HLA Compatibility Research Articles

Poor survival and prediction of prolonged isolated thrombocytopenia post umbilical cord blood transplantationin patients with hematological malignancies.

Prolonged isolated thrombocytopenia (PIT) is a common complication after umbilical cord blood transplantation (UCBT). However, data on PIT prediction and impacts on transplantation outcomes for UCBT patients are rare. We retrospectively analyzed 244 patients with hematological malignancies who received single-unit UCBT at the First Affiliated Hospital of USTC between August 2018 and December 2019. Among them, PIT occurred in 49 recipients, with a crude incidence of 20.1%. In the PIT patients, the 2-year cumulative incidence of transplant-related mortality (TRM) was significantly higher, and the probabilities of 2-year overall survival, leukemia-free survival and graft-versus-host disease (GVHD)-free relapse-free survival were significantly poorer (57.1% vs. 88.6%; 53.1% vs. 81.9%; 22.4% vs. 59.8%; p<0.001), without remarkable increases in the cumulative incidence of relapse or chronic GVHD. Importantly, the multivariate analysis revealed that lower high-resolution HLA compatibility (≤6/10), lower infused CD34+ cell count (≤1.78×105 /kg), grade II-IV acute GVHD preplatelet engraftment, a lower pretransplantation platelet count (≤100×109 /L), and a longer neutrophil engraftment time (≥17 days) were independent risk factors for PIT after UCBT. These results demonstrate that PIT is common after UCBT, predicting inferior survival and the need for more monitoring during the early phase.

Pretransplant HLA mistyping in diagnostic sample of a T-ALL patient due to loss of heterozygosity in the major histocompatibility complex

PurposeThe degree of HLA compatibility between donor and recipient in hematopoietic stem cell transplantation is critical. In this report, we describe an acute lymphoblastic leukemia case with loss of heterozygosity (LOH) encompassing the entire HLA. MethodsHLA molecular typing was performed on peripheral blood (PB) and buccal swabs (BS). Chromosomal microarray analysis (CMA) was performed using a whole genome platform. ResultsTyping results on PB sample collected during blast crisis demonstrated homozygosity at the-B,-C,-DR, and -DP loci. A BS sample demonstrated heterozygosity at the above loci. A subsequent PB sample drawn after count recovery confirmed heterozygosity. The CMA performed on PB samples collected during blast crisis revealed a large terminal region of copy-neutral LOH involving chromosome region 6p25.3p21.31, spanning approximately 33.32 Mb. The results of the CMA assay on sample collected after count recovery did not demonstrate LOH. ConclusionsLOH at the HLA gene locus may significantly influence the donor search resulting in mistakenly choosing homozygous donors. We recommend confirming the HLA typing of recipients with hematological malignancies when homozygosity is detected at any locus by using BS samples, or alternatively from PB when remission is achieved.

Maternal-fetal HLA compatibility in uncomplicated and preeclamptic naturally conceived pregnancies

Maternal-fetal HLA compatibility in uncomplicated and preeclamptic naturally conceived pregnancies

Impact of human leukocyte antigen compatibility on outcomes of living donor liver transplantation: Experience from a tertiary care center.

The role of HLA compatibility in kidney, heart, and stem cell transplantation is well known, but with regard to living donor liver transplantation (LDLT), there is a different scenario. In the present study, we aim to examine the effects of donor-recipient HLA mismatches at A, B, and DR loci on various outcomes of LDLT-like graft survival, early allograft dysfunction (EAD), acute rejection, length of hospital (LOH) stay, sepsis, and cytomegalovirus (CMV) reactivation. This is a retrospective single center study of a cohort of adult patients who underwent first time ABO-compatible (ABOc) LDLT between January 2010 and December 2018. Transplants with incomplete records or without HLA typing data were excluded. Donor-recipient HLA-A, B, and DR mismatches were assessed in the host versus graft (HVG) direction and were correlated with various post-transplant outcomes. Among 140 transplants being evaluated, approximately two third had total HLA mismatches between 2 and 3. HLA mismatches at each locus as well as cumulative HLA mismatches did not show any association with overall graft survival, EAD, acute rejection episodes, and LOH stay. However, the presence of minimum one mismatch at HLA-A and DR loci was associated with the development of CMV reactivation (P=.03) and sepsis (P=.02) post-LDLT respectively. HLA mismatch is not associated with acute rejection, early graft dysfunction, and overall survival in LDLT. Its impact on CMV reactivation and sepsis needs further evaluation.

