Factors Implicated in the Speed and Availability of Unrelated Haematopoietic Cell Donor Provision

REVIEW Beating the odds: factors implicated in the speed and availability of unrelated haematopoietic cell donor provision

RN Lown1 and BE Shaw1,2

The demand for unrelated haematopoietic cell (HPC) donors has risen threefold over the last decade, and is likely to continue to rise over the next 10 years. The time taken from diagnosis to transplant is recognised to adversely affect patient outcome, and provision of unrelated donors (UDs) has been identified as a key source of delay. Obstacles to provision of UD include: delays in referral to a transplant centre, awaiting sibling typing, lack of matched donors (particularly for those from ethnic minorities and/or with rare HLA phenotypes), low- or intermediate-resolution donor HLA typing, donor attrition from the registries, donor ineligibility on grounds of health and difficulties encountered transporting HPC across international borders. There are now over 18 million volunteer donors in registries worldwide, and efficiency has improved, at least in part, because of a switch from paper to electronic searches. As a result, the average time from search request to transplant is estimated to be less than half of what it was two decades ago. Furthermore, registries have developed a number of strategies designed to minimise delays and, ultimately, improve patient outcomes. These include: optimisation of donor numbers and ethnic mix through focused and selective recruitment; high-resolution typing at donor recruitment; cord blood banking with aggressive recruitment in ethnic minorities; early identification of those unlikely to find a match so alternative transplant options may be pursued in a timely manner, through use of HLA-based predictive algorithms; reduction of donor attrition; centralised, registry- based, donor identification services; and provision of a back-up donor.

Bone Marrow Transplantation (2013) 48, 210--219; doi:10.1038/bmt.2012.54; published online 9 April 2012 Keywords: unrelated donor; haematopoietic SCT; time factors; availability; adult; registries

INTRODUCTION are adversely associated with patient outcome. Frassoni et al.18 Allogeneic haematopoietic cell (HPC) transplantation is a curative found in 427 patients with AML achieving a first CR who waited 93 procedure for patients with a wide variety of malignant and non- days or more for transplant had increased transplant-related 1 malignant disorders. The last 10 years have seen a threefold mortality, compared with those waiting o93 days (relative risk increase in the number of recipients of HPCs from unrelated 1.79, P ¼ 0.03). Craddock et al.,19 in a cohort of 168 patients with donors (UDs),2 because of a significant reduction in transplant- primary refractory AML, found a time to transplant from diagnosis 3 related mortality permitting transplantation in those previously of o4 months to be significantly correlated to improved overall thought to be ineligible (such as older patients), an ever-increasing and leukaemia-free survival at 5 years. Finally, in a study of 548 number of indications4,5 and the advent of an international transplant patients, Heemskerk et al.20 found that 30% of patients centralised UD search system.6,7 This number is likely to increase became medically unfit while waiting for an UD transplant. Taking further in the coming decade, such that the National Marrow into account factors such as disease risk, age and gender, they Donor Program (NMDP) anticipates a doubling in the number of concluded that shortening the time taken for donor provision was unrelated HPC donations by the end of this decade.8 key to reducing this rate of clinical deterioration. A central paradigm in UD transplantation is the provision of a A number of obstacles may be encountered in the provision of donor genetically matched to a patient at key HLA loci, as a poor unrelated HPC donors (Figure 1). Many patients are diagnosed in a match may significantly affect patient outcome. In the United non-transplant clinical environment, and there may be a delay in Kingdom, matched allele pairs at HLA-A, -B, -Cw, -DRB1 and -DQB1 referral to a transplant centre. Results of sibling typing may be (the 10/10 match) is considered optimal: overall survival, awaited before initiating an UD search. There may be no matched transplant-related mortality, relapse, engraftment and GVHD have donor found through national or international registry searches, all been adversely associated with increasing degrees of HLA- donors may be typed only at low-resolution, or the individual mismatch.9--13 The development of DNA-based typing methods analysing the search report may not be sufficiently experienced to capable of determining HLA phenotypes to high resolution has select the optimum donor. Once selected for confirmatory typing allowed much greater discrimination between donors compared (CT), the donor may be untraceable, unavailable or medically with traditional low-resolution serological techniques, and this has ineligible for donation. Finally, the donor may be unable to meet improved outcomes.9,14 --17 the timescale demanded by the transplant centre, there may be Inevitably, a proportion of patients will never proceed to delays because of carriage of cells across international borders, transplant, either because an appropriately matched donor cannot or there may be damage or contamination to the cell product be found, or because medical complications in the patient in transit. intervene. Others will encounter delays in the pre-transplant In this first part of this review, the key factors influencing each period (even after a donor has been identified), and these delays stage of unrelated HPC donor provision will be discussed, followed

