Unrelated Donor-recipient Pairs Research Articles

Clonal Hematopoiesis Is Common in Unrelated Stem Cell Donors but Has No Impact on Patient Outcome after Hematopoietic Stem Cell Transplantation

Introduction. Clonal hematopoiesis (CH) has been associated with increased mortality mainly due to associations with cardiovascular diseases and hematologic cancer. Previous studies with predominantly related stem cell donors suggest that donor CH modulates graft-versus-host reactions and may augment graft-versus-leukemia effects after allogeneic hematopoietic cell transplantation (alloHCT). The impact of donor CH in the setting of unrelated alloHCT remains to be determined. To address this question, we initiated a joint study of the Transplant Complications Working Party of EBMT and DKMS. Patients and Methods. Donor samples from the time of stem cell donation were taken from the Collaborative Biobank. Patient baseline and outcome data were retrieved from the EBMT registry. Unrelated donor-recipient pairs were selected for a minimum donor age of 35 years. CH analysis was performed with an error-corrected ultra-deep NGS assay for 45 genes with a median sensitivity of 0.2% variant allele frequency (VAF). Accuracy of low frequency CH findings was checked by cross validation with an orthogonal assay. The primary objective was to assess the impact of donor CH on overall survival (OS). Major secondary endpoints were the risk of relapse/progression and non-relapse mortality (NRM), cumulative incidences of acute and chronic GVHD and event-free survival (EFS). All endpoints were evaluated with (cause-specific) multivariable Cox regression models. Adjustment factors were patient and donor age, diagnosis, disease risk index, Karnofsky performance status, conditioning intensity, GVHD-prophylaxis, graft source, HLA-match, sex match and CMV match. We did not adjust for multiple testing. Results. Data from 2584 unrelated donor-recipient pairs were analyzed. Median patient follow-up after alloHCT was 60 months. The median donor age was 46 years (range, 39-61 years). The median patient age was 54 years (range, 0-79 years). Indications for alloHCT were AML (44%), ALL (10%), MDS (10%), MPN (6%), B-cell lymphoma (6%), Multiple Myeloma (5%), CML 3%, inherited disorders (3%), CLL 2% and other (13%). Transplantations were performed between 2005 and 2018. In vivo or ex vivo T-cell depletion (TCD) was used in 81% of transplants, PTCY in 5% and no TCD in 14%. Mutations in DNMT3A, TET2, and ASXL1 defined CH most frequently. The distribution of donor CH across leukemia driver genes was comparable to previous reports (Panel A). With 0.2% (2%) VAF cutoffs, rates of DNMT3A-mutations were 19% (2%) among donors younger than 41 years compared to 37% (6%) among donors aged 55 years and higher. Corresponding rates for 0.2% (2%) VAF cutoffs for total CH were 38% (4%) among donors younger than 41 years compared to 67% (14%) among donors aged 55 years and higher. We tested systematically increasing VAF cutoffs (≥0.2% versus <0.2%, ≥1% versus <1%, ≥2% versus <2%, ≥5% versus <5%, and ≥5% versus <0.2%) for DNMT3A-CH and total CH for associations with clinical endpoints. Panel B shows results for multivariable regression analyses for total donor CH. Although we observed trends towards increased mortality and inferior EFS for some cutoffs, no incremental impact of donor CH with higher VAF was found and no systematic changes of the risk for GVHD and relapse/progression were observed. Conclusions. We conclude that donor CH has no significant impact on the risk for GVHD, relapse and survival in the context of HLA-compatible unrelated donor alloHCT with GVHD-prophylaxis based predominantly on T-cell depletion with ATG.

Clinical impact of KIR haplotypes in 10/10 HLA-matched unrelated donor-recipient pairs undergoing allogeneic hematopoietic stem cell transplantation

To evaluate the impact of killer immunoglobulin-like receptor (KIR) genotyping in allogeneic hematopoietic stem cell transplantation for myeloid disorders at our institution, retrospective KIR genotyping was performed on 77 patients and their 10/10 matched unrelated donors. In a multivariate model including donor age, HLA-DPB1 permissiveness, and presence of donor KIR B/x, an association with overall survival was observed (p = .047). Within the model, increasing donor age increased risk (RR 1.03 [1.00–1.06]/year, p = .046), while donor KIR and HLA-DPB1 permissiveness were not associated with risk (RR 0.51 [0.26–1.03] and RR 0.68 [0.34–1.36]). Grouping recipients by conditioning regimen or limiting the analysis to recipients of peripheral blood stem cells, no association between donor KIR and survival or relapse was identified. No significant associations were observed between overall survival, relapse, grade III-IV acute, or chronic graft versus host disease and presence of KIR B (B/x), quantity of donor KIR B haplotype motifs, or centromeric KIR type (all p > .05).

