Transplantation of cord blood (CB) is increasingly used as therapy for patients whose own marrow is affected by genetic mutations that prevent the development of normal cells of the blood or immune tissues, or for patients whose marrow has been destroyed in the course of treatment for leukaemia and other malignancies. CB is a rich source of haematopoietic stem cells, can be easily harvested and stored in frozen aliquots in a CB bank. The first public CB bank was established in 1993 allowing unrelated CB transplantation to become an option for patients lacking a suitable adult donor. Today, the results of CB transplantation are comparable to those of bone marrow transplants with several important advantages: the graft is available ‘off the shelf’, thereby reducing the waiting time, and the requirements of human lecucoyte antigen (HLA) matching are less restrictive than those of adult sources. The reduced requirement for HLA matching allows transplants between incompletely matched donors and recipients, thus reducing the size of the inventory required at the national level. This also mitigates the disadvantage encountered by persons of rare HLA genotypes or those who do not belong to populations of North Western European descent. Finally, national CB programmes can easily make available for research individual surplus units not meeting minimal criteria for clinical use.
Allogeneic stem cell transplantation from unrelated donors
Allogeneic haematopoietic stem cell transplantation is the elective treatment for a wide variety of disorders but relies on the presence of an appropriate donor (Appelbaum, 2007). Currently, in the absence of a suitable sibling donor the treatment of choice is a human leucocyte antigen (HLA)-matched volunteer unrelated donor (optimally, having at least nine out of 10 high resolution HLA-A, -B, -C, -DRB1 and -DQB1 matches (Shaw, 2008)). However, the proportion of successfully completed donor searches is, at best, 80% after 6 months with a median time duration of 2 months in extremely large and efficient bone marrow registers (Fig 1) (Heemskerk et al, 2005; Tiercy et al, 2007; Bray et al, 2008; Hirv et al, 2009). This optimal figure is far from being achieved in countries where the ethnic background is more diverse. In this regard, US studies reported that more than 50% of patients lack donors if they belong to populations of non-North Western European descent (Dew et al, 2008; Johansen et al, 2008). Therefore, two issues need to be addressed in order to offer a more effective use of the therapy: (i) access to treatment for patients who lack either a related or unrelated donor (mainly patients of non-North Western European origin), and (ii) the timely provision of stem cells for those patients who require urgent transplants (i.e. within 3 months of initiating a search).
An attractive intuitive option to improve donor availability should be to increase the size of adult donor inventories. But, in practice, even using the inventory provided by Bone Marrow Donor Worldwide, which lists data on more than 12 million donors, a substantial number of searches result in no sufficiently matched donors being found. According to van Rood and Oudshoorn (2008), between 2000 and 2006, 151 000 patients qualified for an HLA unrelated donor transplant but, of these, only 64 720 actually received a transplant. The reasons for that are multiple, including patient condition, but the inability to find a donor on time remains the most important. This includes high rates of attrition reported by registers, meaning that despite the worldwide maintenance of large lists, a large percentage of donors are probably unavailable. This is a major draw back of volunteer registries and incurs substantial cost for their maintenance (Myaskovsky et al, 2004). In addition, the authors stated that, as far as increasing the number of available phenotypes is concerned, increasing the number of adult donors is not cost-effective. Similarly, other authors have presented models indicating that continuing to add more volunteers to the donor registries will have a limited effect. In this regard, Hurley et al (2003) pointed out that continued recruitment of random volunteers would eventually lead to diminishing returns. At a registry size of 10 million donors, approximately 7 million additional donors are needed to increase the chance of matching by only 1%. Also, attempts to collect very rare donor phenotypes that may never appear in the search for an individual patient can be counterproductive. Following the suggestion of Kollman et al (2004), efforts to find and remove barriers to unrelated stem cell transplantation, other than the lack of an HLA-matched donor, may prove more cost-effective in increasing the number of transplants. Cord blood transplantation (CBT) offers that possibility.
