Influence of HLA-DPB1 mismatches on outcome after allogeneic hematopoietic stem cell transplantation.
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ABSTRACT:
SUBMITTER: Hunziker M
PROVIDER: S-EPMC8319557 | biostudies-literature | 2021
REPOSITORIES: biostudies-literature
Publications
Influence of HLA-DPB1 mismatches on outcome after allogeneic hematopoietic stem cell transplantation.
Hunziker Mireille M Passweg Jakob J Medinger Michael M
Leukemia research reports 20210714
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Project description:We investigated the impact of donor-recipient HLA-DPB1 matching on outcomes of allogeneic hematopoietic stem cell transplantation with in vivo T-cell depletion using antithymocyte globulin (ATG) for patients with hematological malignancies. All donor-recipient pairs had high-resolution typing for HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, HLA-DPB1, and HLA-DRB3/4/5 and were matched at HLA-A, HLA-B, HLA-C, and HLA-DRB1. HLA-DPB1 mismatches were categorized by immunogenicity of the DPB1 matching using the DPB T-cell epitope tool. Of 1004 donor-recipient pairs, 210 (21%) were DPB1 matched, 443 (44%) had permissive mismatches, 184 (18%) had nonpermissive mismatches, in graft-versus-host (GVH) direction, and 167 (17%) had nonpermissive mismatches in host-versus-graft (HVG) direction. Compared with HLA-DPB1 permissive mismatched pairs, nonpermissive GVH mismatched pairs had the highest risk for grade II to IV acute graft-versus-host disease (aGVHD) (hazard ratio [HR], 1.4; P = .01) whereas matched pairs had the lowest risk (HR, 0.5; P < .001). Grade III to IV aGVHD was only increased with HLA-DPB1 nonpermissive GVH mismatched pairs (HR, 2.3; P = .005). The risk for disease progression was lower with any HLA-DPB1 mismatches, permissive or nonpermissive. However, the favorable prognosis of HLA-DPB1 mismatches on disease progression was observed only in peripheral blood stem cell recipients who were in the intermediate-risk group by the Disease Risk Index (HR, 0.4; P = .001) but no other risk groups. Our results suggest avoidance of nonpermissive GVH HLA-DPB1 mismatches for lowering the risk for grade II to IV and III to IV aGVHD. Permissive or nonpermissive HVG HLA-DPB1 mismatches may be preferred over HLA-DPB1 matches in the intermediate-risk patients to decrease the risk for disease progression.
| S-EPMC6031309 | biostudies-literature
Project description:HLA-DPB1 antigens are mismatched in about 80% of allogeneic hematopoietic stem cell transplantations from HLA 10/10 matched unrelated donors and were shown to be associated with a decreased risk of leukemia relapse. We recently developed a reliable in vitro method to generate HLA-DPB1 mismatch-reactive CD4 T-cell clones from allogeneic donors. Here, we isolated HLA-DPB1 specific T cell receptors (TCR DP) and used them either as wild-type or genetically optimized receptors to analyze in detail the reactivity of transduced CD4 and CD8 T cells toward primary AML blasts. While both CD4 and CD8 T cells showed strong AML reactivity in vitro, only CD4 T cells were able to effectively eliminate leukemia blasts in AML engrafted NOD/SCID/IL2Rγc-/- (NSG) mice. Further analysis showed that optimized TCR DP and under some conditions wild-type TCR DP also mediated reactivity to non-hematopoietic cells like fibroblasts or tumor cell lines after HLA-DP upregulation. In conclusion, T cells engineered with selected allo-HLA-DPB1 specific TCRs might be powerful off-the-shelf reagents in allogeneic T-cell therapy of leukemia. However, because of frequent (common) cross-reactivity to non-hematopoietic cells with optimized TCR DP T cells, safety mechanisms are mandatory.
