HLA-DRB1 Mismatch Research Articles

Impact of human leukocyte antigen mismatch on outcomes after unrelated bone marrow transplantation in paediatric patients: A retrospective analysis by the JSTCT HLA working group.

The impact of human leukocyte antigen (HLA) mismatching at the HLA-A, -B, -C, and -DRB1 loci after unrelated bone marrow transplantation in paediatric patients with haematological malignancies has not been fully examined. Here, we analysed patients with haematological malignancies (all aged ≤15 years; n=1330) who underwent a first unrelated bone marrow transplantation between 1993 and 2017 in Japan. The results show that although an HLA mismatch was significantly associated with a low relapse rate, it was also associated with higher non-relapse mortality. There was a significant association between HLA mismatch and low overall survival. Locus mismatch analysis revealed that, as in adults, an HLA-C mismatch had a significant negative impact on survival; however, in paediatric patients, an HLA-DRB1 mismatch did not have a negative impact, although these HLA mismatch effects are weakened in recent cases. Taken together, the results suggest that an HLA-matched donor should be the first candidate for paediatric patients; however, for patients without a matched sibling or matched unrelated donor, we can select an unrelated donor with a mismatch at HLA-DRB1 if available.

HLA-B leader and survivorship after HLA-mismatched unrelated donor transplantation

AbstractHematopoietic cell transplantation (HCT) from HLA-mismatched unrelated donors can cure life-threatening blood disorders, but its success is limited by graft-versus-host disease (GVHD). HLA-B leaders encode methionine (M) or threonine (T) at position 2 and give rise to TT, MT, or MM genotypes. The dimorphic HLA-B leader informs GVHD risk in HLA-B–mismatched HCT. If the leader influences outcome in other HLA-mismatched transplant settings, the success of HCT could be improved for future patients. We determined leader genotypes for 10 415 patients receiving a transplant between 1988 and 2016 from unrelated donors with one HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatch. Multivariate regression methods were used to evaluate risks associated with patient leader genotype according to the mismatched HLA locus and with HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatching according to patient leader genotype. The impact of the patient leader genotype on acute GVHD and mortality varied across different mismatched HLA loci. Nonrelapse mortality was higher among HLA-DQB1–mismatched MM patients compared with HLA-DQB1–mismatched TT patients (hazard ratio, 1.35; P = .01). Grades III to IV GVHD risk was higher among HLA-DRB1–mismatched MM or MT patients compared with HLA-DRB1–mismatched TT patients (odds ratio, 2.52 and 1.51, respectively). Patients tolerated a single HLA-DQB1 mismatch better than mismatches at other loci. Outcome after HLA-mismatched transplantation depends on the HLA-B leader dimorphism and the mismatched HLA locus. The patient's leader variant provides new information on the limits of HLA mismatching. The success of HLA-mismatched unrelated transplantation might be enhanced through the judicious selection of mismatched donors for a patient's leader genotype.

Improving Donor Selection for Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide through Selective HLA-Mis/Matching