CB tissue was proposed as an alternative stem cell source after the demonstration of an unexpectedly high amount of haematopoietic progenitor cells in its circulation (Knudtzon, 1974; Broxmeyer et al, 1989; Gonzalez et al, 2009). This capacity was confirmed after the successful engraftment of the first CBT performed in Paris in 1988 (Gluckman et al, 1989). CB has many advantages due to the immunological naïveté of the newborn cells and the high expansion potential of its circulating stem cells; the faster availability of banked cryopreserved CB units; decrease in the donor size inventory due to tolerance of 1–2 HLA mismatches out of six and higher frequency of rare haplotypes by targeting ethnic minorities; lower incidence and severity of graft-versus-host disease (GVHD); lower risk of transmitting infections by latent viruses; lack of donor attrition; and lack of risk to the donor (Gluckman & Rocha, 2009).
These advantages have been verified with the extensive experience on CBT worldwide. Since Rubinstein et al (1993) proposed that panels of stored placental blood (‘public’ CB banks) should be established, this modality of transplantation has developed steadily thanks to the availability of larger and better CB inventories (Rubinstein, 2006). Nowadays, CBT is a widely accepted source of progenitors for haematopoietic transplantation, with more than 20 000 procedures already performed (Gluckman & Rocha, 2009). Clinical results are extremely promising and approach or, in some cases, are superior to those achieved with conventional adult unrelated sources (Laughlin et al, 2004; Rocha et al, 2004; Eapen et al, 2007; Boelens et al, 2009).
CB programmes can be designed to meet the requirements of a national health service by collecting CB units in maternity centres that are representative of the target ethnic diversity. Relevant to the design of a national CB bank is the observation, by researchers at the New York Blood Center National Cord Blood Program, of the impact of cell dose and match in survival (Fig 2) (Barker et al, 2007). Briefly, within the dose range transplanted to date, recipients of 6/6 units had a significantly superior disease-free survival (DFS), which was not explained by other variables such as age, disease risk, or transplant centre. In contrast, recipients of 3/6 units had inferior DFS, also regardless of dose. Further, recipients of 5/6 units with a total nucleated cell (TNC) count of 2·5–4·9 × 107/kg (mean 3·5) had a DFS that was similar to those receiving larger 4/6 units (TNC count 5·0 × 107/kg; mean 5·9) but with a lower risk of severe acute GVHD. Recipients of small (< 2·5 × 107/kg) units that were either 5/6 or 4/6 matched had significantly inferior outcome. Interestingly, the ideal situation seems to require units of at least 2·5 × 107 nucleated cells (NC) per kilogramme recipient body weight and five out of six HLA matches. Cell dose relevance decreases at that match level. Based on these findings, we use the optimal incremental benefit of patients finding donors within the five out of six match category to calculate the suitable size of a national CB registry. Moreover, defining cellular thresholds enables acceptable NC counts (i.e. 1·25 × 109 TNC to target patients of 50 kg body weight) to be set. Finally, study excludes consideration on potential disadvantages of racial disparity between donor and recipient because clinical data reported still is unclear on the effects of potential minor mismatches in CBT.
Establishing a national CB programme
A national CB programme designed to supply thousands of donations will require the participation of many parents-to-be and the involvement of various hospitals and perinatal care providers. Moreover, it will require public health campaigns to promote the concept of CB donation. When designing a national CB bank it is necessary to consider the practical implications and limitations in order to optimize the banks usefulness. First, it is necessary to estimate the number of patients that would benefit from this initiative. Second, it is necessary to determine the optimal size of a CB bank for each country according to pre-defined and quantifiable targets. There are other factors to be considered, such as quality and the costs associated with the project. Below, we present our experience in planning a national CB programme for UK.
How many lives can be potentially saved?
