Selection of unrelated donors and cord blood units for hematopoietic cell transplantation: guidelines from the NMDP/CIBMTR



# Introduction
The National Marrow Donor Program (NMDP) facilitates the identification and procurement of unrelated donor grafts for hematopoietic cell transplantation (HCT). The Center for International Blood and Marrow Transplant Research (CIBMTR) is a research collaboration between the NMDP and the Medical College of Wisconsin. The guidelines below created jointly with the NMDP Histocompatibility Advisory Group, which consists of key opinion leaders in immunogenetics and HCT, update those previously published in 2003, [bib_ref] National Marrow Donor Program HLAmatching guidelines for unrelated marrow transplants, Hurley [/bib_ref] 2008, [bib_ref] National marrow donor program HLA matching guidelines for unrelated adult donor hematopoietic..., Bray [/bib_ref] and 2012and are based on current and relevant data supporting optimal HLA donor-recipient matching criteria and other factors affecting graft selection.
The majority of our recommendations in this review are based on the existing precedent of overall survival (OS) as the primary outcome of interest. While this is an unambiguous measure of success, we note that composite end points such as graft-versushost disease (GVHD), relapse-free survival as well as patientreported outcome measures such as quality of life provide valuable information on HCT outcome beyond survival status. While we acknowledge that multiple pre-and posttransplant patient, disease, and transplantation variables impact outcome, this review focuses primarily on the impact of HLA and non-HLA factors considered in donor selection pretransplant. [bib_ref] Optimal HLA matching in hematopoietic cell transplantation, Petersdorf [/bib_ref] [bib_ref] The effect of donor characteristics on survival after unrelated donor transplantation for..., Kollman [/bib_ref] [bib_ref] Donor and recipient sex in allogeneic stem cell transplantation: what really matters, Kim [/bib_ref] [bib_ref] Bone marrow or peripheral blood for reduced-intensity conditioning unrelated donor transplantation, Eapen [/bib_ref] [bib_ref] Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults..., Eapen [/bib_ref] [bib_ref] Optimal practices in unrelated donor cord blood transplantation for hematologic malignancies, Barker [/bib_ref] [bib_ref] Prospective validation of the predictive power of the hematopoietic cell transplantation comorbidity..., Sorror [/bib_ref] [bib_ref] Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment..., Sorror [/bib_ref] [bib_ref] Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell..., Sorror [/bib_ref] [bib_ref] Validation and refinement of the Disease Risk Index for allogeneic stem cell..., Armand [/bib_ref] [bib_ref] Improved survival after acute graft-versus-host NMDP/CIBMTR DONOR SELECTION GUIDELINES blood, Khoury [/bib_ref] [bib_ref] Predictors of survival, nonrelapse mortality, and failurefree survival in patients treated for..., Palmer [/bib_ref] [bib_ref] Limits of HLA mismatching in unrelated hematopoietic cell transplantation, Petersdorf [/bib_ref] Disease stage is a major determinant of transplant outcome, and prompt transplantation is optimal for patients with high-risk disease. Rapid assessment of the likelihood of unrelated donor search success, clear guidance provided by physicians to their search coordinators, and prioritization of alternative donor strategies are needed to avoid delay associated with futile unrelated donor searches. Since not all patients will have a fully HLA-matched donor, it is important to consider whether such patients should pursue an HCT from an alternative donor source such as cord blood (CB) or haploidentical related or mismatched unrelated donor. We note that these all represent viable alternative donor options. In the absence of definitive comparative outcome data, we do not recommend one as a preferred approach. Individualpatient-(disease risk, urgency in time to HCT, and donor availability) and provider-level considerations influence selection.

