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Previous studies have suggested that HLA-E may have a significant role in the outcome of matched unrelated hematopoietic stem cell transplantation (HSCT), especially for patients with acute leukemia. We used Center for International Blood and Marrow Transplant Research data and samples of 1840 adult patients with acute leukemia and their 10/10 HLA-matched unrelated donors to investigate the impact of HLA-E matching status as well as of donor/recipient (D/R) HLA-E genotype on post-HSCT outcome. Both patients and donors were HLA-E genotyped by next-generation sequencing. All patients received their first transplant in complete remission between 2000 and 2015. Median follow-up time was 90 months. Overall survival, disease-free survival (DFS), transplant-related mortality (TRM), and relapse incidence were primary endpoints with statistical significance set at .01. D/R HLA-E genotype analysis revealed a significant association of donor HLA-E*01:03/01:03 genotype with DFS (hazard ratio [HR] = 1.35, P = .0006) and TRM (HR = 1.41, P = .0058) in patients who received T cell replete (ie, without in vivo T cell depletion) transplants (n = 1297). As for D/R HLA-E matching, we did not identify any significant effect on any of the clinical outcome endpoints. In conclusion, this is the largest study to date reporting an improvement of DFS and TRM after matched unrelated HSCT by avoidance of HLA-E*01:03 homozygous donors in patients transplanted with T cell replete grafts for acute leukemia., (Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

HLA haplotype mismatches have been associated with an elevated risk of acute graft-versus-host disease (aGVHD) in patients undergoing HLA-matched unrelated donor (URD) hematopoietic cell transplantation (HCT). The gamma block (GB) is located in the central MHC region between beta and delta blocks (encoding HLA-B and -C and HLA-DQ and -DR antigens, respectively) and contains numerous inflammatory and immune regulatory genes, including Bf, C2, and C4 genes. A single-center study showed that mismatches in SNPs c.2918+98G, c.3316C, and c.4385C in the GB block (C4 SNPs) were associated with higher risk of grade III-IV aGVHD. We investigated the association of GB SNP (GBS) mismatches with outcomes after 10/10 and 9/10 URD HCT (n = 714). The primary outcome was acute GVHD. Overall survival, disease-free survival, transplantation-related mortality, relapse, chronic GVHD, and engraftment were also analyzed. DNA samples were GBS genotyped by identifying 338 SNPs across 20 kb using the Illumina NGS platform. The overall 100-day incidence of aGVHD grade II-IV and II-IV were 41% and 17%, respectively. The overall incidence of matching at all GBSs tested and at the C4 SNPs were 23% and 81%, respectively. Neither being matched across all GB SNPs tested (versus mismatched) nor having a higher number of GBS mismatches was associated with transplantation outcomes. There was no association between C4 SNP mismatches and outcomes except for an unexpected significant association between having 2 C4 SNP mismatches and a higher hazard ratio (HR) for relapse (association seen in 15 patients only; HR, 3.38, 95% confidence interval, 1.75 to 6.53; P = .0003). These data do not support the hypothesis that mismatching at GB is associated with outcomes after HCT., (Copyright © 2018. Published by Elsevier Inc.)

Increasing donor-recipient HLA disparity is associated with negative outcomes of allogeneic hematopoietic stem cell transplantation (HSCT), but its comparative relevance amid non-HLA donor characteristics is not well established. We addressed this question in 3215 HSCTs performed between 2005 and 2013 in Germany for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Donors were HLA-matched related (MRD; n = 872) or unrelated (10/10 MUD, n = 1553) or HLA-mismatched unrelated (<10/10 MMUD, n = 790). Overall survival (OS) was similar after MRD compared with 10/10 MUD HSCT, reflecting opposing hazards of relapse (hazard ratio [HR], 1.32; P < .002) and nonrelapse mortality (HR, .63; P < .001). After UD HSCT, increasing HLA disparity was associated with inferior OS (HR, 1.21 [P < .02] and HR, 1.57 [P < .001] for 9/10 and ≤8/10 MMUD, respectively, compared with 10/10 MUD). Among non-HLA donor characteristics, age, sex mismatching (male recipient-female donor), and cytomegalovirus (CMV) mismatching (positive recipient-negative donor) impacted OS. Multivariate subgroup analysis showed that OS was similar after HSCT from the youngest 9/10 MMUD (<30 years) compared with the oldest 10/10 MUD (>40 years) (HR, 1.18; P = .25) and also in male patients transplanted from female 10/10 MUD compared with male 9/10 MMUD (HR, .89; P = .46). In contrast, OS of CMV-positive patients tended to be better with CMV-negative 10/10 MUDs compared with CMV-positive 9/10 MMUDs (HR, 1.31; P = .04). Because of low patient numbers in subgroups, definite conclusions and establishment of a hierarchy among HLA matching and non-HLA donor characteristics could not be made. Our data suggest that the impact of donor age and sex mismatch but not CMV mismatch on outcome of allogeneic HSCT may be comparable with that of single HLA disparity., (Copyright © 2018. Published by Elsevier Inc.)

