8. Alternative allogeneic donor sources for transplantation for childhood diseases: Unrelated cord blood and haploidentical family donors. Cairo MS, Rocha V, Gluckman E, Hale G, Wagner J. Biol Blood and Marrow Transplant 2008:14 (Suppl 1):44-53

Cord blood as an alternative allogeneic stem cell source for pediatric recipients:

Several retrospective studies have been unable to identify a significant improvement in outcome or survival following unrelated adult donor stem cell transplantation versus unrelated umbilical cord blood transplantation (UCBT). Netcord and the European Blood and Marrow Transplantation group (EBMT) reported similar 5-year event-free and OS rates. Also, CIBMTR and NCBP demonstrated similar leukemia-free survival in children with acute leukemia. Similarly, the risk of developing serious infections was not statistically different in children following unrelated cord blood versus unrelated adult donor allogeneic stem cell transplantation.

UCBT has extended the availability of allogeneic hematopoietic stem cell transplantation (HSCT) to patients who would otherwise not be eligible for this curative approach. The authors estimate that more than 8,000 patients have undergone UCBT from unrelated donors. The Eurocord registry has collected data on 3,372 related and unrelated CB transplants performed in 373 transplant centers worldwide, 28% for nonmalignant disorders.

Data on the interaction between cell dose and HLA in children with nonmalignant disorders has indicated that the patients must receive a higher cell dose to obtain engraftment compared to patients with a malignant disease. The minimum UCB cell dose should not be below 4.9 x 10⁷NC/kg at collection and 3.5 x 10⁷NC/kg at infusion. A CB graft containing 2 or more HLA disparities with a cell dose inferior to 3.5 x 10⁷NC/kg should be avoided.

Cord blood transplantation for patients with hemoglobinopathies:

Only 7 children with hemoglobinopathies who have received an unrelated CBT have been reported to Eurocord. Clinical data is available in 4 children, 2 with thalassemia and 2 with sickle cell disease (SCD). All 4 patients are alive and well without transfusion dependency. [For additional data, see the Annotated Bibliography, XII Sickle Cell Anemia and Thalassemia]

Data are available for 44 children with thalassemia and 19 with SCD following related UCBT. All 63 patients are alive, and the 5-year DFS us 78% in the 44 thalassemia patients, and 94% for the 19 SCD patients.

The authors “strongly suggest” that the search for an UCB unit should be started simultaneously as for BM unrelated donors in children with either nonmalignant disorders or malignant disorders.

Haploidentical transplants for childhood hematologic malignancies:

Mismatched family member (MMFM) donors are highly motivated and readily available. T-lymphocyte depletion of grafts is typically necessary to reduce the risk of severe GVHD. Typically, CD34⁺ selection using immunomagnetic columns, resulting in a 5-log CD3⁺ depletion of the graft, eliminates posttransplant GVHD requirements. These highly purified grafts, containing megadoses of CD34⁺ hematopoietic stem cells (>10 x 10⁶ CD34⁺/kg) and essentially no B cells, overcome engraftment barriers and make PTLDP rare. Other investigators are employing a CD# depletion strategy with OKT3 on immunomagnetic columns to manufacture a graft containing immunologically active cells such as NK cells, monocytes, dentritic cells and DCD34^- hematopoietic precursors.

[One wonders how many of the 373 transplant centers mentioned above will be capable of such sophisticated pre-transplant manipulation of the stem cell product.]

Recent reports confirm rapid neutrophil engraftment in recipients of MMFM grafts, in contrast to the delayed recovery after cord blood HSCT. Improved T-cell depletion methodologies have dramatically reduced the incidence of severe GVHD so that calcineurin inhibitors, which are associated with significant toxicities, can be omitted. However, delayed immune reconstitution and disease recurrence remain as significant challenges. Serial monitoring of immunologic recovery is important to ascertain infection risk; rapid high-through-put methodologies have been developed to expedite this testing. Patients should be serially monitored for EBV, CMV, and adenovirus DNA reactivation so that preemptive therapy can be initiated early.

