Behind The Medical Headlines

Umbilical cord derived stem cell transplants

• Dr J Davies, Consultant Haematologist and Honorary Senior Lecturer, Lothian University Hospitals and University of Edinburgh, Edinburgh, Scotland.

Summary

Stem cell transplantation from human donors has been established as an effective prospect of cure for certain types of leukaemia. However, shortages of suitable (related) human donor cells have led to trials of cells from unrelated donors. In this article Dr John Davies reviews the latest research underpinning the use of umbilical cord cell transplants for leukaemia.

Declaration of interests: No conflict of interests declared

Despite advances in chemotherapy and supportive care, allogeneic, haemopoietic stem cell transplantation offers the best prospect of cure for certain categories of patients suffering from haematological malignancies. For non-malignant haematological conditions, including those associated with severe immunodeficiency and inherited abnormalities of bone marrow function, allogeneic stem cell transplantation may offer the only prospect of long term survival.

Sibling human leucocyte antigen matched donor

Traditionally, allogeneic stem cell transplantation depended upon the availability of a sibling HLA-matched donor. Although there are clearly many recipient-related considerations around the use of allogeneic transplantation, one of the major constraints to the expansion of sibling allogeneic transplantation arose from issues surrounding donor availability. Various methods have and continue to be explored to solve this problem, with the now best established being the use of unrelated donors recruited worldwide onto various international registries. Even with the time and resource that has been devoted to the development of this donor network, there are still significant numbers of patients for whom no suitable donor can be found.

One approach to resolving this issue is to relax the requirements for HLA compatibility between the donor and recipient. However, this increases the complexity and toxicity of the transplant, which, in turn, directly translates into higher transplant-related morbidity and mortality. For example, although the use of haplo-identical (half-matched) donors is being explored, the problems of delayed or partial immune reconstitution, graft rejection and graft-versus-host disease have not been fully resolved and this treatment remains essentially experimental.

Umbilical cord derived stem cells

It has been known for many years that umbilical cord blood contains haemopoietic stem cells with the ability to repopulate and reconstitute bone marrow. Early clinical attempts to use Umbilical cord derived stem cells (UCDSC) as a transplant source go back over 30 years. However, it is really only in the last decade that the use of such stem cells has become sufficiently common for useful data on biology and outcomes to be accrued.¹

The potential advantages of UCDSC as a donor source, compared to adult donors, include ready availability, ease and low cost of harvesting, the ability to select or discard on the basis of required HLA types, a decreased risk of transmission of transplant-related infection, such as cytomegalovirus infection, and potentially exploitable biological differences in stem cells derived from cord blood.

It appears that UCDSC are relatively immunologically tolerant (i.e. less likely to react immunoligcally against the host) and that this may translate into two important areas of transplantation. Firstly, there may be an absolute decrease in the incidence of acute graft-versus-host disease following UCDSC transplantation and secondly, and possibly more importantly, HLA matching may be less critical with UCDSC, allowing for a greater degree of mismatch for any given outcome when compared to transplantation with adult derived stem cells.

The major disadvantage of UCDSC is the finite number of cells which can be harvested. There is a threshold effect, in terms of the number of allogeneic stem cells required per kilogram of body weight, for early and sustained haemopoietic engraftment.² Low stem cell doses are associated with delayed or partial engraftment and delayed and partial immunological reconstitution. This is not generally an issue where adult donors are used, although attainment of the relevant stem cell threshold may require, for example, an adult donor to undergo peripheral stem cell harvesting on multiple occasions. Cell number has, however, been a barrier to the use of UCDSC in adults, although UCDSC have been used in children, where critical stem cell dose is obviously easier to achieve.

Recent reports

Despite the difficulties described above, UCDSC have been increasingly used in adults and two publications in the New England Journal of Medicine have brought this area of transplant practice into sharper focus. Mary Laughlin and colleagues compared the outcomes of transplants using haemopoietic stem cells from different donor sources in adults with leukaemia.³ This study compared outcomes from transplants using fully HLA-matched bone marrow donors, one HLA antigen mismatched bone marrow donors and one or two HLA antigen mismatched cord blood donations. They concluded that haemopoietic recovery was slower in adults who received cord blood, and perhaps this is not surprising, given that such patients received a lower dose of nucleated cells. Best outcomes were seen in fully HLA-matched bone marrow derived stem cell recipients. However, there was no difference in transplant related mortality or relapse between patients who received either one HLA antigen mismatched bone marrow transplant or a one or two HLA antigen mismatched cord blood transplant. This data shows that HLA mismatched cord blood may be a reasonable alternative source of stem cells for adults who do not have recourse to a fully HLA-matched sibling or unrelated donor, although slow or incomplete engraftment remains a concern.