The survival of patients undergoing hematopoietic cell transplantation (HCT) from unrelated donors for acute leukemia exhibits considerable variation, even after stringent genetic matching. To improve the donor selection process, we attempted to create an algorithm to quantify the likelihood of survival to 5 years after unrelated donor HCT for acute leukemia, based on the clinical characteristics of the donor selected. All standard clinical variables were included in the model, which also included average leukocyte telomere length of the donor based on its association with recipient survival in severe aplastic anemia, and links to multiple malignancies. We developed a multivariate classifier that assigned a Preferred or NotPreferred label to each prospective donor based on the survival of the recipient. In a previous analysis using a resampling method, recipients with donors labeled Preferred experienced clinically compelling better survival compared with those labeled NotPreferred by the test. However, in a pivotal validation study in an independent cohort of 522 patients, the overall survival of the Preferred and NotPreferred donor groups was not significantly different. Although machine learning approaches have successfully modeled other biological phenomena and have led to accurate predictive models, our attempt to predict HCT outcomes after unrelated donor transplantation was not successful., (Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Donor factors, in addition to HLA matching status, have been associated with recipient survival in unrelated donor (URD) hematopoietic cell transplantation (HCT); however, there is no hierarchical algorithm that weights the characteristics of individual donors against each other in a quantitative manner to facilitate donor selection. The goal of this study was to develop and validate a donor selection score that prioritizes donor characteristics associated with better survival in 8/8 HLA-matched URDs. Two separate patient/donor cohorts, the first receiving HCT between 1999 and 2011 (n = 5952, c1), and the second between 2012 and 2014 (n = 4510, c2) were included in the analysis. Both cohorts were randomly spilt, 2:1, into training and testing sets. Despite studying over 10,000 URD transplants, we were unable to validate a donor selection score. The only donor characteristic associated with better survival was younger age, with 2-year survival being 3% better when a donor 10 years younger is selected. These results support previous studies suggesting prioritization of a younger 8/8 HLA-matched donor. This large dataset also shows that none of the other donor clinical factors tested were reproducibly associated with survival, and hence flexibility in selecting URDs based on other characteristics is justified. These data support a simplified URD selection process and have significant implications for URD registries., (Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Even in the modern era of targeted therapies, allogeneic hematopoietic stem cell transplantation (allo-HCT) can offer a chance of extended survival in B cell non-Hodgkin lymphoma (B-NHL) patients who relapse after or are deemed ineligible for autologous transplantation. A better understanding of the factors influencing the graft-versus-lymphoma (GVL) response would be useful in identifying B-NHL patients who may benefit from allo-HCT. Based on prior single-center reports, we hypothesized that certain HLA alleles, or haplotypes, may be associated with superior GVL compared with others after allo-HCT. To test this possibility we retrospectively evaluated whether the presence of HLA-A2, HLA-C1C1, HLA-DRB1*01:01, or HLA-DRB1*13 alleles or the presence of HLA-A1+, HLA-A2-, and HLA-B44- haplotypes is associated with outcomes in a cohort of 1314 HLA-8/8 matched sibling or unrelated donor HCT for relapsed/refractory B-NHL. We observed no significant association between any HLA allele or haplotype and overall survival or any of the secondary endpoints. In conclusion, this study represents the largest reported series of allo-HCT outcomes of B-NHL patients based on HLA type. Identification of other variables will be required to delineate the immunologic impact of donor-host interactions on outcomes of allo-HCT for B-NHL., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Although quantitative PCR (qPCR) has been explored for chimerism monitoring after allogeneic stem cell transplantation (SCT), evidence regarding its clinical utility compared with standard short tandem repeat (STR) is still limited. We retrospectively studied commercial qPCR and STR chimerism with respective positivity thresholds of .1% and 1% in 359 peripheral blood (PB) and 95 bone marrow (BM) samples from 30 adult patients after first HLA-matched SCT for myeloid malignancies or acute lymphatic leukemia. Concordance between the 2 methods was 79.5%, with all discordant samples positive in qPCR but negative in STR. Of the latter, sporadic qPCR positivity without clinical correlates was seen mostly in BM samples