Matched Unrelated Donor Hematopoietic Cell Transplant with Increased Donor Inhibitory KIR Improves Survival in a Pediatric Acute Leukemia: A CIBMTR Cohort Analysis

Natural killer (NK) cells potentially mediate innate immunity early after hematopoietic cell transplantation (HCT). NK cells posses an array of activating and inhibitory receptors on their surface, including killer immunoglobulin-like receptor (KIR) and which interact with KIR-ligands (KIRL) on target cells. The impact of NK cell mediated alloreactivity in pediatric HCT is not well characterized. In this study, we explored a mathematical approach to quantify KIR-KIRL combinations to assess clinical outcomes in a cohort of pediatric patients who underwent HLA-matched unrelated donor (MUD) HCT for acute leukemia including AML and ALL. This retrospective study was performed on deidentified donor and recipient demographic and clinical outcomes data provided by the Center for International Blood and Marrow Transplant Research (CIBMTR). KIR-KIRL interaction values were assigned as previously (Krieger et. al 2021, Bone Marrow Transplantation). Briefly donor inhibitory (iKIR) and activating (aKIR) KIR- recipient KIRL interactions, accounting for missing KIR-L (mKIR), were summed up, using a system of matrices. The study cohort was comprised of 686 pediatric donor-recipient pairs (DRP) who underwent MUD HCT for AML (N=355) and ALL (N=333) and had neutrophil engraftment (Table 1). This cohort of pediatric patients was aged 0-18 years (average 11). All patients received T cell replete grafts; 26% received in vivo T cell depletion, with either anti-thymocyte globulin (ATG) or alemtuzumab. The majority, 77% received a bone marrow graft and 90% received myeloablative conditioning. The effect of all 3 KIR-KIRL interaction scores (absolute values of iKIR, mKIR and aKIR) on clinical outcomes were evaluated. Higher donor iKIR score was associated with improvement in overall survival (OS) SHR 0.73 (multivariate P=0.003) and relapse-free survival (RFS), SHR 0.8 (P=0.019); grade 3-4 acute GVHD was lower in patients transplanted with higher iKIR or mKIR scores (iKIR; SHR 0.58 (P=0.013); mKIR SHR 0.6 (P=0.041)). Higher aKIR scores, were not significantly associated with any clinical outcomes examined. As in previous analysis, the iKIR and mKIR scores were added to give an IM-KIR score, which was dichotomized for analysis into those DRP with an IM KIR score of 5 (IM = 5), and those with an IM-KIR score of 2, 3 or 4 (IM < 5). Of note, KIR haplotype A patients always have an IM KIR score of 4, and are thus categorized among IM<5 donors. In this cohort of pediatric patients transplanted for both AML and ALL, those transplanted with IM=5 donors demonstrated improved OS, SHR 0.75 (P = 0.027), RFS, SHR 0.79 (P=0.05) and grade 3-4 aGVHD incidence, SHR 0.37 (P= 0.003) in multivariate analysis. We next examined outcomes in patients with ALL and AML to understand disease specific effects. Patients transplanted for AML with IM=5 donors had an improvement in OS, SHR 0.62 (P=0.01), as well as RFS, SHR 0.70 (p=0.033) (Fig. 1). There was a trend towards relapse risk reduction in this cohort SHR 0.67 (univariate P=0.048). Patients transplanted for ALL with IM=5 donors demonstrated a marked decrease in grade 3-4 acute GVHD incidence SHR, 0.31 (P=0.017). This large pediatric study confirms that unrelated DRPs with donor haplotype B genotypes and a higher inhibitory KIR content (regardless of KIR ligand status), confer significant improvement in overall survival and severe aGVHD after MUD HCT. Those patients transplanted for AML experienced an improvement in OS and RFS despite the lower event rate observed in pediatric-age patients, the majority of whom receive myeloablative preparatory regimens without the use of in vivo T cell depletion. This challenges the notion that KIR are irrelevant to pediatric donor selection. Future clinical trials evaluating donor selection for URD HCT should include this measure to evaluate its value prospectively. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

How a compensated kidney donation program facilitates the sale of human organs in a regulated market: the implications of Islam on organ donation and sale

BackgroundAdvocates for a regulated system to facilitate kidney donation between unrelated donor-recipient pairs argue that monetary compensation encourages people to donate vital organs that save the lives of patients with end-stage organ failure. Scholars support compensating donors as a form of reciprocity. This study aims to assess the compensation system for the unrelated kidney donation program in the Islamic Republic of Iran, with a particular focus on the implications of Islam on organ donation and organ sales.MethodsThis study reviews secondary documents for philosophical argumentation and ethical analysis of human organ donation and sale for transplantation.Results and discussionAccording to Islamic law, organ donation is an act of sadaqatul jariyah, and individuals are permitted to donate organs with the intention of saving lives. The commercialization of humans as organ sellers and buyers is contrary to the Islamic legal maxim eethaar, undermining donors of ‘selfless’ or ‘altruistic’ motivations. Such an act should be considered immoral, and the practice should not be introduced into other countries for the sake of protecting human dignity, integrity, solidarity, and respect. I, therefore, argue that Iran’s unrelated kidney donation program not only disregards the position of the Islamic religion with respect to the provision or receipt of monetary benefits for human kidneys for transplantation but that it also misinterprets the Islamic legal proscription of the sale of human organs. I also argue that the implementation of Iran’s unrelated kidney donor transplantation program is unethical and immoral in that potential donors and recipients engage in a bargaining process akin to that which sellers and buyers regularly face in regulated commodity exchange markets. Conversely, I suggest that a modest fixed monetary remuneration as a gift be provided to a donor as a reward for their altruistic organ donation, which is permissible by Islamic scholars. This may remove the need to bargain for increased or decreased values of payment in exchange for the organ, as well as the transactional nature of ‘buyer and seller’, ensuring the philosophy of ‘donor and recipient’ is maintained.ConclusionsOffering a fixed modest monetary incentive to organ donors would serve to increase organ supply while protecting donors’ health and reducing human suffering without legalizing the human organ trade.