1Anthony Nolan, London, UK and 2Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, Sutton, UK. Correspondence: Dr RN Lown, Anthony Nolan, 2 Heathgate Place, London NW3 2NU, UK. E-mail: [email protected] Received 28 February 2012; accepted 28 February 2012; published online 9 April 2012 Provision of unrelated HPC donors RN Lown and BE Shaw 211 28 Diagnosis Owing to a recombination hotspot in the HLA class II region, No matched donor available in Delay in referral to national or international registries UDs are most often mismatched (480%) with the patient at HLA- transplant centre or DPB1 despite being matched for the other HLA loci.29 For this sibling typing Lack of expertise in reason, HLA-DPB1 has not been included in global donor selection interpreting search Donors typed at report strategies. In addition, studies over the last 10 years have shown low resolution, and/ or only at HLA-A Donor unable to meet an increase in GVHD associated with a DPB1 mismatch, which is and-B loci timescale set by offset by a decrease in disease relapse, resulting in no additional transplant centre, or 30 --33 Donor unavailable for CT/ withdraws at a late stage survival benefit. Recently, however, there is emerging data harvest, or donor medically supportive of the impact of permissive (clinically tolerated) vs unfit for donation non-permissive (clinically detrimental) mismatches on survival and thus DPB1 typing may be considered in several clinical Delays in transit of HPC 34 across international borders circumstances. Transplant The enormous diversity in the MHC, particularly those regions encoding for HLA-A, -B and -DRB1, has ensured sufficient ‘herd’ Figure 1. Key factors implicated in delaying UD provision. resistance to a wide variety of potentially fatal illnesses.35 To date, 5518 class I alleles (including HLA-A, -B and -C) and 1612 class II alleles (including HLA-DRB1 and -DQB1) have been identified, by a summary of current strategies designed to minimise any leading to several million potential HLA combinations within each potential delay they may cause, improve operational efficiency haplotype.36 This diversity presents a huge challenge for those and, ultimately, improve patient outcomes. hoping to find an UD for HPC transplantation, which necessitates a greater degree of HLA matching than any other human tissue KEY REASONS FOR DELAYS IN UD PROVISION transplant. There are, however, two key factors that increase the odds of Pre-search factors finding a match. First, there is some conservation of HLA The time between the diagnosis of a condition for which haplotypes within ethnic groups, such that certain haplotypes allogeneic HPC transplant is recommended and initiation of an are more common than others. The less ethnically diverse a UD search may be prolonged by a number of factors. Many population is, the more likely it is that two individuals would be patients will not be diagnosed in a transplant centre, but may matched. This is particularly true of small, isolated populations undergo induction therapy there nonetheless. Physicians less that exhibit a strong ‘founder effect’.37 (The founder effect refers experienced in transplantation may not appreciate the time it to the reduction in genetic variation that occurs when a new takes to procure an UD, and miss the opportunity for early referral population is established by a very small number of individuals to a transplant centre or initiating a search process. from a larger population, as may be seen in remote island In addition, an UD search is often not initiated until it is clear populations such as Tristan da Cuhna,38 culturally isolated groups that an HLA-identical sibling is unavailable. In some cases, such as the Amish in North America,39 or certain regions of cities particularly when siblings are estranged or overseas, this can such as Quebec).40 Second, certain HLA loci (for example, HLA-B cause undue delay. and -C) lie closer to each other within the MHC than others, and are less likely to become disassociated from each other by sexual Donor search, and the characteristics of the international donor recombination events through the generations. As a result they inventory are found in association more frequently than would be expected The international donor inventory encompasses a centralised from their respective allele frequencies. This phenomenon is database of donor HLA phenotypes, and other relevant data, from known as linkage disequilibrium.41 UD registries across the world, facilitating the provision of Despite this, the chance of two randomly selected Caucasoid matched donors regardless of international borders.7 The individuals being fully matched is estimated to exceed 1 in composition of the inventory is influenced by a number of 20 000.42 factors, including donor motivations, HLA diversity, ethnicity, typing resolution and non-HLA discriminators, such as gender, age Inventory size. UD registries must therefore, by necessity, recruit and CMV status. large numbers to create the hugely diverse donor panel required to provide matched UD for the majority of those without an HLA- The stem cell donor. At the roots of any donor registry are the identical sibling. Anthony Nolan was the first UD registry to be set donors themselves. Stem cell donation is an altruistic, voluntary and, up precisely for this purpose,43 and other countries soon followed at least currently, unpaid gesture. Positive motivations vary among suit. In 1988, the Immunobiology Working Party of the European UDs and may include solidarity, or a wish to act according to social Group of Blood and Marrow Transplantation set up Bone Marrow or religious precepts, expected positive feelings about donating, Donors Worldwide (BMDW), a voluntary collaboration of stem cell empathy for the recipient and a desire to help another person.21 donor registries and cord blood banks whose goal was to provide There are a number of negative factors that have been documented centralised information on the HLA phenotypes of stem cell to affect a donor’s willingness to donate, including cost, perception donors. Today, over 18 million UDs and half a million cord blood of risk and likelihood of being asked to donate. Motivations also units are currently searchable via BMDW, provided by 66 registries vary by gender, age and the method of recruitment.22--24 from 47 countries across the world.44 In addition, the shift from painstaking paper searches to the provision of an electronic HLA. The six, highly polymorphic, HLA molecules (HLA-A, -B, -C, database capable of being searched worldwide via the Internet -DRB1, -DQB1 and -DPB1), encoded by the MHC on chromosome has dramatically improved search efficiency. 6, are ubiquitous cell surface markers that have a key role in the recognition of foreign Ags25 and the formation of tolerance to self The law of diminishing returns. Although there exist in every and foetal Ags.26,27 Both these concepts are important in SCT, in population particularly common phenotypes that may be shared particular influencing engraftment and the incidence of GVHD. by several thousand people, the majority of individuals will Matching for HLA-A, -B, -C, -DRB1 and -DQB1 molecules (10/10 possess far less common combinations of the key HLA genes. match) has been found to be key in improving the outcome of However, as the size of a registry increases, the chance of HPC transplantation. identifying a new phenotype falls. In 1990, one in two new donors

