What is the Likelihood of Finding a Suitable Stem Cell Donor

What is the Likelihood of Finding a Suitable Stem Cell Donor At present, there are close to 29 million potential stem cell donors in the Bone Marrow Donors  Worldwide registry [4]. Though the number of donors continues to grow worldwide, there are  significant resource implications in donor recruitment and HLA typing. Therefore, the challenge  of thoughtful donor recruitment strategy becomes increasingly relevant. These include  recruitment efforts focused on young male donors [5] or on relatives of registered donors with  rare human leukocyte antigen (HLA) phenotypes [6], minority donor recruitment programs [7-10],  and regional priority setting of recruitment activities based on HLA frequency differences  [11-14].   The decisive question of What is the likelihood of finding a suitable matched adult donor in their  registry? definitely warrants registries strategy planning. Recently, Schmidt, et al [15] reported  that population-specific matching probabilities (MP) are a key parameter to assess the benefits  of unrelated stem cell donor registries and the need for further donor recruitment efforts. The  authors described a general framework for MP estimations of specific and mixed patient  populations under consideration of international stem cell donor exchange. Calculations were  based on HLA-A, -B, -C, -DRB1 loci high-resolution haplotype frequencies (HF) of up to 21  populations. Based on the existing donor numbers, the largest MP increases in addition of  500,000 same-population donors were observed for patients from Greece (+0.21) while only  small MP increases occurred for European Americans (+0.004) and Germans (+0.01). Due to the  large Chinese population, the optimal distribution of 5,000,000 new donors worldwide included 3.9 million Chinese donors [15]. Nevertheless, the authors observed the need for  same-population donor recruitment in order to increase population-specific MP efficiently.   National strategies that neglect domestic donor recruitment should therefore be critically  re-assessed, especially if only few donors have been recruited so far.   As described by Schmidt et al [15], the probability p(n) for a random patient from a given   population to find at least one matching donor in a registry including n individuals of a donor  population is given with p(n) is the matching probability in n sample size, fi  being the frequencies of the i-th genotype and i-th is any genotype from the rank of genotypes in  the order of the highest to the lowest frequencies in a donor population. Genotype frequencies  can be derived from the estimated HF under the assumption of Hardy-Weinberg equilibrium  (HWE).   HF is calculated from DNA-typed registry donors with Markov Chain Monte Carlo (MCMC)  algorithm PHASE [16]. Four-locus high-resolution HF (HLA-A, HLA-B, HLA-C, and HLA-DRB1) were  used for adult donors. The HF and effective adult-donor registry size for each group were then  put into a matching model that assumes genotypes are in HWE [17, 18]. The strategy involved  modeling the likelihood that an 8/8 or 7/8 HLA-matched adult donor was available. For better  analysis, information of adult-donor availability including donor refusal, discrepant donor typing  and loss of contact would be desirable.   According to the calculations, the likelihood of finding an available 8/8 HLA matched donor is  75% for white patients of European descent but only 46% for White patients of Middle Eastern or  North African descent [19]. Similarly, the chance of finding an 8/8 HLA-matched donor for other  groups is lower and varies with racial and ethnic background. For Black Americans of all ethnic  backgrounds, the probabilities are 16 to 19%; for Asians, Pacific Islanders, and Native Americans,  they range between 27% and 52%.   As it was reported that adult-donor availability differs according to racial and ethnic background  [19], models including this variable have substantially lower match likelihoods than those which  did not take into this account. Although the likelihood of HLA matching is the greatest with  donors from the patients racial and ethnic group, donors from other racial and ethnic groups  may increase this likelihood. Patients from groups with relatively low inter-racial or inter-ethnic  marriage, such as Asian groups, are less likely to have donors identified from outside their group. The overall available rate is only 29%. We therefore estimated the donor pool and matching probability in this study based on our  previous published gene and haplotype frequencies in Hong Kong