Rapid identification of a matched unrelated donor is essential for patients in need of hematopoietic SCT. We carried out a retrospective evaluation of 549 unrelated donor searches (UDSs), which were completed in 2005 for 23 German transplant centers. On the basis of the patient's HLA-DRB1 allele and DRB1–DQB1 haplotype frequencies, UDSs were divided into four groups with different search success probability predictions. For 90.5% of the patients, an acceptable HLA-matched, and for 61.6% an HLA-A-B-Cw-DRB1-DQB1-identical (10/10 matched) unrelated donor was found. The median search duration was 22 days. In the groups with high (n=318), medium (n=157), low (n=56) and very low (n=18) UDS success probability, an acceptable donor was found for 99.1, 86.6, 75.0 and 22.2% of the patients, and a 10/10-matched donor was found for 78.3, 49.7, 17.9 and 4.5% of the patients, respectively. The median search duration was 20, 27, 45 and 477 days in the groups with high, medium, low and very low probability, respectively. The search success rate and duration can be predicted on the basis of the patient's HLA-DRB1 allele and HLA-DRB1-DQB1 haplotype frequencies. An unrelated donor can be found for most of the patients, even if the indication for transplantation is urgent.
Allogeneic hematopoietic SCT (HSCT) is used not only for a wide range of hematological diseases but also for many other malignant and non-malignant disorders.1 In almost one-half of allogeneic HSCTs, an unrelated donor is used. In 2006, 44% of all allogeneic HSCTs were carried out in Europe with unrelated donors.2 In Germany, the proportion of unrelated donors is even higher (65%).3, 4 High-resolution 8/8- (HLA-A, -B, -Cw and -DRB1) or 10/10- (HLA-A, -B, -Cw, -DRB1 and -DQB1) matched unrelated HSCT is associated with best survival, and every HLA mismatch contributes to a 9–10% decrease in survival.5
The probability of finding a suitable, HLA-compatible, unrelated donor depends on the local donor selection criteria, as well as on the patient's racial background. Search success rates below 50% and search durations of approximately 4 months have been reported in earlier studies (for a review see Grewal et al.6). Owing to new donor recruitment activities, access to almost 12 million volunteer donors was possible at the beginning of 20087 (for a review see van Rood and Oudshoorn8). In addition, the proportion of allele-level-typed donors has also been increased. However, at the same time, the matching criteria became more stringent, with allele-level matching for HLA-A, -B, -Cw, -DRB1 and -DQB1 being increasingly required. These changes have an effect on the search success rate and duration. In recent studies, the search success rate ranged between 60 and 80%.9, 10, 11
The duration of an unrelated donor search (UDS) varies significantly between patients with common HLA haplotypes, in whom a matched donor can be identified within a few weeks, and patients with uncommon haplotypes, in whom the chances of finding a suitable donor are poor, even after months of searching.12 The median time needed for a successful search for patients of Northwest European origin was 2.9 months in 1996–2000,10 and 49 days in a single-center study from Minneapolis in 2000.13 As recent data for UDS durations and success rates are lacking, one objective of this study is to provide new information about this topic.
The average search duration and success rate are not suitable parameters for predicting the duration and success of a single search process. However, the forecasting of search characteristics is expected by transplant centers in order to decide the best therapeutic option for an individual patient. If it is unlikely to find a 10/10-matched unrelated donor within an appropriate time frame, matching requirements may be loosened, or an alternative therapy may be selected (non-transplant therapy, partially matched related donor or unrelated cord blood (UCB) transplantation and so on). As the risk of mortality for patients with advanced disease is higher than that for a transplant with a single HLA mismatch, the use of an HLA-mismatched donor may be a reasonable alternative to the continuation of an unpromising UDS.5
Usually, only low-resolution HLA-A, -B and -DRB1 typing of registry donors is available at the initiation of the search. The reason for this situation is the strategy, followed by many donor registries, to recruit as many donors as possible while limiting the extent of testing in order to remain cost-effective.14, 15 Only approximately 50% of the HLA-A, -B and -DR low-resolution-matched donors will be 10/10 allele-matched after high-resolution confirmatory typing (CT).16 We used HLA-DRB1 allele, as well as HLA-DRB1-DQB1 haplotype frequencies, for the prediction of the UDS duration and success. On the basis of the patient's HLA-DRB1 and -DQB1 typing results, we defined four groups of patients with high, medium, low and very low probability to find an HLA-A, -B, -Cw, -DRB1 and -DQB1-compatible donor. Our study aimed at answering the following questions:
Are there any differences in the search duration and success rate between the four search success probability prediction groups?