& 2013 Macmillan Publishers Limited Bone Marrow Transplantation (2013) 210 --219 Provision of unrelated HPC donors RN Lown and BE Shaw 212 and cord blood units had an HLA-A, -B and -DR split phenotype high-resolution CT is performed. It may then be necessary to that was not yet present in the BMDW database. However, by revisit the initial search and select more donors for CT, further 2010 only 1 in 15 donors and cord blood units added a new HLA- delaying the process. A, -B and -DR split phenotype to the database.45,46 The cost to the It has thus become a priority for donor registries to increase the donor registries of matching scarce phenotypes is becoming number of new donors typed to high resolution at -A, -B, -C and increasingly prohibitive. -DRB1, and many are now implementing this policy at registration. This benefits both the transplant centre and registry: the matching Ethnic diversity in the donor population. Recruiting ethnic minority process is expedited, and the registry’s donors are more likely to groups as HPC donors remains a chronic problem for UD be selected for transplant, with incumbent financial benefits. Such registries.47 Simply attempting to match the background popula- fiscal rewards cannot be overlooked as it costs considerably more tion proportions is not enough to provide the phenotypic diversity to type a donor at high resolution. required to give patients from an ethnic minority background the same chance of finding an UD as those of a Caucasian Secondary donor selection criteria and HPC source. Many Caucasoid 48 background. For this reason, any single national registry will patients will have the luxury of a several potential 10/10 matched be intrinsically limited in its ability to provide for its ethnic donors available to them, so the transplant centre must then use minority populations: instead there is a necessary reliance on the other characteristics to select the best donor. Although practice import of stem cell donations from the international donor and opinion vary considerably between centres, the donor community, as well as ensuring that attrition rates of donors from characteristics generally perceived to influence transplant out- 45 ethnic minority backgrounds are minimised. The foundation of comes include age,53 --55 gender,56 CMV status,54,57 parity56 and donor registries in countries such as India, China, Taiwan and ABO blood group.58,59 Thailand will go some way to meeting the needs of their Some, and occasionally all, of the secondary donor character- respective e´migre´s but, other than South Africa, no African or istics may be unavailable at initial search, leading to delays while West-Indian registries are currently listed on BMDW. these details are established. Although the ‘ideal’ would be to provide all this information up front, in practice this is difficult. For Resolving resolution. Progress in the field of DNA sequencing has example, many registries are moving away from typing new enabled very fine discrimination between HLA alleles. Tradition- donors using venous blood samples, preferring saliva or cheek ally, serological (Ab-based) techniques identified ‘broad’ and ‘split’ swabs instead for the sake of convenience and improving donor HLA types (antigenic, or low-resolution, typing), but newer DNA- experience. Unfortunately it is not possible to ascertain CMV Ab based phenotyping methods have enabled individual alleles to be status from saliva---it must be determined at the CT stage instead. identified.49 (Definitions of different levels of typing resolution Additionally, although the technology exists to establish the ABO may be found in Table 1.) By reducing the incidence of hidden blood group from saliva, it is not routinely employed, and this mismatches, transplant outcomes are improved.9,50 practice is unlikely to change in the near future. Age and gender More established registries might have thousands of donors are, of course, generally more easily established. recruited and typed many years or decades ago, when only All registries will, however, have a cohort of donors who have serological techniques were available. Out of financial or previously been requested for CT for other patients, and these technological necessity many donor registries perform limited make up a (usually limited) bank of donors typed to high typing of their new donors, either through use of low-resolution resolution with full virology and ABO typing. If one is found to be a typing, through typing at just two HLA loci (for example, HLA-A match at initial search, access to these donors is usually swift. and -B), or both.51 Even by 2008, nearly 20% of donors listed in Other serological and genetic determinants are occasionally BMDW were typed at low resolution for A and B alone2 (and thus used to discriminate between 10/10 matched donors in transplant far less likely to be selected for CT), and 15 registries typed by practice, such as HLA-DPB1(refs 31--33,60,61) (as previously discussed) serological methods only.52 For the majority of others, inter- and KIR (killer Ig-like receptor).62 --71 Further evidence is required, mediate-resolution HLA typing at HLA-A and -B, and high- however, before their utility is widely accepted. resolution typing at -DRB1 is the norm. Although a number of The route of HPC donation has changed significantly since the potential matches may be identified from an initial search request, advent G-CSF mobilised PBSC harvest in the late 1990s. In 1997, many of these may subsequently be mismatched when data collected by the World Marrow Donor Association (WMDA)