Background HLA-haploidentical (haplo) blood or marrow transplantation (BMT) with post-transplantation cyclophosphamide (PTCy) is widely used, but few factors that inform donor selection have been identified. Based on prior observations for HLA-B leader (EW Petersdorf et al. Lancet Haematol 2020), HLA-DRB1 (YL Kasamon et al. BBMT 2010), and HLA-DPB1 (SR Solomon et al. BBMT 2018), we hypothesized that mismatching at individual HLA loci may influence BMT outcomes, but single and additive HLA gene effects have not been evaluated systematically in the context of haploBMT with PTCy. Methods The Center for International Blood and Marrow Transplant Research (CIBMTR) identified 1,434 patients who underwent T-cell-replete haploBMT with PTCy for acute leukemia or myelodysplastic syndrome (MDS) between 2008-2017. Multivariable models assessed transplant outcomes associated with 3 HLA-factors: (1) B-leader dimorphism (MM, MT, TT) matching; (2) HLA-DRB1 mismatching in the graft-versus-host (GVH) direction; and (3) nonpermissive HLA-DPB1 mismatching in the GVH direction using the T-cell epitope-3 model, which classifies HLA-DPB1 mismatches into permissive or non-permissive. All final models contained the HLA factors and adjusted for other significant clinical covariates at p<.05 in univariate analysis. P-values were not adjusted for multiple testing. Results Diagnoses were 58% AML, 23% ALL, 19% MDS. 22% of AML patients were in advanced disease stage (relevant analyses were stratified for disease stage for both acute leukemia and MDS). Median recipient age was 54 (range 1-78) years. Median follow up among survivors was 12 (range 2-119) months. Marrow was the graft source in 43% of recipients. Myeloablative conditioning was used in 45% of recipients. Fifty percent of recipients had hematopoietic cell transplantation-comorbidity index (HCT-CI) scores of ≥3. HLA-DP typing was missing in 52% of cases and thus all models had a "missing" category for HLA-DP. Mismatching in the GVH direction at HLA-A, HLA-C, or HLA-DQ was not associated with study outcomes [overall survival (OS), disease-free survival (DFS), relapse, nonrelapse mortality (NRM), or grade II-IV acute, grade III-IV acute, or chronic graft-versus-host disease (gr2-4a or cGVHD)]. When compared to leader-matched patients, HLA-B leader-mismatching was associated with worse OS and DFS (hazard ratio [HR] 1.25 [95% CI, 1.09 to 1.44]; P=.002, and HR 1.18 [95% CI, 1.03 to 1.34]; P=.01, respectively), and higher risk of NRM (HR 1.38 [95% CI, 1.10 to 1.74]; P=.005), but was not associated gr2-4a or cGVHD, or relapse. In contrast, when compared to matching at HLA-DRB1, the presence of any GVH direction mismatch at HLA-DRB1 was associated with improved DFS (HR 0.80 [95% CI, 0.68 to 0.94]; P=.007) and lower risk of relapse (HR 0.69 [95% CI, 0.56 to 0.86]; P=.0008), but with no effect on OS, gr2-4a or cGVHD, or NRM. Similarly, any nonpermissive GVH mismatching at HLA-DPB1 was also associated with improved DFS (HR 0.72 [95% CI, 0.55-0.94], p=.015) and OS (HR 0.59 [95% CI, 0.43-0.82], p=.002), with a tendency towards lower relapse (HR 0.75 [95% CI, 0.54-1.05], p=.09), but with no effect on gr2-4a or cGVHD, or NRM. When combining the effects of leader matching at HLA-B and mismatching at HLA-DRB1 there was an additive improvement in both DFS and OS (Figure 1 A and B) with significantly lower NRM (p=0.03) and relapse (p=0.008) when compared to other groups. Within this unselected large cohort, favorable haplo donors based on B-leader matching and HLA-DRB1 mismatching were used for 48.5% of recipients and had improved DFS (HR 0.68 [95% CI, 0.52 to 0.88], p=.004) when compared to B-leader mismatched and HLA-DRB1 matched pairs, suggesting that with intentional selection of donors based on these factors, even more could receive a favorable combination. Conclusion HLA-B leader mismatching is a risk factor for NRM and worse OS and DFS, whereas either HLA-DRB1 or nonpermissive HLA-DPB1 mismatch is associated with reduced relapse and improved DFS, after haploBMT with PTCy. PTCy dissociates the graft-versus-leukemia effect of HLA-DRB1 and nonpermissive HLA-DPB1 mismatching from GVHD. The best outcomes after haploBMT with PTCy are seen when a donor is HLA-B leader matched and HLA-DRB1 mismatched. When there is more than one potential haplo donor for an acute leukemia or MDS patient, selection based on HLA considerations may improve DFS and OS. Figure Disclosures Shaw: Orca Bio: Consultancy. Lee:Takeda: Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding; Incyte: Consultancy, Research Funding; Syndax: Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Research Funding; Kadmon: Research Funding.

Impact of HLA allele mismatch at HLA-A, -B, -C, -DRB1, and -DQB1 on outcomes in haploidentical stem cell transplantation.

The impact of human leukocyte antigen (HLA) allele mismatch on transplant outcomes in haploidentical stem cell transplantation (haplo-SCT) has not been established. We retrospectively studied 595 patients with hematologic malignancy who received haplo-SCT. The impact of multiple HLA allele mismatches (HLA-A, -B, -C, -DRB1, and -DQB1) and each HLA allele mismatch on transplant outcomes was analyzed. Greater number of HLA allele disparity does not appear worsen outcome. As for each HLA locus, HLA-A mismatch correlated with decreased rate of platelet engraftment (HR 0.740, P = .003); HLA-B mismatch independently correlated with decreased relapse rate (HR 0.494, P = .032) and improved disease-free survival and overall survival (HR 0.514, P = .003; HR 0.494, P = .002, respectively); HLA-C mismatch appeared to be protective for transplant-related mortality (TRM) (HR 0.567, P = .039); HLA-DRB1 mismatch was associated with increased cumulative incidence of grade II-IV acute graft-vs.-host disease (GVHD) (HR 1.942, P = .002). No associations of any HLA mismatch with delayed neutrophil engraftment or increased cumulative incidence of chronic GVHD were observed. Our data indicated that high degree of HLA allele mismatches did not adversely affect transplant outcomes in haplo-SCT and each HLA allele mismatch had different effect.

