It is not a secret in the hematology/oncology field that the likelihood of finding a fully matched unrelated donor for a patient who needs allogeneic hematopoietic cell transplantation (HCT) varies greatly depending on a patient’s ethnic background. [1] Historically, a patient who is ethnically diverse has been at a disadvantage. However, when donor registry models are expanded to include mismatched unrelated donors (MMUD) down to a 5/8 human leukocyte antigen (HLA) match (considering HLA-A, B, C and DRB1), researchers found it expands access to virtually 100% of patients who need allogeneic HCT. [2]

This is significant because innovative transplant approaches that permit the safe and effective use of MMUD—such as advances in graft-versus-host disease (GVHD) prophylaxis—hold the potential to erase the gap in donor availability and deliver HCT to all patient populations.

Be The Match Registry modeling
Researchers from the CIBMTR (Center for International Blood and Marrow Transplant Research) used registry modeling techniques previously published in the New England Journal of Medicine to understand how less stringent match levels could impact the likelihood of finding an available donor. [1]

The researchers considered high-resolution matching at 8/8, 7/8, 6/8, and 5/8 HLA allele levels using 2020 donor registry population characteristics.

Finding a fully (8/8) matched, available donor on the Be The Match Registry varies greatly depending on a patient’s racial or ethnic background. For example, when considering donors of all ages on the registry, Black and African American patients have only a 29% chance of finding an 8/8 matched, available donor. Those who are European Caucasian have a 79% chance.

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Those numbers decrease further when looking at available donors aged 35 years and younger. This is the donor age group HCT physician request most often as research has shown patient outcomes are better with younger donors. The researchers found that 8/8 match likelihoods for 21 detailed race and ethnic groups ranged from 16% for patients who are African American to 74% for those who are European Caucasian with donors 35 years old and younger.

However, as the HLA match stringency decreased to include less than 8/8 matches, the likelihood of an available match increased. When allowing for HLA-match levels down to 5/8, this likelihood increased to more than 99% for all race and ethnic groups. This was also the case when restricting the donor pool to those 35 years old and younger.

The race and ethnic groups evaluated in the analysis included African American, African, South Asian Indian, American Indian – South or Central American, Alaska Native or Aleut, North American Indian, Caribbean Black, Caribbean Hispanic, Caribbean Indian, Filipino, Hawaiian or other Pacific Islander, Japanese, Korean, Middle Eastern or North Coast of Africa, Mexican or Chicano, European Caucasian, Chinese, Hispanic – South or Central American, Black – South or Central American, Southeast Asian, and Vietnamese, as previously defined by Gragert et al. [1,2]

Clinical trials highlight the safe, effective use of MMUDs
The use of MMUDs in allogeneic HCT is possible because of innovative transplant approaches, such as the advances researchers are making in GVHD prophylaxis following allogeneic HCT.

For example, recent clinical trials have highlighted the safe, effective use of MMUD in the setting of post-transplant cyclophosphamide (PTCy) and other novel GVHD prophylaxis prevention strategies.

The National Marrow Donor Program/Be The Match sponsored a multicenter phase II study (NCT02793544) of PTCy as GVHD prophylaxis in the MMUD adult transplant setting. The trial, called 15-MMUD, sought to assess the safety and efficacy of using bone marrow from MMUDs in combination with PTCy-based GVHD prophylaxis.

The study exceeded its primary endpoint of more than 65% overall survival (OS) at 1 year, with 76% OS observed for all patients. In addition, the OS did not differ among those patients who received 7/8 or less than 7/8 (39% of patients on trial) matched donors. Notably, 48% of patients in the 15-MMUD study were ethnically diverse. These data suggest that the PTCy GVHD prophylaxis strategy can be safe and effective in the setting of multiple mismatches and validate that MMUD can expand access for patients from diverse populations. [3]

The success of the 15-MMUD study supported the development of the ACCESS clinical trial (NCT04904588) that is currently enrolling patients. The ACCESS trial is assessing the safety and efficacy of PTCy as GVHD prophylaxis when using a MMUD HLA-matched between 4 and 7/8. Adult patients receive peripheral blood stem cells as the graft source, and pediatric patients receive bone marrow. Results of the trial are anticipated in early 2024.

