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Published in final edited form as: Biol Blood Marrow Transplant. 2014 Sep 30;21(1):4–7. doi: 10.1016/j.bbmt.2014.09.017

Recommendations for Donor HLA Assessment and Matching for Allogeneic Stem Cell Transplantation: Consensus Opinion of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN)

Alan Howard 1, Marcelo A Fernandez-Vina 2, Frederick R Appelbaum 3, Dennis L Confer 1,4, Steven M Devine 5, Mary M Horowitz 6, Adam Mendizabal 7, Ginna G Laport 8, Marcelo C Pasquini 6, Stephen R Spellman 1
PMCID: PMC4272893  NIHMSID: NIHMS632201  PMID: 25278457

Abstract

The Blood and Marrow Transplant Clinical Trials Network conducts large, multi-institutional clinical trials with the goal of improving the outcomes of hematopoietic cell transplantation (HCT) for patients with life-threatening disorders. Well designed HCT trials benefit from standardized criteria for defining diagnoses, treatment plans and graft source selection. In this perspective, we summarize evidence supporting criteria for the selection of related and unrelated adult volunteer progenitor cell donors or umbilical cord blood units. These standardized criteria for graft source selection have been adopted by the BMT CTN to enhance the interpretation of clinical findings within and among future clinical protocols.

Keywords: allogeneic transplants, cord blood donor, unrelated donor, related donor, recipient

Introduction

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) was established in 2001 to conduct large, multi-institutional clinical trials with the goal of improving the outcomes of hematopoietic cell transplantation (HCT) for patients facing life-threatening disorders. The BMT CTN allows the HCT community to conduct prospective, collaborative, clinical research within an infrastructure designed to offer participation in HCT clinical trials to patients in all regions of the United States (US). Nearly 18,000 HCTs are performed in the US annually and this increases by approximately 5% per year [1]. This growth reflects the utility of HCT in treating both malignant and non-malignant disease, higher donor availability, and treatment advances that allow HCT to be performed in older and sicker patients. While HCT is a rapidly evolving field, HCT clinical trials face unique challenges, including the relatively small number of HCTs performed at any single center, the diverse indications for HCT, the complexities of the procedure and risks for multiple post-transplant complications. The BMT CTN was established to address these challenges and execute multicenter HCT trials with broad national participation. Well designed HCT trials benefit from standardized criteria for defining diagnoses, treatment plans and graft source selection.

The development of clinical guidelines and standards founded on evidence-based research is an important aspect of directing and implementing clinical patient care. Over the past decade, there have been significant developments in HLA typing technologies and in the availability of outcome data from large multi-center studies evaluating a growing number of stem cell sources. Together, these advances provide guidance for consideration in development of clinical trial protocols to ensure generalizability of the results to standard of care treatment.

A recent review of current and completed clinical trials within the BMT CTN illustrated significant variability in the donor and recipient HLA matching criteria used in these trials*. Based upon available clinical research data, it was determined that future clinical studies would benefit from the utilization of consistent criteria regarding the most relevant HLA and non-HLA factors to consider in the selection of related and unrelated adult volunteer progenitor cell donors or umbilical cord blood units. The BMTCTN has adopted the following guidelines for HLA evaluation and donor/recipient matching.

Related Donor Stem Cell Transplants

Fully HLA Matched Sibling

An HLA identical or fully HLA matched sibling is considered the optimal and first choice graft for allogeneic HCT. The recipient, siblings and parents (where available) should be HLAA, -B typed at intermediate or higher resolution and HLA-DRB1 typed at high resolution by DNA-based methods as a minimum requirement. Where possible, familial haplotypes should be assigned to establish presumptive high resolution match identity between the donor and recipient (additional HLA loci may be considered, e.g., HLA-C and -DQB1). The recipient and selected sibling donor should be a 6/6 match at HLA-A, -B and -DRB1. In the absence of family typing to establish familial haplotypes, high resolution typing by DNA based methods should be performed and the recipient and donor fully matched at HLA-A, -B, -C, and -DRB1.