Protecting Minor Donors of Hematopoietic Stem Cells: A Survey in EBMT Transplant Centers

IntroductionHematopoietic stem cell (HSC) donation by minors is a well-established practice. According to the literature, up to one-third of pediatric HSC transplants involves donation by minors, most often siblings. Even though HSC donation involves a medical intervention without direct physical benefit to the donor, a broad consensus exists about its acceptability, as it is potentially life-saving for the recipient and carries no more than small risks but conceivably significant psychosocial benefits for the donor. However, because it concerns an intervention on a patient who is considered vulnerable due to age and from which that person will not physically benefit, protective measures have been proposed in ethical guidelines and position papers published by national ethics committees and professional medical organizations. However, no studies have been conducted to assess whether, and, if so, how, these safeguards are implemented in the practices of transplant centers.MethodsA cross-sectional descriptive survey on practices regarding HSC donation by minors was prepared and distributed via email through the office of the European Society for Blood and Marrow Transplantation (EBMT) to 262 EBMT member centers. The survey included closed-ended as well as open-ended questions that assessed: (i) the conditions that have to be met before HSC donation by a minor is accepted; (ii) the approval process; (iii) how consent is obtained from the minor; and (iv) potential psychological support and follow-up. Answers were collected between March 2016 and June 2017. Descriptive statistics for closed ended questions and qualitative content analysis for open questions were used for data analysis. The study was approved by the EBMT Pediatric Diseases Working Party.ResultsForty out of 262 transplant centers from twenty countries completed the questionnaire, constituting a response rate of 15.3%. Altogether, these centers have reported 5,337 HSC donations since 2010, of which 1,651 donations were made by minors (30.9%). The proportion of HSC donation by minors ranged from 0.5% to 100% among the included transplant centers.Twenty-seven centers (67.5%) reported having in place specific guidelines or protocols with regard to HSC donation by minors. In 80% of centers minors can be evaluated for HLA compatibility simultaneously with adult family members, while in the remaining 20% of centers minors are screened only after all adult family members are found to be medically unsuitable to donate. Nearly half of transplant centers (47.5%) only allow minors to serve as donors for siblings, whereas the others also allowed donation to other close relatives, such as parents, grandparents and cousins.Whereas all of the participating centers described efforts to include minor donors in the decision-making process in a way that is in accordance with their age and maturity, significant differences exist with regard to final approval of the donation. After obtaining consent from the donor and his/her parents, fifteen centers (37.5%) do not require any additional approval, whilst the other centers seek permission from a local or national ethics committee (40%), an independent physician (5%), social worker or donor advocate (5%), or the court (7.5%).An independent donor advocate, whose purpose is to promote the wellbeing of the donor and is not involved in direct care of the recipient, was appointed in about one-third (35%) of the centers. Psychological support to the donor and his family after the donation is routinely provided by 70% of the centers.ConclusionsThis is the first study to examine HSC transplant center practices relating to donation by minors. Although all of the participating centers are members of the EBMT network, our research findings reveal significant differences with regard to: (i) the use of specific guidelines and protocols for HSC donation by minors; (ii) the screening of potential minor donors when a compatible adult minor may be available; (iii) the categories of recipients that may benefit from HSC donation by minors; (iv) the need for, and type of, final approval by an independent body; (v) the availability of a dedicated donor advocate; and (vi) the provision of psychological support to and follow-up of minor HSC donors. On the basis of these findings, we suggest that further efforts to harmonize practices involving HSC donation by minors should be undertaken. DisclosuresNo relevant conflicts of interest to declare.

Maternal-Fetal HLA Compatibility in Uncomplicated and Preeclamptic Naturally Conceived Pregnancies.

IntroductionIn pregnancy, the mother and fetus differ in HLA antigens, and yet the maternal immune system generally tolerates the fetus. KIR receptors expressed by maternal uterine NK cells at the maternal-fetal interface directly interact with HLA-C on extravillous trophoblast cells for optimal placental development. In this study, we aimed to determine whether there is a preferential selection for HLA compatibility and specific KIR/HLA-C combinations in uncomplicated and preeclamptic naturally conceived pregnancies compared to what would be expected by chance.MethodsGenotyping for maternal and fetal HLA-A, -B, -C, -DR, and -DQ, and maternal KIR was performed for 451 uncomplicated pregnancies and 77 pregnancies complicated with preeclampsia. The number of HLA antigen (mis)matches between mother and fetus was calculated and compared to expected values obtained by randomization of the HLA haplotype, inherited from the father, over the existing maternal haplotype of the fetuses. A similar methodology was executed for analysis of the KIR/HLA-C data (n=309).ResultsIn uncomplicated pregnancies, the degree of maternal-fetal HLA matching was not different than expected-by-chance values. In preeclamptic pregnancies, the degree of maternal-fetal HLA matching was different in observed compared to expected-by-chance values (p=0.012). More specifically, the degree of maternal-fetal matching of HLA-C was higher in the actual preeclamptic pregnancies than was expected-by-chance (p=0.007). Preeclamptic pregnancies showed an overall tendency towards higher maternal-fetal HLA compatibility, for total HLA matches (p=0.021), HLA class I (p=0.038) and HLA-C (p=0.025) compared to uncomplicated pregnancies.ConclusionThe data suggest that there is no preferential selection of maternal-fetal HLA compatibility in uncomplicated pregnancies. In contrast, increased total HLA, HLA class I and, especially, HLA-C compatibility is associated with preeclampsia, suggestive for a role of HLA mismatches in immune regulation leading to uncomplicated pregnancy.

