- Email: [email protected]
10 or Better for the Be The Match Unrelated Donor Registry
Biol Blood Marrow Transplant xxx (2016) 1e5
Biology of Blood and Marrow Transplantation journal homepage: www.bbmt.org
High-Resolution Match Rate of 7/8 and 9/10 or Better for the Be The Match Unrelated Donor Registry Kelly Buck 1, *, Kim Wadsworth 1, Michelle Setterholm 1, Martin Maiers 1, Dennis Confer 1, Robert Hartzman 2, Alexander Schmidt 3, Soo Young Yang 4, Jason Dehn 1 1
National Marrow Donor Program, Minneapolis, Minnesota C.W. Bill Young Marrow Donor Recruitment and Research Program, Department of Defense, Bone Marrow Research Directorate, Naval Medical Research Center, Department of the Navy, Washington, DC 3 DKMS German Bone Marrow Donor Center, Tübingen, Germany 4 HistoGenetics LLC, Ossining, New York 2
Article history: Received 6 October 2015 Accepted 15 December 2015 Key Words: HLA matching Transplantation Marrow Stem cell Donor registry
a b s t r a c t Estimation of the National Marrow Donor Program’s Be The Match Registry 8/8 (HLA-A, -B, -C, and -DRB1) high-resolution (HR) unrelated donor (URD) match rate was determined in a prior study for each of the 4 most frequent patient race/ethnic groups in the United States: white (WH), Hispanic (HIS), Asian/Pacific Islander (API), and African American (AFA). For patients without an 8/8 HLA-matched URD, a 7/8 match, with a single allele or antigen mismatch, is often accepted by many transplant centers. A follow-up study was designed to determine the 7/8 or better match rate among the 4 major race/ethnic groups, using the same study cohort. Of previously HR tested URDs in the Be The Match Registry, 1344 were randomly selected and treated as pseudo-patients where HR testing was performed to identify a 7/8-matched URD; 98% of WH and over 80% of non-WH race/ethnic groups (HIS, API, and AFA) had at least a 7/8 match identified. In most cases after first testing to identify an 8/8-matched URD, a 7/8-matched URD was identified after typing just 1 URD. Extending criteria to identify a 9/10 match (included HLA-DQB1) showed the 9/10 absolute match rate decreased between 14% and 21% from the 7/8 match rate for the non-WH groups. This study provides a baseline 7/8 and 9/10 or better HLA match rate that can be further supplemented using the additional worldwide URD inventory. URD match rate information can equip centers in clinical planning and the education of patients seeking a life-saving therapy. Ó 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
INTRODUCTION Many malignant and nonmalignant hematopoietic blood disorders are treated using allogeneic stem cell transplantation. About 70% of patients in need of a transplant do not have an HLA-matched donor within their family. Physicians can then search the Be The Match Registry, along with other registries worldwide, for an adult unrelated donor (URD) or umbilical cord blood unit on behalf of their patient. For transplantation to be successful, HLA matching between patient and URD is crucial. High-resolution (HR) matching at 4 loci (8 alleles), that is, HLA-A, -B, -C, and -DRB1, has been
Financial disclosure: See Acknowledgments on page 4. * Correspondence and reprint requests: Kelly Buck, MT (ASCP), National Marrow Donor Program, 3001 Broadway St. NE, Suite 100, Minneapolis, MN 55413. E-mail address: [email protected] (K. Buck).
found to increase overall survival rate and decrease transplant-related mortality and graft-versus-host disease [1-6]. Thus, the target minimum matching criteria adopted by many transplant centers is 8/8 or expanded to 10/10 (includes HLA-DQB1) alleles. Our prior study of the 2009 and 2012 URD registry aimed to determine the Be The Match Registry 8/8 and 10/10 HR match rate for the 4 most frequent patient race/ethnic groups in the United States: white (WH), Hispanic (HIS), Asian/Pacific Islander (API), and African American (AFA). Results of the study showed that for the non-WH race/ethnic groups, the 8/8 URD match rate was less than 50%, with HIS at 44%, API at 46%, and AFA at 30%. The 10/10 match rate was lower for these groups, at 38% for HIS, 41% for API, and 23% for AFA [7]. Although non-WH race/ethnic groups are less likely to identify a fully matched URD, analyses have shown that if a mismatch is unavoidable, a single-locus-mismatched URD (HLA-A, -B, -C, or -DRB1) can be used with acceptable
http://dx.doi.org/10.1016/j.bbmt.2015.12.012 1083-8791/Ó 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
K. Buck et al. / Biol Blood Marrow Transplant xxx (2016) 1e5
risks of transplant-related mortality [2,5]. Furthermore, in most instances the adverse consequences of using an HLA-mismatched URD are less detrimental than a delay in proceeding to transplant, resulting in more advanced disease, and may still offer better outcomes than other alternative treatments [2]. A 7/8 match, with a single allele or antigen mismatch, is often accepted by many transplant centers for patients without a desired 8/8 match, increasingly competing with unrelated umbilical cord blood and haploidentical related donors as a stem cell source of choice [8-10]. Recognizing that a desired 8/8 or 10/10 match will not be identified for all searching patients, especially those in non-WH populations, this study aimed to determine the 7/8 or better match rate among these 4 race/ethnic groups using the same study cohort [11]. Because many transplant centers prefer to match at 9/10 alleles versus 7/8, a second objective of the study was determining the 9/10 match rate. The cohort consisted of randomly selected, previously HR tested adult URDs from the Be The Match Registry that were treated as searching patients, referred to as “pseudopatients”(PPs). Simulated searches were performed on PPs to identify a 7/8 or better match. Actual searching patients were not used for the study to avoid introducing selection bias caused by variables such as access to patient care, insurance barriers, differences in referral practices, and socioeconomic status [7]. Knowledge