Increased Inhibitory KIR-Ligand Interactions Confer Relapse Protection Following HLA Matched Unrelated Donor HCT for AML

Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer cell-mediated graft versus leukemia effect (GVL) after hematopoietic stem cell transplant (HCT) for AML. There is considerable heterogeneity in the KIR gene and KIRL content of individuals, making it difficult to estimate the full clinical impact of NK cell alloreactivity following HCT. Herein, we validate a mathematical model accounting for KIR-KIRL interactions identifying donors with optimal NK cell-mediated alloreactivity and GVL. This retrospective study was performed on de-identified donor and recipient demographic and clinical outcomes data provided by the Center for International Blood and Marrow Transplant Research (CIBMTR). Donor recipient pairs (DRP) who underwent unrelated donor (URD) HCT for early and intermediate AML were included. KIR-KIRL interaction values were assigned as follows; if an inhibitory KIR (iKIR) on the NK cell encounters a ligand on its target, this will give the NK cell an inhibitory signal and this is scored as a single interaction(Figure 1b), as is the case, if there is no ligand for an inhibitory KIR, i.e., missing KIRL (mKIRL) (Figure 1c). Finally, activating KIR (aKIR) interacting with its ligands is similarly scored(Figure 1a). The absolute values of the iKIR and mKIR scores were summed to calculate the composite inhibitory-missing ligand (IM)-KIR score (Figure 1d). The study cohort was comprised of 2365 donor-recipient pairs (DRP) who underwent URD HCT for early or intermediate AML. Mean age was 53 years; 85% of DRPs were high-resolution 8/8 HLA-matched for HLA-A, -B, -C, and -DRB1. All patients received T cell replete grafts; 42% (n=996) received in vivo T cell depletion, 937 (94%) with anti-thymocyte globulin (ATG); 86% received a graft of mobilized peripheral blood stem cells (PBSC), 59% received myeloablative conditioning. This cohort was primarily of Caucasian descent (89%). When adjusted for recipient age, donor age, CMV status, KPS, GVHD prophylaxis, cytogenetics, disease status, conditioning regimen, in vivo T cell depletion, graft source, and sex match, relapse risk was significantly reduced in donor-recipient pairs (DRP) with higher inhibitory KIR-KIRL interaction and missing KIRL (mKIR) scores, with HR=0.86 (P=0.01) &amp; HR=0.84 (P=0.02) respectively. This effect was not observed with activating KIR-KIRL interactions. Chronic GVHD and TRM were not significantly affected by iKIR, mKIR or aKIR. Given the significant individual impact of iKIR and mKIR, the summed inhibitory-missing ligand (IM-KIR) score was next assessed, and when this score was 5 (as opposed to &amp;lt;5), the IM-KIR score was also associated with lower relapse risk, HR 0.8 (P=0.004) (Figure 2a). Acute and chronic graft vs. host disease (GVHD), survival, GRFS, and relapse-free survival were not significantly different, likely due to increased TRM among these patients, HR 1.32 (P=0.01). Interaction analysis indicated that amongst the HLA matched DRP, ATG recipients with IM-KIR=5, had a lower relapse rate compared to those with an IM-KIR&amp;lt;5, HR 0.61 (p=0.001) (Figure 2b), among the cohort who did not receive ATG there was no significant difference in relapse among IM-KIR=5 and IM-KIR&amp;lt;5; thus, the use of ATG significantly modified the effect of IM KIR score in an interaction analysis (p=0.049), suggesting higher NK cell magnitude of KIR-KIRL interaction may compensate for the general increase of relapse in those who receive in vivo T cell depletion. Nevertheless, TRM was also increased in these patients, HR 1.49 (p=0.034), likely abrogating survival advantage from a lower relapse risk. This large international study confirms that unrelated DRPs with greater magnitude of inhibitory KIR-KIRL interactions confer significant relapse protection after MUD HCT in standard-risk AML. This challenges the notion that KIR are irrelevant to donor selection. Future clinical trials evaluating donor selection for URD HCT should include this measure to evaluate its value prospectively in uniformly treated patient cohorts, with adequate GVHD and antiviral prophylaxis to mitigate TRM. Disclosures No relevant conflicts of interest to declare.