Firstly, we conducted a survey at King’s College Hospital to determine in a practical scenario the number of patients who could benefit from the CB programme (Querol et al, 2009). The survey undertaken looked at allogeneic transplant activity during 2005 and showed that, for 60 patients who underwent an unrelated donor search, the median time from formal search to availability of a donor was 11 (6–45) weeks. If the search for a donor was performed overseas, this time was delayed a further 3 (0–4) weeks. Once the donor was confirmed and judged medically fit to donate, the transplant centre needed an additional 10 (2–24) weeks to proceed with the transplant. Therefore, the waiting time was 26 (11–49) and 29 (12–56) weeks, dependant on whether the patient received a donor from within the UK or outside the UK. This time was 7–10 weeks longer than that of sibling transplants performed during the same period. Importantly, the median time to define a search failure was estimated at 6 months, making any alternative therapy very unlikely. Furthermore, 43 patients (72%) found a donor (38% within a UK register and 33% from registers overseas) but 20 never received a transplant, mainly due to disease progression or deterioration of their medical status. Overall, 38% of patients for whom a search was started were actually transplanted. Taken together, these data clearly show the interrelation of the two major logistic problems in the provision of stem cell donors: access and time. Thus, 28% of patients waited 6 months before failing the search procedure, 33% of patients were not transplanted despite a donor being found within 4 months, and finally, unrelated transplants were performed 2 months later than sibling transplants for the same indications. The outcome of this survey suggested the need to initiate a clinical CB programme.
Secondly, to address the impact that a CB programme could have in the UK, we analysed the ethnic background of the donors and patients registered at the Anthony Nolan Trust during 2005 and the outcome of an individual patient’s search for a donor. Ethnic minorities vary between countries and this can generate a different perception of the real needs of CB registries. Some authors have suggested that the access to treatment in various minority groups is very different because the indications for referral differ (Kollman et al, 2004), but this was not the case in the UK. The ethnic distribution of patients and donors in the register closely matched that of the last published population census, as shown in Table I. There is a trend to fewer transplants in the ethnic minority populations, but the use of CB is increased in these groups.
Table I. Ethnic distribution of donor and patients involved in an unrelated transplant compared to the general UK population.
UK Census 2001
Anthony Nolan donors
Searches for UK patients*
Cords per transplants
Data in percentages.
*16% of unknown ethnicities were excluded from the percentage assignment.
†NWE: North-Western European Caucasian.
Source: Anthony Nolan register for 1079 searches performed during 2005 in the UK.
Altogether, this experience suggests that a timely CB access could benefit about one third of the patients requesting an unrelated donor. Patients from all ethnic groups would potentially benefit despite the fact that the relative number of CBT is higher within the ethnic minorities. Last year 1300 unrelated searches were started in the UK, suggesting that up to 400 patients could benefit annually from the development of a comprehensive CB banking and clinical programme. Additionally, the reduction of the waiting time may improve the therapeutic outcome of the allo-therapy.
How big should the bank be?
To analyse the size requirements for a UK National CB programme, we published the results of a study designed to estimate the proportion of UK patients who can find at least one donor according to different HLA match categories, empirically matching actual patients that request searches for donors with different sizes of the Anthony Nolan Register (Querol et al, 2009). Stevens et al (2005) previously reported this approach using searches requested to the National Cord Blood Program in New York. In that study, 16 222 search requests (with an ethnic background similar to the general US population) and 20 773 CB units, 50% of them from ethnic minority groups, were matched. Match success for the 20 000-donor pool size for the optimal five or six out of six HLA-match category was 61%, showing a progressively diminishing improvement. Their projection suggested that 55 000–60 000 donors would be required to provide matching CB units for up to 80% of the patients. These results are consistent with our findings using a similar empirical analysis (Querol et al, 2009). Table II compares range of patients finding at least one donor considering their ethnic background and the median number of donors found per patient. Below, we present the different scenarios analysed in that publication:
Table II. Range of finding a donor and median number of donors found considering different donor panel size of the Anthony Nolan panel.
Donor panel size
*Minimum figure corresponds to the successful rate for non-north western Europeans and maximum figure for the overall group of patients. Figure in parenthesis represents the median number of potential donors per patient matched in the overall population.
10 000 donors
50 000 donors
100 000 donors
Four out of six or better
Five out of six or better
Six out of six
1) How many patients will find at least one donor according to different donor panel sizes for each of the HLA-match categories tested (four or better, five or better, and six out of six, according HLA-A, -B (antigenic), -DRB1 (allelic) HLA typing resolution)) for the whole population?
The study showed that 50 000 donors would be required to provide at least one donor for 99% of the patients (median 261) in the four out of six antigen match category, for 80% in the five out of six match category (median 9), and for 34% in the six out of six category (median 0) (Fig 3).
2) What is the result for the requesting patients excluding those with a North-Western European background (namely for the ethnic minority groups)?