population [20]. MATERIALS AND METHODS Sample Collection and genotyping As reported previously, 7,595 voluntary unrelated bone marrow donors recruited by the HKBMDR  between January 2013 and June 2014 were included in the analysis [20]. All donors are of  Chinese origin, HLA-A, -B, -C and -DRB1 genotypes were obtained using polymerase  chain-reaction sequence-specific oligonucleotide probe methods using LifeCodes HLA-SSO Typing  Kit (Gen-Probe, Stamford, CT) when analysed by Luminex 200à ¢Ã¢â‚¬Å¾Ã‚ ¢ system (Luminex Corp., Austin,  TX). Typing ambiguity was resolved using sequence specific primer or sequence based typing  methods utilising the specific primers of SBTexcellerator ® HLA typing Kit (Genome Diagnostics,  Utrecht, the Netherlands). Alleles were determined according to IMGT/HLA Database release  3.18.0. Statistics Analysis The frequencies of HLA-A, -B, -C and -DRB1 alleles were calculated from the number of observed  genotype. Hardy-Weinberg equilibrium for each loci was assessed by PyPop using MCMC  simulation from Guo and Thompson [21], and genotype frequency deviance within each loci was  detected by PyPop invoking Arlequin [22]. P value of By using the formulae described by Schmidt et al [15] with modification, the probability p(n) for a  random patient from a given population to find at least one matching donor in a registry  including n individuals of a donor population is given with p(n) is the  matching probability in n sample size, fi being the frequencies of the i-th genotype and i-th is  any genotype from the rank of genotypes in the order of the highest to the lowest frequencies in  a donor population. RESULTS The HLA genotypes and haplotypes frequency mentioned in the following section have been  recently published [20]. HLA-A, -B, -C and -DRB1 genotypes deviated from the expected  Hardy-Weinberg Equilibrium Proportions (HWEP) (p PHASE  [16]; adherence to HWEP was also assessed using PyPop 0.7.0 [23]. A few but significant  deviations from HWEP were detected for all the four loci, HLA-A, -B, -C and -DRB1. Deviation from  HWEP detected at the HLA-A locus is derived primary from an excess of A*02:01 + A*02:03  genotypes (247 observed, 218.5 expected; p = 0.0007) and an undercount of A*02:06 + A*02:03  genotypes (16 observed, 48.2 expected; p = Summary statistics for Hong Kong haplotypes is shown in Table 3. 2,146 A-C-B-DRB1 haplotypes  with frequencies > 0.006% were estimated from these donors. The cumulative frequency distributions for HLA-A, -B, -C and -DRB1 loci in this Hong Kong Chinese cohort are shown in Table 4. Top twenty Haplotype A-C-B-DRB1 frequencies are shown in Table 5 [20]; nine of them have  frequencies of greater than 1%. Our findings on HLA alleles and haplotypes frequencies were  found to be very similar to those of Asian/Pacific Islander (A/PI) Race/Ethnicity of the NMDP  Registry and other studies on Han Chinese population [25]. The most common haplotype  A*33:03-C*03:02-B*58:01-DRB1*03:01 ranked second in the A/PI of NMDP registry (2.3%) and  top in Singapore Chinese (5.1%) [26]. The second most common haplotype  A*02:01-C*01:02-B*46:01-DRB1*09:01 was one of most frequent haplotypes among Chinese  populations, especially the southern area of China and Guangdong [27, 28]. However, the f ifth  common haplotype A*02:03-C*07:02-B*38:02-DRB1*16:02, was found to be less common in the  A/PI of NMDP Registry (0.4%) and the mainland China (0.3%) [25, 28]. We compared the top 100 haplotypes of HKBMDR HKCBB by haplotype frequencies with the  two publications [25, 26]; we noted that 88 are in common, the rank correlation is 0.909 for  HLA-A-B-DRB1 haplotype. There appears to be no excessive immigration from other places to Hong  Kong. We also compared the China population paper which had provided the detailed top  haplotypes for 4 loci, we found that 43 are common in HLA-A-C-B-DRB1 haplotype and the  correlation is low with only 0.477 [28]. With the use of MCMC algorithm to estimate HLA haplotype frequencies [14], it was found that the number of haplotypes increases with number of donor samples studies as summarized in  Table 6. Originally we tested the HLA haplotype frequencies in 2,500 samples and noted a bigger  number of haplotypes as compared with other papers. Then we increased the sample size to  5,000 and 7,500 and noted that the increase was quite significant in our population with many  more haplotypes. However, we usually observed a plateau of number of haplotypes even with  increase in sample size in the Caucasians and European populations. As of December 2015, there were only around 100,000 donors in the