| S-EPMC7290340 | biostudies-literature
Project description:The hematopoietic comorbidity risk index (HCT-CI) is a pre-transplant risk assessment tool used to qualify comorbidities to predict non-relapse mortality (NRM) of patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). HSCT procedures continue to improve. Therefore, the predictive value of HCT-CI needs to be re-evaluated. Our study is a retrospective analysis of pre-existing comorbidities assessing the relevance of the HCT-CI on the outcome of consecutive patients (n = 1102) undergoing allo-HSCT from 2006-2021. HCT-CI was classified as low (HCT-CI 0), intermediate (HCT-CI 1-2) and high-risk (HCT-CI ≥ 3). At 10 years, NRM for low, intermediate, and high-risk HCT-CI group was 21.0%, 26.0%, and 25.8% (p = 0.04). NRM difference was significant between low to intermediate (p < 0.001), but not between intermediate to high-risk HCT-CI (p = 0.22). Overall survival (OS) at 10 years differed significantly with 49.9%, 39.8%, and 31.1%, respectively (p < 0.001). In multivariate analysis of HCT-CI organ subgroups, cardiac disease was most strongly associated with NRM (HR = 1.73, p = 0.02) and OS (HR = 1.77, p < 0.001). All other individual organ comorbidities influenced NRM to a lesser extent. Further, donor (HR = 2.20, p < 0.001 for unrelated and HR = 2.17, p = 0.004 for mismatched related donor), disease status (HR = 1.41, p = 0.03 for advanced disease) and previous HSCT (HR = 1.55, p = 0.009) were associated with NRM. Improvement in transplant techniques and supportive care may have improved outcome with respect to comorbidities.
| S-EPMC11530370 | biostudies-literature
Project description:Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a well-established curative treatment for various malignant hematological diseases. However, its clinical success is substantially limited by major complications including graft-vs.-host disease (GVHD) and relapse of the underlying disease. Although these complications are known to lead to significant morbidity and mortality, standardized pathways for risk stratification of patients undergoing allo-HSCT are lacking. Recent advances in the development of diagnostic and prognostic tools have allowed the identification of biomarkers in order to predict outcome after allo-HSCT. This review will provide a summary of clinically relevant biomarkers that have been studied to predict the development of acute GVHD, the responsiveness of affected patients to immunosuppressive treatment and the risk of non-relapse mortality. Furthermore, biomarkers associated with increased risk of relapse and subsequent mortality will be discussed.
| S-EPMC7461883 | biostudies-literature
Project description:HLA-DP antigens are beta-alpha heterodimers encoded by polymorphic HLA-DPB1 and -DPA1 alleles, respectively, in strong linkage disequilibrium (LD) with each other. Non-permissive unrelated donor (UD)-recipient HLA-DPB1 mismatches across three different T-cell epitope (TCE) groups are associated with increased mortality after hematopoietic SCT (HCT), but the role of HLA-DPA1 is unclear. We studied 1281 onco-hematologic patients after 10/10 HLA-matched UD-HCT facilitated by the National Marrow Donor Program. Non-permissive mismatches defined solely by HLA-DPB1 TCE groups were associated with significantly higher risks of TRM compared to permissive mismatches (hazard ratio (HR) 1.30, confidence interval (CI) 1.06-1.53; P=0.009) or allele matches. Moreover, non-permissive HLA-DPB1 TCE group mismatches in the graft versus host (GvH) direction significantly decreased the risk of relapse compared to permissive mismatches (HR 0.55, CI 0.37-0.80; P=0.002) or allele matches. Splitting each group into HLA-DPA1*02:01 positive or negative, in frequent LD with HLA-DPB1 alleles from two of the three TCE groups, or into HLA-DPA1 matched or mismatched, did not significantly alter the observed risk associations. Our findings suggest that the effects of clinically non-permissive HLA-DPB1 TCE group mismatches are independent of HLA-DPA1, and that selection of donors with non-permissive DPB1 TCE mismatches in GvH direction might provide some protection from disease recurrence.
