The Clinical Significance of Matching for Alleles at the Low Expression HLA Loci DP, DQ and DRB3/4/5 in Unrelated Hematopoietic Stem Cell Transplantation
Authors: Fernandez-Vina Marcelo , Klein John , Haagenson Michael D , Spellman Stephen R , Lee Stephanie J. , Anasetti Claudio , Baxter-Lowe Lee Ann , Cano Pedro , Flomenberg Neal , Horowitz Mary M. , Hurley Carolyn K , Oudshoorn Machteld , Petersdorf Effie W , Setterholm Michelle , Champlin Richard , De Lima Marcos 
Published: April 2020

Abstract
Single or multiple mismatches at HLA-A, B, C, and DRB1 have a detrimental effect on outcome of bone marrow transplantation using unrelated donors. Most of these loci encode for products that are expressed with high density on the surface of many cell types. In contrast, HLA-DRB3, DRB4, DRB5, DQ, DP encode for class II products that are expressed at low levels (LEL); some investigations suggest that mismatches in some of these loci have a minimal impact on outcome. We hypothesized that the influence of the LEL is weak and cumulative and only demonstrable in combination with mismatches (MM) in other loci. National Marrow Donor Program data from 3853 US transplants performed from 1988–2003 were analyzed to investigate this hypothesis. Patients had AML, ALL, CML or MDS and received myeloablative conditioning regimens. Most patients received calcineurin-based GvHD prophylaxis with T-replete grafts (79%). Nearly all received marrow grafts (94%). Median follow-up was 6 years. HLA loci were typed retrospectively by high resolution methods. MM was defined as the difference in the antigen recognition site of the HLA molecule of the patient and donor and computed in GvH and HvG vector, the highest vector mismatch was assigned as overall mismatch for a locus. Because multiple comparisons were made, only p-values &lt;0.01 were considered significant. All analyses were adjusted for patient and transplant characteristics. Transplants were stratified according to match grade in the high expression loci (HEL) as 8/8, 7/8 and &lt;7/8; the MM in LEL were computed as 0, 1, 2 and 3 or more MM. A greater degree of mismatch in the HEL was associated with a greater degree of MM in the LEL (p&lt;0.0001); 3 or more MM in the LEL were found in 6, 11 and 21 percent of the patients receiving transplants matched in 8/8, 7/8 and &lt;7/8 HEL groups, respectively. In the 7/8 group, multiple mismatches in the LEL loci were significantly more common in the patients presenting a mismatch in HLA-DRB1 than in the HLA class I loci (p &lt;0.0001); 3 or more MM in the LEL loci were found in 33 percent of the patients presenting one mismatch in HLA-DRB1 while only 8 percent of the patients with one mismatch in either HLA-A, B or C loci presented 3 or more MM in the LEL loci.
RESULTS: In the 8/8 HEL group, mismatches in LEL did not significantly associate with mortality. In the 7/8 HEL group, patients with 3 or more MM in LEL in the GvH vector had a significantly higher risk for mortality and treatment related mortality than the subgroups with 0MM (RR=1.44; 95% Confidence Interval (CI):1.07–1.94; p=0.015; and RR=1.63; CI:1.17–2.28; p=0.004) and 1MM (RR=1.46; CI:1.12–1.90; p=0.005; and RR=1.50; CI:1.12–2.01; p=0.006) in LEL, and a similar but not significant trend was observed when compared to the 2MM subgroup. No single LEL appeared to have a more pronounced effect on clinical outcome, when mismatched, versus the other LEL.
CONCLUSION: The presence of 3 or more mismatches at LEL may adversely affect clinical outcome after 7/8 matched transplantation. Mismatches at HLA-DRB1 were associated with the occurrence of additional LEL mismatches. Prospective evaluation of matching for HLA-DRB3, 4, 5, DQ and DP loci may be warranted to reduce post-transplant risks in donor recipient pairs matched for 7/8 HEL.