Stem Cell Transplantation |
1 Anthony Nolan Research Institute, Royal Free Hospital, London, UK
2 Department of Haematology, UCL Cancer Institute, Royal Free Campus, London, UK
3 Department of Haematology, Kings College Hospital and Kings College, London, UK
4 Royal Marsden Hospital, Sutton, Surrey, UK
5 Programa de Sang de Cordó, Banc de Sang i Teixits, Barcelona, Spain
Correspondence: J. Alejandro Madrigal, Anthony Nolan Research Institute, Royal Free Hospital, Pond Street, London NW3 2QG, UK. E-mail:a.madrigal{at}medsch.ucl.ac.uk
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Design and Methods: We calculated the actual numbers of possible donors and the chance of finding at least one donor for 2,000 unselected and for 722 non-North Western European patients for whom searches had been initiated as a function of three levels of HLA matching (4, 5 and 6 out of 6 alleles by HLA-A, -B low and -DRB1 high resolution HLA typing) according to various donor bank sizes.
Results: With a bank size of 50,000, 80% of patients will have at least one donor unit available at the 5 out of 6 HLA allele match level (median 9 donors per patient), and 98% will have at least one donor at the 4 out of 6 allele match level (median 261). Doubling the size of the bank yields at least one donor for only an additional 6% of patients at the 5 of 6 allele match level. Moreover, for non-North Western European patients a 50,000 unit bank provides a donor for 50% at the 5 allele match level, and for 96% at the 4 allele match level.
Conclusions: A bank containing 50,000 units is optimal for the UK and larger banks would only marginally increase the chance of finding suitable units.
Key words: cord blood, banking, stem cell transplantation.
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More than 12,000,000 unrelated adult and cord blood units are available worldwide. However, the World Marrow Donor Association (WMDA)4 reported that though there were 9,484 unrelated transplants performed worldwide in 2007, fewer than half of the 32,000 patients who require a transplant actually had a suitable donor. The failure to identify a donor is due to a combination of factors, including inability to identify a well matched donor, inability to locate a donor who does seem to match or a delay in a given donors availability.4,6 In 2007 in the UK a search for an unrelated donor was started for 1,260 patients, but only 40% actually received a transplant even with the contribution of 90 cord blood units (Anthony Nolan Trust annual report). At that time, UK registries had almost 650,000 donors7 but 43% of UK patients still received transplants from overseas donors.3,8 In the case of cord blood units, almost 80% of the donor units were imported. These data support the development of a large cord blood inventory in the UK.
Recently, the US Institute of Medicine at the request of the US Congress prepared a report that strongly encouraged cord blood banking for transplantation. The report stated that by increasing the size and quality of the existing cord blood inventory in the US, nearly 90% of patients who need a transplant should be able to find a suitable match from either cord blood banks or marrow donor registries.9 The committee estimated that though there were already 50,000 units stored in national inventories at least 100,000 additional high quality cord blood units were needed. Most of this analysis was based on estimates of haplotype distribution for the US population.10 A preliminary report presented by Rubinstein et al.11 used an empirical analysis that compared actual patients and donors in their registry and obtained similar figures. This suggests that this practical exercise can be used to address the question of optimal inventory size.
In the UK, there is a public cord blood bank operated by the National Health Service Blood and Transplant Service (the NHS Cord Blood Bank) that currently holds 11,000 units and is aiming to accumulate 20,000 units in the next five years (Watt S, personal communication, Workshop on Developments in Cord Blood Collection for the UK Department of Health, 28th May 2008). To assess the real need for the UK we undertook an analysis using actual patients and donors with the aim of obtaining a more exact estimate of the number of cord blood units required to provide at least one donor for more than 95% of patients. First, to address the number of patients that can benefit, we performed a survey of the search activity and outcomes in a referral center in London with a large transplant practice and considerable ethnic diversity. Then, to calculate the size of such a program according to different degrees of HLA matching we used actual patients and volunteer unrelated donors listed in the Anthony Nolan Trusts register to do the simulation.
The lower stringency required for HLA matching when using cord blood as the source of hemopoietic stem cells (HSC) suggests that this therapy can be offered to most patients in need of a transplant, provided that a sufficiently large national bank containing high quality units can be established.12 The key question addressed in this paper is how large the national inventory has to be in order to provide an acceptable donor for the majority of patients who could not otherwise receive a transplant.
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Analysis of the Anthony Nolan Register
The data used are from the Anthony Nolan Trusts SOLAR database. This database is hosted on Sun V440 server running Solaris 10 (Sun Microsystems Inc, Santa Clara, CA, USA) and Oracle 9.2 RDBMS (Oracle Corporation, Redwood Shores, CA, USA). Programming for the compilation of these statistics was done using a number of Oracle SQL*Plus and PL/SQL scripts. Base scripts were run to extract and then incorporate the relevant data for the donor and patient pools into tables with structures more appropriate for the analyses we wanted to perform. These scripts selected information from the SOLAR donor, patient and HLA tables, using 2 digit allele codes for the HLA-A and -B loci and 4 digit allele codes for the HLA-DRB1 locus. HLA-DRB1 codes specified by the National Marrow Donor Program (NMDP) were converted to 4 digit codes using a probability table (only donors/patients where the 4 digit code was deemed to have a probability of 95% or greater of being correct for that particular NMDP code were included in the pools). One script selected information on all suitable active patients only (first simulation for overall population) and a second script selected information on all suitable patients (active and closed) where the ethnicity was known but not specified as North Western European (second simulation for patients with non-North Western European origin). As a result 2,000 consecutive active patients were selected (first simulation) for analysis, and the ethnic group breakdowns for the 722 non-North Western European patients used is shown in Table 1.
