blood as a stem cell source is thought to be one of the most important advantages compared with unrelated bone marrow grafts. If the patient was eligible for allogeneic transplantation but had no related donor, the authors generally selected a cord blood graft first, rather than waiting for the results of an unrelated marrow donor search. In fact, CBTs were performed at the same timing as BMT/PBSCT from a related donor.

  1. The EBMT activity survey 2006 on hematopoietic stem cell transplantation: focus on the use of cord blood products. Gratwohl A, Baldomero H, Frauendorfer K, Rocha V, Apperley J, Niederwieser D; Joint Accreditation Committee of the International Society for Cellular Therapy (ISCT); European Group for Blood and Marrow Transplantation EBMT (JACIE). Bone Marrow Transplant. 2008;41:687-705.

This report describes the hematopoietic stem cell transplantation (HSCT) activity in Europe in 2006, with the focus on the use of cord blood as a stem cell source. An ongoing increase in allogeneic HSCT has been observed over the last decade for almost all indications, particularly for acute leukemias.

A total of 544 allogeneic transplants were cord blood transplants in 2006 compared to 395 in 2005, 283 in 2004 and 86 in 1997 when this item was introduced into the activity survey. The development over the last 10 years, and the massive increase of cord blood transplantation in the last four years, is illustrated in a figure in the article. The most frequent use of cord blood overall was for acute leukemias, especially for those with advanced disease. The majority of Cord blood transplants were from unrelated donors. Nine percent were from HLA-identical family members and 0.5% from non-identical family members. There were no autologous cord blood transplants reported.

There were marked differences in cord blood use between European countries and the differences were not explained solely by economic factors such as gross national income per capita. Most likely, these differences reflect the activities of the major cord blood banks in Europe and the impact of their leaders on the transplant activities with their countries.

  1. Umbilical cord blood transplantation and banking. Brunstein CG, Wagner JE. Annu Rev Med. 2006;57:403-17.

This is a thorough yet concise review from a leading center of umbilical cord blood transplantation.

Although there are currently seven million adult volunteers registered worldwide, one third of patients still will not find a suitably HLA-matched unrelated donor and thus cannot access this potentially curative therapy. If the patient belongs to an ethnic minority, the probability of not finding an HLA-matched donor is even greater. Moreover, because the search process often takes weeks to months, a significant proportion of patients will die, become higher-risk, or become ineligible for transplantation altogether while they wait for the completion of the donor search. As umbilical cord blood (UCB) units are HLA-typed, tested for infectious agents, and stored, they are immediately available upon request and can be shipped to any transplant center in the world with relative ease. UCBT is associated with a low incidence of acute GVHD, and partial HLA match between the donor and recipient is tolerable.

UCB, however, has limitations. First, multiple registry and single-center analyses have shown that the number of progenitor cells is important in engraftment and survival. The lower the cell dose, the poorer the outcome. Because the cell dose in a single unmanipulated UCB unit is fixed, most adults are denied routine access to UCB. A second obstacle is the inability to go back to the donor to collect lymphocytes or additional HSC, in case of disease progression or relapse, or graft failure. Third, there is substantially less experience with UCBT than with bone marrow transplant (BMT), particularly in adult patients.

UCB transplantation in children: At pediatric centers, the frequency of transplantation of UCB is rapidly approaching that of bone marrow and has surpassed that of PBSC. Clinical studies demonstrate slower but complete hematopoietic reconstitution in the majority of patients. Although factors associated with the speed of neutrophil recovery have varied between reports, most include nucleated cell dose, and some also identify CD34+ or CFU-GM dose. In most reports, the incidence of acute GVHD after UCBT is lower than that expected for BMT. In contrast to acute GVHD, most comparative studies fail to demonstrate a statistical difference between UCB and bone marrow with regard to chronic GVHD in the unrelated setting. The treatment-related mortality (TRM) rate after UCBT is not consistent between reports. The incidence of relapse after UCBT is similar to that in recipients of unmanipulated marrow, suggesting that the graft-versus-leukemia (GVL) effect is intact.

In summary, current evidence demonstrates the safety and efficacy UCBT for children. The speed of the donor search, high likelihood of finding a suitably HLA-matched UCB unit (particularly for patients of ethnic and racial minorities) with an adequate cell dose, and lower rate of acute GVHD despite HLA mismatch lead many centers to choose unrelated donor UCB over unrelated adult marrow or peripheral blood. Major endpoints such as TRM, relapse rate, and overall survival are at least comparable, making UCB frequently the preferred alternative HSC source for children who lack a HLA-matched sibling donor.

UCB transplantation in adults: As expected based on the early results in children, the rate and incidence of neutrophil and platelet engraftment were lower after UCBT than after PBSCT or BMT, with a median time to neutrophil recovery after UCBT ranging between 22 and 32 days. In adults, both cryopreserved and infused nucleated cell dose are associated with speed of hematopoietic recovery. Furthermore, the incidence of graft failure in adult recipients of UCB was as high as 35%. The relatively low nucleated cell dose and greater likelihood of use of a HLA 2-antigen-mismatched graft probably accounts for this slow recovery and high graft failure rate.

Despite a higher degree of HLA mismatch, adult recipients of UCB had a comparable or lower incidence of acute GVHD compared to adult recipients of HLA-matched, T cell–replete bone marrow. Adults who received UCB had a lower incidence of acute GVHD than did those who received HLA-mismatched unrelated marrow. The incidence of chronic GVHD after UCBT has been reported to be as high as 80%, and extensive chronic GVHD is as high as 46%. Comparative studies with unrelated BMT recipients show conflicting results.