## Hla typing
Definition of high resolution Nomenclature for HLA is described at http://hla.alleles.org. DNA-based nomenclature has a potential of 4 numerical fields separated by colons (eg, A*02:01:01:01). "Allele"-level typing, also termed high-resolution typing or 2-field typing, 28 discriminates among HLA genes that encode cell-surface proteins that differ in the amino acid sequence of their antigen recognition domain (ARD). Other designations that indicate ARD identity include G (A*02:01:01G indicating nucleotide sequence identity in the ARD exons) and P (A*02:01P indicating protein sequence identity in the ARD) nomenclature. Both G and P groups of alleles can also be represented as multiple allele codes that are provisioned globally by the NMDP. A description of the alleles included in a specific code can be found at https://hml.nmdp.org/MacUI/. The ARD is the "active" portion of the HLA molecule that binds peptide antigens and interacts with T lymphocyte and natural killer cell receptors. Available data suggest that alleles that are identical in the ARD but differ in amino acid sequence in other regions of the protein do not stimulate direct allorecognition, but this needs to be evaluated in a retrospective large-scale study of outcome. Consequently, HLA reports may designate a donor or recipient as having one of several possible alleles, all with the same ARD, for a given locus and it is standard practice to accept identity of these donor and recipient assignments as a match. A list of alleles that encode the same amino acid sequence in the ARD can be found at http://hla.alleles.org.

## Hla typing recommendations for patients and adult donors
Patients and donors should be typed by DNA-based methods at high resolution for HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DPB1 loci. Other loci (eg, HLA-DQB1, HLA-DRB3/4/5, HLA-DQA1, and HLA-DPA1) have not been shown in isolation to substantially impact survival; however, they may assist in designing an efficient search strategy for the patient and, when possible, for selecting among multiple similar donors and support donor selection in the context of an HLA-sensitized patient to avoid the potential risk of graft failure. 32,33 HLA typing recommendations for umbilical CB units CB units should be typed by DNA-based methods at high resolution for HLA-A, HLA-B, HLA-C, and HLA-DRB1. [bib_ref] Optimal practices in unrelated donor cord blood transplantation for hematologic malignancies, Barker [/bib_ref] The NMDP centralized confirmatory typing program performs highresolution typing and also includes DQB1 and DPB1.

## Selection of adult unrelated donors

## Hla matching considerations
Optimal match criteria for unrelated adult donors HLA-mismatching between donors and recipients in the setting of conventional GVHD prophylaxis is consistently associated with inferior recipient survival in both the myeloablative and the reduced-intensity conditioning context, as well as in the setting of T-cell-replete and T-cell-depleted grafts. [bib_ref] The effect of donor characteristics on survival after unrelated donor transplantation for..., Kollman [/bib_ref] Learning objectives Results apply to both bone marrow (BM) and peripheral blood stem cell (PBSC) grafts. Although the majority of studies have been performed in patients receiving HCT for malignant diseases, there is supporting data for a similar adverse impact on survival in patients with nonmalignant disorders. A recent analysis from the NMDP/CIBMTR affirmed major findings from prior studies, refined donor selection guidelines, and validated the importance of avoiding nonpermissive DPB1 mismatches (described in "Variation in HLA protein structure") to optimize survival. 21 This analysis included adult and pediatric recipients of first myeloablative unrelated donor BM or PBSC transplant for acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome between 1999 and 2011. Importantly, the study population more closely approximated current HCT practices compared with prior analyses, given the greater representation of PBSCs as a graft source and use of non-total body irradiationcontaining myeloablative conditioning regimens. All cases had high-resolution typing for HLA-A, HLA-B, HLA-C, and HLA-DRB1, while a subgroup had typing available for analysis of the effect of mismatch at DPB1 and DQB1. Of the total (n 5 8003), cases were 8/8 HLA-matched (n 5 5449), 7/8 (n 5 2071), or 6/8 (n 5 483) matched at HLA-A, HLA-B, HLA-C, and HLA-DRB1. Several major findings from this study informed current donor selection guidelines [fig_ref] Table 1: Guidelines for unrelated donor selection [/fig_ref] : First, any single mismatch at HLA-A, HLA-B, HLA-C, or HLA-DRB1 was associated with significantly worse OS, and there was no evidence that mismatch at any of the individual loci was better tolerated than others. Multiple mismatches worsened OS further, supporting that 6/8 or less-matched transplants do not provide acceptable OS outcome under conventional HCT