HLA Mismatched Relative

Two thirds or more of all patients in the U.S. will lack an HLA matched sibling and must consider an alternative graft choice [2]. Clinical studies have shown partially HLA-mismatched related (e.g. one HLA antigen mismatched or HLA haplo-identical) hematopoietic stem cell grafts can be a suitable source of donor cells in some settings, thus extending this treatment modality to patients who lack other donors [3-5]. Mismatched related donors are assigned to categories based on the level of HLA match.

  • One Antigen Mismatched Related Donor- The donor differs from the recipient by a single HLA antigen (e.g., sibling with a crossover). The recipient and donor should be HLA-A, -B, -C typed at intermediate or higher resolution and HLA-DRB1 typed at high resolution by DNA-based methods as a minimum requirement. The recipient and selected related donor should be a 7/8 match at HLA-A, -B, -C and -DRB1.

  • Haplo-identical Related Donor- Parents, siblings and other relatives sharing a single HLA haplotype with the recipient are considered haplo-identical. The recipient and the selected donor should be HLA-A, -B, -C typed at intermediate or higher resolution and HLA-DRB1 typed at high resolution by DNA-based methods as a minimum requirement. Where possible, familial haplotypes should be assigned to establish haploidentity between the donor and recipient. The recipient and related donor should be ≥ 4/8 match at HLA-A, -B, -C and -DRB1, with only one mismatch per locus. A significant risk of graft failure exists in the setting of HLA-mismatched related transplantation in HLA sensitized patients [6]. Patients should be screened for the presence of antibodies and donors carrying an HLA target avoided if possible. Data on recipient desensitization to reduce titers of donor specific antibodies is now emerging, but further studies are needed to better refine this strategy.

Unrelated Donor Stem Cell Transplants

Viable alternatives to related donors are well matched unrelated donors and cord blood units. The development of large international volunteer donor registries and cord blood banks facilitate availability of a stem cell source for nearly all patients without a suitable related donor [7].

Adult Unrelated Donor

Based on the findings of numerous large, contemporary retrospective studies and comprehensive reviews, overall survival is increased and transplant-related mortality reduced when recipients of unrelated donor hematopoietic stem cell transplantations are evaluated and matched at high resolution for HLA-A, -B, -C, and HLA-DRB1 (8/8 matched) [8-10]. When 8/8 matched adult volunteer donors are not available, then a single HLA locus mismatched donor (7/8 matched) can be considered with acceptable risks of transplant-related mortality [8]. HLA high-resolution match is defined as equivalent amino acid sequences (G group) in the antigen recognition site (ARS; exon 2 and 3 for HLA Class I and exon 2 for HLA Class II) of the molecule that binds peptide and interacts with the T cell receptor [11]. The impact of variation outside the ARS is not well characterized because of limitations of the current typing methodologies and a lack of clinical correlation studies [12-13].

When multiple equivalently matched unrelated donors are available the consideration of addition HLA loci and non-HLA factors may be used to prioritize the final donor selection. Testing of additional HLA loci (e.g., HLA-DPB1, DQB1 and DRB3/4/5) will assist in selecting donors with minimal mismatching at low expression loci [14] and T-cell epitope permissive HLA-DPB1 mismatches [15-17]. Additionally, extended HLA testing can also support the selection of appropriate donors in the context of HLAsensitized patients to avoid the potential risk of graft failure [18, 19]. In the 7/8 matched setting, donors can also be prioritized for permissive HLA-C*03:03/03:04 mismatches [20] or host versus graft only mismatches [21] to optimize outcomes. Finally, based upon the findings of a recently reported CIBMTR retrospective study [22], centers may want to consider: (1) younger unrelated donors, found to be associated with less aGVHD and better overall survival, and (2) ABO compatible donors, which were also associated with better survival.