Impact of HLA-Mismatch in Unrelated Donor Hematopoietic Stem Cell Transplantation: A Meta-Analysis.

The magnitude of risk associated with 9/10 mismatched unrelated donor (MMURD) hematopoietic stem cell transplantation and that of mismatches at the individual HLA loci remain unclear. We performed a meta-analysis to assess the difference in clinical outcomes between matched unrelated donor (MUD) and MMURD transplantation. A comprehensive search of Medline and Embase for manuscripts regarding transplantation outcomes in primarily adult patients with hematologic malignancies was performed. The pooled effect estimates were calculated using DerSimonian-Laird random effects models. A total of 13 studies were included, reporting on 13,446 transplants. 9/10 MMURD transplantation was associated with worse overall survival compared to 10/10 MUD transplantation (pooled HR: 1.27, 95% CI: 1.12-1.45; n = 7 studies). Mismatch at HLA-A, -B, or -C was associated with significantly worse overall survival compared to MUD transplantation, while there was no significant difference associated with -DQ or -DPB1 mismatch. Inferior survival associated with HLA-DRB1 mismatch could not be ruled out. Data on acute and chronic graft-versus-host disease were scarce but favored MUD transplantation. In summary, this meta-analysis of the available literature favored MUD over MMURD transplantation in hematologic malignancies and further quantifies the risks associated with specific HLA-allele mismatches. Am. J. Hematol. 91:551-555, 2016. © 2016 Wiley Periodicals, Inc.

HLA and Kir Mismatch Transplant Affect Cytopenia Beyond Day 28 after Thalassemia Transplant: A Primary Manifestation of Chronic Graft Versus Host Disease

Background Cytopenia beyond day 28 post-transplant (CB-28PT) following hematopoietic stem cell transplantation (HSCT) with β-thalassemia major (TM) rarely was reported. The exact mechanism for the development of CB-28PT is not well known.Aim To find out causes of CB-28PT cytopenia.Method We retrospectively analyzed data (HLA mismatch status, HLA antibody status of patients, KIR gene mismatch status, KIR-ligand matching status, donor/patient CMV status, donor/patient age and sex) of 93 TM patients underwent HLA 8/8 fully matched or 7/8 matched unrelated donor HSCT. All the patients used sole NF-08-TM protocol with median follow-up time of 19 (r: 2-44) months.Results Results show a significant association between DRB1 mismatch and CB-28PT (P = 0.012). In addition, presence of Class I HLA antibody in the patient’s sera seems increase the chance of CB-28PT. Finally, the matching between inhibitory KIR2DL1 and their corresponding ligand HLA-C2 has a protective effect for CB-28PT.Conclusion We propose that CB-28PT may be a primary manifestation of cGVHD in pediatric TM patients undergoing HSCT positive influenced by HLA DRB1 mismatch, HLA class I antibody and negatively affected by KIR-ligand match. DisclosuresNo relevant conflicts of interest to declare.

Study of the cytokine polymorphisms in correlation to rejection and graft survival in renal allograft donors and recipients from a homogenous Saudi population