Table 1. Deﬁnitions of terms relevant to HLA typing174

Level of resolution Deﬁnition Sample of nomenclature

Antigenic/ HLA type determined by Ab-based assay HLA B27 serological typing Low resolution Identification of serological group only using DNA-based techniques HLA A*01 Intermediate DNA-based testing limited to a subset of alleles expected within a population resolution High resolution Identification of both serological group and allele (or group of alleles which share the same HLA A*01:01 Ag-binding site) using DNA-based techniques Allelic resolution Identification of a specific allele through DNA sequence-based typing HLA A*01:01:01:02N HLA B*27:01 Modern In contemporary nomenclature, the letter prefix indicates the gene locus (for example, A, B, DRB1); an nomenclature asterisk then separates this from the first numeric field, which denotes the serological type. The second field denotes the allele (or group of alleles with identical Ag-binding site sequences); the third indicates a synonymous substitution in the coding region; and the last indicates a mutation outside the coding region. A final letter suffix may be added to indicate variations in expression of the molecule

Bone Marrow Transplantation (2013) 210 --219 & 2013 Macmillan Publishers Limited Provision of unrelated HPC donors RN Lown and BE Shaw 213 showed that over 95% of unrelated adult HPC donations were concentration with a higher proportion of minority ethnic groups obtained through BM harvest; by 2006 this figure had dropped to and less stable populations, were associated with higher rates of 36%.2 In 2011, just 13% of donations provided, or imported, by attrition.86 Anthony Nolan were BM. Although not without its own inherent 72 risks, mobilised PBSC harvest is thought to generate greater HPC Donor health yields,73 be more convenient for donors, and have a lower incidence of serious adverse events.74 There is limited evidence for Strict regulations exist in all developed countries governing the significant survival differences dependant on the stem cell source safety of blood and tissue products to be used for allogeneic (despite obvious differences in certain complications) and thus the donation. Such regulations exist to protect the interest of the product requested varies significantly according to disease, recipient. In addition, by virtue of the voluntary nature of HPC conditioning protocol and physician preference.75 --83 Additionally, donation, donor registries and harvest centres are morally obliged not to subject their donors to any risk to their health, whether even if a physician requests a particular route of donation, the 87 donor may refuse and, instead, opt for the alternative. proven or perceived, which may be avoided. Donors are medically screened at recruitment and again at CT. Considering the time period that may elapse between Interpretation of the search report. As can be seen, an in-depth the two stages (decades in many cases) it is not unusual for knowledge of HLA haplotype frequencies, linkage disequilibrium, health problems that may preclude donation to develop during the influence of ethnicity, mistyping errors and the role of other this time. donor discriminators is vital in both the selection of the best UD, and the ability to decide in a timely fashion whether pursuit of an Risk to the recipient. As with blood donation, donors with a history alternative stem cell source is more appropriate. Such expertise of HIV,88 --92 hepatitis C,93 --95 human T lymphotropic virus type exists within donor registries, but often the interpretation of the I þ II96 --98 and prion-related diseases are excluded from donation. search report is undertaken by transplant centre staff, who may Active hepatitis B,99 --103 recent malaria104 --111 and Chagas not have the same depth of knowledge. disease112 --117 are also excluded. Certain regional infections, such as West Nile virus118 --124 and babesiosis125 may also be tested for Donor availability for CT at later stages, and donors with a history of other potentially Once a potentially matched donor has been identified, CT is chronic infections must be considered on a case-by-case basis. requested to establish not only a high-resolution phenotype, but to The registry also has to consider other potentially transmissible 126 establish donor availability and perform preliminary virology studies illnesses and, as a rule, a history of malignancy, systemic 127 --130 (generally CMV, hepatitis B and C, and HIV serology). It is at this autoimmune disease and some inherited diseases are not stage that