Umbilical Cord Blood

Umbilical cord blood transplants expand access to patients unable to find a suitable unrelated adult donor due to a traditionally lower threshold of HLA match [8, 23]. The recipient and cord blood units should at minimum be typed at HLA-A, and -B at intermediate resolution (or higher) and HLA–DRB1 typed at high resolution by DNA-based methods. The recipient and selected cord blood unit or units, in the case of a multiple cord blood transplant, should be ≥ 4/6 HLA match at HLA-A, B (intermediate resolution) and -DRB1 (high resolution).

A recently published retrospective study [24] supports the consideration of high resolution matching at HLA-A, B, C and DRB1 to maximize graft success and minimize risks of non-relapse mortality. The study also found that the impacts of HLA matching were not offset by increasing cell dose beyond the minimal recommended total nucleated cell dose of ≥ 3 × 107/kg. Future clinical studies may want to consider HLA-A, -B, -C and –DRB1 typing at high resolution by DNA-based methods, with the recipient and selected cord blood unit being a ≥ 6/8 HLA allele match at HLA-A, -B, -C and -DRB1. When multiple suitably matched, adequate cell dose cord blood units are available, additional criteria may help guide the final cord blood unit selection(s). As with mismatched unrelated donors, extended HLA testing can also support the selection of appropriate cord blood units in the context of HLA-sensitized patients to avoid the potential risk of graft failure [25-26]. There is also evidence to suggest that selecting a mismatched cord blood unit where the mismatch involves a non-inherited maternal antigen may improve survival [27-28].

BMT CTN Recommendations

The minimum recommendations for donor/cord blood and recipient HLA testing and matching (Table 1) represent the consensus opinion of the BMT CTN Steering Committee, with support and endorsement by the American Society of Histocompatibility and Immunogenetics. The recommendations have been adopted for use in future BMT CTN clinical trial development and will allow for generalization of donor/recipient compatibility across protocols.

Table 1.

Recommendations for Donor HLA assessment and matching categorization for allogeneic stem cell transplantation clinical trial protocol development.

Allogeneic Transplant Donor and Recipient HLA Matching Recommendation
Matched Sibling 6/6 HLA match
HLA-A and -B (at intermediate or higher resolution using DNA based typing)
HLA-DRB1 (at high resolution using DNA based typing)
1 Antigen Mismatched Related 7/8 HLA match
HLA-A, -B, -C (at intermediate or higher resolution using DNA based typing)
HLA-DRB1 (at high resolution using DNA based typing)
Haploidentical Related ≥4/8 HLA match
HLA-A, -B, -C (at intermediate or higher resolution using DNA based typing)
HLA-DRB1 (at high resolution using DNA based typing)
[fewer than 2 mismatches per locus]
8/8 Matched Unrelated Adult 8/8 HLA match
HLA-A, -B, -C and -DRB1 (at high resolution using DNA based typing)
7/8 Unrelated Adult 7/8 HLA match
HLA-A, -B, -C and -DRB1 (at high resolution using DNA based typing)
[7/8 donor available in most situations, do not recommend ≦6/8]
Umbilical Cord Blood ≥4/6 HLA match
HLA-A, -B (intermediate resolution or higher using DNA based typing)
and -DRB1 (at high resolution using DNA based typing)
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Acknowledgments

The authors thank all the members of the BMT CTN Steering Committee for their valuable discussions that contributed to the development and application of these guidelines in both current and future clinical trial design. Finally, the authors would like to thank Alyssa Carlson of the Center for International Blood and Marrow Transplant Research for assistance in manuscript preparation.

Financial Disclosure: Support for this manuscript was provided by grant #U10HL069294 from the National Heart, Lung, and Blood Institute and the National Cancer Institute. Any views, opinions, findings, conclusions or recommendations expressed in this manuscript are those of the author(s) and do not reflect the views or the official policy or position of the above mentioned parties.

Footnotes

*

BMT CTN clinical protocols can be accessed on the public BMT CTN website https://web.emmes.com/study/bmt2/index.html.