For the 13% of patients in this category the effectiveness of a CB bank in providing a match was significantly reduced. In this case 50 000 donors would provide at least one donor (median 35) for 96% of the patients in the four out of six category, 50% (median 0) in the five out of six match category, and 9% (median 0) in the six out of six category (Fig 4).
3) What is the benefit of a CB bank that focuses completely on collecting units only from minority groups in the UK?
One potential strategy to improve effectiveness is to collect CB units mainly from the groups considered as ethnic minorities. We conducted an exercise to address the possible impact if only ethnic minority groups were enrolled. Figure 5 shows this prediction using the 26 925 donors available from these groups on the Anthony Nolan Register and HLA-typed at the level of resolution required. A panel of that size would provide at least one donor for 99% of the patients for the four out of six category, and 67% and 11% for the five out of six and six out of six categories, respectively. Therefore, the data show that a bias towards collecting ethnic minority groups increased the likelihood of finding a donor.
4) What is the benefit of enlarging or diversifying the inventory?
An enlarged inventory shows a progressive decrease in the benefit observed, requiring many more donors to achieve the same degree of improvement. In this regard, the inventory should reach 150 000 donors to offer an 80% chance to the minority groups using the whole population but, by doing that, there is a great deal of redundancy in the number of potential donors found for patients in the most-predominant ethnic group. In terms of cost-benefit, it might be more adequate to bias the CB bank by collecting a relatively higher proportion of units from less-predominant ethnic groups within a size of around 50 000 and rely on international cooperation for a specific patient with a very rare phenotype. Table III compares these outcomes.
Table III. Quality of a cord blood bank according to cellular thresholds in units received.
Threshold at reception (×108)
Median NC at reception (×108)
Patient body weight* (kg)
Discarded † (%)
*Equivalent patient body weight benefited according cell dose of 2·5 × 107 NC/kg.
†Percentage of units discarded due to cell counts below the threshold of acceptation.
Source: figures were calculated by analysing 13 799 CB units received at the Barcelona CB bank between 1995 and 2005.
Importantly, an optimal and cost-effective CB bank design may be based on diversity rather than quantity. In this regard and using the plots presented, we can extrapolate the following outcomes for matching predominant versus less-predominant ethnic groups in the UK using UK donors. A non-biased bank of 50 000 would have around 15% of minority ethnic groups (about 7500 donors) and give a 36% chance of match for this group, and 80% for the whole population. If we bias collection towards the minority groups (i.e. doubling their representation to 30% of the inventory) the predicted figures are 74% for the whole population but 52% for the non-predominant ethnic groups. If we further increase this bias towards 50% of minority ethnic origin, the numbers become similar for both groups (71% and 67%, respectively). Taken together, these figures show a higher benefit in increasing the representation from ethnic minority populations and therefore, a national CB programme should pursue collection centres with the highest ethnic mixture (ideally achieving between 30–50% of the CB units from ethnic minority populations).
Quality issues in CB banking
The design of a new and efficient public CB bank should take into account quality. Each specific processing centre needs to follow tight quality management systems and accept expert recommendations from accreditation bodies, such as Netcord and the Foundation for Accreditation on Cell Therapy (FACT) who edit the NETCORD-FACT International Standards for CB Collection, Processing, Testing, Banking, Selection and Release, to maximize their abilities. Safety issues are well described in many national and international regulations and closely resemble blood transfusion policies. Issues of efficacy are more controversial as we still lack a good laboratory test that can predict engraftment potential. For general purposes, NC count is an acceptable surrogate of graft efficacy but, more specifically, a good measure of CD34+ cell numbers, provided that a viability marker is added, is a better predictor for engraftment (Rodrigues et al, 2009). Nevertheless, a colony-forming unit (CFU) assay after thawing is still the best marker predicting engraftment and overall outcomes (Prasad et al, 2008), suggesting that other efficacy tests need to be developed for a proper assessment of the CB unit before freezing.