of the 7/8 and 9/10 URD match rate for a particular race/ethnic group may be helpful for physicians who are weighing the potential time needed to identify a suitable source of stem cells against patient disease status, transplant center protocols, and potential alternative treatment plans. METHODS This study used the same cohort to determine the 7/8 and 9/10 match rate as our previously described study where a more detailed description of the study cohort and initial study methods can be found [7]. In summary, randomly selected URDs, registered with the Be the Match Registry, that had HR typing at HLA-A, -B, -C, -DRB1, and -DQB1 for each of the 4 broad race/ethnic groups had a URD search run. PP URD searches were evaluated until 200 cases needing further donor typing to identify an 8/8 HR HLA match were accumulated for each race/ethnic group. This enrollment resulted in populations by race/ethnic group of 377 WH, 307 HIS, 270 API, and 390 AFA for a total cohort of 1344. The definition of HR match was defined as (1) an allele match, (2) an allele match within the exons encoding the antigen recognition site, and (3) an allele match when restricting to genotypes containing alleles on the Common and Well-Documented HLA Allele list [12]. After completing the HLA testing of potential 8/8 URDs, a renewed search was performed on each PP to determine the 7/8 or better match rate, regardless of whether an 8/8 match was previously identified. In some cases the process of seeking to identify an 8/8 match in the previous study resulted in a fully HR typed 7/8-matched URD being presented on the subsequent search list output. The searches used a fixed Be The Match Registry file from January 2012 that was composed of over 8.6 million HLA-A/B/DRB1 typed URD (ie, excluded URDs only typed at HLA-A/B). The race/ethnic composition of the file was 65% WH, 10% HIS, 7% API, 7% AFA, and 11% miscellaneous categories that included URDs self-designated as multiple races, unknown, American Indian-Alaska Native, and those who declined to answer. PP search results were calculated using the HapLogic matching algorithm and viewed within the National Marrow Donor Program (NMDP)’s Traxis software. PP cases were classified into 3 categories based on outcomes: (1) 7/8 or better matched URD identified, (2) URD has potential to match at 7/8 but further HLA typing is needed, or (3) no possible 7/8 URD exists on the search. Only 3 PP cases had no 7/8 potential URD on the search before HLA testing. PP searches that resulted in category 2 above were reviewed by an HLA specialist and potential URDs were ranked according to 7/8 HR matching likelihood and typed in order. Typing results were evaluated to determine HR match status with consecutive rounds of URD testing performed until either a 7/8-matched URD was identified, no potential URD with stored samples remained, or a PP maximum number of URD testing was reached.
Because many PP searches had greater than 100 potential 7/8 URDs, it was not feasible to type every URD on the list. In these cases a maximum of 50 URDs were tested per PP at which time the patient was considered as having no match. URD tested for this study were mainly from NMDP donor centers, including the US C.W. Bill Young Department of Defense Marrow Donor Program and the German and US DKMS Donor Centers. The German DKMS donor center obtained new samples from willing URDs if no stored sample was available. German DKMS samples were typed at the DKMS Life Science Lab (Dresden, Germany), whereas NMDP and US DKMS URD samples were typed by HistoGenetics, LLC (Ossining, NY, USA). Both laboratories used HR sequence-based typing techniques and are American Society of Histocompatibility and Immunogenetics (ASHI) accredited. Blind quality control samples were included in the URD typing process to verify overall accuracy rates. Because many transplant centers extend their matching criteria to a 9/10 match rather than a 7/8 match, a secondary goal of the study was to determine 9/10 match rate. In many cases the identified 7/8 HR-matched URD was also matched at DQB1, resulting in both a 7/8 and a 9/10 HR match. However, in several PP cases the previously identified 7/8 HRmatched URD did not match at DQB1 or no longer had samples remaining to type the additional locus. In these cases, when possible, additional rounds of URD HLA typing were performed in an attempt to identify a URD that was both 7/8 and 9/10 HR matched. URDs with a stored sample and a 9/10 HapLogic prediction of greater than 10% were typed to determine if they were a 9/10 match. In each race/ethnic group there were a few cases where a 9/10-matched URD was possible but no sample was available for further typing.
RESULTS Figure 1 shows the 7/8 or better HR HLA match rate for each race/ethnic group. This represents both cases where a 7/8-matched URD already existed on the search and where URDs were HLA typed to identify a 7/8 match. For cases where an 8/8-matched URD had been previously identified, all but 7 PPs also had a 7/8 match (1 WH, 1 HIS, 3 API, 2 AFA). The 7/8 or better match rate for WH was 98%; HIS, 86%; API, 88%; and AFA, 82%. Table 1 shows the median and range of URDs tested for the PP cases resulting in a 7/8 match compared with no match by PP race/ethnicity. An HLA expert review of cases where no 7/8 match was identified but additional 7/8 potential URDs remained suggests that few additional cases would likely yield HR matches. Figure 2 shows the 9/10 or better match rate for each race/ ethnic group, with the WH group having the highest match rate at 94% and the AFA group with the lowest at 61%. The WH 9/10 match rate decreased only slightly from the 7/8 match rate with a 4% absolute percentage decrease and the 9/10 match rate for HIS and API decreased 14% from the 7/8 match rate. The AFA 9/10 match rate had the largest decrease from the 7/8 match rate at 21%. Most PP cases that had a 10/10 match previously identified also had a 9/10 match, except 1 WH, 6 HIS, 13 API, and 7 AFA cases.