| S-EPMC4154997 | biostudies-literature
Project description:HLA-C locus mismatches (MMs) are the most frequent class I disparities in unrelated hematopoietic stem cell transplantation (HSCT) and have a detrimental impact on clinical outcome. Recently, a few retrospective clinical studies have reported some variability in the immunogenicity of HLA-C incompatibilities. To get better insight into presumably permissive HLA-C MMs, we have developed a one-way in vitro mixed lymphocyte reaction (MLR) assay allowing to quantify activated CD56-CD137+CD8+ lymphocytes in HLA-C incompatible combinations. T cell-mediated alloresponses were correlated with genetic markers such as HLA-C mRNA expression and the number of amino acid (aa) MMs in the α1/α2 domains (peptide-binding region). Because of the high rate of HLA-DPB1 incompatibilities in HLA-A-, B-, C-, DRB1-, and DQB1-matched unrelated HSCT patient/donor pairs, the impact of HLA-DPB1 mismatching, a potential bystander of CD4+ T cell activation, was also considered. Heterogeneous alloresponses were measured in 63 HLA-C-mismatched pairs with a positive assay in 52% of the combinations (2.3-18.6% activated CTLs), representing 24 different HLA-A~B~DRB1~DQB1 haplotypes. There was no correlation between measured alloresponses and mRNA expression of the mismatched HLA-C alleles. The HLA-C*03:03/03:04 MM did not induce any positive alloresponse in five MLRs. We also identified HLA-C*02:02 and HLA-C*06:02 as mismatched alleles with lower immunogenicity, and HLA-C*14:02 as a more immunogenic MM. A difference of at least 10 aa residues known to impact peptide/T cell receptor (TCR) binding and a bystander HLA-DPB1 incompatibility had a significant impact on CTL alloreactivity (p = 0.021). The same HLA-C MM, when recognized by two different responders with the same HLA haplotypes, was recognized differently, emphasizing the role of the T-cell repertoire of responding cells. In conclusion, mismatched HLA-C alleles differing by 10 or more aas in the peptide/TCR-binding region, when occurring together with HLA-DPB1 incompatibilities, should be considered as high-risk MMs in unrelated HSCT.
| S-EPMC5151176 | biostudies-literature
Project description:ImportanceMyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is curative for children with severe sickle cell disease, but toxicity may be prohibitive for adults. Nonmyeloablative transplantation has been attempted with degrees of preparative regimen intensity, but graft rejection and graft-vs-host disease remain significant.ObjectiveTo determine the efficacy, safety, and outcome on end-organ function with this low-intensity regimen for sickle cell phenotype with or without thalassemia.Design, setting, and participantsFrom July 16, 2004, to October 25, 2013, 30 patients aged 16-65 years with severe disease enrolled in this nonmyeloablative transplant study, consisting of alemtuzumab (1 mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and infusion of unmanipulated filgrastim mobilized peripheral blood stem cells (5.5-31.7 × 10(6) cells/kg) from human leukocyte antigen-matched siblings.Main outcomes and measuresThe primary end point was treatment success at 1 year after the transplant, defined as a full donor-type hemoglobin for patients with sickle cell disease and transfusion independence for patients with thalassemia. The secondary end points were the level of donor leukocyte chimerism; incidence of acute and chronic graft-vs-host disease; and sickle cell-thalassemia disease-free survival, immunologic recovery, and changes in organ function, assessed by annual brain imaging, pulmonary function, echocardiographic image, and laboratory testing.ResultsTwenty-nine patients survived a median 3.4 years (range, 1-8.6), with no nonrelapse mortality. One patient died from intracranial bleeding after relapse. As of October 25, 2013, 26 patients (87%) had long-term stable donor engraftment without acute or chronic graft-vs-host disease. The mean donor T-cell level was 48% (95% CI, 34%-62%); the myeloid chimerism levels, 86% (95% CI, 70%-100%). Fifteen engrafted patients discontinued immunosuppression medication with continued stable donor chimerism and no graft-vs-host disease. The normalized hemoglobin and resolution of hemolysis among engrafted patients were accompanied by stabilization in brain imaging, a reduction of echocardiographic estimates of pulmonary pressure, and allowed for phlebotomy to reduce hepatic iron. The mean annual hospitalization rate was 3.23 (95% CI, 1.83-4.63) the year before, 0.63 (95% CI, 0.26-1.01) the first year after, 0.19 (95% CI, 0-0.45) the second year after, and 0.11 (95% CI, 0.04-0.19) the third year after transplant. For patients taking long-term narcotics, the mean use per week was 639 mg (95% CI, 220-1058) of intravenous morphine-equivalent dose the week of their transplants and 140 mg (95% CI, 56-225) 6 months after transplant. There were 38 serious adverse events: pain and related management, infections, abdominal events, and sirolimus related toxic effects.Conclusions and relevanceAmong 30 patients with sickle cell phenotype with or without thalassemia who underwent nonmyeloablative allogeneic HSCT, the rate of stable mixed-donor chimerism was high and allowed for complete replacement with circulating donor red blood cells among engrafted participants. Further accrual and follow-up are required to assess longer-term clinical outcomes, adverse events, and transplant tolerance.Trial registrationclinicaltrials.gov Identifier: NCT00061568.