practices represented in that study. In addition, there was no difference in the impact of mismatch on OS according to allele-level vs antigen-level mismatch, supporting a need to match at the allele level. The effect of HLA mismatch differed according to disease risk, as the greatest negative impact on OS was observed for those with early-stage disease. Among 8/8 matched cases, DPB1 and DQB1 mismatch resulted in increased acute GVHD, but DPB1 mismatch decreased relapse risk. Building from preclinical observations regarding the immunogenicity of specific HLA-DPB1 alleles, 39-42 this analysis also confirmed the adverse impact of nonpermissive HLA-DPB1 mismatch (described in "Variation in HLA protein structure") on OS. 21 Similar results were obtained in other large studies. The directionality of nonpermissive HLA-DPB1 mismatches does not appear to alter this impact. Criteria for the best partially matched unrelated donor Although multiple algorithms for selecting permissive or tolerated mismatches have been proposed (eg, location and characteristics of amino acid mismatches), 46-55 most have failed to be validated in large data sets. [bib_ref] Analysis of predicted indirectly recognizable HLA epitopes (PIRCHE) in mismatched unrelated donor..., Spierings [/bib_ref] The immunologic impact of HLA mismatches is thought to be contingent upon 3 major factors: (1) effect of the mismatch on the physical and chemical structure of the HLA molecule and its bound peptide 53 ; (2) direction of the mismatch, either in the GVHD vector or in the host-versus-graft direction (HvG) vector or bidirectional 57 ; and (3) level of expression of the mismatched HLA molecule on the cell surface. [bib_ref] High HLA-DP expression and graft-versushost disease, Petersdorf [/bib_ref] [bib_ref] International Histocompatibility Working Group in Hematopoietic Cell Transplantation. HLA-C expression levels define..., Petersdorf [/bib_ref] Variation in HLA protein structure One example of an acceptable mismatch is the HLA-C*03:03 vs HLA-C*03:04 allele combination. HLA-C*03:03/03:04 is the most frequent HLA-C mismatch in individuals of European ancestry, and both alleles are associated with B*15:01. [bib_ref] Analysis of the frequencies of HLA-A, B, and C alleles and haplotypes..., Cao [/bib_ref] These 2 HLA proteins differ subtly from one another and do not appear to result in allorecognition. [bib_ref] Functional versus structural matching: can the CTLp test be replaced by HLA..., Oudshoorn [/bib_ref] [bib_ref] HLA allotype expressivity in transplantation, Fernandez-Vina [/bib_ref] [bib_ref] Biologic markers of chronic GVHD, Pidala [/bib_ref] In a retrospective study, 7/8 matched pairs with the HLA-C*03:03/ 03:04 mismatch had similar outcomes (mortality, disease-free survival, grade 3-4 acute GVHD) to 8/8 matched pairs. [bib_ref] Identification of a permissible HLA mismatch in hematopoietic stem cell transplantation, Fernandez-Vina [/bib_ref] Due to weak linkage disequilibrium with other HLA loci and lack of historic typing available on donor registries, DPB1 mismatches were shown to be present in .80% of unrelated HCT.Since DPB1 matches are less common and typing less frequently available at initial search, searches should not focus on identifying a DPB1 matched donor. Rather, the goal is to generate limited alloreactivity needed for a graft-versus-leukemia effect while preventing excessive alloreactivity associated with acute GVHD. Therefore, differentiation between low-risk DPB1 mismatches and high-risk DPB1 mismatches is clinically important. [bib_ref] HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities, Fleischhauer [/bib_ref] One model to predict level of immunogenicity is based on the ability of specific DP allotypes to induce T-cell alloreactive responses. [bib_ref] Peripheral blood stem cell allograft rejection mediated by CD4(1) T lymphocytes recognizing..., Fleischhauer [/bib_ref] Three T-cell epitope (TCE) groups 41,67 differing by the strength of their immunogenicity are assigned; most recently, these epitope groups have been expanded to include more DP allotypes based on amino acid sequence similarities. [bib_ref] The impact of amino acid variability on alloreactivity defines a functional distance..., Crivello [/bib_ref] Direction of the mismatch If either the recipient or donor expresses only a single HLA allele at a locus (ie, is homozygous), then a unidirectional mismatch will occur. There are 2 types of unidirectional mismatches in HCT. If the recipient is homozygous at a specific locus, including presence of a null allele, and the donor is heterozygous and mismatched at that particular locus, then the mismatch is in the HvG vector. If, in contrast, the donor is homozygous at a specific HLA locus and the recipient is heterozygous at the same locus, then the mismatch is in the graftversus-host vector. When both recipient and donor are homozygous and mismatched at that locus or when both are heterozygous with a 7/8 match, then the mismatch is bidirectional.