HLA-DPB1 allele frequencies in the West Midlands region of the United Kingdom: A critical evaluation against the common, intermediate and well-documented allele catalogues CWD 2.0.0, EFI CWD and CIWD 3.0.0.

The Birmingham H&I laboratory performed HLA typing on 456 potential deceased solid organ donors in the UK between 2014 and 2016. Accurate DPB1 typing is essential for determining HLA compatibility in transplantation, thus we report HLA-DPB1 for potential deceased solid organ donors. To correctly interpret HLA typing data, laboratories must understand both international and local HLA allele frequencies. In this analysis, we determined HLA-DPB1 allele and genotype frequencies for these 456 donors. HLA-DPB1 diversity was evaluated against the common and well-documented (CWD) alleles 2.0.0 catalogue, the European Federation for Immunogenetics (EFI) CWD catalogue and the common, intermediate and well-documented (CIWD) 3.0.0 catalogue. Additionally, we determined which alleles are common in our local deceased donor population. We observed 27 HLA-DPB1 alleles with DPB1*04:01 being the most frequently observed (allele frequency=0.4342). All alleles detected locally were present in CIWD 3.0.0, however, DPB1*124:01 and *135:01 were not present in CWD 2.0.0 and DPB1*104:01 and *135:01 were not present in EFI CWD. Twenty of 27 DPB1 alleles identified were defined as locally common and also listed as common in CIWD 3.0.0 representing 62.5% of common alleles in the subset of CIWD 3.0.0 from individuals of a European geographic, ancestral or ethnic background. The alleles HLA-DPB1*16:01 and *20:01 are locally common but not listed as common in EFI CWD and DPB1*104:01 is not listed as common in CWD 2.0.0 catalogue. Our analysis showed that the detected alleles and locally common alleles within our population were aligned with the CIWD 3.0.0 catalogue.

Concurrent typing of over 4000 samples by long-range PCR amplicon-based NGS and rSSO revealed the need to verify NGS typing for HLA allelic dropouts

Hematopoietic stem cell transplantation (HSCT) from HLA-matched donors significantly decreases the risks of graft-rejection and graft-versus-host disease. Long-range PCR- amplicon-based next-generation sequencing (NGS) is increasingly used as a standalone method in clinical laboratories to determine HLA compatibility for HSCT and solid-organ transplantation. We hypothesized that an allelic dropout is a frequent event in the long-range PCR amplicon-based NGS HLA typing method. To test the hypothesis, we typed 4,006 samples concurrently using a commercially available long-range PCR amplicon-based NGS-typing and short exon-specific amplicon-based reverse sequence-specific oligonucleotide (rSSO) methods. The concordance between the NGS and rSSO typing results was 100% at HLA-A, -B, -C, -DRB1, -DRB3, -DRB5, -DQA1, DPA1 loci. However, 4.5% of the samples (179/4006) showed allelic-dropouts at one of the other three loci: HLA-DRB4 (3.9%), HLA-DPB1 (0.4%), and HLA-DQB1*(0.15%). The allelic-dropouts are not associated with specific haplotypes, and some dropouts can be reagent lot-specific. Although DRB1-DRB3/4/5-DQB1 linkages help to diagnose these allelic-dropouts in some cases, the rSSO typing was crucial to identify the dropouts in DQB1 and DPB1 loci. These results uncover the critical limitations of using long-range PCR amplicon-based NGS as a standalone method in clinical histocompatibility laboratories and advocate the need for strategies to diagnose and resolve allelic-dropouts.

Suppression by Allogeneic-Specific Regulatory T Cells Is Dependent on the Degree of HLA Compatibility

Regulatory T cell (Treg) infusion for graft-versus-host disease treatment has been increasingly investigated. However, polyclonal Treg may suppress the desired graft-versus-leukemia effect. Although allogeneic-specific (allo-specific) Treg may provide a more-targeted graft-versus-host disease treatment, there is the need to develop easily translatable expansion protocols and to better characterize their specificity and mechanisms of suppression. In this article, we provide a robust protocol for human allo-specific Treg expansion and characterize their phenotype, potency, and specificity of suppression by testing different expansion conditions and suppression assay milieus. We found that higher concentrations of IL-2 during expansion with allogeneic APC yielded allo-specific Treg that were more-potent suppressors and displayed a more activated phenotype. Although responses to the same APC present during expansion were the most suppressed, responses to third-party APC partially matched to the expansion APC were still significantly more suppressed than responses to fully mismatched APC. Furthermore, suppression of responses to the expansion APC was strictly contact dependent, whereas suppression of responses to mismatched APC was partially independent of contact. Finally, distinct subsets in fresh and expanded Treg could be described using multidimensional visualization techniques. We propose that allo-specific Treg are HLA specific and that the mechanisms of suppression elicited depend on their compatibility with the stimulators.