Analytical Validation of a Single-nucleotide Polymorphism-based Donor-derived Cell-free DNA Assay for Detecting Rejection in Kidney Transplant Patients.

Early detection of rejection in kidney transplant recipients holds the promise to improve clinical outcomes. Development and implementation of more accurate, noninvasive methods to detect allograft rejection remain an ongoing challenge. The limitations of existing allograft surveillance methods present an opportunity for donor-derived cell-free DNA (dd-cfDNA), which can accurately and rapidly differentiate patients with allograft rejection from patients with stable organ function. This study evaluated the analytical performance of a massively multiplexed polymerase chain reaction assay that targets 13 962 single-nucleotide polymorphisms, characterized and validated using 66 unique samples with 1064 replicates, including cell line-derived reference samples, plasma-derived mixtures, and transplant patient samples. The dd-cfDNA fraction was quantified in both related and unrelated donor-recipient pairs. The dd-cfDNA assay showed a limit of blank of 0.11%, a limit of detection and limit of quantitation of 0.15% for unrelated donors, and limit of blank of 0.23%, a limit of detection and limit of quantitation of 0.29% for related donors. All other metrics (linearity, accuracy, and precision) were observed to be equivalent between unrelated and related donors. The measurement precision of coefficient of variation was 1.8% (repeatability, 0.6% dd-cfDNA) and was <5% for all the different reproducibility measures. This study validates the performance of a single-nucleotide polymorphism-based massively multiplexed polymerase chain reaction assay to detect the dd-cfDNA fraction with improved precision over currently available tests, regardless of donor-recipient relationships.

Direct HLA Genetic Comparisons Identify Highly Matched Unrelated Donor-Recipient Pairs with Improved Transplantation Outcome.

HLA matching by allele-level genotyping is largely based on genetic similarity between a few exons that encode the antigen recognition domain (ARD) of the HLA protein. Next-generation sequencing (NGS) can identify HLA genetic polymorphisms in non-ARD-encoding exons, introns, and untranslated regions, but the impact of these polymorphisms on hematopoietic cell transplantation (HCT) outcome is unclear. We performed NGS-based sequencing of 11 HLA loci on a well-characterized retrospective cohort of 166 unrelated donor-recipient HCT pairs. Genetic differences between HCT pairs were identified and visualized using a novel bioinformatics approach that directly compares phased full-length HLA sequences. Our approach was able to correctly classify HCT pairs without known HLA allele-level mismatches and also to identify a subset of HLA allele-matched HCT pairs with very few to no genetic differences in the sequenced HLA regions. This highly HLA genetically matched unrelated HCT group shows improved overall survival and reduced acute graft-versus-host disease compared with HCT pairs with HLA allele-level mismatches. These results suggest that direct genetic matching of HLA loci may offer an additional means of HCT donor selection beyond traditional HLA allele comparisons and suggests that genetic similarity as defined by HLA sequencing may have a novel role in unrelated HCT donor selection. Finally, our approach can enable larger cohort studies with adequate power to detect differences in other HCT outcomes based on genetic similarity within the HLA loci.

Does matching for SNPs in the MHC gamma block in 10/10 HLA-matched unrelated donor-recipient pairs undergoing allogeneic stem cell transplant improve outcomes?

BackgroundMatching at the HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci is important in donor selection for patients undergoing unrelated allogeneic hematopoietic stem cell transplantation (ASCT). Additional matching across the MHC gamma region may further improve outcomes. MethodsThe MHC gamma region was retrospectively genotyped in 66 adult recipients of ASCT and their 10/10 matched unrelated donors. A chart review was performed to determine whether MHC gamma matching impacted survival, relapse, or graft-versus-host disease. ResultsOf 66 donor-recipient pairs, 26(39.4%) were gamma-type matches, 34(51.5%) were mismatches, and 6(9.1%) were “indeterminate.” Matching status was not associated with overall survival (p = 0.43), relapse (p = 0.21), acute GVHD (p = 0.43), severe aGVHD (p = 0.31), or chronic GVHD (p = 0.23) in univariate analyses, nor in multivariate analyses (p = 0.28, 0.13, 0.29, 0.16, and 0.67, respectively), with or without adjusting for HLA-DPB1 matching status. ConclusionsIn our single institution study, gamma-type matching status was not associated with outcomes of adult ASCT recipients.

