INTRODUCTION Background

The first recorded use of umbilical cord blood was in 1963, when it was used in the treatment of a patient with lymphangiosarcoma¹. But it was the successful transplantation of cord blood into a patient with Fanconi’s anaemia in 1988² that was the landmark case which indicated that cord blood might be a viable alternative to bone marrow in the treatment of haematopoietic disorders, particularly in children.

Historically, bone marrow transplantation has been used in the treatment of patients with blood and immune disorders requiring a source of haematopoietic stem cells (HSC). Until recently, the blood remaining in the placenta and umbilical cord following the birth of a baby was discarded as a waste product. However, it has been determined that umbilical cord blood is some ten times richer than bone marrow in its proportion of progenitors of haematopoietic stem cells³. Moreover, lymphocytes in cord blood appear to be less immunologically active than those found in bone marrow⁴ and the incidence of graft versus host disease (GVHD) was lower. These factors make cord blood an attractive alternative to bone marrow for a number of conditions and, following the report of the 1988 case, cord blood banks were established first in the USA and Europe and now there are many such banks world-wide both in the public and private sectors.

Advantages and disadvantages of using cord blood Advantages

• Cord blood units (CBU) are more rapidly available than bone marrow. Bone marrow is obtained from volunteer donors who are recruited by blood and transplantation services and other organisations. Donor details, including ethnicity, HLA and blood type, are held in registers. If a transplant is needed by a patient, their clinician will search the bone marrow registries for a match. The volunteer will then be approached for a bone marrow donation and tests for disease and other exclusion criteria will be carried out. This process is time consuming and it may take many weeks before a suitable donation becomes available, if at all, for the critically ill patient. There is always a risk that the volunteer will change their mind about donating. Cord blood units are stored frozen after thorough testing for contamination and specified diseases, such as Hepatitis B and C and HIV, and there is no risk of last minute consent refusal.

• Cord blood is less risky to collect. The collection of cord blood following delivery is a harmless process that does not affect the mother or her newborn.

1 Ende M, Lymphangiosarcoma: Report of a Case, Pac Med Surg, 1966;74:80-82

2 Gluckman E, Broxmeyer HE, Auerbach AD, et al., Haematopoietic reconstitution in a patient with Fanconi anaemia by means of umbilical-cord blood from an HLA identical sibling, N Eng J Med, 1989;321: 1174-1178

3 Broxmeyer HE, Douglas GW, Hangoe G, et al., Human umbilical cord blood as a potential source of transplantable haematipoietic stem progenitor cells, Proc Natl Acad Sci USA, 1989: 86:3828-3832

4 Cohen SBA, Madrigal JA, Immunological and functional differences between cord and peripheral blood, Bone Marrow Transplant, 1998:21 (suppl 3): S9-S12

Cord blood can, therefore, be collected at no risk to the donor and stored, frozen, until needed. The harvesting of bone marrow is an invasive process that can cause some risk and discomfort to the donor. Bone marrow is therefore not collected until it is needed.

• The number of potential donors is high. Recruitment of cord blood donors from antenatal clinics is relatively easy and only a very small number of women, from amongst those who might be willing to donate, is ever approached. Potential bone marrow donors are not so readily identifiable although many will be blood donors.

• There is a decreased risk of GVHD. The cells in cord blood appear to be more

‘naive’ than their counterparts in bone marrow because of the immune immaturity of the newborn. It has also been shown been shown that the low number or absence of CD8⁺ natural killer (NK) T cells in cord blood may also be a relevant factor⁵.

• Cord blood units do not have to be a perfect HLA match because of the reduced incidence of GVHD. This means that it is possible to use unrelated and mismatched donors^6,7. While sibling donors were used in early cord blood transplants, the establishment of cord blood banks means that it has been possible increasingly to use unrelated donors.

• The risk of transmission of infectious disease is diminished for cord blood because all CBU are screened for disease and any infected or contaminated units discarded.

Disadvantages

• The time to platelet engraftment is prolonged in the transplantation of cord blood in comparison to bone marrow⁸. This study also showed that engraftment time was strongly related to cell dose.