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Table 1. Ethnic background of 722 patients registered with a known non-North Western European origin.
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Figure 1. Flowchart on the outcome of patients requiring allogeneic hemopoietic stem cell transplantation at Kings College Hospital during 2005. During this period 104 candidates for allogeneic transplantation were identified. Eleven sibling transplants were considered second line therapy and 20 unrelated searches were withdrawn after the original request. The survey analyses outcome after intention-to-treat of 73 patients whose allogeneic transplantation was their first option (allo-mandatory). Time is expressed in median weeks (range). Figures in the boxes represent the actual number of patients reaching each stage and the percentage from the starting 60 patients requesting an unrelated donor.
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Figure 2. The probability of finding at least one donor 4, 5 or 6 out 6 HLA A, B by low and DRB1 by high resolution according to different inventory size for 2,000 consecutive patients requesting stem cell grafts recently at the Anthony Nolan Trust. Curves were calculated after assessing percentage of patients finding at least one donor for each predefined donor size (1, 10, 100, 1,000, 10,000, 50,000, 100,000 and 150,000) selected from those listed having a known DRB1 high resolution typing.
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Table 2. Comparison of the efficiency of a cord blood inventory of 50,000 vs. 100,000 units: percentage of patients finding at least one donor and median number of donor found in each category.
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Figure 3. The probability of finding at least one donor 4, 5 or 6 out 6 HLA A, B by low and DRB1 by high resolution according to different inventory size for 2,000 consecutive patients with a known non-North Western Europe origin and high resolution DRB1 typing. Curves were calculated after assessing the percentage of patients finding a donor for each predefined donor registry size (1, 10, 100, 1,000, 10,000, 50,000, 100,000 and 150,000) selected from those listed with a known DRB1 high resolution typing.
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Establishing a cord blood program can reduce the proportion of patients for whom no donor is found. Importantly, using a combined adult donor and cord blood search, fewer than 5% of patients would have failed to find a match in our Kings College Hospital study. If then one considers transplant activity for 2006 (496 unrelated transplants) summarized by the British Society for Blood and Marrow Transplantation (BSBMT) the data would suggest that up to 100 additional patients could be transplanted in the UK with a cord donor. This combined search of donor registries and a cord bank of appropriate size would increase the access to transplantation and reduce the time from decision-to-treat to the actual transplant.
Our data define the size for a UK National Cord Blood Bank based on the probability of finding at least one HLA matched donor for each patient. The calculation used HLA phenotypes of actual patients and actual adult donors listed in the register. Ethnical composition of donor and recipient pools were similar reflecting the expected population published by the UK 2001 Census. The ideal size appeared to be around 50,000 units. Using the Anthony Nolan Trust register, this size allows identification of at least one 5 out of 6 HLA matched donor for up to 80% of the patients. Moreover, the median number of donors found per patient matched is 9, increasing the probability of finding at least one donor at an optimal cell dose. Larger banks would only marginally increase the chance of finding suitable units, and as reported, would substantially raise the cost per life-year gained.16
If we accept that 50,000 units is the optimal size of the bank, the next question is what is the minimum number of cells required to make storage of a given unit cost-effective. Using data provided by the Programa Sang de Cordó in Barcelona and illustrated in Table 3, the minimal pre-freezing cell number, based on storage efficiency and cost, seems to be 9x108 total NC. Using this cutoff a bank might need to discard 45% of units collected, while providing 5 out of 6 matched cords for 70% of patients weighing more than 50 Kg. This would cost
1,120 per stored unit. Even the cut-off of 9x108 might in fact prove to be too low if enough large banks containing cord units with many more cells per unit were established worldwide, because cord units with relatively low cell numbers, even though they were above the designated threshold, might not be selected.
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Table 3. Cost benefit analysis for a bank targeting 50,000 units according to different minimum numbers of cells in stored units.1
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In general terms it would be desirable for each country to develop its own cord blood program, since this would increase the diversity of available donor units. The advantage for each country would be that using their own resources a substantial proportion of their population could be covered by their own donors with a reasonable investment. Moreover, international co-operation could guarantee universal access to therapy for practically all patients in need. To make it possible, international standards and accreditation processes are mandatory since quality is paramount for the success of this stem cell modality.17 Consequently, we support proposals from Netcord-FACT for a rigorous international accreditation system for cord blood banking.18 Further studies are required to define the efficacy of a global inventory including the units from all banks accredited at the international level. Furthermore, if appropriately stored, cord blood units may remain viable for many years or even decades19 and could become a valuable resource for possible future clinical techniques that require stem cells or lymphocytes.
In conclusion, given the increased need for stem cells for transplantation from an ethnically diverse UK population those responsible for public health policy may need to review this issue. Here we show clearly that a national UK public cord blood bank should contain at least 50,000 high quality units and this could reasonably be achieved if the necessary funds were made available from a consortium comprising government (through the NHS cord blood bank) and various charitable institutions including the Anthony Nolan Trust. Cord blood banking complements the volunteer adult register and both should be independently efficient to make the allogeneic transplant a certainty. The availability of cord blood units that were not suitable for clinical use could be valuable for stem cell research and staff in cord blood banks could explore the possibility that specific components could be pooled for universal, non-personalized cell-based therapy.
SQ, JAM: study design, data analysis and writing the manuscript; SGE, AML: study design and data analysis; GJM, JG: data collection and analysis; AP, BES, JMG: data analysis and writing the manuscript. The authors reported no potential conflicts of interest.
Received for publication October 29, 2008. Revision received December 2, 2008. Accepted for publication December 3, 2008.
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