OR7 MiHAIP: Comprehensive pipeline to discover immunogenic minor histocompatibility antigens via whole genome sequences of HLA-matched donor-recipient pairs

Aim Allogeneic hematopoietic cell transplantation (AlloHCT) is a curative therapy for certain hematological malignancies, immune deficiencies and inborn errors of metabolism. A major complication of alloHCT is graft-versus-host disease (GVHD) mediated by immunogenic minor histocompatibility antigens (MiHAs). To date, a limited number of MiHAs with HLA restrictions have been identified and well characterized. We developed a comprehensive pipeline to predict potential MHC class I-restricted MiHAs. Methods The MiHA identification pipeline (MiHAIP) integrates diverse biological data sources, including whole genome sequences, HLA genotypes, clinical outcomes, tissue-specific expression, known MiHAs, and minor allele frequencies. MiHAIP incorporates third-party bioinformatics toolboxes, such as RTGtools, snpEff, netchop-3.1 and netMHCpan-3.0, to predict the potential MiHAs in parallel by comparing variants between the donor and recipient. Subsequently, the pipeline simulates antigen processing and presentation on recipients’ cell surface via HLA molecule restriction (figure). Results Whole genome sequences and HLA typing of a cohort of unrelated donor-recipient pairs (n = 205) were loaded to MiHAIP to predict potential MiHAs. It takes on average 22 min to process each donor-recipient pair of whole genome sequence data on a cloud computing environment. Known autosomal MiHAs were examined to validate the sensitivity of the pipeline. MiHAIP outputs the predicted HLA-restricted antigens and their potential GVHD effects. Conclusions The proposed MiHAIP is the first MHC class I-restricted MiHA prediction tool for analyzing whole genome sequences of donor-recipient pairs with HLA matches. It accurately and efficiently identifies known well-characterized MiHAs and new potential MiHAs with high sensitivity.

Replication of associations between genetic polymorphisms and chronic graft-versus-host disease

AbstractPrevious studies have identified single-nucleotide polymorphisms (SNPs) associated with the risk of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation. The current study determined whether these associations could be replicated in large cohorts of donors and recipients. Each SNP was tested with cohorts of patients having the same donor type (HLA-matched related, unrelated, or both) reported in the original publication, and testing was limited to the same genome (recipient or donor) and genetic model (dominant, recessive, or allelic) reported in the original study. The 21 SNPs reported in this study represent 19 genes, and the analysis encompassed 22 SNP association tests. The hazard ratio (HR) point estimates and risk ratio point estimates corresponding to odds ratios in previous studies consistently fall outside the 95% confidence intervals of HR estimates in the current study. Despite the large size of the cohorts available for the current study, the 95% confidence intervals for most HRs did not exclude 1.0. Three SNPs representing CTLA4, HPSE, and IL1R1 showed evidence of association with the risk of chronic GVHD in unrelated donor-recipient pairs from 1 cohort, but none of these associations was replicated when tested in unrelated donor-recipient pairs from an independent cohort. Two SNPs representing CCR6 and FGFR1OP showed possible associations with the risk of chronic GVHD in related donor-recipient pairs but not in unrelated donor-recipient pairs. These results remain to be tested for replication in other cohorts of related donor-recipient pairs.

Donor-Recipient Matching for KIR Genotypes Reduces Chronic GVHD and Missing Inhibitory KIR Ligands Protect against Relapse after Myeloablative, HLA Matched Hematopoietic Cell Transplantation

BackgroundAllogeneic hematopoietic cell transplantation (HCT) can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD) and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR)-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG) is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCTMethods and FindingsThe study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into ‘discovery’ (135 pairs) and ‘validation’ (146 pairs) cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD), chronic GVHD needing systemic therapy (cGVHD) and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS), cGVHD & relapse free survival (cGRFS) and overall survival (OS)] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa) and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50–5.17) and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33–5.11). High incidence of cGVHD associated with KIR genotype mismatching was applicable to both sibling and unrelated donors and was specific to recipients who had one or two C1 bearing HLA-C epitopes (HLA-C1/x, p = 0.001; SHR = 2.40; 95%CI: 1.42–4.06). When compared with KIR genotype mismatched transplants, HLA-C1/x patients receiving grafts from KIR genotype matched donors had a significantly improved cGRFS (p = 0.013; HR = 1.62; 95%CI: 1.11–2.39). Although there was no effect of KIR genotype matching on survival outcomes, a significantly reduced incidence of relapse (p = 0.001; SHR = 0.22; 95%CI: 0.10–0.54) and improved relapse-free survival (p = 0.038; HR = 0.40; 95%CI: 0.17–0.95) was observed with one or more missing ligands for donor inhibitory KIR among the recipients of unrelated donor transplants.ConclusionsThe present study for the first time presents the beneficial effects of KIR genotype matching in reducing cGVHD in myeloablative transplant setting using HLA matched (sibling and unrelated) donors. The findings offer a clinically applicable donor selection strategy that can help control cGVHD without affecting the risk of relapse and/or identify patients at a high risk of developing cGVHD as potential candidates for preemptive therapy. The findings also affirm the beneficial effect of one or more missing inhibitory KIR ligands in the recipient in reducing relapse and improving a relapse free survival in unrelated donor transplants.