7/8 or BeƩer HR Match Rate 100%
2%
90% Percentage Matched
2
14%
12%
18%
86%
88%
82%
HIS
API
80% 70% 60% 50%
98%
40%
No 7/8 Match
30%
7/8 Match
20% 10% 0% WH
AFA
Figure 1. 2012 Registry that represents PPs with 7/8 or 8/8 HR match rate by race/ethnicity.
K. Buck et al. / Biol Blood Marrow Transplant xxx (2016) 1e5
3
Table 1 URDs Typed for 7/8 or No 7/8 Match by Race/Ethnicity WH PPs
Median no. of URDs tested Range of URDs tested
HIS PPs No 7/8 HR Match
7/8 HR Match
No 7/8 HR Match
7/8 HR Match
No 7/8 HR Match
7/8 HR Match
No 7/8 HR Match
1 1-2
12 1-50
1 1-37
29 0-50
1 1-10
50 1-50
1 1-25
15 0-50
DISCUSSION This study used empirical data to provide a 7/8 and 9/10 or better match rate estimate for WH, HIS, API, and AFA patients through the Be the Match Registry. This had only been previously accomplished using biostatistical modeling methods of the registry [13]. However, unlike the 8/8 match rate estimates, the impact of race/ethnicity is not as pronounced for the 7/8 match rates, with all 4 broad race/ethnic groups showing greater than 80% likelihood of identifying at least a 7/8-matched URD. The additional worldwide URD inventory and the inclusion of public cord blood registries provide additional sources of stem cells that can be used to increase transplants beyond these match rates. The NMDP donor registry has also increased and now includes over 12.5 million HLA-A/B/DRB1 typed donors compared with the fixed registry file of under 9 million A/B/DRB1 typed donors used for this study. Although a 7/8 match is accepted by many transplant centers, as stated earlier, some centers prefer to match out of 10 alleles. Previous studies have shown that matching at DQB1 did not have a significant impact on survival after URD hematopoietic stem cell transplant [2,3]. However, a publication indicated that a DQB1 mismatch combined with 2 or
9/10 or BeƩer HR Match Rate 6%
Percentage Matched
90%
28%
80%
26%
39%
70% 60% 50%
No 9/10 Match
94%
40% 30%
72%
74%
HIS
API
9/10 Match
61%
20% 10% 0% WH
AFA PPs
7/8 HR Match
Given the historic preferential selection of URDs with non-DRB1emismatched URDs for transplant, Table 2 shows the number of cases in each race/ethnic group where a mismatch at the DRB1 locus was the only option for a 7/8-matched URD. The API group had the highest percentage (20%) of PP cases where a DRB1 mismatch was the only 7/8 option, with 64% of those cases not having a 9/10 match identified. This compares with the WH group, which had only 5% of the cases where a DRB1 mismatch was the only 7/ 8 option; of these cases only about 28% did not have a 9/10 match identified. For all 4 race/ethnic groups, DRB1 mismatches made up less than 10% of the total 9/10-matched cases, with the non-WH groups having about twice the frequency of these cases compared with the WH group.
100%
API PPs
AFA
Figure 2. 2012 Registry that represents PPs with 9/10 or 10/10 HR match rate by race/ethnicity.
more mismatches at additional low expression loci, including DRB3, -4, and-5 and DP, may adversely affect clinical outcome after transplant with a donor already mismatched in 1 (7/8) of the high expression loci (HLA-A, -B, -C, and -DRB1) [14]. Another recent analysis showed that among 8/8-matched cases, mismatching at DQB1 was associated with increased acute graft-versus-host disease grades II to IV. However, for 7/8 cases no significant effects of HLA-DQB1 mismatches were observed [3,6]. Our study results show that the additional consideration of DQB1 matching does result in a decrease in the 9/10 match rate compared with the 7/8 match rate in all 4 groups. This difference is most prominent in the non-WH race/ethnic groups with the largest decrease in match rate occurring in the AFA group. A few factors contribute to the decreases seen in the 9/10 match rates for the non-WH race/ethnic groups. First, an increased variation in DRB1wDQB1 haplotype blocks in the non-WH race/ethnic groups contributes to the decrease [15]. In addition, our results showed a larger number of non-WH PP cases had only a DRB1 locus mismatched URD as the option for a 7/8 match. This often led to an additional DQB1 mismatch for those cases because of the strong linkage disequilibrium. Finally, a small number of cases had potential to be 9/10 matched but the DQB1 match could not be confirmed because of a lack of additional sample for testing. Although many centers will allow a single mismatch at any locus, HLA-A, -B, -C, or -DRB1, many centers still prefer not to mismatch at the DRB1 locus. Our 7/8 study results are consistent with a previous study that used population genetics modeling to predict the likelihood of identifying an 8/8- or 7/8-matched URD in 21 detailed patient race/ethnic groups [13,16]. Although broad race/ethnic groups were used for this study, 7/8 match rates were very similar to the 7/8 match rates determined through the modeling method. Using weighted average calculations for the modeling match rates, 2 WH groups in the modeling study had a 7/8 match rate of 97% versus the WH group in this study at 98%. Three HIS groups in the modeling study had a match rate of 91% compared with our HIS group at 86%. Eight API groups in the modeling study had a match rate of 91%, whereas our API group had a match rate of 88%. Four AFA groups in the modeling study had a match rate of 88% compared with 82% for the AFA group in this study. The WH 9/10 match rate comparisons between this study and another recent biostatistical modeling study (2014 nonpublished NMDP data) were nearly identical, with 96% for the 2 WH groups in the modeling method compared with 94% for this study, using the same weighted average calculations. However, the 9/10 match rate comparisons for the non-WH groups were not as consistent as the 7/8 match rates, with the modeling method match rates about 10% to 15% higher than those for this study. There are a few possible reasons for the difference in the non-WH 9/10 match rates between this study and the modeling method. One likely reason for the differences specific to the 9/10 match rates is