How many donors need to be initially requested for CT in the four prediction groups?
How can the search duration be shortened and the search success rate be improved for patients with rare HLA phenotypes?
Materials and methods
On the basis of the German Standards for Unrelated Blood Stem Cell Donations, service facilities, called search units, are responsible for UDS in patients with an indication for HSCT.17 The search unit in Ulm, Germany, carries out UDSs for 23 German transplant centers. It is accredited by the German National Bone Marrow Donor Registry according to the standards of the World Marrow Donor Association.18 Procedures for international UDS, as suggested by the ‘donor registries’ and the ‘quality assurance’ working groups of the World Marrow Donor Association, were followed during the search process.19
In 2005, 572 UDSs were initiated in our search unit. Twenty-three searches were excluded from the analysis for the following reasons: 12 searches were re-activated; nine were canceled before the CT sample of the first donor had been tested (0–10 days after search initiation, five patients died and four searches were canceled for other reasons) and two were transferred to another search unit during the search process. Accordingly, 549 completed searches were included in the analysis.
According to the second German consensus on immunogenetic donor search for allotransplantation of hematopoietic stem cells,20 at the beginning of the year 2005, HLA-A, -B and -Cw typing at a low-resolution level and HLA-DRB1 and -DQB1 typing at a high-resolution level were considered to be relevant for transplant outcome. Since August 2005, the third German consensus requires matching of patients and their unrelated donors at a high-resolution level for the loci HLA-A, -B, -Cw, -DRB1 and -DQB1.21
High-resolution HLA-DRB1-DQB1 typing of the patient was carried out twice before search initiation using a Luminex-SSO (One Lambda, Canoga Park, CA, USA) and sequence-based typing (CE-certified in-house reagents, IKT Ulm, Ulm, Germany). Similarly, high-resolution HLA-DRB1 and -DQB1 CT of unrelated donors was also carried out using a Luminex-SSO and sequence-based typing. HLA-A, -B and -Cw typing of patients and unrelated donors was carried out either at a low-resolution level using a Luminex SSO (222 searches) or at a high-resolution level by sequence-based typing (218 searches). In 109 searches, HLA-A and -B were typed at a high-resolution and HLA-Cw at a low-resolution level.
Assignment of patients to groups with different search success probabilities
HLA-DRB1 alleles can be divided into 13 different groups, defined by serological split-level (low-resolution) typing: HLA-DRB1*01, *03, *04, *07, *08, *09, *10, *11, *12, *13, *14, *15 and *16. In most cases, only a low-resolution HLA-DRB1 typing of donors is available at the time of UDS initiation but high-resolution-matched donors are required for the transplantation. Therefore, HLA-DRB1 allele frequencies within their serological split groups were used to assess the patient's HLA-DRB1 alleles as very frequent (>80%), frequent (20–80%) or rare (<20%). For example, the overall frequency of the HLA-DRB1*01 antigen group is 13.3% and that of HLA-DRB1*0101—being the most frequent allele in this serological group—is 9.3%. Accordingly, 69.9% (9.3%/13.3%) of all HLA-DRB1*01 alleles would be an HLA-DRB1*0101. In our study, HLA-DRB1*0101 was therefore assigned as a frequent allele. HLA-DRB1 allele frequencies were calculated on the basis of the dataset of 65 752 individuals published by the National Marrow Donor Program.22
Histocompatibility testing of most of the unrelated donors in the donor registries does not include HLA-DQB1 typing. However, because of the strong linkage disequilibrium between the two HLA class II loci, HLA-DRB1-DQB1 haplotypes can be predicted with high confidence on the basis of the HLA-DRB1 high-resolution typing alone.23 The probability of finding a certain HLA-DQB1 allele in the presence of a particular HLA-DRB1 allele was assigned as very frequent (>80%), frequent (20–80%) or rare (<20%).23, 24, 25 Classification of HLA-DRB1 alleles (with an overall frequency of >0.1%) and HLA-DRB1-DQB1 haplotypes, on the basis of their frequency estimation, is shown in Table 1A.
The patient's most uncommon HLA-DRB1 allele or HLA-DRB1-DQB1 haplotype was used to divide the individuals into four groups with different predicted probabilities for a successful search (Table 1B):
Very frequent HLA-DRB1 allele and DRB1-DQB1 haplotype=high search success probability.
Frequent DRB1 allele or DRB1-DQB1 haplotype=medium search success probability.
Rare DRB1 allele or DRB1-DQB1 haplotype=low search success probability.