A second study, published in the same edition of the New England Journal of Medicine, looked at outcomes in over 600 adult patients with acute leukaemia who had undergone haemopoietic stem cell transplantation.⁴ Nearly 100 patients received cord blood, with the remainder being transplanted conventionally using bone marrow. The data was derived from European registry sources. All the bone marrow recipients were fully HLA-matched, while over 90% of the cord blood recipients received at least a one HLA antigen mismatched transplant. Again, there was a lower risk of acute graft-versus-host disease after umbilical cord transplantation, accompanied by an increased incidence of delayed haemopoietic recovery. The risk of chronic graft-versus-host disease, relapse rate, leukaemia-free survival and, importantly, transplant related mortality did not differ depending upon stem cell source.

New approaches

What then are the novel approaches which might be applied to umbilical cord transplants to make them more universally applicable? Firstly, there are ongoing efforts to manipulate stem cells in the laboratory, with the aim of stem cell expansion. This science remains in its infancy, but the principle of stem cell culture in the presence of cytokine cocktails (small protein molecules released by cells and affecting other cells - e.g. proliferation) to expand stem cell harvests is well-established. This technique is likely to become increasingly important in the future, as our understanding of the biology of stem cell expansion improves.

The second approach to increasing the umbilical cord stem cell dose is simply to use donations from more than one donor. This raises the spectre of complex biological interrelationships, including graft-versus-host effects, graft-versus-leukaemia effects, host-versus-graft interactions and graft-versus-graft interactions, some or all of which may be transient or biologically stable. The situation is further complicated, in that grafts may be further manipulated by the addition or subtraction of other cells, such as T lymphocytes, more unusual cell populations, such as mesenchymal derived stem cells or even purified haplo-identical CD34 derived marrow cells.

Reports describing the use of more than one cord donation in a single adult patient suggest that the technique is feasible with, interestingly, one of the umbilical cord derived donors becoming predominant by day 100.⁵ In terms of outcome, the incidence of acute graft-versus-host disease appears low, and event-free survival, at least in small series, approaches that seen in the unrelated setting after infusion of either bone marrow or peripheral blood derived stem cells. There is, however, a significant amount of work still to be done in this area, particularly to determine the impact of HLA matching, T cell number and the number of stem cells infused on immune recovery and transplant outcome.

Conclusions

What conclusions can we draw at the moment, regarding the potential or actual use of umbilical cord derived stem cells? The use of fully HLA-matched sibling-derived or unrelated cord blood stem cells in children is established and provides an alternative stem cell source appropriate for some children. In adults, the question of stem cell number has still not been fully addressed and translates into a risk of 10–15% at least of primary graft failure or significantly delayed time to haemopoietic recovery. This also translates into longer periods of supportive care, with both economic and clinical consequences. However, where an adequate stem cell dose is available from a single umbilical cord blood unit (UCBU), then cord blood does provide a viable alternative. There may be particular utility in using cord blood in the context of HLA mismatch between available donor and recipient. For those adult patients where an adequate number of UCDSC cannot be obtained and who have no recourse to conventional stem cell sources, then entry into an experimental programme, using more than one UCBU, may be justified. This, however, should only be in the context of a properly constituted research study.

These are exciting times for transplant immunology, with exploration of different forms of allogeneic transplantation, either conventional or reduced intensity, being combined with conventional and alternative donor sources, including UCDSC. At the present time, the use of UCDSC is limited, but in selected cases, this may be the only route to effective haemopoietic stem cell transplantation. Umbilical cord derived stem cells will continue to be intensively studied. If sufficient stem cell numbers can be obtained, either from multiple donations or laboratory expansion, then it is likely that UCDSC will become increasingly used in both paediatric and adult stem cell transplantation in the future.

References

1. 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; 344:1815–22.
2. Mavroudis D, Read E, Cottler-Fox M et al. CD34+ cell dose predicts survival, post transplant morbidity and rate of hematologic recovery after allogeneic marrow transplants for hematologic malignancies. Blood 1996; 88:3223–9.
3. Laughlin MJ, Eapen M, Rubinstein P et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukaemia. N Engl J Med 2004; 351:2265–75.
4. Rocha V, Labapin M, Sanz G et al. Transplants of umbilical cord blood or bone marrow from unrelated donors in adults with acute leukaemia. N Engl J Med 2004; 351:2276–85.
5. Barker JN, Weisdof DJ, DeFor TE et al. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood 2005; 105:1343–7.