CD34+ Stem Cell Selection and CD3+ T Cell Add-Back from Matched Unrelated Adult Donors in Children with Primary Immunodeficiencies and Hematological Diseases

Less than 25% of children who require hematopoietic stem cell transplantation (HSCT) for primary immunodeficiencies (PIDs) or genetic hematological diseases have an HLA-identical sibling. For them, a matched unrelated donor (MUD), although baring a greater risk of graft failure, delayed engraftment and immune reconstitution, and severe graft-versus-host disease (GvHD), represents a valid alternative. The stem cell source is also important, as unprocessed peripheral blood stem cells (PBSCs) contain 5 to 10 times more T cells than bone marrow (BM)-derived grafts, a major risk especially for small children with PID. A CD34+ positive selection can mitigate HLA compatibility issues, but the resulting CD3+ T cell depletion hampers engraftment and facilitates infections. To mitigate those problems, we decided to add back a certain number of T cells (30×106 cells/kg body weight [BW]) to the positive CD34+ selection derived from MUD BM or PBSCs and report the results in terms of time to engraftment and immune reconstitution, GvHD incidence, infections, and survival. Our aim was to show not only the feasibility and clinical efficacy of this addback but also that PBSC-derived CD34+ selected grafts with calibrated T cell addback would be equivalent to BM-derived grafts. We analyzed retrospectively our single-center cohort of 76 children (median age, 1.9 years) affected by PID (61) and hematological diseases (15) who received a total of 79 MUD HSCTs with CD34+ selection and addback of 30×106 CD3+ cells/kg BW between 2001 and 2019. We used descriptive and analytic statistics (chi-square, Student's t-test, Mann-Whitney U test, as appropriate) and constructed Kaplan-Meier curves using the log-rank test to compare patients grafted with BM or PBSC-derived inocula. The two groups showed no statistically significant differences in terms of age, sex, HLA-mismatch, or amount of CD3+ cells/kg BW added back to the CD34+ selection. However, the latter being higher in the PBSC group (P=.0001). Overall engraftment rate was 96% (73/76) and occurred faster in the PBSC group than in BM recipients: polymorphonuclear cells, 16 versus 21 days (P=.006); platelets, 15 versus 22 days (P=.001). GvHD incidence was low. No acute GvHD was diagnosed in 24 children, whereas grades I, II, III, and IV occurred in 19, 28, five, and three children, respectively (P not significant). Chronic GvHD was seen in only two children. The CD4+ count at six months after HSCT was higher in PBSC recipients as compared to those receiving BM (184 versus 88 CD4+ cells; P=.003). Overall survival for the whole cohort was 80% at 10 years, with no significant difference between the two stem cell sources (P not significant). Viral infections occurred among five of the PBSC grafted children and 14 in the BM group (P not significant), and no patient suffered from post-transplant lymphoproliferative disorder (PTLD). The results we present show that an addback of 30×106 donor CD3+ cells/kg recipient BW to a MUD BM or PBSC-derived CD34+ selection gives promising results in infants and young children undergoing HSCT for PID or hematological diseases. Furthermore, with this manipulation the inherent limits of PBSC-derived grafts can be overcome, allowing both swift engraftment and immune reconstitution without an increase in GvHD, infections, or PTLD.

Matchmaker, matchmaker make me a match: Opportunities and challenges in optimizing compatibility of HLA eplets in transplantation.

The development of donor-specific antibodies (DSAs) is a major complication in transplantation, which is associated with inferior graft survival, impaired quality of life, and increased healthcare costs. DSA develop upon recognition of nonself HLA by the recipient's immune system. HLA molecules contain epitopes, which are the surface regions of HLA molecules recognized by antibodies. HLAMatchmaker is an algorithm for assessing donor:recipient HLA compatibility at the level of structurally defined HLA targets called eplets. The consideration of eplets, rather than the whole HLA molecule, could offer some advantages when classifying the immune risk associated with particular donor:recipient pairs. Assessing compatibility at the level of HLA eplets could decrease misclassification of post-transplant immune risk by improving specificity, when antibodies are confirmed to be directed against donor eplets missing from the recipient's repertoire of eplets. Consideration of eplets may also increase the sensitivity of immune risk assessment, when identifying mismatched eplets that could give rise to new, not previously detected, donor-specific antibodies post-transplant. Eplet matching can serve as a rational strategy for immune risk mitigation. Herein, we review the evolution of HLA (in) compatibility assessment for organ allocation. We outline challenges in the implementation of eplet-based donor:recipient matching, including unavailability of allele-level donor genotypes for 11 HLA loci at the time of organ allocation and difficulty in assessing the hierarchy of immune risk associated with particular HLA eplet mismatches. Opportunities to address some of the current shortcomings of donor genotyping and HLAMatchmaker are also discussed. While there is a demonstrated benefit in the application of HLAMatchmaker for donor: recipient HLA (in)compatibility assessment, evolving long-read genotyping methods, compilation of large data sets with allele-level genotypes, and standardization of methods to verify eplets as determinants of immune-mediated injuries are required before HLA eplet matching is implemented in organ allocation to improve upon transplant outcomes.

