HLA Association with Hematopoietic Stem Cell Transplantation Outcome: The Number of Mismatches at HLA-A, -B, -C, -DRB1, or -DQB1 Is Strongly Associated with Overall Survival

Abstract

HLA matching between the donor and recipient improves the success of unrelated hematopoietic stem cell transplantation (HSCT). Because many patients in need of an unrelated transplant have only donors with mismatch, information is needed to evaluate the limits of HLA mismatching. We examined the association of survival, acute graft-versus-host disease (aGVHD) and relapse with HLA-A, -B, -C, -DRB, -DQB1, and -DPB1 mismatching in 334 patients coming from 12 French transplant centers and who received a non-T cell-depleted bone marrow graft from an unrelated donor. All patients were prepared with the use of myeloablative conditioning regimens. Our analyses demonstrate negative effects of HLA mismatching for either HLA-A, -B, -C, -DRB1, or -DQB1 loci on survival. Multivariate Cox analyses showed that a single mismatch was associated with a significant decrement in survival (P=.046, hazard ratio [HR]=1.41, confidence interval [CI] 95% 1.1-1.98). The presence of multiple mismatches was worse for survival (P=.003, HR=1.91, CI 95% 1.26-2.91) and severe aGVHD (grade III-IV) (P=.002, HR=2.51, CI95% 1.41-4.46). The cumulative incidences of aGVHD and relapse in those HLA-A, -B, -C, -DRB1, and -DQB1 identical pairs with 2, 1, or 0 DPB1 incompatibilities were 63%, 50%, and 51%, and 12%, 27%, and 20%, respectively, but these differences were not statistically significant. Similar differences of aGVHD and relapse, but not statistically significant, were observed in those HLA-A, -B, -C, -DRB1, and -DQB1 identical pairs with DPB1 disparities classified into permissive or nonpermissive mismatches according to Zino's classification based on a hierarchy of the immunogenicity of the HLA-DP molecules. "Missing killer cell immunoglobulin-like receptor (KIR) ligand" evaluated on the presence of HLA-C1, -C2, and Bw4 groups in the recipients was not associated with aGVHD, survival, and relapse in this cohort of non-T cell-depleted HSCT.

Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

“…[3][4][5] Increasing the degree of HLA matching between the donor and the recipient is one of the most important paths to decrease the risk for post-HCT complications, and for GVHD in particular. 6,7 That is why, in the absence of an HLA-identical sibling donor, an 8/8 or preferably a 10/10 allele-matched (HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1) unrelated donor is the best alternative option. But even under these stringent matching conditions, the incidence of GVHD remains quite high (ie, 50% of patients develop grade II-IV acute GVHD, up to 35% grade III-IV acute GVHD, and 40% to 50% chronic GVHD).…”

HLA matching affects clinical outcome of adult patients undergoing haematopoietic SCT from unrelated donors: a study from the Gruppo Italiano Trapianto di Midollo Osseo and Italian Bone Marrow Donor Registry

“…2 As the '10/10 matched' (that is, high-resolution identity at loci HLA-A, -B, -C, -DRB1 and -DQB1) donor is not always available, some extent of HLA mismatch (Mm) can be accepted; however, there is still some controversy about the precise impact of HLA mismatching on HSCT outcomes, because published reports indicate discordant results about the relative importance of loci involved. [3][4][5][6][7][8][9][10][11][12][13][14] A recent study by Lee et al 3 indicated that both class I and class II Mms affect survival, suggesting that each HLA Mm is associated with an additional unadjusted survival impairment of 9-10%. The same study did not find a significant role played by HLA-DP or -DQ on survival.…”

In a 12-allele analysis HLA-DPB1 matching is associated with improved OS in leukaemic and myelodysplastic patients receiving myeloablative T-cell-depleted PBSCT from unrelated donors

“…1,2 Center for International Blood and Marrow Transplant Research data, predominantly in T-replete transplants, shows a detrimental effect of mismatching (mm) on OS that is dependent on disease stage. 1 In contrast, T-depleted transplants may be intrinsically more permissive of mismatches at all stages, especially when reduced-intensity conditioning (RIC) is employed.…”