considerable delay may be introduced to the search permissible. Donors perceived to be at high risk of contracting HIV process. Several donor-related issues may arise before CT can take and hepatitis are also excluded (although the definition of high- place. The donor may fail to respond to attempts to contact them risk behaviour is nebulous and registry policies show marked by letter, telephone or email. The registry may be unable to trace differences worldwide, particularly with regards to male homo- the donor: they have moved house or changed telephone number sexuality). Some countries exclude donors who have resided in the without informing the registry. The donor may be unwilling to United Kingdom between 1980 and 1996 from joining, because of 131 --136 proceed with testing and possible donation (either temporarily or concerns about ‘variant’ Creutzfeldt-Jacob disease, but permanently) for personal reasons, may be medically unfit for others will consider such donors on a case-by-case basis. Although donation, or may have passed the age limit for donation. the Food and Drug Agency in the United States, for example, have The resultant problem is considerable: in the NMDP in the recommended permanent deferral of any donor having resided in United States, 46.9% of donors were deferred at ‘activation’ for the United Kingdom for 43 months between 1980 and 1996 domestic requests in the first half of 2011.84 Of 2002 CT requests (Guidance for Industry: Revised Preventive Measures to Reduce the in 2011 at Anthony Nolan, 4% of donors were not contactable, had Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and emigrated or were dead, 17% did not proceed for personal Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood reasons, and 6% did not proceed for medical reasons (internal Products, FDA May 2010), this is a non-binding guideline and in audit), giving an overall ‘attrition’ rate of 27%. practice use of HPC from such donors may be permitted, including It is important, then, for donor registries to establish those imports from the United Kingdom. factors that may predict donor attrition, so they might intervene both at recruitment and during donor latency to be able to Risk to the donor. As previously mentioned, two routes of HPC create a more readily available donor pool. Switzer et al.85 donation exist: BM and PBSC harvest. Donors generally undertake published a large prospective cross-sectional study looking at a non-binding commitment to be able to donate by both routes at demographic and psycho--social factors influencing donor attri- registration. Currently, however, around 70--80% of donations are tion. Interestingly, donor demographics (for example, gender, age PBSC,137 and under certain circumstances many registries will and ethnicity) were not shown to have a significant impact on allow donors to register for PBSC donation only. attrition rates, whereas certain psychosocial factors had a large Certain donor health conditions preclude donation by either effect. Through multivariate analysis, blood donors were shown to route: moderate-to-severe cardiovascular, respiratory, liver or renal have the lowest rate of attrition (odds ratio 0.42, Pp0.001), disease, for example. History of uncontrolled hypertension, whereas those on the registry 44 years had the highest rate (odds arrhythmia, diabetes requiring medication, recurrent venous ratio 5.56, Pp0.001). Other factors, such as method of recruitment thrombosis, symptomatic haemoglobinopathy, epilepsy and and concerns about health were important predictors. A follow-on severe latex allergy will also prohibit donation. to this study published in 2004 examined psycho--social factors in Obesity is by far the most common cause of donor deferral at greater detail: lower rates of attrition were found to be recruitment, and accounted for 19% of deferrals at CT at Anthony significantly associated with intrinsic commitment to donation, Nolan in 2010 (internal audit). Registries may determine the more realistic expectations, fewer medical concerns and greater eligibility of donors to donate by body mass index (BMI). A BMI contact with the donor centre.24 cut-off of 435 kg/m2 is used in the United Kingdom (which is also A further NMDP study examined the effect of donor centre on the definition of morbid obesity), whereas DKMS (Germany), attrition. The authors showed recruitment in both larger, busier, NMDP (USA) and OneMatch (Canada) employ a cut-off of donor centres, and in those in areas of high population 40 kg/m2. Pulsipher et al.138 showed a slightly higher risk of