4
K. Buck et al. / Biol Blood Marrow Transplant xxx (2016) 1e5
Table 2 HLA-DRB1 Mismatches in 7/8 and 9/10 Matched Donors by Race/Ethnicity Race/ Ethnicity
Total No. of 7/8 Matches
No. of DRB1 Mismatches
Percent of Total 7/8 Matches
Total No. of 9/10 Matches
No. of DRB1 Mismatches
Percent of Total 9/10 Matches
WH HIS API AFA
369 262 235 318
18 33 47 51
5 12 20 16
355 216 186 230
13 15 17 16
4 7 9 7
that the DQB1 locus has the least amount of registry typing data available combined with overall smaller non-WH reference populations, which may produce a larger margin of error in the 5 locus haplotype frequencies used for the modeling method. Second, the modeling method assumes HLA alleles are distributed within a population consistent with Hardy-Weinberg equilibrium [13]. Our study used donors in actual populations, which likely have substructure that leads to higher than expected homozygosity and causes deviation from Hardy-Weinberg. Other factors that could contribute to the differences in the non-WH 9/10 match rates include limitations in the sampling method used for the registry modeling, the relatively small sample size of PPs used for this study, and the inclusion of URDs that are only typed at HLA-A/B, which were excluded for our study. Our results showed a median of 1 URD was tested to identify a 7/8 match for each of the race/ethnic groups, with 1 notable outlier in the HIS group and 1 in the AFA group. Although this study was not specifically designed to identify the number of URDs tested to achieve a 7/8 match, given the exhaustive testing allowed for the 8/8 match rate study, the results here show that in most cases a 7/8-matched URD can be identified quickly either through the typing of potential 8/8 URD or by moving directly to the 7/8 potential pool. In addition, the current level of HLA typing for recently recruited URDs has improved since this study was performed in 2012, which often requires less additional HLA typing for match identification. However, testing additional URDs may be necessary for patients with less common HLA typing, particularly with non-WH race/ethnic groups. Selection of URDs for patients should also include more than 1 URD to act as a backup in case the primary URD cannot proceed. The overall testing allowed for PPs in this study is generous given the current practice of most transplant centers is often to not select more than 10 URDs per patient for HLA testing. One limitation of this study was that not every potential 7/8 URD on each PP search could be typed. For cases where no 7/8 match was identified, either all 7/8 potential URDs with a stored sample or up to 50 potential URDs were tested for each case. This could result in a conservative estimate of the match rate, although in most cases the samples that were not tested had a low probability to match and most likely would not have resulted in a 7/8 match. An additional limitation to the study was that URD availability was not a consideration for the PP searches. However, in practice, availability can greatly affect the ability to identify and proceed with a suitably matched URD. URD availability remains an obstacle for unrelated hematopoietic stem cell transplant and historically has been a larger problem among the non-WH groups. Unlike the 8/8 and 10/10 match rate study, where many of the non-WH PP cases had few or only 1 potential 8/8-matched URD, most PP cases in all the race/ethnic groups had several potential 7/8-matched URDs. This allows for a better ability to over-select potential
URDs for testing, which can compensate for availability issues, particularly in non-WH URD pools [5,17]. This likely translates to low overall impact of URD availability on the match rates identified in this study. Other factors not considered for this study were non-HLA selection criteria such as URD age, gender, ABO type, and cytomegalovirus status. Transplant centers may use these criteria to rule out URDs that may otherwise be a suitable HLA match. The results of this study provide a 7/8 and 9/10 match rate estimate that can supplement the 8/8 and 10/10 match rates published in our earlier study. In addition, this study validates prior statistical approaches used to predict match rates. This information can be valuable for predicting the likelihood of identifying a suitable match for patients with varying racial and ethnic backgrounds, informing clinical decisions on treatment options, and for the education of patients seeking transplant.
ACKNOWLEDGMENTS The authors are thankful for all the efforts of the C.W. Bill Young Marrow Donor Recruitment and Research Program, DKMS German Bone Marrow Donor Center, DKMS Americas (United States), HistoGenetics LLC, and NMDP Immunogenetic Specialists and Biorepository staff. Special thanks to Hugo Araujo, Alois Grathwohl, and Julia Selje for their assistance. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the US Government. Financial disclosure: This research was funded by Office of Naval Research Grants N00014-11-1-0339 and N0001412-1-0142. Conflict of interest statement: There are no conflicts of interest to report. Authorship statement: K.B. had full access to all data in the study and had final responsibility for the integrity of the data, the accuracy of the data analysis, and the responsibility for the decision to submit for publication. All authors designed research, K.B. and K.W. collected data, J.D. and K.B. performed statistical analysis, all authors interpreted data, K.B. drafted the manuscript, and all authors critically revised and reviewed the manuscript.