TRM in adult recipients of UCB after a myeloablative regimen has been reported to be as high as 60%. Studies comparing recipients of UCB and bone marrow yield conflicting results; some studies demonstrate lower TRM, some higher TRM, and some similar TRM. For example, Rocha et al reported similar TRM in recipients of HLA-mismatched UCB and HLA-matched unrelated marrow, whereas Laughlin et al found that TRM after UCBT was higher than that observed with HLA-matched unrelated-donor BMT, but similar to that observed with HLA-mismatched BMT.

As reported for children with malignant disease, the incidence of disease relapse was not increased among adult UCBT recipients. It remains to be proven whether survival after UCBT is comparable to that in recipients of HLA-matched unrelated bone marrow.

In summary, the above data suggest that UCBT is a reasonable alternative for adult patients who lack an HLA-matched sibling or unrelated marrow donor. Various strategies to overcome the principal limitation of cell dose in the adult population are being tried.

Multiple Umbilical Cord Blood Units: Barker et al were the first to report the successful use of two UCB units to overcome the cell-dose limitation. Others have subsequently utilized two or more UCB units with variable results.

In the Minnesota experience in adult and adolescent recipients of "double" UCBT for hematologic malignancies the graft consisted of two units that were matched at a minimum of 4 out of 6 HLA A, HLA B, and DRB1 antigens with the recipient and each other (not necessarily at the same HLA loci). In the original cohort, the total graft nucleated cell dose had to exceed 1.5 x 107/kg, with the one unit containing a minimum cell dose of 1.0 x 107/kg. Median time to neutrophil engraftment was 23 days, and all evaluable patients developed complete chimerism with no secondary graft failure. Notably, double chimerism (i.e., contributions from both UCB units) was detectable in the bone marrow in only ~25% between days 21 and 28. By day 100, hematopoiesis was derived from a single unit in all patients. Importantly, no factor (i.e., total nucleated cell dose, CD34 dose, CD3 dose, HLA match, ABO match, sex match, order of infusion) predicts the long-term engrafting unit; the clinical experience to date suggests that engraftment is random. TRM and survival after double UCB transplantation appear superior to those reported in recently published series. Kai et al reported similar results on a smaller number of patients with hematological malignancies who received double UCB grafts, utilizing the same HLA-matching criteria.

In summary, the above data suggest that the utilization of two UCB units in combination with fludarabine in the preparative regimen has overcome, at least in part, the cell-dose limitation for UCBT, with improved engraftment and survival. The relative contributions of double UCBT and the benefit of fludarabine to the overall success of the transplant procedure remains to be determined; it is possible that cell dose has a markedly diminished effect in recipients of fludarabine in combination with cyclophosphamide and TBI. Multi-institutional randomized trials have been proposed to address this issue in both children and adults.

Nonmyeloablative UCB transplantation: The Minnesota group evaluated the potential benefit of UCBT in the setting of a reduced-intensity preparative regimen. However, it was recognized that, in contrast to sibling or unrelated adult donor HSCT, donor lymphocyte infusions to enhance engraftment or promote GVL would not be possible. In order to meet the cell-dose criteria, approximately three quarters of the patients received two partially HLA-matched UCB units. The regimen consisted of cyclophosphamide 50 mg/kg on day -6, fludarabine 40 mg/m2 on days -6 to -2, and TBI 200 cGy on day -1 with cyclosporine and mycophenolate mofetil immunoprophylaxis.

The results in the first 59 adult recipients of NST and UCBT have been analyzed. Neutrophil recovery was rapid (median of 8 days). The cumulative incidence of sustained donor-derived engraftment was 89%. As observed in recipients of a myeloablative preparative regimen, one unit ultimately predominates with no factor predictive of the long-term engrafting UCB unit. Importantly, the cumulative incidence of acute GVHD may be higher than that previously reported in children or adults after a myeloablative regimen, with 65% of the patients developing grades II–IV acute GVHD and 25% developing grades III–IV acute GVHD. However, despite the higher incidence of acute GVHD, TRM is low (19%). Thus far, only fitness status at the time of transplant is associated with TRM; age by itself is not a limiting factor. The probability of overall and progression-free survival is 44% and 35% at two years. Insufficient numbers for any one disease group prevent disease-specific evaluations, which are the goal of ongoing multi-institutional trials.

Future directions: Brief comments are made about T regulatory cells, ex-vivo expansion of progenitor cells, intra-bone marrow injection, mesenchymal stem cells and cord blood banking.

Conclusions: The increasing experience with UCBT is changing the standard of care in many institutions. Initial concerns regarding the potency of the GVL effect of UCB have been dismissed by publications from several experienced groups showing relapse rates similar to those associated with other HSC sources. In the pediatric setting, UCBT is now established practice and will soon surpass the number of unrelated adult volunteer donor transplants. Favorable results compared with historical controls have contributed to changes in clinical practice.

In the adult setting, progress has been slower owing to the cell-dose limitation. Engraftment and survival of adult patients who received single UCB unit grafts have been suboptimal. Strategies focused on overcoming this limitation are under intense investigation. Thus far, ex vivo expansion of UCB has not yet been shown to influence engraftment. Recent registry-based studies suggest that the results of adult UCBT are comparable to those of HLA-matched and -mismatched unrelated-donor BMT. Notably, the utilization of double UCB unit grafts has shown promising results. Engraftment rates and survival seem to be superior to historical data. However, this strategy still requires validation with larger patient numbers and longer follow-up at multiple institutions.

The utilization of nonmyeloablative preparative regimens broadens the range of patients who might benefit from UCBT. The fludarabine, cyclophosphamide, TBI regimen proposed at the University of Minnesota has shown encouraging results with high engraftment rates and low TRM for a high-risk group of patients.

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