A retrospective multicenter study found a significantly lower risk of acute GVHD in the 7/8 HvG group compared with 7/8 graftversus-host and bidirectional mismatched groups. [bib_ref] The impact of HLA unidirectional mismatches on the outcome of myeloablative hematopoietic..., Hurley [/bib_ref] However, no difference was observed on OS between unidirectional or bidirectional mismatches and all carried a higher risk of death compared with an 8/8 match.
Matching consideration of expression level of HLA loci Impact of HLA mismatches on allorecognition is dependent on the ability of donor T lymphocytes to detect foreign HLA on the surface of cells. HLA loci vary in their level of expression on the surface of the cells, and these differences may affect allorecognition and impact transplant outcomes. [bib_ref] International Histocompatibility Working Group in Hematopoietic Cell Transplantation. HLA-C expression levels define..., Petersdorf [/bib_ref] [bib_ref] Structural and regulatory diversity shape HLA-C protein expression levels, Kaur [/bib_ref] A study of registry data with predominantly BM transplant recipients demonstrated significant lower OS and increased transplant related mortality in 7/8 unrelated donor cohort with $3 mismatches in low expression HLA loci, HLA-DRB3/4/5, DQB1, and DPB1. While mismatches at these loci do not appear to impact outcomes in the 8/8 cohort, it is recommended that matching in the 7/8 situation consider these secondary loci. [bib_ref] Multiple mismatches at the low expression HLA loci DP, DQ, and DRB3/4/5..., Fernandez-Vina [/bib_ref] More recently, studies have begun to evaluate the role of expression of specific HLA allelic products on outcome. [bib_ref] International Histocompatibility Working Group in Hematopoietic Cell Transplantation. HLA-C expression levels define..., Petersdorf [/bib_ref] [bib_ref] Differential microRNA regulation of HLA-C expression and its association with HIV control, Kulkarni [/bib_ref] It is likely that other key HLA loci also differ in expression but more research is needed.
Matching requirements for BM and PBSCs Currently, most unrelated adult donor transplantations use granulocyte colonystimulating factor mobilized PBSC grafts. We acknowledge that a major randomized trial demonstrated increased risk of chronic GVHD, [bib_ref] Blood and Marrow Transplant Clinical Trials Network. Peripheral-blood stem cells versus bone..., Anasetti [/bib_ref] as well as long-term impairment in quality of life when PBSC grafts are used rather than BM in unrelated donor HCT. [bib_ref] Comparison of patient-reported outcomes in 5-year survivors who received bone marrow vs..., Lee [/bib_ref] prior pregnancies, and larger body weight. In a recent large study that specifically addressed donor characteristics, the only characteristic associated with OS was donor age; recipient mortality was higher with increasing donor age. [bib_ref] The effect of donor characteristics on survival after unrelated donor transplantation for..., Kollman [/bib_ref] Donor age was also the only characteristic associated with OS in a study attempting to validate a donor selection score. [bib_ref] Development of an unrelated donor selection score predictive of survival after HCT:..., Shaw [/bib_ref] Logistical issues may determine the selection between these secondary donor characteristics if multiple equally matched and age donors are available.
Impact of race/ethnicity in the selection process Many HLA alleles and haplotypes are distributed at different frequencies among different racial/ethnic groups. 25,92,93 HLA alleles at low frequency in the general population are more likely found on distinct haplotypes along with the remainder of the HLA alleles from an ancestral racial/ethnic group in common between patient and donor. NMDP's predictive matching algorithm, HapLogic, takes the race/ethnic group into account when predicting the likelihood of a high-resolution match, so centers should attempt to accurately obtain and enter these patient details for the search.