Clinical Outcomes of HLA-DPB1 Mismatches in 10/10 HLA-Matched Unrelated Donor-Recipient Pairs Undergoing Allogeneic Stem Cell Transplant

(n1⁄44) or unrelated CB (n1⁄419). The conditioning regimens were myeloablative in 20 patients and reduced-intensity in 9. Twenty-seven patients achieved neutrophil engraftment at a median day of 19 (range, 10-34). The cumulative incidence of neutrophil engraftment was 93.1% at day 42 (patients engrafted, n1⁄427; dead before day 19, n1⁄42). At 3 years, the cumulative incidence of relapse and non-relapse mortality was 32.3% and 14.0%, respectively. In 15 patients who did not achieve CP before transplantation, 11 patients (73.3%) achieved CR after transplantation. With a median follow-up of survivors of 1144 days (range, 127-3705), overall survival (OS) and event free survival (EFS) at 3 years was 63.2% and 56.3%, respectively. In univariate analysis, the variables that influenced on OS were disease status at transplantation (CP vs. AP/BC, 85% vs. 42%, p1⁄40.012), karyotype (sole Ph-chromosome vs. additional cytogenetic abnormalities, 90% vs. 47.5%, p1⁄40.042) and conditioning regimen (MAC vs. RIC, 72.7% vs. 41.7%, p1⁄40.039). In multivariate analysis, the only variable that influenced on OS was disease status at transplantation (p1⁄40.015). Conclusion: We concluded that allogeneic hematopoietic cell transplantation from any cell sources could become a promising option for the patients with CML in advanced stage, especially if they achieved CP before transplantation.

A study of HLA-DPA1 and DPB1 matching status for unrelated donor-recipient pairs matched at allele level for HLA-A, -B, -C, -DRB1 and -DQB1 loci

To analyze the status of HLA-DPA1 and DPB1 matching for unrelated donor-recipient pairs matched at high-resolution allele level for HLA-A, B, C, DRB1 and DQB1 loci. A total of 76 unrelated donor-recipient pairs matching at allele level for HLA-A, B, C, DRB1 and DQB1 loci were subjected to HLA-DPA1 and DPB1 sequence-based typing (SBT). HLA-DPA1and DPB1 matching status at high-resolution allelic level was also analyzed. The allelic identity ratio for single HLA-DPA1 and DPB1 were 17.1% and 9.2%, respectively. HLA-DPA1 and DPB1 allelic identity ratio were both very low. The majority of unrelated donor-recipient pairs (73.7%) had an incompatibility at 1 HLA-DPA1 allele, 9.2% of pairs had an incompatibility at 2 DPA1 alleles. As for the high-polymorphic HLA-DPB1 gene, 57.9% of studied donor-recipient pairs had an incompatibility at 1 HLA-DPB1 allele, almost 1/3 (32.9%) of them were completely incompatible. When HLA-DPA1 and DPB1 genes were analyzed together, the donor-recipient pairs matched at 2/4 was the most common (51.4%), 4/4 allelic complete matched pairs accounted for 5.6%, and 0/4 matched pairs accounted for 8.3%. Our results indicated that the ratio of HLA-DPA1 and DPB1 complete match in the unrelated donor-recipient pairs matching at allelic level for HLA-A, B, C, DRB1 and DQB1 loci were very low. The effect of HLA-DPA1 and DPB1 matching status on clinical unrelated stem cell transplantation still needs to be elucidated.

Einfluss von beziehungsdynamischen Aspekten auf den psychosozialen Outcome von genetisch verwandten und nicht-verwandten Nierenlebendspendern und -empfängern

Renal diseases and their treatment can cause distress and psychosocial problems for both patients and relatives. Relationship dynamics and parameters of quality of life were assessed in 10 genetically related (brothers) and 14 genetically unrelated donor-recipient pairs (spouses) involved in living kidney donation (LKD). LKDs were described by related donors and recipients as fundamentally positive and in many cases led to an intensification of the relationship between donor and recipient. LKDs between unrelated donors and recipients appeared to achieve the same results as donations between related donors and recipients. Particularly the general desire to help determined the decision-making process of donors. In addition to general clinical parameters, especially motivational and relationship dynamics should be evaluated in the pre- and postoperative clinical psychological assessment of potential donors and recipients of LKD.

Effect of Race on Outcomes After Allogeneic Hematopoietic Cell Transplantation for Severe Aplastic Anemia