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References

  • 1.Pasquini MC, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides. 2013 Available at: http://www.cibmtr.org.
  • 2.Ballen KK, King RJ, Chitphakdithai P, et al. The National Marrow Donor Program 20 Years of Unrelated Donor Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant. 2008;14(9):2–7. doi: 10.1016/j.bbmt.2008.05.017. [DOI] [PubMed] [Google Scholar]
  • 3.Luznik L, O'Donnell PV, Symons HJ, et al. HLA-Haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14:641–650. doi: 10.1016/j.bbmt.2008.03.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Shaw PJ, Kan F, Woo Ahn K, Spellman SR, et al. Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors. Blood. 2010;116(19):4007–4015. doi: 10.1182/blood-2010-01-261958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Valcárcel D, Sierra J, Wang T, et al. One-antigen mismatched related versus HLA-matched unrelated donor hematopoietic stem cell transplantation in adults with acute leukemia: Center for International Blood and Marrow Transplant Research results in the era of molecular HLA typing. Biol Blood Marrow Transplant. 2011;17(5):640–648. doi: 10.1016/j.bbmt.2010.07.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Ciurea SO, de Lima M, Cano P, et al. High risk of graft failure in patients with anti-HLA antibodies undergoing haploidentical stem-cell transplantation. Transplantation. 2009;88(8):1019–1024. doi: 10.1097/TP.0b013e3181b9d710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Gragert L, Eapen M, Williams E, et al. HLA Match Likelihoods for Patients Seeking Unrelated Donor Grafts in the U.S. Registry. N Engl J Med. 2014;371:339–348. doi: 10.1056/NEJMsa1311707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Lee SJ, Klein J, Haagenson M, et al. High resolution donor-recipient HLA matching contributes to the success of unrelated donor marrow transplantation. Blood. 2007;110(13):4576–4583. doi: 10.1182/blood-2007-06-097386. [DOI] [PubMed] [Google Scholar]
  • 9.Woolfrey A, Klein JP, Haagenson M, et al. HLA-C antigen mismatch is associated with worse outcome in unrelated donor peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2011;17(6):885–892. doi: 10.1016/j.bbmt.2010.09.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Spellman SR, Eapen M, Logan BR, et al. A perspective on the selection of unrelated donors and cord blood units for transplantation. Blood. 2012;120(2):259–265. doi: 10.1182/blood-2012-03-379032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Marsh SG, Albert ED, Bodmer WF, et al. An update to HLA nomenclature, 2010. Bone Marrow Transplant. 2010;45(5):846–848. doi: 10.1038/bmt.2010.79. [DOI] [PubMed] [Google Scholar]
  • 12.Xiao Y, Lazaro AM, Masaberg C, et al. Evaluating the potential impact of mismatches outside the antigen recognition site in unrelated hematopoietic stem cell transplantation: HLA-DRB1*1454 and DRB1*140101. Tissue Antigens. 2009;73(6):595–598. doi: 10.1111/j.1399-0039.2009.01245.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Pasi A, Crocchiolo R, Bontempelli M, et al. The conundrum of HLA-DRB1*14:01/*14:54 and HLA-DRB3*02:01/*02:02 mismatches in unrelated hematopoietic SCT. Bone Marrow Transplant. 2011;46(7):916–22. doi: 10.1038/bmt.2010.246. [DOI] [PubMed] [Google Scholar]
  • 14.Fernández-Viña MA, Klein JP, Haagenson M, 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(22):4603–4610. doi: 10.1182/blood-2013-02-481945. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Crocchiolo R, Zino E, Vago L, et al. Nonpermissive HLA-DPB1 disparity is a significant independent risk factor for mortality after unrelated hematopoietic stem cell transplantation. Blood. 2009;114(7):1437–1444. doi: 10.1182/blood-2009-01-200378. [DOI] [PubMed] [Google Scholar]