Infection Related Immunoglobulin-M Antibodies Cross Reactive with Human Leucocyte Antigens

Objective: The first required feature for the patients, who will undergo allotransplantation, is HLA compatibility between donor and the recipient. In this study, it was aimed to indicate whether IgM antibodies that are produced during acute infection phase affect crossmatch tests or not, in addition to hitches that can occur in HLA incompatible transplants. Methods: Eighty-two patients with acute infection due to only one infectious agent and high serum IgM antibody levels were involved in this study. The patients had no alloimmunization (blood transfusion, pregnancy, and/or previous transplants). Fifty-five healthy individuals were used as HLA antigen source in order to evaluate Ab-Ag lymphocytotoxicity reactions. Results: The infectious agent distribution in the sera samples were as 25.6% Anti-Epstein-Barr virus capsid antigen (EBV VCA), 14.6% Anti-Cytomegalovirus (CMV), 17.1% Anti-Toxoplasma, 11% Anti-Hepatitis A Virus (HAV), 7.3% Anti-Rubella, 7.3% Anti-Varicella zoster virus (VZV), 4.9% Anti-Brucella, 3.7% Anti-Mumps, 2.97% Anti-Parvovirus B19, 1.9% Anti-Herpes simplex virus (HSV)-1, and 3.7% Anti-HBc. IgM antibody and HLA antigen reactions were analyzed by lymphocytotoxicity method in terasaki plates using peripheral blood lymphocytes of 55 healthy individuals. Conclusion: In lymphocytotoxicity test, the distribution of reactions that IgM antibodies gave to HLA antigens without class I-II differentiation according to infections were identified as 50% Brucella, 50% VZV, 44.4% HAV, 41.7% CMV, 42.9% EBV, 35.7% Toxoplasma, and 33.3% Rubella.

Что мы знаем о фетальном и материнском микрохимеризме?

Microchimerism is a condition characterized by the presence of a small number of foreign cells genetically different from the host cells. Thus, during pregnancy maternal and fetal cells cross the placental barrier, enter the foreign bloodstream and settle in the organs, which leads to the formation of fetal-maternal microchimerism. This review covers some aspects of fetal-maternal microchimerism, including its impact on the course of pregnancy. The existence of fetal micro-chimerism during pregnancy confirms the fact that the maternal immune system interacts with fetal antigens long before delivery. Also, fetal microchimerism may influence the course of auto-immune diseases during pregnancy, which is associated with the fetal-maternal HLA compatibil-ity. Scientists suggest that autoimmune processes that develop after pregnancy are in fact “graft versus host” reactions that occur in response to fetal allogeneic cells. Maternal cells can also cross the placental barrier. This results in the development of tolerance to maternal antigens that are foreign to the fetus. This postnatal immune tolerance is presumably involved in the immuno-suppressive mechanisms that contribute to fetal survival in utero. It has been proven that the fetal immune system is functionally active and is formed in utero due to fetal-maternal microchimerism, non-sterile placental environment under the impact of maternal microbiota and transplacental transfer of immunoglobulins, by inflammatory mediators and cytokines. An important finding is the absence of signs of maternal microchimerism (MMc) in women with preeclampsia. Many questions remain unanswered, therefore, further studies on fetal-maternal microchimerism are needed to assess its impact on the human body. Key words: fetal-maternal microchimerism, immune tolerance, placental barrier, pregnancy, preeclampsia

Young haploidentical donor versus fully matched elderly donor: An observational study on patients aged 50 years or older underwent hematopoietic progenitor cells transplantation

IntroductionStem cell transplantation has been a therapeutic option for increasingly older patients but the search for the donor is an additional question in this context. Currently the ideal donor is a sibiling with fully compatible human leukocyte antigens, but when it is an elderly patient there is a high probability that this donor is also elderly, and the donor age has been related to worse outcomes and the possible comorbidities may render the donor ineligible. ObjectiveTo compare, in patients aged 50 years or older, the overall survival of patients whose donor had haploidentical HLA compatibility and under 50 years of age (“young” donor) versus patients whose donor had a total HLA compatibility and 50 years of age or older (“elderly” donor). MethodsThis is a consecutive retrospective descriptive observational epidemiological study. All patients were treated during the period from January, 2010 to April, 2019. Overall survival of patients 50 years of age and older was the primary outcome of the study. ResultWe included 53 patients. In the multivariate analysis we found no statistically significant difference in overall survival between patients whose donor had fully HLA compatible aged 50 years and older and patients whose donor had haploidentical HLA compatible and aged up to 50 years (p = 0.135). ConclusionThe results obtained in the study show that for patients aged 50 years or older, a donor with haploidentical human leukocyte antigen compatibility and age below 50 years can be chosen without impairing overall survival.