If no HLA-A, -B or -DRB1 low-resolution-typed donors were available for the patient at the beginning of the search, the search success probability was considered to be very low, irrespective of the patient's HLA-DRB1 and -DQB1 typing results. For these patients, the initial search strategy focused on the identification of HLA-A-, -B and -DRB1 low-resolution-matched donors, among those who were typed only for HLA-A and -B at the time of search initiation.
Cases in which at least one matched HLA-DRB1 and -DQB1 high-resolution-typed donor was available at the time of search initiation were considered to have a high search success probability, irrespective of the patient's HLA-DRB1-DQB1 allele or haplotype frequencies. Finally, if, on UDS initiation, at least one of the donors were HLA-DRB1 matched at a high-resolution level, but no HLA-DQB1 typing was available, the frequency of the patient's HLA-DRB1 alleles was not taken into account. In such cases, the assignment to a search success probability group was carried out by considering the patient's HLA-DRB1-DQB1 haplotype frequencies only.
The proportion of successful searches and the median UDS duration were calculated in the groups with different search success probability predictions. A UDS was successful if at least one donor could be identified, either 10/10 matched or accepted by the transplant center in spite of HLA mismatches (acceptable donor). A search was unsuccessful if it was terminated without finding a donor who could be accepted for transplantation by the transplant physician. The search duration was counted in days from the initiation of the search until the identification of the first 10/10 matched or acceptable donor, or up to the termination of the search without finding any acceptable donor. The start of search initiation was taken to be the date when the search request was submitted to the national hub after the patient's HLA type was confirmed on two separate independent blood samples.
The average number of donors requested for CT was calculated in the different patient groups. The availability of donors was also assessed. A donor was deemed unavailable if no CT blood samples were received.
An explorative data analysis was conducted. For descriptive statistical analysis, absolute and relative frequencies were calculated for categorical variables. Median, minimum, maximum, 25- and 75%-quantiles were calculated for quantitative data and illustrated with boxplots. To describe differences between groups, search success rates are given with exact 95% confidence intervals. Differences in search duration between the UDS success probability groups were compared with the exact Kruskal–Wallis test. Statistical analysis was carried out using SAS Version 9.1 and GraphPad Prism Version 5.01.
Of the 549 searches, 318 (57.9%) were predicted to have high, 157 (28.6%) medium and 56 (10.2%) low probability of finding an HLA-matched unrelated donor. For 18 patients (3.3%), no HLA-A, -B and -DRB1 low-resolution-typed donors were available at the time of search initiation. The probability of finding an HLA-matched donor for these patients was expected to be very low.
The overall search success rate was 90.5%. The median UDS duration of all searches (n=549) was 22 days (minimum 2, maximum 2870 days). The median duration of successful searches was 21 days (7–2275) in contrast to 98.5 days (2–2870) for unsuccessful cases. Some of these unsuccessful searches were terminated after only a few days (for example, 2, 11 or 12 days) because of the very poor prospects of finding a 10/10-matched donor and because mismatched donors would not be accepted by the transplant center.
The average number of donors requested for CT was higher in the groups with medium and low search success probability than in the group with high probability (5.5, 8.1 and 4.5, respectively). In the group with very low search success probability, the number of donors requested for CT was also small (0.8 per patient) because of the lack of available HLA-A, -B and -DRB1 low-resolution-matched donors at the beginning of the search. On an average, 21.9% of the donors were not available for CT. The CT's unavailability rate in the groups with high, medium, low and very low search success probability was 20.1, 24.4, 22.5 and 28.6%, respectively.
The proportion of successful searches (10/10 matched or acceptably mismatched donor found) is shown in Figure 1a. A 10/10-matched unrelated donor was found for 338 of 549 (61.6%) patients, varying from 78.3 to 5.6% in the groups with high, medium, low and very low search success probability (Figure 1b). In the subgroup of searches in which HLA-A, -B and -Cw typing was carried out at a high-resolution level (n=218), the percentage of patients with 10/10-matched donors was 67.0% (146 patients). This value is even higher than that in the whole study cohort. Among the searches in which an HLA-DRB1-DQB1 identical donor could be identified, the proportion of 10/10-matched donors was 79.0% (249/315), 61.9% (78/126), 55.6% (10/18) and 25% (1/4) in the groups with high, medium, low and very low search success probability, respectively. The highest UDS success rate was found in the group of patients for whom at least one HLA-DRB1-DQB1 high-resolution-matched donor was available at the time of search initiation (a subset of the high search success probability group). An accepted unrelated donor was found for all but one of the 194 (99.5%) patients and a 10/10-matched donor for 166 (85.6%) patients in this subgroup.