Abstract 1020Severe aplastic anemia (SAA) is the most common non-malignant indication for hematopoietic cell transplantation (HCT). Although survival after HCT for SAA has improved in recent years, it is not known whether the observed higher survival rates are uniform across racial groups or whether there are differences similar to those seen with HCT for hematologic malignancies. Our primary objective was to compare overall survival after HCT for SAA in patients of African American and Caucasian races. The study population included patients who received HCT in the U.S. between 1990 and 2008. Eighty-four African Americans (cases) and 215 Caucasians (controls) were matched on factors known to be associated with survival after HCT for SAA, including age at HCT (±3 years), donor type (HLA-matched sibling, matched unrelated donor, mismatched unrelated donor), graft type (bone marrow or peripheral blood progenitor cells) and transplant year (±1 year). For 39 cases the match ratio for controls was 1:4, for 14 cases, 1:3, for 22 cases, 1:2 and the remaining 9 cases, 1:1. The median age of cases and controls was 17 years and the median interval from diagnosis to HCT was 3.4 months. Forty-five percent of transplants were from unrelated and 55% from HLA-matched sibling donors. A third of unrelated donor-recipient pairs were HLA-mismatched. Bone marrow was the predominant source of stem cells. The median follow-up of cases and controls was 5 years. In multivariate analysis, risk of overall mortality was higher for African Americans compared to Caucasians, relative risk [RR] 1.75, 95% CI 1.14–2.69, p=0.01. Risks of overall mortality were also higher during the early post-transplant period; odds ratio (OR) 2.42, 95% CI 1.09–5.37, p=0.03) and OR 2.61, 95% CI 1.33–5.47, p=0.005) at 3-months and 1-year post-transplantation, respectively. The 5-year probability of overall survival adjusted for interval from diagnosis to HCT, performance score and conditioning regimen, the other significant variables associated with higher mortality was 58% for African Americans and 73% for Caucasians. The likelihood of neutrophil recovery was similar in both groups (OR 1.03, 95% CI 0.46–2.33, p=0.94). Acute grades II–IV graft-versus-host disease (GVHD) risks did not differ between African Americans and Caucasians (RR 0.81, 95% CI 0.56–1.17, p=0.26). However, chronic GVHD risk was higher for African Americans, although the difference did not reach statistical significance (RR 1.55, 95% CI 0.98–2.44, p=0.06). Thirty-seven (45%) of 82 African Americans died compared to 56 (27%) of 207 Caucasians. The proportion of patients dying with GVHD was higher in African Americans (12 of 37; 32%) than among Caucasians (9 of 56; 16%). Death secondary to organ failure was higher in Caucasians (12 of 56; 26%) compared to African Americans (4 of 37; 11%). There were no differences between African Americans and Caucasian in regards to deaths from graft failure, infection or hemorrhage. These data suggest recent improvements in overall survival rates after HCT for SAA are largely limited to Caucasians. Higher mortality in African Americans may be explained by greater genetic diversity, which renders the identification of donors by high-resolution HLA-typing more challenging, genetic polymorphisms impacting drug metabolism and unmeasured co-morbidities. Novel strategies aimed at lowering acute and chronic GVHD rates are needed to lower GVHD-related deaths. Disclosures:No relevant conflicts of interest to declare.

HLA-C Antigen Mismatch Is Associated with Worse Outcome in Unrelated Donor Peripheral Blood Stem Cell Transplantation

The association between HLA matching and outcome in unrelated-donor peripheral blood stem cell (PBSC) transplantation has not yet been established. In the present study, a total of 1933 unrelated donor-recipient pairs who underwent PBSC transplantation between 1999 and 2006 for acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia and received high-resolution HLA typing for HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 were included in the analysis. Outcomes were compared between HLA-matched and HLA-mismatched pairs, adjusting for patient and transplant characteristics. Matching for HLA-A, -B, -C, and -DRB1 alleles (8/8 match) was associated with better survival at 1 year compared with 7/8 HLA-matched pairs (56% vs 47%). Using 8/8 HLA-matched patients as the baseline (n = 1243), HLA-C antigen mismatches (n = 189) were statistically significantly associated with lower leukemia-free survival (relative risk [RR], 1.36; 95% confidence interval [CI], 1.13-1.64; P = .0010), and increased risk for mortality (RR, 1.41; 95% CI, 1.16-1.70; P = .0005), treatment-related mortality (RR, 1.61; 95% CI, 1.25-2.08; P = .0002), and grade III-IV graft-versus-host disease (RR, 1.98; 95% CI, 1.50-2.62; P < .0001). HLA-B antigen or allele mismatching was associated with an increased risk for acute GVHD grade III-IV. No statistically significant differences in outcome were observed for HLA-C allele (n = 61), HLA-A antigen/allele (n = 136), HLA-DRB1 allele (n = 39), or HLA-DQ antigen/allele (n = 114) mismatches compared with 8/8 HLA-matched pairs. HLA mismatch was not associated with relapse or chronic GVHD. HLA-C antigen-mismatched unrelated PBSC donors were associated with worse outcomes compared with 8/8 HLA-matched donors. The study's limited power due to small sample size precludesconclusions about other mismatches.

2163 THE SOCIOECONOMIC STATUS OF LIVING UNRELATED RENAL TRANSPLANT DONORS IN THE US IS CONSISTENT WITH ALTRUISTIC MOTIVATION

