1. Umbilical Cord Blood (UCB) Transplantation: An Alternative to the Use of Unrelated Volunteer Donors? Barker JN Hematology Am Soc Hematol Educ Program. 2007;2007:55-61.

This is a succinct and authoritative review of the present state of the art of umbilical cord blood (UCB) transplantation as presented by Dr. Barker as part of the Educational Program at the American Society of Hematology Meeting, December 8-11, 2007.

The article summarizes the current status of unrelated donor UCBT and describes both the challenges and current areas of research associated with this HSC source. The author points out that the success of UCB transplants has resulted in dramatic increases in the number of such transplants being performed. UCB has clear benefits of rapid availability and a reduced stringency of requirement for HLA match. The latter attribute has the potential to extend the donor pool, which is of great importance for racial and ethnic minorities. Furthermore, new preparative regimens combined with double-unit grafts have been associated with improved engraftment and survival in larger children and adults, making UCBT a viable potential alternative to unrelated volunteer donor transplantation, especially in preference to transplantation using mismatched volunteers.

Topics reviewed include: Cell Dose and HLA Match; Impact on UCBT Outcome; Strategies to Improve UCBT in Adults; UCBT for Nonmalignant Diseases; Comparisons of Unrelated Donor UCB and Bone Marrow; and Current Areas of Research and Development.

The author concludes by pointing out that the US General Accounting Office has documented that more than 10,000 patients per year in the US need an unrelated donor HSC transplantation and do not receive one. UCB has the potential to nearly resolve the limitations of search time, donor availability, and the lack of suitably matched donors for many patients. UCBT is currently considered by many as a valid potential alternative for any patient who requires an unrelated donor allograft and who is without a suitably matched and readily available volunteer. Some transplantation centers now give UCB the priority as the unrelated HSC source of choice in children and, albeit less frequently, also in adults. Others conduct a simultaneous search for both unrelated volunteers and UCB, thus offering UCB as an immediate potential alternative to unrelated volunteers. It is possible that UCB (particularly 5-6/6 HLA-matched) may become the preferred HSC source even for those patients with fully matched unrelated volunteer donors. Finally, assuming we can increase the global UCB inventory, UCB is likely the best way to extend transplantation access to minorities; thus, in the future we may be able to offer an HSC source to all.

2. 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.

3. 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 not the primary unrelated source of HSCs for transplantation in children.

4. 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.

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