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11. Pidala J, et al. Race/ethnicity affects the probability of finding an HLA-A, -B, -C and -DRB1 allele-matched unrelated donor and likelihood of subsequent transplant utilization. Bone Marrow Transplant. 2013;48: 346-350. 12. Cano P, et al. Common and well-documented HLA alleles: report of the Ad-Hoc committee of the American Society for Histocompatiblity and Immunogenetics. Hum Immunol. 2007;68:392-417. 13. Gragert L, et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med. 2014;371:339-348. 14. Fernandez-Vina MA, et al. Multiple mismatches at the low expression HLA loci DP, DQ, and DRB3/4/5 associate with adverse outcomes in hematopoietic stem cell transplantation. Blood. 2013;121: 4603-4610. 15. Maiers M, Gragert L, Klitz W. High-resolution HLA alleles and haplotypes in the United States population. Hum Immunol. 2007;68: 779-788. 16. Gragert L, et al. Six-locus high resolution HLA haplotype frequencies derived from mixed-resolution DNA typing for the entire US donor registry. Hum Immunol. 2013;74:1313-1320. 17. Switzer GE, et al. Race and ethnicity in decisions about unrelated hematopoietic stem cell donation. Blood. 2013;121:1469-1476.
Biology of Blood and Marrow Transplantation journal homepage: www.bbmt.org
High-Resolution Match Rate of 7/8 and 9/10 or Better for the Be The Match Unrelated Donor Registry Kelly Buck 1, *, Kim Wadsworth 1, Michelle Setterholm 1, Martin Maiers 1, Dennis Confer 1, Robert Hartzman 2, Alexander Schmidt 3, Soo Young Yang 4, Jason Dehn 1 1
National Marrow Donor Program, Minneapolis, Minnesota C.W. Bill Young Marrow Donor Recruitment and Research Program, Department of Defense, Bone Marrow Research Directorate, Naval Medical Research Center, Department of the Navy, Washington, DC 3 DKMS German Bone Marrow Donor Center, Tübingen, Germany 4 HistoGenetics LLC, Ossining, New York 2
Article history: Received 6 October 2015 Accepted 15 December 2015 Key Words: HLA matching Transplantation Marrow Stem cell Donor registry
a b s t r a c t Estimation of the National Marrow Donor Program’s Be The Match Registry 8/8 (HLA-A, -B, -C, and -DRB1) high-resolution (HR) unrelated donor (URD) match rate was determined in a prior study for each of the 4 most frequent patient race/ethnic groups in the United States: white (WH), Hispanic (HIS), Asian/Pacific Islander (API), and African American (AFA). For patients without an 8/8 HLA-matched URD, a 7/8 match, with a single allele or antigen mismatch, is often accepted by many transplant centers. A follow-up study was designed to determine the 7/8 or better match rate among the 4 major race/ethnic groups, using the same study cohort. Of previously HR tested URDs in the Be The Match Registry, 1344 were randomly selected and treated as pseudo-patients where HR testing was performed to identify a 7/8-matched URD; 98% of WH and over 80% of non-WH race/ethnic groups (HIS, API, and AFA) had at least a 7/8 match identified. In most cases after first testing to identify an 8/8-matched URD, a 7/8-matched URD was identified after typing just 1 URD. Extending criteria to identify a 9/10 match (included HLA-DQB1) showed the 9/10 absolute match rate decreased between 14% and 21% from the 7/8 match rate for the non-WH groups. This study provides a baseline 7/8 and 9/10 or better HLA match rate that can be further supplemented using the additional worldwide URD inventory. URD match rate information can equip centers in clinical planning and the education of patients seeking a life-saving therapy. Ó 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
INTRODUCTION Many malignant and nonmalignant hematopoietic blood disorders are treated using allogeneic stem cell transplantation. About 70% of patients in need of a transplant do not have an HLA-matched donor within their family. Physicians can then search the Be The Match Registry, along with other registries worldwide, for an adult unrelated donor (URD) or umbilical cord blood unit on behalf of their patient. For transplantation to be successful, HLA matching between patient and URD is crucial. High-resolution (HR) matching at 4 loci (8 alleles), that is, HLA-A, -B, -C, and -DRB1, has been
Financial disclosure: See Acknowledgments on page 4. * Correspondence and reprint requests: Kelly Buck, MT (ASCP), National Marrow Donor Program, 3001 Broadway St. NE, Suite 100, Minneapolis, MN 55413. E-mail address: [email protected] (K. Buck).
found to increase overall survival rate and decrease transplant-related mortality and graft-versus-host disease [1-6]. Thus, the target minimum matching criteria adopted by many transplant centers is 8/8 or expanded to 10/10 (includes HLA-DQB1) alleles. Our prior study of the 2009 and 2012 URD registry aimed to determine the Be The Match Registry 8/8 and 10/10 HR match rate for the 4 most frequent patient race/ethnic groups in the United States: white (WH), Hispanic (HIS), Asian/Pacific Islander (API), and African American (AFA). Results of the study showed that for the non-WH race/ethnic groups, the 8/8 URD match rate was less than 50%, with HIS at 44%, API at 46%, and AFA at 30%. The 10/10 match rate was lower for these groups, at 38% for HIS, 41% for API, and 23% for AFA [7]. Although non-WH race/ethnic groups are less likely to identify a fully matched URD, analyses have shown that if a mismatch is unavoidable, a single-locus-mismatched URD (HLA-A, -B, -C, or -DRB1) can be used with acceptable
http://dx.doi.org/10.1016/j.bbmt.2015.12.012 1083-8791/Ó 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
K. Buck et al. / Biol Blood Marrow Transplant xxx (2016) 1e5