9. Clinical use of umbilical cord blood hematopoietic stem cells. Rocha V, Gluckman E; Eurocord and European Blood and Marrow Transplant Group. Biol Blood Marrow Transplant. 2006;12(1 Suppl 1):34-41.

This is a concise review with emphasis on outcome results as reviewed by the Eurocord and European Blood and Marrow Transplant Group (EBMT). Included in the review are comparisons of UCBT with BMT, and UCBT with haploidentical PBSCTs.

A recent survey by the IBMTR estimates that after 1998, 20% of stem cell transplantations performed in patients <20 years old have been cord blood transplantations. In Japan, approximately 50% of HSCTs from unrelated donors are being performed with cord blood cells.

Advantages of UCBs are (1) significantly faster availability, with patients receiving UCBTs a median of 25-36 days earlier than those receiving bone marrow, (2) expansion of the donor pool, because sufficiently large UCB units mismatched for 1 or 2 HLA-A, -B and –DR antigens seem tolerated for survival, (3) lower incidence and severity of aGVHD, (4) lower risk of transmitting infections, (5) reduced donor attrition, (6) easier targeting of ethnic minorities.

Disadvantages of UCBs are (1) the low number of hematopoietic progenitor cells which translates into an increased risk of graft failure and delayed hematopoietic engraftment, (2) increased resource utilization in hospitalization days and blood and platelet transfusions, and (3) the impossibility of using donor lymphocyte transfusion for immunotherapy.

UCBT from related donors: Present findings suggest that in the HLA-identical sibling setting, UCBT is as useful as BMT in children. On the basis of these results, the authors recommend collecting and freezing cord blood units in families in which a sibling child is affected with genetic or hematologic diseases.

UCBT from unrelated donors in children: The review of results of unrelated UCBT in children with AML, ALL, Hurler syndrome, Krabbe disease and primary immunodeficiencies led the authors to conclude that UCBT can be considered as a source of allogeneic stem cells for transplantation of children who need an HSCT and who lack an HLA-identical sibling.

UCBT compared with BM from unrelated donors in children: No randomized clinical trial has been conducted although 3 published studies have reported retrospective analyses. The data from these studies strongly suggest that UCB is an acceptable alternative to matched unrelated BM in children. As a result, the authors emphasize that for children in need of a HSCT, a simultaneous search for BM and UCB unrelated donors should be carried out. For children who require an urgent transplantation, UCB is advantageous for faster procurement.

UCBT from unrelated donors in adults: Six major reports of unrelated donor UCBT in adults have been published. As expected from retrospective studies and multicenter studies, the series were heterogeneous. The incidence of acute and chronic GVHD has ranged widely, as has TRM at 100 days (0%-54%) and disease-free survival (15%-76%). It is difficult to explain the reasons for such differences, because factors such as patient and cord blood graft selection, disease and disease, status, center effect, and period of transplantation may be involved.

Results of unrelated UCBT and unrelated BMTs in adults with hematologic malignancies: Three retrospective studies have been recently published. Although definitive conclusions will require larger and more homogeneous series of patients with longer follow-up, the results showed that UCBT is feasible in adults when a cord blood unit contains a higher number of cells and should be considered an option as an allogeneic stem cell source for patients lacking an HLA-matched BM donor. Accordingly, as with children, the donor search process for BM and UCB from unrelated donors should be started simultaneously, especially in patients with acute leukemia, for whom the time factor is crucial.

Results of unrelated UCBT compared with haploidentical PBSCT in adults with hematologic malignancies: A registry-based retrospective analysis showed that UCBT and haploidentical transplants showed similar TRM, relapse, and LFS for adults with AML. However, LFS was superior after UCBT for patients with ALL because of a decreased incidence of relapse.