& 2013 Macmillan Publishers Limited Bone Marrow Transplantation (2013) 210 --219 Provision of unrelated HPC donors RN Lown and BE Shaw 214 adverse events related to donation in donors with a BMI 430 kg/m2, only by logistical factors such as harvest centre availability and BM biopsy is likely to be a more hazardous procedure in the and donor travel times. However, unexpected and unpredictable obese patient.139 However, there is little evidence linking obesity events do occur, which may add considerable delay to to adverse events in HPC donation. As a result, the decision to the process. Life events or injury may cause the donor to become prohibit donations from those with morbid obesity is based on unavailable, or the donor may fail their medical assessment epidemiological studies and anaesthetic risk. The risk of premature because of an incidental, but prohibiting, finding, such as death doubles in those with a BMI 435 kg/m2,140,141 and the structural cardiac disease or an abnormal chest X-ray. Rarely, incidence of cardiovascular,142 cerebrovascular, respiratory143 and venous access is difficult and a donor may refuse central venous endocrine disease,144 --147 certain cancers,148 --151 as well as venous access or BM harvest. thrombosis,152 - 155 are all significantly greater. Anaesthetic complications may arise from difficulty in assessing the airway,156 restrictive 157 International borders. Finally, there may be problems in exporting respiratory physiology with reduced lung volumes and subopti- HPC when not intended for use in their country of origin. Each mal gas exchange,158 cardiac decompensation,159 increased throm- 160 161 country will have specific regulations governing the import and botic risk and altered drug handling. export of human tissue, and HPC are no exception. In addition, Donors with a wide range of back complaints may be excluded regulations regarding the safety of tissues will vary from country from donating by BM, where the forces exerted by the harvest to country, especially with regard to infectious diseases. Donor procedure are deemed to risk exacerbating pre-existing back registries must keep up to date with these regulations in their own conditions. However, these donors are often permitted to donate country, and be familiar with those overseas in order to ensure by the PBSC route. there are no delays in the provision of HPC donations. Shipment is particularly vulnerable to events that may cripple Assessment of borderline cases. The worldwide donor pool has international transit networks, particularly air travel. For example, increased considerably over the last decade and, as a conse- several transplants were delayed during the Icelandic ash cloud in quence, there has been a paradigm shift away from donor 2010, and 16 patients in the United Kingdom had delays in quantity to donor quality. In a sense, this makes the task of receiving stem cells after conditioning had commenced.162 deciding donor eligibility much more simple at recruitment, particularly in less clear-cut cases. As rejection of a donor is statistically unlikely to have an impact on HLA diversity within the STRATEGIES TO SPEED DONOR PROVISION register, the decision of the recruitment officer or medical officer A summary of strategies devised to improve the speed and can be made without being influenced by concern for registry efficiency of UD provision is shown in Figure 2. numbers, at least in Caucasoid donors. In practical terms, it means that if there is any doubt regarding the donor’s fitness, it is feasible to adopt a ‘zero-tolerance’ policy towards borderline cases, At recruitment rejecting all donors where it is uncertain whether their health Modern donor recruitment strategies, particularly in larger problems subject them to increased risk by donation. registries, have moved away from donor quantity, where unselected donor recruitment leads to decreased marginal benefit Permissiveness in assessing donor health. This policy may not be to the HLA pool, to donor quality. This is reflected in a number of so appropriate at CT or workup, where the medical officer may policies. exercise a certain degree of discretion. A key example is where only one potential donor is available for a patient. Any donor Focused recruitment in ethnic minority communities. Barriers to with a clear contraindication to donation should, of course, be recruiting from ethnic minorities include cultural and religious deferred: however, medical conditions where the risk to the factors, education and awareness, cost and opportunity.47 patient or, indeed, the donor are poorly defined or subject to Strategies to overcome these barriers include minority drives that clinical conjecture need to be carefully considered on a case- may be linked to a patient of a particular ethnic background, by-case basis. In cases where there is a potential risk to the employing public figureheads, collaboration with ethno-specific patient, such as a history of donor autoimmune disease or high- health charities (such as the African--Caribbean Leukaemia Trust in risk sexual behaviour, this risk must be weighed against the the United Kingdom), cooperation with press read specifically by inferior outcomes associated with delays to transplant and minority ethnic groups and providing printed information and pursuit of alternative treatments. In these cases, it is usually marketing literature in foreign languages.163 appropriate to discuss the risk with the transplant centre, who will Although such strategies have met with some success, it make the final decision on whether they wish to accept the remains difficult to recruit in some ethnic groups. donation. In cases where the potential risk is to the donor, then the route of donation, donor age and general fitness, and any published evidence supporting the case for deferral must be reviewed to Recruitment in areas of high HLA diversity inform the decision. Typical scenarios in this category include Recruitment Focused ethnic minority recruitment donors falling slightly above or below weight limits set by High resolution typing at recruitment the registry, those who pass the age limit for donation during the Cord blood collection search and workup process or between first and subsequent Predictive search tools donations, and donors who have undergone major surgical Search Graft identification services procedures recently enough to exclude them from donation Donor ‘freshness’ initiatives under normal circumstances. The responsibility of the registry/ & pre-screening CT donor centre is always primarily towards the donor, such that if Additional typing of existing any concern exists the donor must be deferred. donors

Backup donor Work-up & WMDA & Delays late in the process of donor provision export global policy Late donor attrition. Once the donor is identiﬁed and their availability established then the time to harvest is usually limited Figure 2. Strategies to overcome obstacles to UD provision.