risks of transplant-related mortality [2,5]. Furthermore, in most instances the adverse consequences of using an HLA-mismatched URD are less detrimental than a delay in proceeding to transplant, resulting in more advanced disease, and may still offer better outcomes than other alternative treatments [2]. A 7/8 match, with a single allele or antigen mismatch, is often accepted by many transplant centers for patients without a desired 8/8 match, increasingly competing with unrelated umbilical cord blood and haploidentical related donors as a stem cell source of choice [8-10]. Recognizing that a desired 8/8 or 10/10 match will not be identified for all searching patients, especially those in non-WH populations, this study aimed to determine the 7/8 or better match rate among these 4 race/ethnic groups using the same study cohort [11]. Because many transplant centers prefer to match at 9/10 alleles versus 7/8, a second objective of the study was determining the 9/10 match rate. The cohort consisted of randomly selected, previously HR tested adult URDs from the Be The Match Registry that were treated as searching patients, referred to as “pseudopatients”(PPs). Simulated searches were performed on PPs to identify a 7/8 or better match. Actual searching patients were not used for the study to avoid introducing selection bias caused by variables such as access to patient care, insurance barriers, differences in referral practices, and socioeconomic status [7]. Knowledge of the 7/8 and 9/10 URD match rate for a particular race/ethnic group may be helpful for physicians who are weighing the potential time needed to identify a suitable source of stem cells against patient disease status, transplant center protocols, and potential alternative treatment plans. METHODS This study used the same cohort to determine the 7/8 and 9/10 match rate as our previously described study where a more detailed description of the study cohort and initial study methods can be found [7]. In summary, randomly selected URDs, registered with the Be the Match Registry, that had HR typing at HLA-A, -B, -C, -DRB1, and -DQB1 for each of the 4 broad race/ethnic groups had a URD search run. PP URD searches were evaluated until 200 cases needing further donor typing to identify an 8/8 HR HLA match were accumulated for each race/ethnic group. This enrollment resulted in populations by race/ethnic group of 377 WH, 307 HIS, 270 API, and 390 AFA for a total cohort of 1344. The definition of HR match was defined as (1) an allele match, (2) an allele match within the exons encoding the antigen recognition site, and (3) an allele match when restricting to genotypes containing alleles on the Common and Well-Documented HLA Allele list [12]. After completing the HLA testing of potential 8/8 URDs, a renewed search was performed on each PP to determine the 7/8 or better match rate, regardless of whether an 8/8 match was previously identified. In some cases the process of seeking to identify an 8/8 match in the previous study resulted in a fully HR typed 7/8-matched URD being presented on the subsequent search list output. The searches used a fixed Be The Match Registry file from January 2012 that was composed of over 8.6 million HLA-A/B/DRB1 typed URD (ie, excluded URDs only typed at HLA-A/B). The race/ethnic composition of the file was 65% WH, 10% HIS, 7% API, 7% AFA, and 11% miscellaneous categories that included URDs self-designated as multiple races, unknown, American Indian-Alaska Native, and those who declined to answer. PP search results were calculated using the HapLogic matching algorithm and viewed within the National Marrow Donor Program (NMDP)’s Traxis software. PP cases were classified into 3 categories based on outcomes: (1) 7/8 or better matched URD identified, (2) URD has potential to match at 7/8 but further HLA typing is needed, or (3) no possible 7/8 URD exists on the search. Only 3 PP cases had no 7/8 potential URD on the search before HLA testing. PP searches that resulted in category 2 above were reviewed by an HLA specialist and potential URDs were ranked according to 7/8 HR matching likelihood and typed in order. Typing results were evaluated to determine HR match status with consecutive rounds of URD testing performed until either a 7/8-matched URD was identified, no potential URD with stored samples remained, or a PP maximum number of URD testing was reached.
Because many PP searches had greater than 100 potential 7/8 URDs, it was not feasible to type every URD on the list. In these cases a maximum of 50 URDs were tested per PP at which time the patient was considered as having no match. URD tested for this study were mainly from NMDP donor centers, including the US C.W. Bill Young Department of Defense Marrow Donor Program and the German and US DKMS Donor Centers. The German DKMS donor center obtained new samples from willing URDs if no stored sample was available. German DKMS samples were typed at the DKMS Life Science Lab (Dresden, Germany), whereas NMDP and US DKMS URD samples were typed by HistoGenetics, LLC (Ossining, NY, USA). Both laboratories used HR sequence-based typing techniques and are American Society of Histocompatibility and Immunogenetics (ASHI) accredited. Blind quality control samples were included in the URD typing process to verify overall accuracy rates. Because many transplant centers extend their matching criteria to a 9/10 match rather than a 7/8 match, a secondary goal of the study was to determine 9/10 match rate. In many cases the identified 7/8 HR-matched URD was also matched at DQB1, resulting in both a 7/8 and a 9/10 HR match. However, in several PP cases the previously identified 7/8 HRmatched URD did not match at DQB1 or no longer had samples remaining to type the additional locus. In these cases, when possible, additional rounds of URD HLA typing were performed in an attempt to identify a URD that was both 7/8 and 9/10 HR matched. URDs with a stored sample and a 9/10 HapLogic prediction of greater than 10% were typed to determine if they were a 9/10 match. In each race/ethnic group there were a few cases where a 9/10-matched URD was possible but no sample was available for further typing.
RESULTS Figure 1 shows the 7/8 or better HR HLA match rate for each race/ethnic group. This represents both cases where a 7/8-matched URD already existed on the search and where URDs were HLA typed to identify a 7/8 match. For cases where an 8/8-matched URD had been previously identified, all but 7 PPs also had a 7/8 match (1 WH, 1 HIS, 3 API, 2 AFA). The 7/8 or better match rate for WH was 98%; HIS, 86%; API, 88%; and AFA, 82%. Table 1 shows the median and range of URDs tested for the PP cases resulting in a 7/8 match compared with no match by PP race/ethnicity. An HLA expert review of cases where no 7/8 match was identified but additional 7/8 potential URDs remained suggests that few additional cases would likely yield HR matches. Figure 2 shows the 9/10 or better match rate for each race/ ethnic group, with the WH group having the highest match rate at 94% and the AFA group with the lowest at 61%. The WH 9/10 match rate decreased only slightly from the 7/8 match rate with a 4% absolute percentage decrease and the 9/10 match rate for HIS and API decreased 14% from the 7/8 match rate. The AFA 9/10 match rate had the largest decrease from the 7/8 match rate at 21%. Most PP cases that had a 10/10 match previously identified also had a 9/10 match, except 1 WH, 6 HIS, 13 API, and 7 AFA cases.