The overall median search duration was 20 (7–330), 27 (8–539), 45 (7–1225) and 477 (2–2870) days in the groups with high, medium, low and very low search success probability, respectively. The cumulative search success rate in relation to the elapsed time is shown in Figure 2. The higher proportion of unsuccessful searches (which usually last longer) in the groups with medium, low and very low search success probability leads to a longer overall median search duration. To compare the search duration in the different groups independently from the search success rate, successful and unsuccessful searches were analyzed separately. If a UDS led to the identification of an acceptably mismatched or a 10/10-matched donor, the median search duration still varied in the groups with high, medium and low search success probability (20, 25 and 37 days, respectively, P<0.001) (Figure 3).The availability of at least one HLA-DRB1-DQB1 high-resolution-matched donor at the time of search initiation reduced the search duration to 19 (7–134) days in median.
In the group of patients with high search success probability, the effect of the number of CT requests on the search success rate and its duration was evaluated. The patients with HLA-DRB1-DQB1 high-resolution-matched donors at the initiation of the search were excluded, and two subsets of patients were compared with each other: (1) patients with up to three CT requests (n=85) and (2) patients with more than three CT requests at the time of search initiation (n=39). The median search duration differed by only 3 days in these two subsets (24 days (7–330) in the group with up to three CT requests, 21 days (11–109) in the group with more than three CT requests). An acceptable donor was found for 83 (97.6%) and 39 (100%) patients, and a 10/10-matched donor for 57 (67.1%) and 26 (66.7%) patients, respectively.
Finally, the distribution of accepted mismatches was evaluated. For 114 (20.8%) patients, an isolated HLA mismatch, and for 45 (8.2%) patients, a combined HLA mismatch was accepted (Figure 4a). Sixty-eight (12.4%) patients had an isolated HLA-Cw mismatch, which was the most common incompatibility in our study cohort. The HLA-Cw mismatch contributed the largest percentage (51.7%) of all counted mismatches (Figure 4b).
We analyzed the UDS success rate and its duration in a population of 549 German patients in need of a hematopoietic stem cell transplant. The probability of finding a suitable unrelated donor was predicted on the basis of the patient's HLA-DRB1 allele and DRB1-DQB1 haplotype frequencies. HLA-A, -B and -Cw high-resolution typing of the patient was not considered in the probability estimation because of the lower diversity of HLA-A and -B alleles within broad Ag specificity groups in Caucasians,16, 25 and also because HLA-Cw matching was not included in HLA compatibility assessment at the beginning of 2005 in Germany. Furthermore, one of the intentions was to keep the prediction of the search success probability as simple as possible. In contrast to the available UDS assistance tools, our search success prediction model does not need any technical equipment or software installation. Search prospects can be assessed even before the search is officially initiated at donor registries.
Assignment of UDSs into four groups on the basis of the criteria described in this paper allowed a reliable estimation of search success prospects and duration. The overall search success rate was 90.5% and spanned from 99.1% in the high to 75.0 in the low and to 22.2 in the very low search success probability groups. A 10/10-matched donor was found for 61.6% of patients, varying between 78.3 and 5.6%. In the subgroup of searches in which the matching for HLA-A, -B and -Cw was defined at a high-resolution level, a 10/10-matched donor was found for 67.0% of patients. For patients with a high search success probability estimation (57% of all patients), the first acceptable unrelated donor (10/10 matched or mismatched) could be identified in only 20 days in median. In contrast, for patients with low search success probability (approximately 10% of all patients), a UDS lasted more than twice as long (45 days in median). An extraordinarily long search duration (477 days in median) for patients with predicted very low search success probability did not lead to the identification of a 10/10 HLA-matched donor. According to our experience, a donor can be found for these patients only if an HLA antigen mismatch would be accepted by the transplant center.
It is very likely that the high search success rate and short search duration shown are not reproducible for patients of races other than Caucasian. Patients of non-Caucasian origin would more frequently be assigned to the groups with low or very low search success probability, in which the average search success rate and the search duration are significantly less. However, because the assessment of HLA-DRB1 alleles as very frequent, frequent and rare was made on the basis of the National Marrow Donor Program donor dataset, which represents the ethnic composition of worldwide available donors, we believe that the search prospects can be estimated with the same accuracy in other populations as well. Nevertheless, only a prospective evaluation of our search strategy with patients of non-Caucasian origin can confirm the reliability of the study results.
The prediction of the search success rate and duration is of clinical value when therapeutic alternatives for patients are discussed at the beginning of the treatment. In some clinical situations, such as high-risk AML patients in first CR who proceed directly to transplantation after successful induction therapy, there are only few weeks for the completion of a UDS.26, 27 If the likelihood of finding a suitable, unrelated hematopoietic stem cell donor is poor, or if the UDS is predicted to last long, an alternative therapeutic option may be chosen in due time. Alternatively, an HLA mismatch may be weighed against the disadvantages of a non-transplant therapy or against the possibility of the disease progression during the search process. Then, if the situation dictates, an early decision to use a donor with an HLA mismatch may be made.