## Consideration of patient sensitization
Approximately onethird of adults with hematologic malignancies are sensitized to HLA antigens as demonstrated by the presence of circulating antibodies. The incidence of humoral sensitization against HLA is 2 to 3 times higher in females than in males and increases with the number of pregnancies. Although several studies have shown a strong association of preformed donor-specific HLA antibodies (DSA) with primary graft failure after unrelated donor transplantation 32,33 and related haploidentical donor transplantation, [bib_ref] Complement-binding donor-specific anti-HLA antibodies and risk of primary graft failure in hematopoietic..., Ciurea [/bib_ref] [bib_ref] High risk of graft failure in patients with anti-HLA antibodies undergoing haploidentical..., Ciurea [/bib_ref] the data in the setting of CB transplants are mixed, with some reporting an adverse effect and others none. [bib_ref] The impact of anti-HLA antibodies on unrelated cord blood transplantations, Takanashi [/bib_ref] [bib_ref] Donor-specific anti-HLA antibodies predict outcome in double umbilical cord blood transplantation, Cutler [/bib_ref] [bib_ref] Anti-HLA antibodies in double umbilical cord blood transplantation, Brunstein [/bib_ref] [bib_ref] Sustained donor engraftment in recipients of double-unit cord blood transplantation is possible..., Dahi [/bib_ref] Thus, for patients with anti-HLA antibodies and a mismatched allograft, careful antibody specificity analysis and/or testing of the patient's serum for reactivity with cells from potential donors (ie, cross-matching) should be done prior to transplantation Developed by the ASBMT CB Special Interest Group. For successful engraftment, optimal CB graft selection and the patient's rejection risk must be considered. [bib_ref] Optimal practices in unrelated donor cord blood transplantation for hematologic malignancies, Barker [/bib_ref] CBT, CB transplant; RBC, red blood cell; TNC, total nucleated cell.
*RBC-replete units have been associated with life-threatening infusion reactions. Washing is difficult due to the lack of a clear interface after centrifugation; washing also risks cell loss. Therefore, RBC-replete units should be used with caution. They should only be considered in the absence of RBC-depleted CB units meeting acceptable criteria. Incorporation of nucleated red cell content in unit selection is not recommended at this time. Some expert centers prefer to use an RBC-depleted unit that has a post-cryopreservation volume of ;25 mL/bag. If a unit was divided into 2 bags for storage, then each bag should contain ;25 mL. Regarding the significance of HLA antibodies, DSAs must be considered on a case-by-case basis based on diagnosis and prior immunosuppressive therapy that determine rejection risk, the intensity of planned conditioning, and the number, titer, specificity, and complement fixation of DSAs. DSA targeted units should be avoided in nonmalignant diagnoses. In patients with malignancies, avoid if possible, but use caution if avoidance of units against which the patient has antibodies compromises the selected CB unit dose and HLA match.
||For single-vs double-unit CB transplant, if no adequate single-unit graft is available, then a double-unit graft is recommended. Clinical trials investigating the addition of other cellular products to a single-unit graft can also be considered. For prioritization of cell dose vs HLA match (applies to single-and double-unit transplants), cell dose frequently needs to take priority over HLA match for adult and larger pediatric patients. HLA-match can take priority in children or smaller adults or those with common HLA typing who have multiple units with high cell dose. Optimizing HLA-match is very important in CB transplant for nonmalignant diagnoses. In children with nonmalignant diagnoses, higher cell doses ($5 3 10 7 /kg) should be selected. Further data are required as to how to balance cell dose against HLA match. A current guidance for consideration is as follows: if high doses (eg, TNC $3 3 10 7 /kg and CD34 1 $2 3 10 5 /kg), consider optimizing high-resolution HLA match over cell dose; if lower TNC and CD34 1 doses, optimize dose first and high-resolution HLA match second; and if units have similar cell doses, optimize high-resolution HLA match.
