Recent research on mismatched unrelated donor (MMUD) transplant is pivotal to combating disparities in access to allogeneic hematopoietic cell transplant (HCT). Research now suggests that all patients who have a disease that requires HCT may, in fact, have access to a suitable donor.1

The road to HCT and other cellular therapies is quite complex, with multiple points along the patient journey that can act to widen gaps in health equity. Barriers to care exist at the patient, community hematology/oncology practice, and transplant center levels. Factors like race and ethnicity, socioeconomic status, insurance coverage, and caregiver availability all impact overall access to HCT.2  

The National Marrow Donor Program (NMDP)/Be The Match provides access to more than 39 million donors through the Be The Match Registry and has made significant progress in ensuring a donor for all patients who could benefit from HCT.3

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Matched unrelated donors (MUDs) are not available for everyone, particularly for ethnically diverse patient populations. Though the registry provides access to the most diverse global listing of unrelated donors, the chance of having a MUD varies greatly by race/ethnicity, from 79% for non-Hispanic White patients to 29% for Black/African-American patients.3

When a matched related donor or MUD transplant is not possible, haploidentical, MMUD, or umbilical cord blood transplants become essential alternatives for patients who require HCT. Haploidentical transplant enables more people who are ethnically diverse to proceed to HCT, but research suggests the risk of graft-vs-host disease (GVHD) and overall mortality are higher with haploidentical transplants than with MUD transplants.5

Given the successful application of post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis in haploidentical HCT, NMDP/Be The Match and its research arm, the Center for International Blood and Marrow Transplant Research (CIBMTR), conducted a trial of PTCy as GVHD prophylaxis in the MMUD transplant setting.6,7

The multicenter, phase 2 trial (ClinicalTrials.gov Identifier: NCT02793544) is called 15-MMUD. Conducted between December 2016 and March 2019 at 11 transplant centers, the trial was designed to assess the safety and efficacy of using bone marrow (BM) from MMUDs in combination with PTCy-based GVHD prophylaxis.8

The trial enrolled 80 adults with hematologic malignancies who had MMUDs. The donor-recipient pairs were matched at 4/8 to 7/8 loci (HLA-A, -B, -C, and DRB1). The 80 patients were divided evenly into 2 groups receiving either myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC) prior to MMUD BM transplant.

Despite the historically low enrollment of ethnically diverse patients in clinical trials,9 48% of patients enrolled on 15-MMUD were from racial or ethnic minority groups.

The study met its primary endpoint of exceeding 65% overall survival (OS) at 1 year, with a 1-year OS rate of 76%. Researchers ultimately concluded that using MMUD in combination with PTCy was safe and effective and could significantly expand access and even expedite time to HCT for ethnically diverse populations.8

Three-year outcomes for this cohort were reported at the European Group for Blood and Marrow Transplantation Annual Meeting in March 2022 and have remained strong (Table 1).10 The 3-year OS rates were similar between patients receiving MAC (62%) and those receiving RIC (70%).

Table 1: Outcomes at 3 years for patients enrolled on 15-MMUD. Provided by Dr Jeffery J. Auletta.

In the RIC cohort, the nonrelapse mortality (NRM) rate was 15%, and the relapse rate was 29%. Rates of chronic GVHD were low, at 20% for all grades and 5% for severe chronic GVHD.

In the MAC cohort, the relapse rate was 51%, likely reflecting the fact that more patients in the MAC group had leukemia or myelodysplasia. The NRM rate was 10%. Chronic GVHD occurred in 38% of the cohort, with 13% of patients having severe chronic GVHD.

Of note, the degree of HLA mismatching did not appear to impact OS. The 3-year OS rate was 63% in patients with a 7/8 match and 71% in patients with less than a 7/8 match (P =.733; Figure 1).10

Figure 1: Probability of overall survival over time by the degree of HLA mismatching. Provided by Dr Jeffery J. Auletta.

Given these favorable 3-year outcomes, 15-MMUD provides early reassurance that access to transplant can be safely expanded to patients with no 7/8 or 8/8 matched donors. In fact, recent modeling of the Be The Match Registry shows that including MMUD donors down to a 5/8 HLA match expands access to nearly 100% of patients in need of HCT.11

There is a need for a multifaceted approach when looking to close gaps in access to HCT. First, we continue to increase diversity on the registry. Community outreach programs in diverse communities aim to provide education and encourage people of diverse ethnic backgrounds to join the registry.