To assess the quality of a national CB programme, we calculated the median body weight for the patient using the minimal threshold of an optimal transplant as shown in Fig 2 (2·5 × 107 NC/kg). But, what would the impact on quality be according to different cell thresholds of the CB units when banked? To address this question, we analysed available data from 13 799 CB units received at the Barcelona CB bank between 1995–2005 as a surrogate of cells found in a typical collection. Ethnic background at the Barcelona CB Bank is quite homogeneous and almost 85% of donors are of western Mediterranean Caucasian descent. Reported data are an approximation because what we call ‘typical number’ might vary, depending on collection strategies and ethnic background of the donors. Table IV shows the impact on median cell dose banked and the median weight of the patient that could benefit from the inventory according to three different thresholds. As shown, increasing the NC threshold 1·8-times, from 5 to 9 × 108 results in an increase 1·4-times the median patient’s body-weight. Furthermore, an additional 1·4-times increase, to 12·5 × 108, results in less than 1·2-times increase in the median body weight. However, the number of discarded units rises to 62% making collection programmes highly inefficient. This observation has important implications for the cost calculation of a national CB programme.
Table IV. Effectiveness of 50 000 units stored for patients up to 50 kg body weight* according different cell thresholds when banked and the correspondent cost of the overall programme.
Nucleated cell threshold
5 × 108
9 × 108
12·5 × 108
*Median body weight of patients requesting cord blood donors in the Anthony Nolan register. For patients with higher body weight, a double cord blood transplant might be possible.
†Match probability corresponds to the percentage of finding at least one donor within the five out of six match category. Minimum figure corresponds to the successful rate for non-North Western Europeans and maximum figure for all patients up to 50 kg in each of the scenarios. Figure in parenthesis represent the median number of units found for a patient matched on the overall population.
Suitable units (n)
Match probability (%)
Units disposed (n)
Cost of programme (£)
How much does it cost?
Considering that the cost of the collection and transport of the CB units can account for up to one third of the total cost of the programme, we can calculate the equivalent number of units to be funded according the different thresholds. If our target is 50 000 donors, discarding units below 5 × 108 NC will require collecting 58 139 donors and funding an equivalent number of 52 325. These donor figures are 90 909 and 63 636, and 131 579 and 77 193 for 9 and 12·5 × 108 NC, respectively.
If we apply the cost of a clinical CB unit in the Anthony Nolan CB Bank (£878), it means that a national programme of 50 000 stored units would cost £46M, £56M or £68M for each of the proposed thresholds, covering an average population of 38, 55 and 64 kg body weight, respectively.
But, finally, which threshold is the most cost-effective both for the bank and for the collection programmes? If we plot all data available and compare the number of units with five out of six matches for a recipient body weight of at least 50 kg, there is a 69% probability of finding a median of 3 units in a bank using a threshold of 5 × 108. For a threshold of 9 × 108, there is a 75% probability of finding a median of 6 units, and for 12·5 × 108, an 80% probability of finding a median of 9 units (Table IV). According to these data it seems difficult to identify the best strategy, but our position is that an intermediate threshold can better balance the effort to run a collection programme and the high cell dose required for an adult patient.
Finally, it is worth mentioning that, despite the fact that we can predict the probability of finding a donor, the actual number of units transplanted is difficult to predict because the final decision to select a unit will also depend on the availability of similar or better units found in other accredited registers worldwide. But, in terms of design, it seems reasonable to bank 50 000 units of more than 9 × 108 NC in order to provide nationally up to 6 potential units matching the five out of six category for 75% of the patients of a median of 50 kg body weight.
Recommendations for a national CB programme and potential benefits
Consequent to these data, we propose that using 50 000 high-quality units (i.e. acceptance thresholds of 9 × 108 and, maybe, at least 3 × 106 viable CD34+ cells), with a high ethnic diversity (at least 70–30% ratio between predominant and non-predominant ethnic groups), the National CB programme can be reasonably cost-effective. In addition, if one accepts that by combining 2 units CBT can even be used successfully to treat adults with a high body weight (Brunstein et al, 2007), this inventory may potentially offer an acceptable alternative even to those patients with a body weight of up to 100 kg just by combining 2 units if necessary. If this is the case, this national inventory could guarantee an optimal CBT option for three quarters of the patients in need.