• The cell dose of CBU is generally insufficient for adults. Although cord blood is enriched in HSC its volume is less than is collected from bone marrow.

This makes CBU more suited to paediatric use. Clinical experience has shown that to successfully treat an adult the nucleated cell dose in the CBU must be at least 1.5 – 2.0x10⁷ per kilogram body weight^9,10 and it has been shown that a

5 Kim YJ, Broxmeyer HE. CD8+ NKT cells, low in cord blood, preferentially require 4-1BB rather than CD28 for costimulation [abstract] Blood . 96(suppl 1, pt 1), 240a abstract 1031

6 Wagner JE, Rosenthal J, Sweetman R et al., Successful transplantation of HLA matched and HLA mismatched umbilical cord blood from unrelated donors: analysis of engraftment and acute graft versus host disease, Blood. 1996; 88:795-802

7 Gluckman E, Roahc V, Bayer-Chammard A et al., Outcome of cord blood transplantation from related and unrelated donors, N EnglJ Med. 1997; 337:373-378

8 Rubinstein P, Carrier C, Scaradovou A, et al., Outcomes among 562 recipients of placental-blood transplants from unrelated donors, N Engl J Med,. 1998; 22:1565-1577

9 Ballen K, Broxmeyer HE, McCullough J, et al., Current Status of Cord Blood Banking and

Transplantation in the United States and Europe, Biology of Blood and Marrow Transplantation. 2001;

7:635-645

cord blood nucleated cell dose of 0.37x10⁸ per kilo increased the speed and probability of engraftment (E Gluckman personal communication). The Düsseldorf NetCord bank has had a policy of collecting only units larger than 80ml since 1997. In these units the median number of nucleated cells was 10

± 5x10⁸ per unit and only 25% of the units contained enough cells to engraft patients of 50-70 kilograms. To overcome this problem multiple units of cord blood have been transplanted but usually only one CBU engrafts. Cord blood has a higher potential for in vitro proliferation than adult bone marrow¹¹ and, currently, a considerable body of research is being undertaken into cell expansion to overcome the cell dose problem. Most of this research is being validated in mouse models^12,13 but some expanded units have already been used in the human clinical context as part of a trial^14,15. Eurocord III, funded by the EU under the Cell Factory area of FP5, will carry out an evaluation of umbilical cord blood transplant engraftment using ex vivo haematopoietic progenitors/stem cell expansion. The study will collect and compare techniques of ex vivo stem cell expansion; interact with biotechnology companies to procure cytokines and other reagents for clinical use; compare pre-clinical animal models in mice and sheep and then design clinical protocols for ex vivo expansion of cord blood stem cells and multiple transplants. The results will be analysed and compared with the Eurocord database registry.

• There is a risk that hereditary disorders, undiagnosed in the donor at birth, may be transmitted to the recipient.

10 Gluckman E, Rocha V, Chastang C on behalf of Eurocord-Cord Blood Transplant Group, Cord blood hematopoietic stem cells: biology and transplantation, Haematology, American Society of Hematology, Washington DC, pp. 1-14, 1998

11 Piacibello W, Sanavio F, Garetto L, et al., Extension self-renewal of hum primitive hematopoietic stem cells from cord blood. Blood. 1997;89:2644-2653

12 Ohishi K, Varnum-Finney B, Bernstein ID, Delta-1 enhances marrow and thymus repopulating ability of human CD34(+) CD38(-) cord blood cells, J Clin Invest. 2002; 110(8): 1165-74

13 Encabo A, Mateu E, Carbonell-Uberos F, Minana MD, CD34+CD38- is a good predictive marker of cloning ability and expansionpotential of CD34+ cord blood cells.Transfusion. 2003; 43(3): 383-9.

14 Jaroscak J, Martin PL, Waters-Pick B, et al., A phase 1 trial of augmentation of unrelated cord blood transplantation with ex vivo expanded cells . [abstract] Blood. 1998; 92: 646a (suppl 1, part 1).

15 Stiff P, Pecora A, Parthasarathy M, et al., Umbilical cord transplants in adults using a combination of unexpanded and ex vivo expanded cells: preliminary observations. [abstract] Blood. 1998; 92: 646a (suppl 1, part 1).