early post-transplant. In 7 of 21 patients with available follow-up samples in the first months after transplantation, qPCR but not STR revealed low levels (<1%) of sustained host chimerism in PB, reflecting delayed engraftment or persistent mixed chimerism (PMC). These conditions were associated with donor-recipient cytomegalovirus (CMV) serostatus and early CMV reactivation but not with immunosuppressive regimens or clinical outcome. qPCR predicted all 8/8 relapses with samples in the 6 months before onset by sustained positivity in both PB and BM compared with 1/8 relapses predicted by STR mainly in BM. The response kinetics to donor lymphocyte infusions for the treatment of PMC or relapse was shown by qPCR but not STR to be protracted over several months in 3 patients. Our results demonstrate the superior clinical utility of qPCR compared with STR for monitoring subtle changes of host chimerism associated with different clinical conditions, making a case for its use in the clinical follow-up of transplant patients., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Disparities in survival after allogeneic hematopoietic cell transplantation have been reported for some race and ethnic groups, despite comparable HLA matching. Individuals' ethnic and race groups, as reported through self-identification, can change over time because of multiple sociological factors. We studied the effect of 2 measures of genetic similarity in 1378 recipients who underwent myeloablative first allogeneic hematopoietic cell transplantation between 1995 and 2011 and their unrelated 10 of 10 HLA-A, -B, -C, -DRB1, and-DQB1- matched donors. The studied factors were as follows (1) donor and recipient genetic ancestral admixture and (2) pairwise donor/recipient genetic distance. Increased African genetic admixture for either transplant recipients or donors was associated with increased risk of overall mortality (hazard ratio [HR], 2.26; P = .005 and HR, 3.09; P = .0002, respectively) and transplant-related mortality (HR, 3.3; P = .0003 and HR, 3.86; P = .0001, respectively) and decreased disease-free survival (HR, 1.9; P = .02 and HR, 2.46; P = .002 respectively). The observed effect, albeit statistically significant, was relevant to a small subset of the studied population and was notably correlated with self-reported African-American race. We were not able to control for other nongenetic factors, such as access to health care or other socioeconomic factors; however, the results suggest the influence of a genetic driver. Our findings confirm what has been previously reported for African-American recipients and show similar results for donors. No significant association was found with donor/recipient genetic distance., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Single-center studies have previously reported associations of MHC Class I Chain-Related Gene A (MICA) polymorphisms and donor-recipient MICA mismatching with graft-versus-host disease (GVHD) after unrelated donor hematopoietic cell transplantation (HCT). In this study, we investigated the association of MICA polymorphism (MICA-129, MM versus MV versus VV) and MICA mismatches after HCT with 10/10 HLA-matched (n = 552) or 9/10 (n = 161) unrelated donors. Included were adult patients with a first unrelated bone marrow or peripheral blood HCT for acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome that were reported to the Center for International Blood and Marrow Transplant Research between 1999 and 2011. Our results showed that neither MICA mismatch nor MICA-129 polymorphism were associated with any transplantation outcome (P < .01), with the exception of a higher relapse in recipients of MICA-mismatched HLA 10/10 donors (hazard ratio [HR], 1.7; P = .003). There was a suggestion of association between MICA mismatches and a higher risk of acute GVHD grades II to IV (HR, 1.4; P = .013) There were no significant interactions between MICA mismatches and HLA matching (9/10 versus 10/10). In conclusion, the findings in this cohort did not confirm prior studies reporting that MICA polymorphism and MICA mismatches were associated with HCT outcomes., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

A major challenge in unrelated hematopoietic stem cell transplantation (HSCT) is the prediction of permissive HLA mismatches, ie, those associated with lower clinical risks compared to their nonpermissive counterparts. For HLA-DPB1, a clinically prognostic model has been shown to be matching for T cell epitope (TCE) groups assigned by cross reactivity of T cells alloreactive to HLA-DPB1∗09:01; however, the molecular basis of this observation is not fully understood. Here, we have mutated amino acids (aa) in 10 positions of HLA-DPB1∗09:01 to other naturally occurring variants, expressed them by lentiviral vectors in B cell lines, and quantitatively measured allorecognition by 17 CD4(+) T cell effectors from 6 unrelated individuals. A significant impact on the median alloresponse was observed for peptide contact positions 9, 11, 35, 55, 69, 