7/8 or BeƩer HR Match Rate 100%
2%
90% Percentage Matched
2
14%
12%
18%
86%
88%
82%
HIS
API
80% 70% 60% 50%
98%
40%
No 7/8 Match
30%
7/8 Match
20% 10% 0% WH
AFA
Figure 1. 2012 Registry that represents PPs with 7/8 or 8/8 HR match rate by race/ethnicity.
K. Buck et al. / Biol Blood Marrow Transplant xxx (2016) 1e5
3
Table 1 URDs Typed for 7/8 or No 7/8 Match by Race/Ethnicity WH PPs
Median no. of URDs tested Range of URDs tested
HIS PPs No 7/8 HR Match
7/8 HR Match
No 7/8 HR Match
7/8 HR Match
No 7/8 HR Match
7/8 HR Match
No 7/8 HR Match
1 1-2
12 1-50
1 1-37
29 0-50
1 1-10
50 1-50
1 1-25
15 0-50
DISCUSSION This study used empirical data to provide a 7/8 and 9/10 or better match rate estimate for WH, HIS, API, and AFA patients through the Be the Match Registry. This had only been previously accomplished using biostatistical modeling methods of the registry [13]. However, unlike the 8/8 match rate estimates, the impact of race/ethnicity is not as pronounced for the 7/8 match rates, with all 4 broad race/ethnic groups showing greater than 80% likelihood of identifying at least a 7/8-matched URD. The additional worldwide URD inventory and the inclusion of public cord blood registries provide additional sources of stem cells that can be used to increase transplants beyond these match rates. The NMDP donor registry has also increased and now includes over 12.5 million HLA-A/B/DRB1 typed donors compared with the fixed registry file of under 9 million A/B/DRB1 typed donors used for this study. Although a 7/8 match is accepted by many transplant centers, as stated earlier, some centers prefer to match out of 10 alleles. Previous studies have shown that matching at DQB1 did not have a significant impact on survival after URD hematopoietic stem cell transplant [2,3]. However, a publication indicated that a DQB1 mismatch combined with 2 or
9/10 or BeƩer HR Match Rate 6%
Percentage Matched
90%
28%
80%
26%
39%
70% 60% 50%
No 9/10 Match
94%
40% 30%
72%
74%
HIS
API
9/10 Match
61%
20% 10% 0% WH
AFA PPs
7/8 HR Match
Given the historic preferential selection of URDs with non-DRB1emismatched URDs for transplant, Table 2 shows the number of cases in each race/ethnic group where a mismatch at the DRB1 locus was the only option for a 7/8-matched URD. The API group had the highest percentage (20%) of PP cases where a DRB1 mismatch was the only 7/8 option, with 64% of those cases not having a 9/10 match identified. This compares with the WH group, which had only 5% of the cases where a DRB1 mismatch was the only 7/ 8 option; of these cases only about 28% did not have a 9/10 match identified. For all 4 race/ethnic groups, DRB1 mismatches made up less than 10% of the total 9/10-matched cases, with the non-WH groups having about twice the frequency of these cases compared with the WH group.
100%
API PPs
AFA
Figure 2. 2012 Registry that represents PPs with 9/10 or 10/10 HR match rate by race/ethnicity.
more mismatches at additional low expression loci, including DRB3, -4, and-5 and DP, may adversely affect clinical outcome after transplant with a donor already mismatched in 1 (7/8) of the high expression loci (HLA-A, -B, -C, and -DRB1) [14]. Another recent analysis showed that among 8/8-matched cases, mismatching at DQB1 was associated with increased acute graft-versus-host disease grades II to IV. However, for 7/8 cases no significant effects of HLA-DQB1 mismatches were observed [3,6]. Our study results show that the additional consideration of DQB1 matching does result in a decrease in the 9/10 match rate compared with the 7/8 match rate in all 4 groups. This difference is most prominent in the non-WH race/ethnic groups with the largest decrease in match rate occurring in the AFA group. A few factors contribute to the decreases seen in the 9/10 match rates for the non-WH race/ethnic groups. First, an increased variation in DRB1wDQB1 haplotype blocks in the non-WH race/ethnic groups contributes to the decrease [15]. In addition, our results showed a larger number of non-WH PP cases had only a DRB1 locus mismatched URD as the option for a 7/8 match. This often led to an additional DQB1 mismatch for those cases because of the strong linkage disequilibrium. Finally, a small number of cases had potential to be 9/10 matched but the DQB1 match could not be confirmed because of a lack of additional sample for testing. Although many centers will allow a single mismatch at any locus, HLA-A, -B, -C, or -DRB1, many centers still prefer not to mismatch at the DRB1 locus. Our 7/8 study results are consistent with a previous study that used population genetics modeling to predict the likelihood of identifying an 8/8- or 7/8-matched URD in 21 detailed patient race/ethnic groups [13,16]. Although broad race/ethnic groups were used for this study, 7/8 match rates were very similar to the 7/8 match rates determined through the modeling method. Using weighted average calculations for the modeling match rates, 2 WH groups in the modeling study had a 7/8 match rate of 97% versus the WH group in this study at 98%. Three HIS groups in the modeling study had a match rate of 91% compared with our HIS group at 86%. Eight API groups in the modeling study had a match rate of 91%, whereas our API group had a match rate of 88%. Four AFA groups in the modeling study had a match rate of 88% compared with 82% for the AFA group in this study. The WH 9/10 match rate comparisons between this study and another recent biostatistical modeling study (2014 nonpublished NMDP data) were nearly identical, with 96% for the 2 WH groups in the modeling method compared with 94% for this study, using the same weighted average calculations. However, the 9/10 match rate comparisons for the non-WH groups were not as consistent as the 7/8 match rates, with the modeling method match rates about 10% to 15% higher than those for this study. There are a few possible reasons for the difference in the non-WH 9/10 match rates between this study and the modeling method. One likely reason for the differences specific to the 9/10 match rates is