Incidence and risk factors of early severe infections after unrelated cord blood transplantation. In a retrospective analysis, the authors observed that bacterial infections appeared early, followed by viral and fungal infections during the first 100 days after UCBT. Delayed engraftment was frequently associated with an increased risk of all types of infections. Approaches that will improve time to engraftment after UCBT might decrease the incidence and severity of early infections after UCBT.

The authors discuss strategies to improve outcomes of UCBT and conclude by stating that UCB has emerged as an appealing alternative source of hematopoietic cells for transplantation. All available data suggest that unrelated donor UCBT should be considered an acceptable option in children and adults with hematologic and nonhematologic malignancies for whom an HLA-matched unrelated BM donor is not readily available. Increasing the available pool of UCB units probably offers much more room for improvement in outcomes than expanding the current pool of unrelated BM donors.

10. Cord blood transplantation. Gluckman E. Biol Blood Marrow Transplant. 2006; 12: 808-12. (The E. Donnall Thomas Lecture at the Tandem BMT Meetings held on February 18, 2006. )

The author provides, in narrative form, a summary of data and conclusions reached regarding critical aspects of cord blood transplantation.

The Eurocord registry has collected data from 2310 CBTs performed from 1988 to October, 2005. Although there has been no increase in the number of related CBTs performed annually, there has been a sharp increase in the number of unrelated CBTs in 2004 and 2005, with a higher proportion of recipients being adults.

For unrelated CBT, data were colleted from 1320 children and 693 adults, the majority with malignant diseases (962). Among those transplanted for malignant disorders, survival for ALL was 50% in first complete remission (CR1), 45% in CR3 and 29% in more advanced disease. For AML, survival was 70% in CR1, 55% in CR2 and 27% for more advanced disease. These results are quite comparable with the results of matched unrelated BMTs.

A comparison of outcomes was performed among three groups of children with acute leukemia—those who had received a T-replete unrelated BMT, a T-depleted unrelated BMT, or an unrelated CBT. A number of differences in outcomes were found but, overall, there was no difference between the unrelated BMT and CBT in terms of survival and event-free survival.

Comparisons of CBT and BMT in adults have been published. (see II. Transplantation of adults, Citation 4B and Citation 4C) To summarize: mismatched CBT compared with HLA-matched unrelated BMT gives delayed engraftment, decreased or same aGVHD, decreased or same cGVHD, increased or same transplant-related mortality and similar degree of survival.

Studies were also performed on the impact of HLA compatibility and cell dose on outcomes of unrelated CBT for patients with malignant and nonmalignant disorders. For patients with malignant disorders, the data indicated that cell dose is the most important factor for outcome requiring a minimum of 3 x 10⁷ nucleated cells (NCs)/kg at collection and 2 x 10⁷ NCs/kg at infusion. HLA mismatches increase the risk of delays of engraftment and increase transplant mortality and cGVHD, and decrease the risk of relapse. The fact that relapse was higher with 0-1 HLA mismatches compared with 2-4 HLA mismatches (due to GVL effect) explains why survival was not influenced by the number of HLA mismatches. Increasing the cell dose overcomes the effect of HLA mismatches.

For nonmalignant disorders, the cell requirement was higher, and fewer than 4. 9 x 10⁷ NCs/kg collected gave a low rate of engraftment. For the infused cells, it was fewer than 3. 5 x 10⁷ NCs/kg. Survival was affected by the number of HLA mismatches and the cell dose; it was different from the malignant diseases where HLA mismatches did not influence survival, because there was no need for GVL effect.

CBT protocols under investigation include studies of double cord blood transplants, the use of ex-vivo expanded cells, administration directly into the bone to avoid loss of cells before homing, the addition of mesenchymal cells to improve engraftment, and nonmyeloablative conditioning regimens.

Finally, in regard to regenerative medicine, umbilical cord is highly proliferative and can divide into almost all different cell types so there is hope that embryonic properties that are retained in cord blood stem cells will make them the ideal source for all possible clinical applications in the future.

