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1045 Combined Effect of Unrelated Donor Age and HLA Peptide-Binding Motifs (PBM) Match Status on HCT OutcomesClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 732. Allogeneic Transplantation: Disease Response and Comparative Treatment Studies: Donor and Conditioning Regimen Selection
Hematology Disease Topics & Pathways:
Research, Lymphoid Leukemias, ALL, Acute Myeloid Malignancies, AML, MDS, adult, Clinical Research, health outcomes research, Chronic Myeloid Malignancies, Diseases, registries, Lymphoid Malignancies, Myeloid Malignancies, Study Population, Human
Monday, December 11, 2023: 4:30 PM

Rohtesh S. Mehta, MD1, Effie W. Petersdorf2*, Stephen R. Spellman, MBS3,4* and Stephanie J. Lee5

1Clinical Research Division, Fred Hutchinson Cancer Center, Houston, TX
2Fred Hutchinson Cancer Research Center, Seattle, WA
3Center for International Blood and Marrow Transplant Research, Minneapolis, MN
4National Marrow Donor Program, Minneapolis, MN
5Fred Hutchinson Cancer Center, Seattle, WA

Background: HLA-mismatched unrelated donors (MMUDs) can be either matched or mismatched at protein binding motifs (PBM), while all HLA-matched donors are PBM-matched. A MMUD who is class I PBM-matched in the graft-vs-host (GVH) direction is preferred over a PBM-mismatched donor [JCO.2023;41(13):2416]. As donor age is also an important prognostic factor, we hypothesized that using a younger donor could compensate for the inferior overall survival (OS) associated with PBM-mismatches. Specifically, we tested if OS after transplantation with HLA-mismatched/PBM-matched/younger donors is similar to that with HLA-matched/older donors, and if OS is similar with HLA-mismatched/PBM-mismatched/younger donors as with HLA-mismatched/PBM-matched/older donors.

Methods: We analyzed the outcomes of patients with acute leukemia or myelodysplastic neoplasms who underwent HLA-matched or single class I MMUD HCT with a calcineurin inhibitor (CNI) for GVHD prophylaxis using a publicly available Center for International Blood and Marrow Transplant Research dataset. HLA class I MMUDs were categorized as “PBM-mismatched” if there was any GVH mismatch for the PBM, or “PBM-matched” if there was PBM-matching or only host-versus-graft mismatching. Donor age was dichotomized as “older” (> 35 years) or “younger” (< 35 years).

Six groups were compared: HLA-matched/younger donor (n=10,531), HLA-matched/older donor (n=3572), PBM-matched/younger donor (n=357), PBM-matched/older donor (n=257), PBM-mismatched/younger donor (n=616), and PBM-mismatched/older donor (n=339). The primary outcome of interest was OS.

Results: Median patient age was 50.3-56.2 years. Acute myeloid leukemia was the most common diagnosis in all groups (53-60%), most had early/intermediate disease (64-70%), most received myeloablative conditioning (60-69%) and peripheral blood (PB) graft (76-81%). A minority (18-23%) had T-cell epitope -DPB1 non-permissive GVH mismatched. All patients received CNI-based prophylaxis, without post-transplant cyclophosphamide (PTCy). Median follow-up among survivors was 48-61 months.

In multivariate analysis, transplantation from HLA-matched/younger donors was associated with superior OS relative to any other group [Figure]. The notable findings of pairwise comparisons were three-fold. First, donor age significantly impacts OS in both HLA-matched and HLA-mismatched groups, but the negative impact of older donors relative to younger donors increases with increased mismatching for the PBM (18%, 25% and 35% increased mortality in older compared to younger donors within HLA-matched, PBM-matched and PBM-mismatched groups, respectively) [Table, pairwise comparison group 1]. Secondly, younger donors appear to negate the detrimental effect of PBM-mismatching [comparison group 2]. Specifically, the PBM-matched/younger donor group had similar OS as the HLA-matched/older donor group and the PBM-mismatched/younger donor group had similar OS as the PBM-matched/older donor group. Thirdly, HLA/PBM-matching is important within the younger and the older donor groups [comparison group 3]; however, the impact of PBM-mismatching was higher with older donors (25% and 62% increased risk of mortality with PBM-matched and PBM-mismatched, respectively than HLA-matched) than with younger donors (18% and 42% increased risk of mortality with PBM-matched and PBM-mismatched than HLA-matched).

Conclusion: Older unrelated donor age and PBM-mismatching confer similarly adverse effects on OS after transplantation with CNI prophylaxis and the impacts are additive. The preferred donor is HLA-matched, followed by HLA-mismatched/PBM-matched, and HLA-mismatched/PBM-mismatched. Transplantation from younger donors with inferior matching led to comparable outcomes as the older donors with better matching - a finding which may widen the “acceptable” donor pool. The best OS is observed with HLA-matched/younger donors and the worst with PBM-mismatched/older donors. Whether the use of PTCy modifies the impact of donor age and/or HLA/PBM-mismatching needs investigation.

Disclosures: Mehta: Incyte: Research Funding; CSL Behring: Research Funding; Kadmon: Research Funding. Lee: Novartis: Other: Steering Committee member; Janssen: Other: Study medication provider; Amgen, AstraZeneca, Incyte, Kadmon, Pfizer, Syndax: Research Funding; Equillium, Kadmon, Mallinckrodt: Consultancy.

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