If the indication for a fast transplantation is given at the time of diagnosis and the UDS is initiated immediately, an HLA-matched unrelated donor can be identified in <4 weeks for almost two-thirds of the patients. Including the additional 2–3 weeks, which are needed for donor work-up and graft collection, a large number of patients could be scheduled for HSCT from an unrelated donor within 6–7 weeks from the time of diagnosis. As an alternative, UCB transplantation can be considered, which is suggested to be an acceptable option for patients with no HLA-matched BM or PBSC donors, as well as for patients in urgent need of a transplant.28, 29, 30, 31, 32 One of the particular advantages of cord blood is its rapid availability. A median UCB search duration of only 13.5 days has been reported.13 Owing to the median search duration of 22 days in our study, for most of the patients of Caucasian origin, the decision for a UCB transplantation must not be conducted because of shorter search duration. But for patients with low or very low search success probability, UCB transplantation should be considered early and a simultaneous search for a UCB unit should be initiated.
One of the basic intentions of UDS is to run the search as fast as possible. At the same time, the number of CT requests should be kept to a minimum in order to save costs. Every search unit must develop its own strategy depending on its financial resources and on the needs of the transplant centers that it serves. We analyzed the success rate and duration of UDS in relation to the number of donors requested for CT at the time of search initiation. In the group of patients with high search success probability, the initial request of more than three donors did not enhance the chances of finding an acceptable donor, and shortened the search process by only 3 days in median. Owing to the small number of searches, this analysis could not be carried out in the other groups of search success probability. On the basis of our data, 2–3 CT requests are sufficient for patients belonging to the high search success probability group. For patients with medium search success probability, we would recommend the initial request of four CTs, if available. In the group with low probability, no general recommendation can be given. Every search in this category should be handled individually. If the patient is a carrier of uncommon, but not very rare HLA alleles or haplotypes, six or even more unrelated donors should be requested for CT in the first step, if such a number of low-resolution matched donors is available in the worldwide registries. In the case of very rare alleles or allele combinations and for patients in the group with very low search success probability, the acceptance of an HLA mismatch, or of an alternative therapeutic option, must be discussed with the transplant physician as soon as possible on UDS initiation.
Although in our study, the probability of finding an HLA-matched unrelated HSCT-donor was based on the patient's high-resolution HLA-DRB1-DQB1 typing only, it allowed the prediction of the prospects to find a 10/10-matched donor. This may be because very frequent HLA-DRB1 alleles and DRB1-DQB1 haplotypes are associated with common HLA-A-B-Cw-DRB1-DQB1 haplotypes. In view of the relatively high proportion of HLA-Cw mismatches among the acceptable donors, we aim at refining our search success prediction model by adding the option of HLA-Cw compatibility forecasting on the basis of the HLA-A-B-Cw haplotype data.
Our study shows remarkably shortened overall UDS duration and enhanced search success rates in comparison with earlier reports.6, 10, 11, 33 Considering the shortened search duration over the last decade and the availability of alternative hematopoietic stem cell sources, only for a very small part of patients an unrelated HSCT must be revoked because of the lack of a suitable donor, even if the need for a transplant is urgent. The patient's HLA-DRB1-DQB1 typing results allow a reliable prediction of UDS duration and of the prospects of finding an HLA-matched unrelated donor. Patients with a poor chance to find an HLA-matched donor can be identified at the time of search initiation, and alternatives to the 10/10-matched transplantation can be discussed with the transplant center at an early stage.
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We thank S Sander for her constructive comments on this paper, and SC Martindale for his editorial corrections of the English grammar. This analysis has been presented in part at the European Bone Marrow Transplantation Annual Meeting in Lyon, March 2007.
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Hirv, K., Bloch, K., Fischer, M. et al. Prediction of duration and success rate of unrelated hematopoietic stem cell donor searches based on the patient's HLA-DRB1 allele and DRB1-DQB1 haplotype frequencies. Bone Marrow Transplant 44, 433–440 (2009) doi:10.1038/bmt.2009.53
- donor search
Current Opinion in Hematology (2016)
International Journal of Immunogenetics (2016)
Bone Marrow Transplantation (2016)
HLA allele and haplotype polymorphisms among Croatian patients in an unrelated hematopoietic stem cell donor search program
Transplant Immunology (2014)
Tissue Antigens (2014)