The HLA diversity of the Anthony Nolan register.

While the success of allogeneic stem cell transplantation depends on a high degree of HLA compatibility between donor and patient, finding a suitable donor remains challenging due to the hyperpolymorphic nature of HLA genes. We calculated high‐resolution allele, haplotype and phenotype frequencies for HLA‐A, ‐C, ‐B, ‐DRB1 and ‐DQB1 for 10 subpopulations of the Anthony Nolan (AN) register using an in‐house expectation‐maximisation (EM) algorithm run on mixed resolution HLA data, covering 676 155 individuals. Sample sizes range from 599 410 for British/Irish North West European (BINWE) individuals, the largest subpopulation in the United Kingdom to 1105 for the British Bangladeshi population. Calculation of genetic distance between the subpopulations based on haplotype frequencies shows three broad clusters, each following a major continental group: European, African and Asian. We further analysed the HLA haplotype and phenotype diversity of each subpopulation, and found that 35.52% of BINWE individuals ranging to 98.34% of Middle Eastern individuals on the register had a unique phenotype within their subpopulation. These analyses and the allele, haplotype and phenotype frequency data of the subpopulation on the AN register are a valuable resource in understanding the HLA diversity in the United Kingdom and can be used to improve the accuracy of match likelihoods and to inform future donor recruitment strategies.

How Ancestry Influences the Chances of Finding Unrelated Donors: An Investigation in Admixed Brazilians.

A match of HLA loci between patients and donors is critical for successful hematopoietic stem cell transplantation. However, the extreme polymorphism of HLA loci – an outcome of millions of years of natural selection – reduces the chances that two individuals will carry identical combinations of multilocus HLA genotypes. Further, HLA variability is not homogeneously distributed throughout the world: African populations on average have greater variability than non-Africans, reducing the chances that two unrelated African individuals are HLA identical. Here, we explore how self-identification (often equated with “ethnicity” or “race”) and genetic ancestry are related to the chances of finding HLA compatible donors in a large sample from Brazil, a highly admixed country. We query REDOME, Brazil’s Bone Marrow Registry, and investigate how different criteria for identifying ancestry influence the chances of finding a match. We find that individuals who self-identify as “Black” and “Mixed” on average have lower chances of finding matches than those who self-identify as “White” (up to 57% reduction). We next show that an individual’s African genetic ancestry, estimated using molecular markers and quantified as the proportion of an individual’s genome that traces its ancestry to Africa, is strongly associated with reduced chances of finding a match (up to 60% reduction). Finally, we document that the strongest reduction in chances of finding a match is associated with having an MHC region of exclusively African ancestry (up to 75% reduction). We apply our findings to a specific condition, for which there is a clinical indication for transplantation: sickle-cell disease. We show that the increased African ancestry in patients with this disease leads to reduced chances of finding a match, when compared to the remainder of the sample, without the condition. Our results underscore the influence of ancestry on chances of finding compatible HLA matches, and indicate that efforts guided to increasing the African component of registries are necessary.

Hyperbaric Oxygen Therapy for Late-Onset Hemorrhagic Cystitis after Allogeneic Hematopoietic Stem Cell Transplantation and Effective Factors Prediction