  • 16.Fleischhauer K, Shaw BE, Gooley T, et al. Effect of T-cell-epitope matching at HLA-DPB1 in recipients of unrelated-donor haemopoietic-cell transplantation: a retrospective study. Lancet Oncol. 2012;13(4):366–374. doi: 10.1016/S1470-2045(12)70004-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Pidala J, Lee SJ, Ahn KW, et al. Non-permissive -DPB1 mismatch among otherwise HLA-matched donor-recipient pairs results in increased overall mortality after unrelated allogeneic hematopoietic cell transplantation: A CIBMTR/NMDP Analysis. Blood. 2014;123(8):1270–1278. [Google Scholar]
  • 18.Spellman S, Bray R, Rosen-Bronson S, et al. The detection of donor-directed, HLA-specific alloantibodies in recipients of unrelated hematopoietic cell transplantation is predictive of graft failure. Blood. 2010;115(13):2704–2708. doi: 10.1182/blood-2009-09-244525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Ciurea SO, Thall PF, Wang X, et al. Donor specific anti–HLA Abs and graft failure in matched unrelated donor hematopoietic stem cell transplantation. Blood. 2011;118(22):5957–5964. doi: 10.1182/blood-2011-06-362111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Fernandez-Viña MA, Wang T, Lee SJ, et al. Identification of a permissible HLA mismatch in hematopoietic stem cell transplantation. Blood. 2014 doi: 10.1182/blood-2013-10-532671. Published online before print January 9, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Hurley CK, Woolfrey A, Wang T, et al. The impact of HLA unidirectional mismatches on the outcome of myeloablative hematopoietic stem cell transplantation with unrelated donors. Blood. 2014 doi: 10.1182/blood-2013-01-480343. Published online before print May 1, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Kollman C, Klein JP, Spellman S, et al. The effect of donor characteristics on graft vs. host disease (GVHD) and survival after unrelated donor transplantation for hematologic malignancy. Blood. 2014 doi: 10.1182/blood-2015-08-663823. submitted. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Ballen KK, Koreth J, Chen YB, Dey BR, Spitzer TR. Selection of optimal alternative graft source: mismatched unrelated donor, umbilical cord blood, or haploidentical transplant. Blood. 2012;119(9):1972–1980. doi: 10.1182/blood-2011-11-354563. [DOI] [PubMed] [Google Scholar]
  • 24.Eapen M, Klein JP, Ruggeri A, et al. Impact of allele-level HLA matching on outcomes after myeloablative single unit umbilical cord blood transplantation for hematologic malignancy. Blood. 2014 doi: 10.1182/blood-2013-05-506253. Published online before print October 18, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Takanashi M, Atsuta Y, Fujiwara K, Kodo H, Kai S, Sato H, Kohsaki M, Azuma H, Tanaka H, Ogawa A, Nakajima K, Kato S. The impact of anti-HLA antibodies on unrelated cord blood transplantations. Blood. 2010;116(15):2839–2846. doi: 10.1182/blood-2009-10-249219. [DOI] [PubMed] [Google Scholar]
  • 26.Cutler C, Kim HT, Sun L, Sese D, Glotzbecker B, Armand P, Koreth J, Ho V, Alyea E, Ballen K, Ritz J, Soiffer RJ, Milford E, Antin JH. Donor-specific anti-HLA antibodies predict outcome in double umbilical cord blood transplantation. Blood. 2011;118(25):6691–6697. doi: 10.1182/blood-2011-05-355263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Rocha V, Spellman S, Zhang MJ, et al. Effect of HLA-matching recipients to donor noninherited maternal antigens on outcomes after mismatched umbilical cord blood transplantation for hematologic malignancy. Biol Blood Marrow Transplant. 2012;18(12):1890–1896. doi: 10.1016/j.bbmt.2012.07.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.van Rood JJ, Stevens CE, Smits J, et al. Re-exposure of cord blood to noninherited maternal HLA antigens improves transplant outcome in hematological malignancies. Proc Natl Acad Sci USA. 2009;106(47):19952–19957. doi: 10.1073/pnas.0910310106. [DOI] [PMC free article] [PubMed] [Google Scholar]

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