PTCy is not the only promising approach for expanding use of MMUD. The U.S. Food and Drug Administration (FDA) approved abatacept for the prevention of acute GVHD for patients aged 2 and older who receive an 8/8 or 7/8 MMUD transplant. [4] It is the first drug the FDA approved for acute GVHD prevention. The FDA based its approval on the safety and efficacy data from the Abatacept 2 (ABA2) multi-center phase II clinical trial as well as a CIBMTR real-world database study that supported the ABA2 results. [5][6]

In this clinical trial and analysis, the researchers found that when abatacept was added to standard of care acute GVHD prophylaxis, patients experienced significant reductions in acute GVHD and improvements in severe acute GVHD-free survival. Its effects were particularly striking for those patients who received 7/8 MMUD HCT who had overall survival outcomes similar to 8/8 matched patients receiving standard of care GVHD prophylaxis. [6,7] However, use of abatacept did not result in lower rates of chronic GVHD compared to the standard of care treatment. A follow-on trial, ABA3 (NCT04380740), is evaluating the effectiveness of extended abatacept treatment (4 doses vs 8 doses) to reduce chronic GVHD risk.

Thanks to advances in strategies to prevent GVHD in the HLA-mismatched setting, donor availability is becoming a smaller barrier to transplant, particularly for those patients who are ethnically diverse. With registry modeling demonstrating it is possible to find a donor for virtually all, the hematology/oncology community must unite to ensure patients receive a timely referral for transplant consultation and all appropriate patients are given the option of enrolling in a clinical trial.

Taking these steps will help the field advance quickly, increase access to those who are ethnically diverse, and provide HCT to all patients who need this life-saving therapy.

Clinical trials
HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation With Post-Transplantation Cyclophosphamide (ACCESS) – NCT04904588
Extended vs Short-term Abatacept Dosing for Graft Versus Host Disease Prophylaxis (ABA3) – NCT04380740

[1] Gragert L, Eapen M, Williams E, et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med. 2014;371:339-348. doi: 10.1056/NEJMsa1311707.[Article]
[2] Chowdhury AS, Maiers M, Spellman S, Bolon Y-T, Devine SM. Unrelated donor registry HLA match likelihoods in the mismatched setting. Transplantation and Cellular Therapy. 2022;28(3):S261-S262. doi:10.1016/s2666-6367(22)00497-3. [Article]
[3] Shaw BE, Jimenez-Jimenez AM, Burns LJ, et al. National Marrow Donor Program-sponsored multicenter, phase II trial of HLA-mismatched unrelated donor bone marrow transplantation using post-transplant cyclophosphamide. J Clin Oncol. 2021;39(18):1971-1982. doi: 10.1200/JCO.20.03502. [Article]
[4] Voelker R. Drug approved to prevent graft-vs-host disease. 2022;327(5):417. doi: 10.1001/jama.2021.24966. [Article]
[5] Watkins B, Qayed M, McCracken C, et al. Phase II trial of costimulation blockade with abatacept for prevention of acute GVHD. J Clin Oncol. 2021;39(17):1865-1877. doi: 10.1200/JCO.20.01086.[Article]
[6] Kean LS, Burns LJ, Kou TD, et al. Improved overall survival of patients treated with abatacept in combination with a calcineurin inhibitor and methotrexate following 7/8 HLA-matched unrelated allogeneic hematopoietic stem cell transplantation: Analysis of the Center for International Blood and Marrow Transplant research database. Blood. 2021;138 (Supplement 1):3912. doi: 0.1182/blood-2021-150742. [Article]
[7] Qayed M, Watkins B, Gillespie S, et al. Abatacept for GVHD prophylaxis can reduce racial disparities by abrogating the impact of mismatching in unrelated donor stem cell transplantation. Blood Adv. 2022;6(3):746–749. doi: 10.1182/bloodadvances.2021005208. [Article]

Featured image: Doctor discussing treatment options with a patient. Photo courtesy: © 2019 – 2022 Fotolia/Adobe. used with permission.

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