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K. Buck et al. / Biol Blood Marrow Transplant xxx (2016) 1e5
Table 2 HLA-DRB1 Mismatches in 7/8 and 9/10 Matched Donors by Race/Ethnicity Race/ Ethnicity
Total No. of 7/8 Matches
No. of DRB1 Mismatches
Percent of Total 7/8 Matches
Total No. of 9/10 Matches
No. of DRB1 Mismatches
Percent of Total 9/10 Matches
WH HIS API AFA
369 262 235 318
18 33 47 51
5 12 20 16
355 216 186 230
13 15 17 16
4 7 9 7
that the DQB1 locus has the least amount of registry typing data available combined with overall smaller non-WH reference populations, which may produce a larger margin of error in the 5 locus haplotype frequencies used for the modeling method. Second, the modeling method assumes HLA alleles are distributed within a population consistent with Hardy-Weinberg equilibrium [13]. Our study used donors in actual populations, which likely have substructure that leads to higher than expected homozygosity and causes deviation from Hardy-Weinberg. Other factors that could contribute to the differences in the non-WH 9/10 match rates include limitations in the sampling method used for the registry modeling, the relatively small sample size of PPs used for this study, and the inclusion of URDs that are only typed at HLA-A/B, which were excluded for our study. Our results showed a median of 1 URD was tested to identify a 7/8 match for each of the race/ethnic groups, with 1 notable outlier in the HIS group and 1 in the AFA group. Although this study was not specifically designed to identify the number of URDs tested to achieve a 7/8 match, given the exhaustive testing allowed for the 8/8 match rate study, the results here show that in most cases a 7/8-matched URD can be identified quickly either through the typing of potential 8/8 URD or by moving directly to the 7/8 potential pool. In addition, the current level of HLA typing for recently recruited URDs has improved since this study was performed in 2012, which often requires less additional HLA typing for match identification. However, testing additional URDs may be necessary for patients with less common HLA typing, particularly with non-WH race/ethnic groups. Selection of URDs for patients should also include more than 1 URD to act as a backup in case the primary URD cannot proceed. The overall testing allowed for PPs in this study is generous given the current practice of most transplant centers is often to not select more than 10 URDs per patient for HLA testing. One limitation of this study was that not every potential 7/8 URD on each PP search could be typed. For cases where no 7/8 match was identified, either all 7/8 potential URDs with a stored sample or up to 50 potential URDs were tested for each case. This could result in a conservative estimate of the match rate, although in most cases the samples that were not tested had a low probability to match and most likely would not have resulted in a 7/8 match. An additional limitation to the study was that URD availability was not a consideration for the PP searches. However, in practice, availability can greatly affect the ability to identify and proceed with a suitably matched URD. URD availability remains an obstacle for unrelated hematopoietic stem cell transplant and historically has been a larger problem among the non-WH groups. Unlike the 8/8 and 10/10 match rate study, where many of the non-WH PP cases had few or only 1 potential 8/8-matched URD, most PP cases in all the race/ethnic groups had several potential 7/8-matched URDs. This allows for a better ability to over-select potential
URDs for testing, which can compensate for availability issues, particularly in non-WH URD pools [5,17]. This likely translates to low overall impact of URD availability on the match rates identified in this study. Other factors not considered for this study were non-HLA selection criteria such as URD age, gender, ABO type, and cytomegalovirus status. Transplant centers may use these criteria to rule out URDs that may otherwise be a suitable HLA match. The results of this study provide a 7/8 and 9/10 match rate estimate that can supplement the 8/8 and 10/10 match rates published in our earlier study. In addition, this study validates prior statistical approaches used to predict match rates. This information can be valuable for predicting the likelihood of identifying a suitable match for patients with varying racial and ethnic backgrounds, informing clinical decisions on treatment options, and for the education of patients seeking transplant.
ACKNOWLEDGMENTS The authors are thankful for all the efforts of the C.W. Bill Young Marrow Donor Recruitment and Research Program, DKMS German Bone Marrow Donor Center, DKMS Americas (United States), HistoGenetics LLC, and NMDP Immunogenetic Specialists and Biorepository staff. Special thanks to Hugo Araujo, Alois Grathwohl, and Julia Selje for their assistance. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the US Government. Financial disclosure: This research was funded by Office of Naval Research Grants N00014-11-1-0339 and N0001412-1-0142. Conflict of interest statement: There are no conflicts of interest to report. Authorship statement: K.B. had full access to all data in the study and had final responsibility for the integrity of the data, the accuracy of the data analysis, and the responsibility for the decision to submit for publication. All authors designed research, K.B. and K.W. collected data, J.D. and K.B. performed statistical analysis, all authors interpreted data, K.B. drafted the manuscript, and all authors critically revised and reviewed the manuscript.
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