| S-EPMC4698790 | biostudies-literature
Project description:Donor lymphocyte infusion (DLI) prevents acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) relapses following hematopoietic stem cell transplantation. Given the life-threatening toxicities such as graft versus host disease (GVHD), the identification of variables associated with response without toxicities is warranted. We hypothesized that HLA evolutionary divergence (HED), defined by the diversity between two given alleles of the same HLA gene, may be such a factor. A retrospective multicenter case-control study was conducted to evaluate the outcomes of pre-emptive (preDLI) and prophylactic DLI (proDLI) regarding their HED score, in AML or MDS patients. DLI-treated patients were matched with controls (1:2 matched) from French transplantation centers according to hospital, hemopathy, donor type, and risk classification. In total, 201 patients were included (N = 147 in the preDLI group, N = 54 in the proDLI group). Relapse-free survival was significantly better in the preDLI group (hazard ratio [HR] = 0.23, 95% confidence interval [CI]: 0.14-0.55, p < 0.001) than in controls. However, this benefit was offset by a higher incidence of severe GVHD (HR = 4.88, 95% CI: 2.30-10.32, p < 0.001). HED A, B, C, DQA1, DQB1, DPB1, and DRB1 were calculated for 65 DLI-treated patients. High-class II HED was significantly associated with higher GVHD and relapse-free survival (GRFS, HR = 0.33, 95% CI: 0.20-0.77, p = 0.005). Specific DQAB associations directly improved GRFS (HR = 0.23, 95% CI: 0.09-0.58, p = 0.004). In conclusion, screening the class II HED score identifies patients eligible for DLI treatment who will benefit the most from this strategy.
| S-EPMC11822263 | biostudies-literature
Project description:In 8/8 HLA-matched unrelated donor (UD) hematopoietic cell transplants (HCT), HLA-DPB1 mismatches between alleles from different T-cell epitope (TCE) groups (non-permissive mismatches) are associated with significantly higher risks of mortality compared with those between alleles from the same TCE group (permissive mismatches); however, the relevance of mismatch directionality, that is (host vs graft (uni-directional HvG), graft vs host (uni-directional GvH) or both (bi-directional) in the non-permissive setting is unknown. We show here significantly higher in vitro relative responses (RR) to bi-directional mismatches compared with uni-directional HvG or GvH mismatches in a total of 420 one-way mixed lymphocyte reactions between 10/10 matched pairs (RR 27.5 vs 7.5 vs 15.5, respectively, P<0.001). However, in 3281 8/8 matched UD HCT for leukemia or myelodysplastic syndrome, the hazards of transplant-related mortality (TRM) were similar for uni-directional HvG or GvH mismatches and bi-directional mismatches (hazard ratio (HR) 1.32, P=0.001 vs HR 1.28, P=0.005 and HR 1.34, P=0.046), compared with permissive mismatches. Similar results were observed for overall survival. No statistical differences between the uni- and the bi-directional non-permissive groups were detected in pairwise comparisons for any of the outcomes tested. We conclude that consideration of directionality does not improve risk stratification by non-permissive HLA-DPB1 TCE mismatches in UD searches.
| S-EPMC5968827 | biostudies-literature
Project description:Pleural effusion is a known entity in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT); however, the incidence, risk factors, and morbidity-mortality outcomes associated with pleural effusions remain unknown. We retrospectively evaluated pleural effusions in 618 consecutive adult patients who underwent allogeneic HSCT from January 2008 to December 2013 at our institution. Seventy one patients developed pleural effusion at a median of 40 days (range, 1 - 869) post-HSCT with the cumulative incidence of 9.9% (95% CI, 7.7 - 12.5%) at 1 year. Infectious etiology was commonly associated with pleural effusions followed by volume overload and serositis type chronic GVHD. In multivariate analysis, higher comorbidity index (P = 0.03) and active GVHD (P = 0.018) were found to be significant independent predictors for pleural effusion development. Higher comorbidity index, very high disease risk index, ≤7/8 HLA matching, and unrelated donor were associated with inferior overall survival (OS) (P < 0.03). More importantly, patients with pleural effusion were noted to have poor OS in comparison to patients without pleural effusion (P < 0.001). Overall, pleural effusion is a frequently occurring complication after allogeneic HSCT, adding to morbidity and mortality and hence, early identification is required. Am. J. Hematol. 91:E341-E347, 2016. © 2016 Wiley Periodicals, Inc.
| S-EPMC6852667 | biostudies-literature