You have accessJournal of UrologyTransplantation & Vascular Surgery: Renal Transplantation, Vascular Surgery II1 Apr 20102163 THE SOCIOECONOMIC STATUS OF LIVING UNRELATED RENAL TRANSPLANT DONORS IN THE US IS CONSISTENT WITH ALTRUISTIC MOTIVATION John L. Gore, Gabriel M. Danovitch, Arleen Brown, and Jennifer S. Singer John L. GoreJohn L. Gore Seattle, WA More articles by this author , Gabriel M. DanovitchGabriel M. Danovitch Los Angeles, CA More articles by this author , Arleen BrownArleen Brown Los Angeles, CA More articles by this author , and Jennifer S. SingerJennifer S. Singer Los Angeles, CA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.2266AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The National Organ Transplant Act of 1984 prohibited the buying and selling of human organs for transplantation. In other countries, despite similar laws, ecologic evidence of large socioeconomic discrepancies between unrelated donor-recipient pairs suggests the possibility of subversive payment for donated organs. We sought to evaluate the presumption that living unrelated renal transplants (LURTS) in the US are performed for altruistic motives by examining differences in socioeconomic status (SES) in donor-recipient pairs. METHODS We accessed the United Network for Organ Sharing research files to identify adult living donor renal transplant recipients transplanted between 1997-2007. We used a validated composite index (SESI) of the SES characteristics of the ZIP code of residence for each donor and recipient, derived from 2000 US Census Files. An index of 0 represented a patient living in a ZIP code with the median national SES. An index below 0 represented lower SES, and indices above 0 represented higher SES. We compared the SESI of living related and LURT pairs and examined factors associated with a large SESI difference (> 3.0) with logistic regression. RESULTS 51,057 subjects underwent live donor renal transplantation between 1997-2007, of whom 26,978 (53%) lived in higher SES ZIP codes than their donors (p=0.19 compared with related pairs). Although LURT donor-recipient pairs had a higher mean SES index difference (-0.18±3.61 vs 0.04±3.86, respectively), LURT pairs lived in higher SES ZIP codes than their related counterparts (SESI 0.33±3.61 and 0.51±3.74 for LURT donors and recipients; SESI -0.07±3.88 and -0.11±3.85 for related donors and recipients). Being in a LURT pair was associated with higher odds of having a large donor-recipient SESI difference among white recipients (OR 1.50, 95%CI 1.34-1.68, compared with OR 0.99, 95%CI 0.73-1.32 for African Americans, and OR 1.19, 95%CI 0.80-1.75 for Hispanics) and those recipients with at least some college education (OR 0.95, 95%CI 0.41-2.19 for those with less than a high schooled education, OR 1.20, 95%CI 0.98-1.43 for high school-educated recipients, OR 1.54, 95%CI 1.28-1.86 for those with some college, and OR 1.50, 95%CI 1.28-1.75 for those with at least a college degree). CONCLUSIONS We did not identify large discrepancies between the SES of LURT donors and their recipients, suggesting that subversive payment does not confound US LURT. The finding that among certain recipient categories, SES differences tended to be larger requires further evaluation. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e841 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information John L. Gore Seattle, WA More articles by this author Gabriel M. Danovitch Los Angeles, CA More articles by this author Arleen Brown Los Angeles, CA More articles by this author Jennifer S. Singer Los Angeles, CA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Donor and recipient chemokine receptor CCR5 genotype is associated with survival after bone marrow transplantation

AbstractDespite continual improvement, morbidity and mortality after hematopoietic stem cell transplantation (HSCT) remain high. The importance of chemokines in HSCT lies in their regulation of immune responses that determine transplantation outcomes. We investigated the role of recipient and donor chemokine system gene polymorphisms by using a candidate gene approach on the incidence of graft-versus-host disease and posttransplantation outcomes in 1370 extensively human leukocyte antigen–matched, unrelated donor-recipient pairs by using multivariate Cox regression models. Our analysis identified that recipients homozygous for a common CCR5 haplotype (H1/H1) had better disease-free survival (DFS; P = .005) and overall survival (P = .021). When the same genotype of both the donor and recipient were considered in the models, a highly significant association with DFS and overall survival was noted (P < .001 and P = .007, respectively) with absolute differences in survival of up to 20% seen between the groups at 3 years after transplantation (50% DFS for pairs with recipient CCR5 H1/H1 vs 30% for pairs with donor CCR5 H1/H1). This finding suggests that donor and/or recipient CCR5 genotypes may be associated with HSCT outcome and suggests new diagnostic and therapeutic strategies for optimizing therapy.

The impact of HLA-B allele level matching on unrelated stem cell donor transplants in Germany

The German Consensus for matching allogeneic donors of hematopoietic progenitor cell (1996/2000) recommends matching donors for HLA-A,B on serological level (2 digit allele level matching within split groups for B15, B40) and by allele level for DRB1 and, if possible, DQB1. We have retrospectively performed sequencing based HLA-A,B,C analyses for 262 adult unrelated donor recipient pairs matching for A, B, and DRB1 according to the above definition in order to see if outcome could be improved by more stringent selection criteria.

Molecular characterization of HLA-A mismatches for modeling outcomes analyses

For allogeneic transplant candidates who have no HLA matched donor, there are no well accepted guidelines for selecting an HLA mismatched (MM) donor. To provide a foundation for developing new models for ranking HLA MM donors, this investigation focuses on HLA-A MM because single HLA-A MM are observed in a large proportion of patients. The molecular characteristics of 832 HLA-A MM were examined in 3,687 unrelated donor-recipient pairs from NMDP facilitated transplants which had retrospective high resolution HLA typing.