The data shown is consistent with the comprehensive US study by the Institute of Medicine, to assess the funding requirements for the CW Bill Young Cell Transplantation Program. The analysis was based very much on a cost-effectiveness assessment, taking into account life-years gained as criteria for public health investment (Howard et al, 2008). The entire rationale for these approaches is that, notwithstanding the larger the inventory of stored cord units and the greater the likelihood that transplant candidates will match to a unit, storing units indefinitely is costly. To calculate the size that is affordable in terms of cost-benefit, the authors estimated the likelihood that transplant candidates will find a donor as a function of the CB inventory size and then calculated the life-years gained using historical data. Data published showed that, by increasing the inventory from 50 000 to 100 000 units, the cost per life-year gained was $44 000 to $86 000 and they concluded that expanding the CB inventory above current levels was still cost-effective using current standards. If this analysis proved to be true, it is very likely that our current proposal to increase the current UK inventory to 50 000 could be far more cost-effective.
National CB bio-resource for research
Large CB bank initiatives, such as the national CB programme under discussion here, have a unique opportunity to make available for research a useful number of ethically collected, clinical grade CB units that must be discarded when received in the processing centres because they do not meet the strict cellular thresholds required for clinical use. Therefore, this is a great opportunity to use this material for biological research and developmental purposes.
Unfortunately, access to cord stem cells for research is very limited and entirely dependent on the individual provision of small quantities after direct arrangements with labour wards, with the obvious ethical and logistical implications. The establishment of a CB National Biobank that could satisfy the demands of the research community would immediately change the scientific landscape with substantial benefits in all areas, including clinical applications.
A ‘scientific’ CB bank could retain CB units judged to be inadequate for transplantation, as they could easily meet research needs at relatively low cost. Given that public CB collection depends on an altruistic donation, a programme that combines clinical and research use for general benefit makes excellent sense. Once established, a public CB bank would have access to a large number of CB cells that could be the basis for a new development, such as a provision centre of CB cells for research. With this huge potential comes a new responsibility for CB banks to open new avenues for those facilities. This ‘second generation of CB banks’ has the objective to increase the effectiveness of the collection programmes by transferring many units collected for approved research. These banks would liaise with the scientific community, eventually providing reliable and ethically approved clinical grade products.
CB is an alternative source for stem cell therapies beyond its usage in haematopoietic transplantation. There are many examples in the literature of the potential effects of CB stem cells in different models of disease (Körbling et al, 2005; Bhakta & Laughlin, 2008). Using this extra-supply, CB banks can produce specific by-products for cellular therapy. These components can be either non-cellular (as red blood cells and plasma) or cellular including CB stem cells (i.e. non-haematopoietic stem cells, CD34+ or CD133+ progenitor cells, placental-derived stromal cells and unrestricted somatic stem cells) and CB immune cells (i.e. innate and adaptive components, especially naturally arising naïve regulatory T cells).
Adult bone marrow registers have successfully provided donors for up to 80% of patients in a reasonable time. In order to increase the access of this therapy to almost all patients in need of a reduced waiting time, the complementary development of a national CB bank has become highly attractive. A national CB programme will build strength on the altruistic allogeneic donor networks and will provide an unlimited source of unique cell types for both clinical use and research.
We would like to thank the intensive commitment and participation of many colleagues that made possible the development of the Anthony Nolan Cord Blood Bank, especially Dr Susana G Gomez, Dr Roger Horton, Mr Robert Davy, Ms Laura Fry, Mr Daniel Gibson, Ms Salmah Mahmood in the Processing Centre and Prof G Mufti, Dr A Pagliuca, Ms Terie Duffy, and Ms Katie Yannouzis in the Collection Centre. Also, thanks to members of the Anthony Nolan Trust, especially the Operations (Ms Pauline Makoni) and IT Departments (Gary Banner, Peter Chenery, Robert Jeffery) for their help in preparing the graphs. Finally, the authors would like to acknowledge the fruitful discussion with our colleagues at Banc Sang i Teixits in Barcelona, Dr Joan Garcia, Dra Marta Torrabadella, and Dr Ramon P Pla. We are very grateful to prof Carlheinz Muller for his useful comments and contribution in this paper.
Our last thought is for every people working altruistically to make possible the public cord blood programmes and for parents donating cord blood units on behalf of their babies.
Partially supported with grants from European Commission (FP6 AlloStem IP).