ObjectivesAllograft outcome can be improved with the discovery of risk factors that influence adverse events and may allow individualization of patients' treatment. Rejection is the main hurdle to successful transplantation and the immune response is the key effecter to rejection development. Hence, the major objective of the present study was to assess the relationship between single nucleotide polymorphisms (SNPs) in 5 cytokine genes, HLA mismatch and graft outcome in a cohort of 100 Saudi kidney transplant recipients and 100 living related donors at a single transplant center. Materials & methodsGenotyping of the following positions: TNFA (−308G/A), TGFB1 (codon 10T/C, codon 25C/G), IL-10 (−1082G/A, −819C/T, −592C/A), IL-6 (−174C/G), and IFNG (+874T/A) were performed. ResultsThe majority of the donors whose recipients presented with either cellular or antibody mediated graft rejection (90% and 100%) respectively were found to be significantly (p=0.0351) associated with intermediate or high IL-10 producing haplotypes, compared to those with stable grafts (58.66%). Haplotypes linked with lower IL-10 production were not detected in the donors or their recipients with antibody mediated graft rejection compared to donors with stable graft (41.33%). The distribution of donor IL-10-1082 haplotypes (GG, GA, AA) showed a statistically significant association of IL-10-1082 GA genotype (p=0.0351) with rejection, when grouped according to patients' rejection status. No other statistically significant deviations were observed in the donors' genotypes. Analyses of cytokine polymorphisms in the recipients revealed no significant association. Multivariate logistic regression analyses showed that only HLA-DRB1 mismatch significantly influenced graft loss (p=0.0135). ConclusionThis study demonstrates that the donor IL-10 genotypes and HLA-DRB1 mismatch are key determinants in graft outcome after renal transplantation.

Deleterious Impact of HLA-DRB1 Allele Mismatch in Sensitized Recipients of Kidney Retransplants

The impact of human leukocyte antigen (HLA) disparity on graft survival following kidney transplantation in the era of modern immunosuppression remains a matter of debate. There have been reports on a diminishing effect of HLA-DR mismatch on graft outcome in recent years. We examined the influence of HLA-DRB1 mismatch on graft survival based on high resolution typing data, utilizing blood samples and clinical data provided by the Collaborative Transplant Study. HLA-DRB1*04 was selected for our study because it is the most common HLA-DRB1 allele group and consists of several alleles with relatively high frequencies, ensuring a high proportion of transplants which are matched at the antigen level but mismatched at the allele level. 996 recipient/donor pairs were typed for HLA-DRB1 at high resolution. No effect of HLA-DRB1* 04 allele mismatch was observed in first transplants (n = 702). However, in retransplants (n = 294), HLA-DRB1*04 allele mismatch was associated with significantly decreased one-year graft survival, albeit only in sensitized (PRA > 5%) patients (hazard ratio 3.78, P = 0.017). Our finding reinforces the concept that HLA compatibility significantly influences the outcome of kidney transplants, in sensitized patients even at the allele level.

Outcome of allogeneic bone marrow transplantation from unrelated donors for adult Philadelphia chromosome-negative acute lymphocytic leukemia in first complete-remission

The indication of allogeneic stem cell transplantation (allo-SCT) for Philadelphia chromosome-negative acute lymphocytic leukemia [Ph(-) ALL] from unrelated donors is not established. To assess its potency of unrelated patients in first complete-remission (CR1) transplanted from unrelated donors and the potential prognostic factors affecting the probability of survival, we retrospectively analyzed a total of 41 adult Ph(-) ALL patients in CR1 who underwent unrelated bone marrow transplantation at 6 transplantation centers of the Nagoya Blood and Marrow Transplantation Group between 1993 and 2006. The median age of the 41 patients was 28 years (range, 18-51 years). HLA was matched in 33 transplants, with mismatches in 8 (HLA-A allele mismatch:1, HLA-DR serological mismatch: 2, HLA-DRB1 mismatch: 5). Leukemia-free survival (LFS) at 3 and 6 years from allo-SCT was 60.3 and 47.7%, respectively. LFS at 5 years was 62.1% for those transplanted from HLA-matched donors. LFS was significantly lower with HLA-mismatched donors due to higher transplantation-related mortality. Relapse was observed in 3 patients. Our study suggested that unrelated allo-SCT could improve LFS of patients with a potential graft-versus-leukemia effect. Unrelated allo-SCT for Ph(-) ALL patients in CR1 could be more beneficial by reducing TRM, such as selecting a HLA-matched donor.

Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia.

Chronic myeloid leukemia can be cured by marrow transplantation from an HLA-identical sibling donor. The use of transplants from unrelated donors is an option for the 70 percent of patients without an HLA-identical sibling, but the morbidity and mortality associated with such transplants have been cause for concern. We analyzed the safety and efficacy of transplants from unrelated donors for the treatment of chronic myeloid leukemia and identified variables that predict a favorable outcome. Between May 1985 and December 1994, 196 patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase received marrow transplants from unrelated donors. The median follow-up was 5 years (range, 1.2 to 10.1). Graft failure occurred in 5 percent of patients who could be evaluated. Acute graft-versus-host disease of grade III or IV severity was observed in 35 percent of patients who received HLA-matched transplants, and the estimated cumulative incidence of relapse at five years was 10 percent. The Kaplan-Meier estimate of survival at five years was 57 percent. Survival was adversely affected by an interval from diagnosis to transplantation of one year or more, an HLA-DRB1 mismatch, a high body-weight index, and an age of more than 50 years. Survival was improved by the prophylactic use of fluconazole and ganciclovir. The Kaplan-Meier estimate of survival at five years was 74 percent (95 percent confidence interval, 62 to 86 percent) for patients who were 50 years of age or younger who received a transplant from an HLA-matched donor within one year after diagnosis. Transplantation of marrow from an HLA-matched, unrelated donor is safe and effective therapy for selected patients with chronic myeloid leukemia.