Background: Late-onset hemorrhagic cystitis (LO-HC) is one of the common complications and major causes of morbidity in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). The classic treatment for HC includes hydration, alkalization, bladder irrigation, immunosuppressant reduction, and platelet transfusion. When the HC was considered to be associated with aGVHD, more immunosuppressive agents such as glucocorticoids will be added in. However, too intensive immunosuppressive measures leave the patients susceptible to infection and, in turn, increases the accidence of non-relapse mortality (NRM). It is important to explore novel, less-toxic, more effective, and cost-effective strategies for LO-HC. Hyperbaric oxygen therapy (HBOT) can stimulate fibroblast proliferation, angiogenesis, and wound healing. We deduce that HBOT might benefit patients with LO-HC after allo-HSCT. Methods: In this study, we retrospectively analyzed 238 patient underwent allo-HSCT in our center. From 2018, patients with LO-HC have been given HBOT in addition to conventional treatment in our center. The data in HBOT and the control group were collected and compared. Patients' characteristics were compared using the x2 test in case of discrete variables or the Mann-Whitney test in case of continuous variables. Logistic regression examined factors might be used as effective predictors for HBOT. Sensitivity and specificity were estimated based on four parameters cut-off point for additional glucocorticoid necessity. Results: A total of 238 patients who underwent allo-HSCT from 2014 to 2020 were enrolled in this study. Among them, 55 (23.11%) developed LO-HC (36 received regular treatment, and 19 received HBOT in addition to the regular therapy). The clinical &amp; transplantation parameters of the patients with LO-HC were listed in table 1. There is no significant difference in the age, gender, primary disease distribution, conditioning regimen, donor, HLA compatibility, stem cell sources, the occurrence of aGVHD between two groups. There is also no significant difference in the initial day of LO-HC post-HSCT and duration, peak red cells count in the urine, and whether additional glucocorticoid for HC control had been added between the two groups. It is worth noting that compared with the HBOT group, we found higher HC grade distribution, higher CMV-DNA copies, and decreased levels of SOD2 within the 1st week of the initial therapy for LO-HC in the control group. The comparison of the demographic and medical characteristics of subjects with LO-HC were listed in table 2. According to the results of logistic regression analysis, patients who developed LO-HC with higher HC grade (p = 0.001) and decreased SOD2 level (p = 0.002) might benefit more from HBOT, indicating that they might be used as effective predictors for HBOT (Figure 1A). Only higher HC grade (p = 0.011) could predict whether or not additional glucocorticoid would be necessary for LO-HC control (Figure 1B). The predictive power of additional glucocorticoid during the LO-HC treatment process for 4 different titers (HC grade and duration, CMV, and SOD2 level) was evaluated by ROC analysis. According to the area under the curve (AUC), the best diagnostic capabilities of four parameters were shown in Figure 2A, 2B, 2C, and 2D. None of our patients experienced severe adverse events of HBOT, such as gas emboli, pulmonary edema, and seizures. Only one patient with AML discontinued after 1 session due to the reversible ear barotrauma which was suspected with HOBT. Conclusions: In summary, HBOT was effective and well-tolerated in patients with LO-HC post-allo-HSCT. Patients who received HBOT exhibited with short disease duration and mild LO-HC grade. Higher HC grade and decreased SOD2 levels might be used as effective predictors for HBOT. Higher HC grade might be used as a predictor to determine whether or not additional glucocorticoid would be necessary for HC control. In the future, HBOT might be not only used as an adjunctive care application for LO-HC, but also might be as the first-line treatment therapy for this population, regardless of the causes of LO-HC. Based on our preliminary result, we plan to enroll more eligible patients to establish the definitive efficacy and safety of HBOT in patients with LO-HC after allo-HSCT (NCT04502628). Disclosures No relevant conflicts of interest to declare.

Efficacy of Remestemcel-L Treatment in Steroid Refractory Acute Graft-Versus-Host Disease in Children: An Aggregate Analysis

Introduction: Steroid-refractory acute graft-versus-host dose disease (SR-aGVHD) is a frequent and potentially fatal complication of hematopoietic stem cell transplantation (HSCT). There are no approved therapies specifically indicated for use in children with SR-aGVHD &amp;lt; 12 years old. Treatment with culture-expanded, adult human allogeneic bone marrow (BM)-derived mesenchymal stromal cells (remestemcel-L) has shown excellent safety and efficacy in clinical trials conducted over the past 10 years. Here we describe aggregate results of remestemcel-L treatment of SR-aGVHD in the pediatric population. Methods: 309 pediatric subjects with SR-aGVHD were treated with remestemcel-L across 3 protocols. Data were derived from a phase 3, single arm study as first line after steroid failure with no other second line aGVHD therapies added through day 28 (NCT02336230, n=54), an expanded access program in subjects with aGVHD that had not responded to multiple other treatments (NCT00759018, n=241) and the pediatric subset of a randomized controlled trial (NCT00366145, n=14) in which remestemcel or placebo were given with a concomitant second line aGVHD therapy. Subjects in each protocol received 8 intravenous infusions of remestemcel-L (2 x 106 cells/kg twice weekly for 4 weeks). Those achieving a partial response could receive an additional 4 doses (once weekly for the subsequent 4 weeks). This analysis included 309 subjects who received at least one remestemcel-L dose. Response was assessed 28 days after the first dose. Survival was evaluated through day 100. Results: At baseline, mean age was 8.9 years (range 0.3 to 18.2 years) and aGVHD severity by IBMTR grade was C or D in n=252 (82%). Sources of grafts were bone marrow (BM: 46%), mobilized blood (MB: 20%) and cord blood (CB: 31%). Donor grafts were HLA matched related (9%) or unrelated (44%) or HLA-mismatched (46%). Subjects received a mean (standard deviation) of 10.3 (4.2) remestemcel-L infusions for a mean cumulative dose of 660.8 (484.1) x 106 cells. The primary endpoint, overall response (complete + partial response) at day 28 (OR) was observed in 66% of subjects (204/309) and survival at day 100 (OS) was 68% (211/309). Day 28 OR strongly predicted day 100 survival. Among subjects who were alive at day 28 (N=284), 170 of the 204 (83%) responders survived through day 100. In contrast, 41/80 (51%) of non-responders survived through day 100. Day 28 OR frequencies and day 100 OS rates were consistent across baseline aGVHD grades: Grade B OR 70%, OS 77%; Grade C or D OR 65%, OS 66%. Comparable day 28 response frequencies and day 100 survival rates were observed across type of HSCT: OR was achieved in 65%, 64% and 71% of BM, MB and CB, respectively and 67%, 70% and 70% of BM, MB and CB recipients survived through day 100. Comparable OR and OS were observed in HLA compatibility and donor types with OR in 71%, 66% and 66% and day 100 OS in 64%, 66% and 71% of matched related or unrelated and mismatched, respectively. Remestemcel-L was well tolerated with no infusion-related toxicity or other safety concerns. Most treatment-emergent serious adverse events were attributable to aGVHD or the underlying pre-transplant disease. Conclusions: In this large, diverse sample of pediatric subjects with SR- aGVHD, treatment with remestemcel-L was associated with a high and consistent overall response rate and survival rate through 100 days. Day 28 OR was highly predictive of day 100 survival. Remestemcel-L was well tolerated and effective across transplant types, donor sources, moderate to severe grades of GVHD and prior or concurrent treatment paradigms as defined by the individual protocols in this aggregate analysis. Remestemcel-L is a safe and effective treatment for children with SR- aGVHD addressing an unmet medical need for this highly vulnerable population. Disclosures Kurtzberg: Mesoblast, Inc,: Consultancy, Honoraria. Martin:Abgenomics: Research Funding; Enlivex: Consultancy; Procter and Gamble: Current equity holder in publicly-traded company; Pharmacyclics LLC: Membership on an entity's Board of Directors or advisory committees; Neovii: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfzier: Membership on an entity's Board of Directors or advisory committees; Xenikos: Research Funding; Talaris: Consultancy; Rigel: Consultancy; Mesoblast, Inc.: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Prockop:Atara: Research Funding; Jasper: Research Funding; Mesoblast, Inc,: Consultancy, Honoraria, Research Funding. Burke:Mesoblast, Inc,: Current Employment. Segal:Mesoblast, Inc,: Current Employment.