Equally important is leading and performing transformational research like the 15-MMUD trial. To this end, researchers are conducting the ACCESS trial (ClinicalTrials.gov Identifier: NCT04904588). The aim of this trial is to define the safety and efficacy of using peripheral blood stem cells (PBSCs) from MMUD in adults with hematologic malignancies receiving MAC and RIC, as well as BM from MMUD in pediatric patients with hematologic malignancies receiving MAC.12

The ACCESS trial marks the first time that researchers are studying the use of MMUD in pediatric patients. Findings from the trial could potentially expand the use of MMUD hematopoietic graft sources in adults as well.

In summary, the MMUD platform has the potential to transform outcomes of allogeneic HCT by providing donors for all patients, particularly those who are ethnically diverse. The NMDP/Be The Match and CIBMTR research programs are committed to evaluating novel treatment strategies that improve HCT outcomes.

Disclosures: Jeffery J. Auletta, MD, serves as senior vice president of patient outcomes and experience at NMDP/Be The Match and chief scientific director for CIBMTR. Please refer to the original studies referenced for a full list of disclosures.

References

  1. Chowdhury AS, Maiers M, Spellman S, Bolon Y-T, Devine SM. Unrelated donor registry HLA match likelihoods in the mismatched setting. Transplant Cell Ther. 2022;28(3):S261-S262. doi:10.1016/s2666-6367(22)00497-3
  2. Hong S, Majhail NS. Increasing access to allotransplants in the United States: The impact of race, geography, and socioeconomics. Hematology. 2021;2021(1):275-280. doi:10.1182/hematology.2021000259
  3. National Marrow Donor Program (NMDP)/Be the Match. Be the Match Registry. Accessed July 25, 2022. https://bethematch.org/about-us/how-we-help-patients/be-the-match-registry/
  4. National Marrow Donor Program (NMDP)/Be the Match. How does a patient’s ethnic background affect matching? Published February 2021. Accessed June 28, 2022. https://bethematch.org/transplant-basics/matching-patients-with-donors/how-does-a-patients-ethnic-background-affect-matching/
  5. Gooptu M, Romee R, St. Martin A, et al. HLA haploidentical versus matched unrelated donor transplants with post-transplant cyclophosphamide based prophylaxis. Blood. 2021;138(3):273-282. doi:10.1182/blood.2021011281
  6. 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(6):641-650. doi:10.1016/j.bbmt.2008.03.005
  7. Nagler A, Kanate AS, Labopin M, et al. Post-transplant cyclophosphamide versus anti-thymocyte globulin for graft-versus-host disease prevention in haploidentical transplantation for adult acute lymphoblastic leukemia. Haematologica. 2021;106(6):1591-1598. doi:10.3324/haematol.2020.247296
  8. 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
  9. Horowitz MM, Kaur M, Mendizabal A, et al. Racial and ethnic diversity on Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trials — We can do better. Transplant Cell Ther. 2022;28(3):S71. doi:10.1016/s2666-6367(22)00244-5
  10. National Marrow Donor Program (NMDP)/Be the Match Network. 3-year outcomes remain very good in mismatched unrelated donor HCT patients, highlighting potential to expand access. Accessed July 5, 2022. https://network.bethematchclinical.org/research/research-and-publications/3-year-outcomes-remain-very-good-in-mismatched-unrelated-donor-hct-patients–highlighting-potential-to-expand-access/
  11. National Marrow Donor Program (NMDP)/Be the Match Clinical Trials Search & Support. Allogeneic (cells from a donor) blood or marrow transplant (BMT) with an unrelated mismatched donor and post-transplant cyclophosphamide (PTCy) to treat blood cancers in children and adults. Accessed June 28, 2022. https://www.ctsearchsupport.org/clinical-trials/hla-mismatched-unrelated-donor-hematopoietic-cell-transplantation-with-post-transplantation-cyclophosphamide
  12. 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

Topics:

General Hematology Health Disparity Hematopoietic Stem Cell Transplantation