HKBMDR. Applying the  similar methodology in calculating the likelihood of finding a matched donor in US [19],  likelihood of finding an 8/8 HLA match or > 7/8 HLA Match by different donor registry size in the  HKBMDR was shown in Figure 1. The likelihood of finding an available 8/8 HLA matched donor is  45% while increases to 65% for finding 7/8 HLA matched donor. It is similar to the finding of  other studies conducted among Asians, Pacific Islanders, and Native Americans which reported a  likelihood ranging between 27% and 52% [19]. DISCUSSION The chance of successful engraftment and disease free survival are associated with the HLA  compatibility between the recipient and the prospective donor. The diversity of the HLA genes at  the allelic level and the heterogeneity of HLA data of the registered donors have a significant  bearing on the probability of finding a volunteer unrelated HSC donor for patients from a  particular population. This can be seen in the existence of many populations including Hong Kong  or Chinese with significant heterogeneity among recruitment centers. HLA frequencies estimated  at the Hong Kong Bone Marrow Donor Registry or China Marrow Donor Program Registry are not  in equilibrium and should not be relied on as characteristic of a Chinese population. The probabilities of finding a match would increase substantially when the registry size grows. As reported in [19], the NMDP has added slightly more than 1 million adult donors to the registry  in 2012 and plans recruitment growth of 9% cumulatively each year through 2017. HLA typing of Chinese in Hong Kong were found to be more heterogeneous and this points to the  need of a larger donor pool in bone marrow registry to optimize the chance of successful  matching. The study findings provide vital information for defining donor recruitment target and  planning for extra resources in order to support the cost in donor recruitment and HLA typing.  Establishment of a more cost-effective bone marrow donor registry with a larger pool of donors  could increase chance of matching and the success rate of haematopoietic stem cell  transplantation. Assuming 25,000 per 10-year age range of even distribution, it is projected that the number of  retired and non-contact to be around 2,000. Based on the projection in Figure 1, if one would like  to achieve MP for 50% 8/8 HLA Match or 70% >7/8 HLA Match, HKBMDR should have about  150,000 donors. Considering the HKBMDR registry size to grow to 150,000 in five-year time, it  will require 12,000 new donors recruitment per year. To further increase MP to nearly 55% for  8/8 HLA Match or about 75% >7/8 HLA Match, donor registry size should be expanded to  200,000 (Figure 1). Similarly, an annual recruitment of 22,000 new donors is required. Either of  them is much higher than the current recruitment target of 5,000 donors per year. As such, the  associated resource implication in donor recruitment and HLA typing will need to be carefully  addressed. In our previous study on the survey on Hong Kong donation [29], factors associated  with HSC donation motivation in Hong Kong were identified. The results highly suggested that  recommendations on promoting BM donation to the younger and higher education may allow  better recruit rate and longer maintenance for donation. The government should consider  launching educational activities such as bone marrow donation campaign, educational series and  school talks to students and parents. However, it should be noted that the above estimation has not taken into account of the  potential matches from around 2,400,000 Chinese donors registered in China and Taiwan  registries. In addition, the use of cord blood units which are readily available and require less  stringent HLA matching has not been added into the matching probability. Many transplant  centers in particular those in the States and East Asia would switch to use cord blood when adult  donor is not available. But the relatively low stem cell dose may be inadequate for adult size  recipient. Recently, double cord blood or even haploidentical transplant has been applied  clinically with success. Whether they will eventually replace the need of a large registry is  currently under debate. But at the moment, these approaches are mainly indicated when  conventional related or unrelated donors are not readily available or accessible. On the other  hand, one should also be bear in mind the time re quired from matching, donor work up to  donation of overseas donors and other cost implication factors when building up the model for  estimation of registry size