Long-Term (≥25 Years) Kidney Allograft Survivors: Retrospective Analysis at a Single Center

IntroductionDespite great improvements in the short-term patient and kidney graft survival, the long-term morbidity and mortality in kidney transplant recipients still remains a significant problem. The aim of the study was to evaluate the impact of both donor and transplant recipient factors, as well as renal function indices on the very long-term (>25 years) kidney allograft survival. Material and MethodsRetrospective analysis was performed on the data of 41 kidney transplant recipients (KTR), group A: follow-up = 25 years, 20 KTR, 10 male, mean age (mean [M] ± standard deviation [SD]): 34.6 ± 12.6 years, 14 living donors (LD), 6 cadaveric donors (CD); group B: follow-up > 25 years, 21 KTR, 16 male, mean age (M ± SD): 30.86 ± 12.37 years, 14 LD, 7 CD). Kidney graft origin, post-kidney transplantation diabetes mellitus, HLA compatibility, delayed graft function, and acute rejection episodes were also analyzed retrospectively. Statistical analysis with Mann-Whitney test and Kaplan-Meier survival analysis was performed (SPSS 20.0 for Windows). ResultsThe mean age of CDs was lower than that of LDs: CD mean age (M ± SD): 23.84 ± 16.26 years vs LD mean age: 52.75 ± 12.42 years (P < .001). Cadaveric kidney graft was associated with better renal allograft function 10, 15, and 25 years post kidney transplant. None of the other factors analyzed reached statistical significance between the 2 groups. ConclusionThe age of the donor and the kidney graft origin are important co-factors of the very long-term kidney allograft survival.

P0588TUBULAR EPITHELIUM INJURY BIOMARKERS AND SURVIVAL AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

Abstract Background and Aims In our recent study we have shown, that some tubular epithelium injury molecular biomarkers (MBMs) may be used for acute kidney injury (AKI) prediction in a specific category of patients, receiving hematopoietic stem cell transplantation (HSCT). Here we aimed to determine the value of this MBMs for the evaluation of the mortality following HSCT. Method 90 HSCT recipients (46 males, 44 females) were enrolled. All-cause mortality was registered along 1 year of posttransplant period. MBM’s (calbindin, clusterin, IL-18 (interleukin-18), KIM-1 (kidney injury molecule-1), GST-π (glutathione S-transferase- π), MCP-1 (monocyte chemoattractant protein-1)) relative concentration increase was determined in alive and deceased patients after HSCT. MBM’s associations with death risk were estimated in multivariate models adjusted for clinical factors related to the prognosis (AKI, progression of the underlying disease, incomplete HLA compatibility, etc.). Results It was found that the relative increase in the concentrations of some MBMs was significantly higher in the group of deceased HSCT recipients (Figure). In multivariate models the associations of KIM-1, MCP-1, and calbindin with mortality were not reliable (data not shown). As for clusterin, this relationship was reliable and independent of other significant clinical factors, including overt AKI (HR=1,085 (1,034-1,139; p=0,001). Conclusion Urinary MBMs, taking into account their independent association with posttransplant all-cause mortality risk, may become a useful tool not only for AKI prediction, but also for HSCT prognosis evaluation.