Bone Marrow Transplantation (2013) 210 --219 & 2013 Macmillan Publishers Limited Provision of unrelated HPC donors RN Lown and BE Shaw 215 Focused recruitment in geographic areas of proven high HLA with positive predicative results. Neither tool was compared diversity. Schmidt et al.164 looked at 320 000 German donors, against the predictive ability of an experienced senior search specifically analysing the variation in HLA Ag and phenotype scientist. frequencies across the country. Areas where phenotypic diversity was higher were identified, and provided a rationale for focused Donor selection algorithms and graft advisory services. The recruitment in these areas, with the hope of identifying greater individual or team performing the initial search and selection of numbers of new or rare phenotypes than might be gained from donors for CT may differ by country, region or even centre. This unselected recruitment. A similar study is underway in the United may in some cases be centralised, but may also be performed by Kingdom, specifically looking at geographical HLA diversity in medical or nursing staff (with or without specific training) in the donors of North-European origin.165 transplant centre. In the United Kingdom, a combination of these approaches is Improving typing resolution. In 2011, Anthony Nolan completed found. Anthony Nolan has initiated a system called Graft the Get10K campaign, which successfully recruited 10 000 healthy Identification and Advisory Service (GIAS) to assist those centres male donors under the age of 30, the population most sought by where the search was historically predominantly centre based. transplant physicians, and typed them to high resolution at HLA-A, GIAS is a centralised service that expedites high-quality graft -B, -C, -DRB1 and -DQB1. selection. Although the transplant centre specifies the donor An alternative approach is to take existing donors typed only at selection algorithm for ranking donors according to local practice HLA-A and -B, and retype them at additional HLA loci, for example (for example, including both HLA and secondary donor character- HLA-DRB1. By carrying this out on donors appearing on search istics), the GIAS team performs the remainder of the search, requests as potential matches for patients in need of a transplant, selection and request functions. By deferring donor selection to DKMS concluded that the chance of patients finding an HLA- the donor registry, the transplant centre benefits from faster matched UD could be improved.166 search times and fewer donors selected for CT, with additional financial benefits. Cord blood collection. There are now many well-established cord blood centres across the world, collectively holding over 500 000 At CT cord units. As the standard of HLA matching is considerably more The ‘fit panel’ of donors. In order to overcome the delays to donor permissive (recommended 5--6/6, rather than 9--10/10), cord provision presented by donor attrition, the concept of the ‘fit panel’ blood is invaluable in overcoming the difficulties encountered by of donors has been proposed. These are donors that are ‘fit’ not just transplant centres attempting to match patients with rare from a health, age and gender perspective, but those whose phenotypes. The use of cord blood units also has the potential contact details are contemporary and current health and availability to overcome much of the disadvantage borne by ethnic minority is already known. Such a panel of donors would speed up CT times patients, and many countries now aggressively recruit expectant considerably, eliminating timely processes such as donor tracing. mothers from these backgrounds to donate their child’s umbilical However, considering most registries have several hundreds of cord blood, which would otherwise be discarded.167 The recruit- thousands (if not millions) of donors, constantly updating records ment of cord blood donors in these groups is perceived to be for donor availability could be a huge financial burden. more readily attainable than adult donors.168 As part of its ‘Phoenix Initiative’ in the United States, the NMDP found a novel way of establishing the availability of a At search core group of donors. During a trial period, they took all those donors identified as potential matches at initial (preliminary) Predictive search tools. Experienced search staff in donor registries search (sometimes several hundred donors) and contacted have a very broad knowledge of national and global HLA them, with the aim of screening and removing donors ‘who are haplotype frequencies and linkage disequilibrium that enables deemed unavailable or medically unsuitable before formal them to make a judgement on how likely it is that a given patient activation.’84 Establishing donor availability and donor selection will find a matched UD. Such knowledge is invaluable in were thus performed in parallel, so that availability was known identifying those patients in whom the chance of finding a when selecting donors for CT, reducing turnover times. In matched UD is very low, and who would benefit from early pursuit addition, a core group of available donors was established of alternative transplant strategies, such as a mismatched, cord 169 whose availability at future searches and CT was indicated with blood or haplo-identical transplant. a ‘readiness score’, which would expedite future donor provision Recently, attempts have been made to consolidate this by indicating to transplants centres those donors most likely experience into predictive algorithms that categorise patients to follow through. Compared with a 46.9% background according to the likelihood of finding a match. In the United deferral rate, only 11% of pre-screened donors deferred at States, the Haplogic system used by the NMDP estimates the activation for domestic requests in the first half of 2011. Similarly, likelihood of a donor finding an allele level match at HLA-A, -B and as part of the GIAS program, the search team pro-actively contact -DRB1, based on haplotype frequencies in the four major US 170 UK donors who may act as a backup to ascertain their fitness ethnic groups. Similarly, in Germany, the OptiMatch system and availability, even if these donors have not been actively combines intermediate-resolution donor typing from recruitment selected for CT. with high-resolution three-locus-haplotype frequencies in the In addition, registries must prospectively engage those donors underlying population in order to calculate the probability of a most likely to be called to donate, in particular younger donors donor being matched at each of HLA-A, -B and -DRB1, as well as all and those who have already been typed to high resolution. three loci combined. 171 Strategies vary between registries, and the details are beyond the Tiercy et al. developed a broad predictive tool in which scope of this review, but should be influenced by those patients were ranked as low, intermediate and high probability demographic and psychosocial factors previously identified as of finding a donor, according to the presence of rare alleles, contributing towards donor attrition. unusual allele linkage, and number of potential donors identified in a BMDW search. Hirv et al.172 developed a simpler, yet equally efficacious, tool, ranking patients according to the At workup population frequency of their HLA-DRB1 allele and DRB1-DQB1 The backup donor. Delays at the workup stage are often very haplotype. Both these techniques were validated retrospectively unpredictable and risk delaying the provision of HPC considerably.