11. Why cord blood? Rubinstein P. Hum Immunol. 2006;67:398-404.

This is a highly readable review which will be useful for medical professionals working in the field of cord blood transplantation as well as for anyone not familiar with cord blood transplantation. In this review, a number of issues that are relevant to the history and development of an effective system for cord blood banking are discussed. The author estimates that 7,000-8,000 unrelated donor cord blood transplants have been performed world-wide.

The Congress of the United States has recently authorized funds for, and the President signed into law, a U.S. National Program that will support the creation of a large inventory of new, high-quality, cord blood units for unrelated transplantation. The legislation recognized the ability of Cord Blood Banks to provide hematopoietic stem cell-rich grafts derived from cord blood, a major new source of donor tissue for marrow reconstitution.

Because of a relatively weaker ability to induce severe GVHD, mismatched cord blood transplants can be used effectively, although HLA-matched grafts engraft faster and reduce post-transplant morbidity and mortality. The pursuit of better chances to obtain HLA-well-matched grafts has driven the evolution of unrelated cord blood banking into broad national and international cooperation.

The author provides a short historical description of the development of cord blood transplantation. The initial transplants were done using HLA-identical sibling donors, but it was known that only a minority of patients have access to such a donor. Thus, "public" cord blood banks have been developed in support of unrelated-donor cord blood transplantation. Key to the success of cord blood transplantation is the finding that GVHD is less of a problem with HLA-mismatched cord blood transplants than with adult stem cells from the marrow or peripheral blood. The possibility of partially mismatched transplantation with good outcomes should help reduce the ethnic imbalance that has plagued patients from minority groups searching for a bone marrow donation. Other important advantages of unrelated cord blood are the logistics (no donor attrition, grafts prepared in advance and available "off-the-shelf" within days), the much lower incidence of latent viral infections (mostly CMV and EBV) in the grafts, and the ability to build the inventory with appropriate consideration of donor ethnicity.

Registries of adults willing to provide bone marrow for hematopoietic cell transplantation have been developed in Europe and in the U.S. (the National Marrow Donor Program -NMDP). The NMDP has recruited over 6,000,000 donors and Bone Marrow Donors Worldwide (BMDW) lists 10 million volunteers. This is an astonishing and heartening demonstration of altruism on an awesome scale, but the polymorphism of the HLA system and the logistic difficulties of timely access to particular individuals among such large numbers pose enormous, often insurmountable challenges to the provision of a matched bone marrow or peripheral blood stem cell donation. Histocompatibility barriers to transplantation, therefore, are difficult, if not impossible, to overcome using adult donors. Cord blood solves these problems.

Collection of cord blood units, processing, testing, cryopreserving and HLA typing entail significant expense and there is urgent need for government help for cord blood banks, as has been done for bone marrow registries. The passage of the "Stem Cell Therapeutic and Research Act of 2005," authorizing over 80 million dollars for the establishment of a National Cord Blood Inventory of 150,000 new units in the next 5 years will begin to satisfy that need.

The ratio between transplants of cord blood and of adult donors varies among countries, ethnic groups, and by patient age, but in recent years the ratio has moved definitely toward an increase in cord blood use essentially everywhere and in patients of all ages. Japan leads the world in this movement: more than half of all transplants (adults and children) were performed with cord blood in 2003. In the U.S., cord blood is now being used in more than half of the transplants to children and the ratio in adults is approaching 20%. Numerous reasons account for this continued increase in cord blood use in hematopoietic cell transplantation:

1. Rapid availability of cord blood units.
2. Better long-term prognosis for well-matched cord blood graft recipients compared with recipients of equally well-matched bone marrow.
3. More ethnically diverse inventories.
4. Stringent inspection by government and volunteer accrediting agencies.
5. The limitation of low cell counts being overcome by the use of two-unit transplants and possibly by new cell expansion technologies.
6. Modern information technology supporting more direct collaboration between cord blood banks and transplant centers.

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