76, and 84, but not for positions 8, 56, and 57 pointing away from the groove. A score for the "functional distance" (FD) from HLA-DPB1∗09:01 was defined as the sum of the median impact of polymorphic aa in a given HLA-DPB1 allele on T cell alloreactivity. Established TCE group assignment of 23 alleles correlated with FD scores of ≤0.5, 0.6 to 1.9 and ≥2 for TCE groups 1, 2, and 3, respectively. Based on this, prediction of TCE group assignment will be possible for any given HLA-DPB1 allele, including currently 367 alleles encoding distinct proteins for which T cell cross reactivity patterns are unknown. Experimental confirmation of the in silico TCE group classification was successfully performed for 7 of 7 of these alleles. Our findings have practical implications for the applicability of TCE group matching in unrelated HSCT and provide new insights into the molecular mechanisms underlying this model. The innovative concept of FD opens new potential avenues for risk prediction in unrelated HSCT., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The majority of unrelated donor (UD) hematopoietic stem cell (HSC) transplants are performed across HLA-DP mismatches, which, if involving disparity in a host-versus-graft (HVG) direction for an alloreactive T cell epitope (TCE), have been shown by our group to be associated with poor clinical outcome in 2 cohorts of patients transplanted for hematopoietic malignancies and beta-thalassemia, respectively. Using site-directed mutagenesis of DPB1*0901, we show here that the TCE is abrogated by the presence of amino acids LFQG in positions 8-11 of the DP beta-chain. Based on this and on alloreactive T cell responsiveness, we have determined the presence or absence of the TCE for 72 DPB1 alleles reported in the ethnic groups representative of the worldwide UD registries, and predict that 67%-87% (mean 77%) of UD recipient pairs will not present a DPB1 TCE disparity in the HVG direction. We developed and validated in 112 healthy Italian blood donors an innovative approach of DPB1 epitope-specific typing (EST), based on 2 PCR reactions. Our data show that DPB1 TCE disparities may hamper the clinical success of a considerable number of transplants when DPB1 matching is not included into the donor selection criteria, and that a donor without DPB1 TCE disparities in the HVG direction can be found for the majority of patients. Moreover, the study describes the first protocol of targeted epitope-specific DPB1 donor-recipient matching for unrelated HSC transplantation. This protocol will facilitate large-scale retrospective clinical studies warranted to more precisely determine the clinical relevance of DPB1 TCE disparities in different transplant conditions.

Minor histocompatibility antigens (mHags) HA-1 and HA-2 are encoded by biallelic loci, with immunogenic variants, HA-1H and HA-2V, which induce strong HLA-A2-restricted alloreactive T-cell responses, and nonimmunogenic counterparts, HA-1R and HA-2M, which represent functional null alleles that are poorly presented by HLA class I molecules. HA-1 and HA-2 are potential targets of selective graft-versus-leukemia and graft-versus-tumor reactivity after allogeneic hematopoietic stem cell transplantation (HSCT); however, these applications are restricted to a limited number of patients. Here, we show that a far more frequent application of HA-1 and HA-2 disparity relies on their use as markers for the state of host chimerism after allogeneic HSCT. We have determined allelic frequencies of 29.3% and 70.7% for HA-1H and HA-1R, respectively, and of 83.7% and 16.3% for HA-2V and HA-2M, respectively, in >200 healthy individuals from northern Italy. Similar frequencies were observed in nearly 100 patients affected by hematologic malignancies or solid tumors, thus showing that HA-1 and HA-2 variability are not associated with the presence of cancer. On the basis of these data, we predict that HA-1 and HA-2 can be used in 32.8% and 23.5% of Italian transplant patients, respectively, as markers for the state of host chimerism, whereas exploitation of disparity for these mHags for targeted immunotherapy will be possible in 10.7% and 1.1% of Italian patients, respectively. Retrospective HA-2 typing of bone marrow aspirates obtained from a patient during complete remission or recurrence of acute myeloid leukemia after haploidentical HSCT showed the feasibility of using HA-2 as a surrogate marker for disease monitoring. Because of an apparent north-south gradient for HA-1 allelic frequencies, with higher frequencies for the HA-1H variant reported in white populations from Southern Europe as compared with Northern Europe and North America, the diagnostic applicability of HA-1 disparity will be slightly more frequent in transplant patients from the north. Taken together, our data show that determination of HA-1 and HA-2 variability can be an important parameter for the selection of allogeneic stem cell donors, in particular for patients affected by hematologic malignancies without a tumor-specific molecular marker.