& 2013 Macmillan Publishers Limited Bone Marrow Transplantation (2013) 210 --219 Provision of unrelated HPC donors RN Lown and BE Shaw 216 One effective strategy in minimising this impact of donor deferral 10 Keever-Taylor CA, Bredeson C, Loberiza FR, Casper JT, Lawton C, Rizzo D et al. at a late stage is the provision of a ‘backup donor’. Not all patients Analysis of risk factors for the development of GVHD after T cell-depleted will have this luxury, but they can be kept on standby and rapidly allogeneic BMT: effect of HLA disparity, ABO incompatibility, and method of accessed should the initial donor become unavailable. However, T-cell depletion. Biol Blood Marrow Transplant 2001; 7: 620 --630. there are cost implications and not all transplant centres will be 11 Lee SJ, Klein J, Haagenson M, Baxter-Lowe LA, Confer DL, Eapen M et al. High- willing to reserve a backup donor. resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood 2007; 110: 4576 --4583. 12 Morishima Y, Sasazuki T, Inoko H, Juji T, Akaza T, Yamamoto K et al. The clinical Global policy significance of human leukocyte antigen (HLA) allele compatibility in patients The World Marrow Donor Association was founded in 1994 as an receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors. Blood 2002; 99: 4200 --4206. international collaboration aiming to facilitate the exchange of 13 Morishima Y, Yabe T, Matsuo K, Kashiwase K, Inoko H, Saji H et al. Effects of HLA high-quality haematopoietic stem cells for clinical transplantation allele and killer immunoglobulin-like receptor ligand matching on clinical worldwide and to promote the interests of donors (www.world outcome in leukemia patients undergoing transplantation with T-cell-replete marrow.org). It monitors trends in the exchange of HPC products marrow from an unrelated donor. Biol Blood Marrow Transplant 2007; 13: and uses this information to recommend benchmarks for 315 --328. standardised global policy and to identify barriers to donor 14 Perz JB, Szydlo R, Sergeant R, Sanz J, O’Shea D, Khan T et al. Impact of HLA class I exchange.173 Published recommendations include: registry orga- and class II DNA high-resolution HLA typing on clinical outcome in adult nisation; donor recruitment; donor characterisation; search unrelated stem cell transplantation after in vivo T-cell depletion with requests; collection, processing and transport; patient and donor alemtuzumab. Transpl Immunol 2007; 18: 179 --185. follow-up; and financial and legal liabilities. Regular meetings of 15 Maury S, Balere-Appert ML, Chir Z, Boiron JM, Galambrun C, Yakouben K et al. Unrelated stem cell transplantation for severe acquired aplastic anemia: the WMDA and its working groups ensure contemporary review improved outcome in the era of high-resolution HLA matching between donor and opinions of relevant issues affecting global transplantation. and recipient. Haematologica 2007; 92: 589 --596. 16 Vanichsetakul P, O-Charoen R, Seksarn P, Kupatawintu P. Outcome of pediatric hematopoietic stem cell transplantations from Thai unrelated donors matched CONCLUSION with high-resolution HLA typing. J Med Assoc Thai 2005; 88(Suppl 4): S1 --S6. 17 Ottinger HD, Beelen DW, Grosse-Wilde H. What is the impact of HLA mismatches Many pitfalls may be encountered during the provision of an detected by high-resolution techniques on the outcome of unrelated donor unrelated HPC donor, all of which may cause delays, to the bone marrow transplantation? Bone Marrow Transplant 2005; 35: 1211. detriment of the patient in need of a transplant. Several strategies 18 Frassoni F, Labopin M, Powles R, Mary JY, Arcese W, Bacigalupo A et al. Effect of are being implemented to reduce such delays, and continued centre on outcome of bone-marrow transplantation for acute myeloid perseverance by national registries as well as continued interna- leukaemia. Lancet 2000; 355: 1393 --1398. tional collaboration are required to ensure that as many patients 19 Craddock C, Labopin M, Pillai S, Finke J, Bunjes D, Greinix H et al. Factors as possible are given the opportunity of cure through allogeneic predicting outcome after unrelated donor stem cell transplantation in primary transplantation. refractory acute myeloid leukaemia. Leukemia 2011; 25: 808 --813. 20 Heemskerk MB, van Walraven SM, Cornelissen JJ, Barge RM, Bredius RG, Egeler RM et al. How to improve the search for an unrelated haematopoietic stem cell donor. Faster is better than more!. Bone Marrow Transplant 2005; 35: 645 --652. 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