#Reporting of unit viability testing is not fully standardized. Flow-based assays of CD34 1 cell viability on a segment can be informative but have not been validated in multiple banks/centers. The NMDP will facilitate discussion between centers and the bank if questions concerning viability testing arise. and the threshold determined by local laboratory standards. It should be noted that the specificity of some DSA results from the recognition of epitopes determined by the DQA1, DPA1 or present in some loci (DRB3/4/5, DQ, DP) not included in the protocols to define the match grade between the patient and the selected donor. The presence of these antibodies should prompt further HLA testing of these loci. When DSA is identified, the most straightforward choice to reduce the risk for HLA antibodymediated graft failure is to select donors with mismatched alleles that are not the target of DSA. If no HLA antibody-compatible donors can be identified, desensitization treatment of reducing the levels or eliminating DSA before transplantation may improve the chances of successful donor engraftment. 94

## Selection of umbilical cb units
Non-HLA criteria: unit quality and cell dose
In HCT with CB, unlike adult volunteer donors, non-HLA factors are as critical as HLA matching in unit selection. CB has the major advantage of rapid availability and a markedly reduced stringency of HLA-matching compared with adult unrelated PBSC or BM. Consequently, use of CB has dramatically extended allograft access to racial and ethnic minorities. [bib_ref] Optimal practices in unrelated donor cord blood transplantation for hematologic malignancies, Barker [/bib_ref] [bib_ref] Optimal practices in unrelated donor cord blood transplantation for hematologic malignancies, Barker [/bib_ref] Unit quality results from banking practices. It has increasingly been recognized as a critical factor in unit selection (factors outlined in [fig_ref] Table 2: Unrelated CB unit selection guidelines [/fig_ref]. This is because unit quality is highly associated with unit potency, including postthaw CD34 1 cell viability and recovery. [bib_ref] Dominant unit CD341 cell dose predicts engraftment after double-unit cord blood transplantation..., Purtill [/bib_ref] [bib_ref] Total colony-forming units are a strong, independent predictor of neutrophil and platelet..., Page [/bib_ref] In a collaborative analysis by the CIBMTR, Eurocord and the European Group for Blood and Marrow Transplantation, TNC doses of $3.0 3 10 7 /kg recipient body weight for single units was associated with sufficient progenitor cells for successful transplantation. [bib_ref] Center for International Blood and Marrow Transplant Research, Netcord, Eurocord, and the..., Eapen [/bib_ref] Increasing TNC dose beyond 3.0 3 10 7 /kg did not confer an advantage in regards to hematopoietic recovery or survival, but lower TNC was associated with higher [bib_ref] Blood and Marrow Transplant Clinical Trials Network. One-unit versus two-unit cord-blood transplantation..., Wagner [/bib_ref] [bib_ref] Double unit grafts successfully extend the application of umbilical cord blood transplantation..., Scaradavou [/bib_ref] In the absence of an adequately dosed single unit, infusion of 2 units is the standard, with each unit containing a minimum TNC of 1.5 3 10 7 /kg. Experienced CB transplant programs now consider CD34 1 progenitor content a better measure of unit potency, and incorporation of CD34 1 dose in unit selection is now considered standard practice. 9,101 Minimum prefreeze CD34 1 of 1.5 3 10 5 /kg for single unit or 1.0 3 10 5 /kg for each unit when infusing 2 units is desirable [fig_ref] Table 2: Unrelated CB unit selection guidelines [/fig_ref]. Caution is warranted when there are disparities between the CD34 1 dose and the TNC dose (ie, one is high and the other is low) that may reflect a laboratory or unit report listing error.

## Hla matching requirements for umbilical cb units
While the historical standard for selecting unrelated CB has been based on HLA-A, HLA-B antigen (ie, first field typing equivalent to a serologic match) and HLA-DRB1 allele (ie, high-resolution or 2-field match), the available data in 2012 3 supported the inclusion of the HLA-C antigen in the matching calculation to minimize mortality risks. [bib_ref] Center for International Blood and Marrow Transplant Research. Effect of donor-recipient HLA..., Eapen [/bib_ref] Later reports confirmed the importance of counting matches at the high-resolution level for HLA-A, HLA-B, HLA-C, and HLA-DRB1 for malignant and nonmalignant diseases. [bib_ref] Center for International Blood and Marrow Transplant Research, Netcord, Eurocord, and the..., Eapen [/bib_ref] [bib_ref] Allele-level HLA matching for umbilical cord blood transplantation for non-malignant diseases in..., Eapen [/bib_ref] The incidence of neutrophil recovery was lower and graft failure and mortality rates were higher when the recipient and the CB unit were mismatched at $2 HLA highresolution types. In the setting of double CB unit transplantation, the same HLA match criteria that guide single-unit selection should be applied to the selection of both units. [bib_ref] Matching at human leukocyte antigen-C improved the outcomes after double umbilical cord..., Brunstein [/bib_ref] There are no data that support consideration of interunit HLA matching in double-unit graft selection. [bib_ref] Dominant unit CD341 cell dose predicts engraftment after double-unit cord blood transplantation..., Purtill [/bib_ref] [bib_ref] The effect of inter-unit HLA matching in double umbilical cord blood transplantation..., Brunstein [/bib_ref] [bib_ref] Influence of infused cell dose and HLA match on engraftment after double-unit..., Avery [/bib_ref] Taken together, guidelines have been developed by the ASBMT CB Special Interest Group (summarized in [fig_ref] Table 2: Unrelated CB unit selection guidelines [/fig_ref]. Overall, the current data support selecting units using the following unit principles: (1) adequate unit quality, (2) minimum required TNC and CD34 1 cell doses, and (3) optimal HLA high-resolution matched unit considering HLA-A, HLA-B, HLA-C, and HLA-DRB1. To date, there are no data to further guide how to balance CD34 1 dose against HLA high-resolution match grade. Further study of this question is required and recommendations may differ for single-vs doubleunit grafts. A general guidance in this evolving field is provided in [fig_ref] Table 2: Unrelated CB unit selection guidelines [/fig_ref].

