Breaking Human Leukocyte Antigen-related Barriers in Allogeneic Hematopoietic Cell Transplantation

The likelihood of an 8/8 HLA match varies dramatically according to race and ethnicity.¹¹  Currently, the chance of having an 8/8-matched, available donor on the NMDP Registry ranges from 29 to 79% depending on the patient’s ethnic background.¹²  However, recent analysis of the NMDP Registry down to a 5/8 mismatch level showed that the potential donor pool increased approximately 20-fold with each additional mismatch. At a match level of 5/8 or higher, the likelihood of a match was nearly 100% regardless of donor age or the patient’s ethnic background (Figure).¹⁰ 

Historically, MMUD use has been limited, as MMUD transplant using traditional calcineurin inhibitor-based GVHD prophylaxis has been associated with increased risks of GVHD, transplant-related mortality (TRM), and diminished overall survival (OS) relative to that observed for MUD.³  However, these outcomes have shifted with the introduction of post-transplant cyclophosphamide (PTCy) GVHD prophylaxis, abatacept, and other novel approaches.

PTCy in particular is a current standard-of-care that was first shown to be effective in haploidentical related transplant.¹  The success in haploidentical related transplant prompted NMDP to sponsor a prospective phase II clinical trial called 15-MMUD (NCT02793544). In this trial, adult patients received bone marrow matched at no more than 7/8 HLA alleles along with PTCy prophylaxis. A remarkable 48% of enrolled patients were Black/African American, Asian, Hispanic, or mixed race. The clinical trial far exceeded its primary endpoint of greater than 65% overall survival (OS) at one year with an OS of 76%.⁵ 

These outcomes remained very good in the analysis at three years, particularly among patients who had undergone reduced-intensity conditioning (RIC) (70% OS). In addition, OS did not significantly differ based on HLA match grade (7/8 vs. 4 to 6/8 strata).⁶ 

The 15-MMUD trial demonstrated encouraging survival but did not compare outcomes to those observed for matched unrelated donor recipients. More recently, NMDP sought to understand differences in both OS and GVHD-free, relapse-free survival (GRFS) between patients receiving 8/8 unrelated donor allografts and those receiving 7/8 allografts with PTCy prophylaxis. An abstract presented at the 65th ASH Annual Meeting & Exposition revealed an unexpected finding.

An analysis of the Center for International Blood and Marrow Transplant Research (CIBMTR) database showed no significant differences in OS or GRFS between 8/8 (N=1,517) and 7/8 (N=540) recipients at 1, 2, or 3 years post-HCT. A secondary analysis of other clinical outcomes also revealed no significant differences.⁴ 

PTCy is not the only drug that has demonstrated efficacy in the MMUD setting. The U.S. Food and Drug Administration (FDA) approved abatacept in 2021 for the prevention of aGVHD for patients aged 2 and older who receive an 8/8 MUD or 7/8 MMUD transplant. The FDA based its approval on safety and efficacy data from the multicenter phase II Abatacept 2 (ABA2) trial and findings from a real-world CIBMTR database study, which provided historical control data for comparison with the ABA2 results.

The ABA2 trial demonstrated that, when abatacept was added to standard-of-care calcineurin/methotrexate GVHD prophylaxis, patients experienced significant reductions in aGVHD and improved severe aGVHD-free survival (SGFS) in both the MUD and MMUD HCT cohorts.^7-9 

With encouraging outcomes in the initial PTCy and abatacept trials, additional clinical trials are underway, including the NMDP-sponsored ACCESS trial (NCT04904588) and the ABA3 trial (NCT04380740). The ACCESS trial is investigating the use of peripheral blood stem cells as the graft source in two adult strata and the use of bone marrow in one pediatric stratum. As with 15-MMUD, ACCESS aims to assess the safety and efficacy of PTCy as GVHD prophylaxis when using an MMUD when HLA is matched between 4/8 and 7/8 loci.

As of November 2023, approximately two-thirds of donors are matched at a level of 7/8, while one-third are matched at a level of 5/8 or 6/8. More than 50% of patients enrolled are Black/African American, Asian, Hispanic, or mixed race. The study accrued briskly, and, at the request of investigators, NMDP reopened the adult RIC stratum to add an additional 100 patients. This will allow for more granular data on outcomes between MMUDs at 7/8 versus <7/8.¹³  Both adult strata have completed accrual, while accrual for the pediatric stratum is ongoing. Results from the initial 70 RIC recipients will be available in early 2024.

NMDP is also sponsoring the OPTIMIZE trial, activated in late 2023, as a third clinical trial in its series of MMUD studies. OPTIMIZE uses a reduced dose of PTCy with the aim of improving infection-free survival while maintaining the same level of GVHD prevention.¹³ 

The ongoing ABA3 clinical trial also aims to analyze additional dosing of abatacept and its effects on the incidence and severity of chronic GHVD.

These studies have already impacted clinical practice, and the use of MMUDs has increased rapidly in just a few years. Unpublished NMDP operations data show that NMDP-facilitated mismatched transplants are up 29% in the United States year-over-year when comparing fiscal year (FY) 2023 (Oct. 1, 2022, to Sept. 30, 2023) to FY22 (Oct. 1, 2021, to Sept. 30, 2022).¹³  A secondary analysis of the BMT CTN 1702 study (NCT03904134) also demonstrated this shift, showing increased use of MMUDs for adult recipients at transplant center study sites in the United States from 2019 to 2022.¹⁴  While 7/8 MMUDs account for most of this growth, unpublished NMDP operations data also suggest a more than 40% increase in the use of 5/8 to 6/8 MMUDs from FY21 through FY23 (S. Devine, unpublished observation).

The growth in mismatched donor transplants highlights an unmet need even with the use of haploidentical related and mismatched UCB HCT. For continued progress, the hematology/oncology community must work together. Such collaboration begins in community hematology/oncology practices, with early referral for HCT consultation regardless of the likelihood of finding an 8/8-matched donor for the patient, and continues with HCT clinicians joining research efforts to enroll a diverse population of patients in these clinical trials.

Crossing the HLA barrier and improving outcomes expands access to transplant, regardless of a patient’s racial/ethnic background. Continued research into all types of HLA-mismatched HCT allows us to make progress toward creating a world where every patient can receive life-saving cellular therapy.

Dr. Devine is a full-time employee of NMDP.