Definition of HLA-DQ as a transplantation antigen.

Recent studies have demonstrated the importance of recipient HLA-DRB1 allele disparity in the development of acute graft-versus-host disease (GVHD) after unrelated donor marrow transplantation. The role of HLA-DQB1 allele disparity in this clinical setting is unknown. To elucidate the biological importance of HLA-DQB1, we conducted a retrospective analysis of 449 HLA-A, -B, and -DR serologically matched unrelated donor transplants. Molecular typing of HLA-DRB1 and HLA-DQB1 alleles revealed 335 DRB1 and DQB1 matched pairs; 41 DRB1 matched and DQB1 mismatched pairs; 48 DRB1 mismatched and DQB1 matched pairs; and 25 DRB1 and DQB1 mismatched pairs. The conditional probabilities of grades III-IV acute GVHD were 0.42, 0.61, 0.55, and 0.71, respectively. The relative risk of acute GVHD associated with a single locus HLA-DQB1 mismatch was 1.8 (1.1, 2.7; P = 0.01), and the risk associated with any HLA-DQB1 and/or HLA-DRB1 mismatch was 1.6 (1.2, 2.2; P = 0.003). These results provide evidence that HLA-DQ is a transplant antigen and suggest that evaluation of both HLA-DQB1 and HLA-DRB1 is necessary in selecting potential donors.

Delayed graft function does not influence long-term outcome in cadaver kidney transplants without mismatch for HLA-DRB1

Abstract The currently study focused on the influence of delayed graft function on the long-term graft success rate in cadaver kidneys without any mismatches for HLA-DRB1. Donor-recipient HLA-DRB1 was determined by the significant two-locus linkages of HLA-B and -DRB1. The overall 5-year graft success rate was 88 % in an HLA-DRB1-compatible group, significantly higher than the 69 % in an HLA-DRB1 mismatch group (P < 0.05) and the 66 % in an HLA-DR mismatch (P < 0.01). Delayed graft function was observed in 182 of 223 transplants. This high incidence of 82 % is due to the fact that, in Japan, kidney procurement may only occur after cardiac arrest. The incidence did not differ in each group. The 5-year success rate for grafts with delayed function was 87 % in the HLA-DRB1-compatible group, again significantly superior to the 68 % in the HLA-DRB1 mismatch group and the 63 % in the HLA-DR mismatch cases (P < 0.05). There was, thus, no difference in graft success rate for each group, with or without delayed graft function. Consequently, we feel that delayed graft function has no impact on the long-term outcome in transplants without mismatches for HLA-DRB1.

Delayed graft function does not influence long-term outcome in cadaver kidney transplants without mismatch for HLA-DRB1.

The currently study focused on the influence of delayed graft function on the long-term graft success rate in cadaver kidneys without any mismatches for HLA-DRB1. Donor-recipient HLA-DRB1 was determined by the significant two-locus linkages of HLA-B and -DRB1. The overall 5-year graft success rate was 88% in an HLA-DRB1-compatible group, significantly higher than the 69% in an HLA-DRB1 mismatch group (P < 0.05) and the 66% in an HLA-DR mismatch (P < 0.01). Delayed graft function was observed in 182 of 223 transplants. This high incidence of 82% is due to the fact that, in Japan, kidney procurement may only occur after cardiac arrest. The incidence did not differ in each group. The 5-year success rate for grafts with delayed function was 87% in the HLA-DRB1-compatible group, again significantly superior to the 68% in the HLA-DRB1 mismatch group and the 63% in the HLA-DR mismatch cases (P < 0.05). There was, thus, no difference in graft success rate for each group, with or without delayed graft function. Consequently, we feel that delayed graft function has no impact on the long-term outcome in transplants without mismatches for HLA-DRB1.