## Adult donor search

## Search strategy
Consistent with the recommended HLA typing for the patient, the search should be based on high-resolution HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DPB1, with additional loci (eg, HLA-DQB1 and DRB3/4/5) optional but often helpful in designing an efficient search strategy. Although the practice of many registries in recent years is to high-resolution type new donors at recruitment, the majority of worldwide donors do not have extended high-resolution typing of all of these loci available. The NMDP search algorithm, HapLogic, leverages data on the frequencies of alleles and haplotypes defined by ethnic populations to predict the probability of high-resolution matches at individual HLA loci and at all key loci simultaneously [fig_ref] Figure 1: Example of an NMDP search report [/fig_ref] for the patient and each potential donor. [bib_ref] HapLogic: a predictive human leukocyte antigen-matching algorithm to enhance rapid identification of..., Dehn [/bib_ref] [bib_ref] Information Technology Working Group of the World Marrow Donor Association. An update..., Bochtler [/bib_ref] An NMDP search includes donors from all registries that list their donors in the World Marrow Donor Association Search and Match listing (previously known as Bone Marrow Donors Worldwide) via download and direct electronic connections. [bib_ref] Bone Marrow Donors Worldwide: a successful exercise in international cooperation, Oudshoorn [/bib_ref] Transplant centers can use the World Marrow Donor Association listing or the listing of their selected registry, if also globally comprehensive, for the evaluation of donors and CB units. Most registries provide free patient preliminary searches to member centers.
The optimal number of potential donors to select from the search report for additional HLA typing should be individualized for each patient since many factors influence the likelihood of finding a compatible donor.
[fig] Figure 1: Example of an NMDP search report. HLA assignments shown include high-resolution/2-field assignments (eg, A*02:01) and the use of multiple allele codes (eg, A*02: ANGA).115 These codes indicate that the assignment has not discriminated among $2 alternative alleles. A description of the alleles included in a specific code can be found at https://hml.nmdp.org/MacUI/. The columns labeled "HLA Typing/Match Grade/Calculation" use a letter indicating the match status of each allele at the locus (A indicates allele match; P, potential allele match; and M, mismatch) and the probability of matching both alleles at the locus (99% for the first donor at each locus). The columns labeled "Composite Predictions" provide the probability of a 10 of 10 HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 allele match (99% for the first donor) and 8 of 8 HLA-A, HLA-B, HLA-C, and HLA-DRB1 allele match (99% for the first donor). Donor DPB1 alleles and TCE group designations are provided when the donor is typed at DPB1, and DPB1 TCE Match Assignments ("DPB1 TCE") are provided when both donor and patient are typed at DPB1. Non-HLA donor demographics are also displayed, including donor age, gender, blood type, cytomegalovirus serostatus, number of prior pregnancies, and last date the registry had contact with the donor ("Last Donor Contact"). [/fig]
[table] Table 1: Guidelines for unrelated donor selection [/table]
[table] Table 2: Unrelated CB unit selection guidelines [/table]