Pretransplant Donor Research Articles

Transfer and loss of allergen-specific responses via stem cell transplantation: A prospective observational study.

Currently, no estimates can be made on the impact of hematopoietic stem cell transplantation on allergy transfer or cure of the disease. By using component-resolved diagnosis, we prospectively investigated 50 donor-recipient pairs undergoing allogeneic stem cell transplantation. This allowed calculating the rate of transfer or maintenance of allergen-specific responses in the context of stem cell transplantation. Allergen-specific IgE and IgG to 156 allergens was measured pretransplantation in 50 donors and recipients and at 6, 12 and 24months in recipients post-transplantation by allergen microarray. Based on a mixed effects model, we determined risks of transfer of allergen-specific IgE or IgG responses 24months post-transplantation. After undergoing stem cell transplantation, 94% of allergen-specific IgE responses were lost. Two years post-transplantation, recipients' allergen-specific IgE was significantly linked to the pretransplantation donor or recipient status. The estimated risk to transfer and maintain individual IgE responses to allergens by stem cell transplantation was 1.7% and 2.3%, respectively. Allergen-specific IgG, which served as a surrogate marker of maintaining protective IgG responses, was highly associated with the donor's (31.6%) or the recipient's (28%) pretransplantation response. Hematopoietic stem cell transplantation profoundly reduces allergen-specific IgE responses but also comes with a considerable risk to transfer allergen-specific immune responses. These findings facilitate clinical decision-making regarding allergic diseases in the context of hematopoietic stem cell transplantation. In addition, it provides prospective data to estimate the risk of transmitting allergen-specific responses via hematopoietic stem cell transplantation.

One Year of Preemptive Valganciclovir Administration in Children After Liver Transplantation

ObjectivesValganciclovir (VGCV) is used as prophylaxis against cytomegalovirus (CMV) infection after pediatric living donor liver transplantation (LDLT). The purpose of this study was to examine the efficacy of 1 year of preemptive VGCV administration compared with a shorter administration after pediatric LDLT. MethodsVGCV was administered to 56 children who underwent LDLT. CMV and Epstein-Barr virus (EBV) antibody status, pp65 antigenemia, and other laboratory data were assessed at 1 year after LDLT. Patients were divided into the 1-year group (n = 32) (patients who had 1 year of VGCV administration) and the <1-year group (n = 24) (patients who had less than 1 year of VGCV administration). ResultsStudy participants consisted of 34 females and 22 males, with a mean age of 4.2 years at transplant. Regarding pretransplant donor (D)/recipient (R) CMV antibody status, 13 were D positive (+)/R negative (-), 27 were D+/R+, 8 were D-/R+, and 8 were D-/R-. For EBV, 22 were D+/R+, 32 were D+/R-, and 2 were D-/R-. In the 1-year group, only 2 patients (6.5%) developed CMV infection, whereas 8 patients (33.3%) developed CMV infection in the <1-year group. The CMV pp65 antigenemia assay was positive in 2 patients. CMV IgM was positive in 7 patients. One year of preemptive VGCV administration was associated with a lower incidence of CMV infection (P = .008), but not EBV infection. No adverse effects were observed. ConclusionsOne year of preemptive VGCV administration after LDLT is safe and suppresses CMV infection. It was useful after pediatric LDLT.

Donor bone-marrow CXCR4+ Foxp3+ T-regulatory cells are essential for costimulation blockade-induced long-term survival of murine limb transplants

Vascularized composite allotransplantation (VCA) allows tissue replacement after devastating loss but is currently limited in application and may be more widely performed if maintenance immunosuppression was not essential for graft acceptance. We tested whether peri-transplant costimulation blockade could prolong VCA survival and required donor bone-marrow cells, given that bone-marrow might promote graft immunogenicity or graft-versus-host disease. Peritransplant CD154 mAb/rapamycin (RPM) induced long-term orthotopic hindlimb VCA survival (BALB/c->C57BL/6), as did CTLA4Ig/RPM. Surprisingly, success of either protocol required a bone-marrow-associated, radiation-sensitive cell population, since long-bone removal or pre-transplant donor irradiation prevented long-term engraftment. Rejection also occurred if Rag1−/− donors were used, or if donors were treated with a CXCR4 inhibitor to mobilize donor BM cells pre-transplant. Donor bone-marrow contained a large population of Foxp3+ T-regulatory (Treg) cells, and donor Foxp3+ Treg depletion, by diphtheria toxin administration to DEREG donor mice whose Foxp3+ Treg cells expressed diphtheria toxin receptor, restored rejection with either protocol. Rejection also occurred if CXCR4 was deleted from donor Tregs pre-transplant. Hence, long-term VCA survival is possible across a full MHC disparity using peritransplant costimulation blockade-based approaches, but unexpectedly, the efficacy of costimulation blockade requires the presence of a radiation-sensitive, CXCR4+ Foxp3+ Treg population resident within donor BM.

Prognostic impact of Epstein-Barr virus serostatus in patients with nonmalignant hematological disorders undergoing allogeneic hematopoietic cell transplantation: the study of Infectious Diseases Working Party of the European Society for Blood and Marrow Transplantation

AbstractBackgroundIn patients with acute leukemia, lymphoma and chronic malignancies, donor and/or recipient Epstein-Barr virus (EBV) seropositive status increases the risk of development of chronic graft-versus-host disease (cGVHD) after allo-hematopoietic cell transplantation (allo-HCT), while it has no influence on other transplant outcomes. No data are available on the impact of EBV serostatus on transplant outcomes in patients with nonmalignant hematological disorders.ObjectiveWe analyzed the influence of the recipient's (R) and donor's (D) EBV serostatus on transplant outcomes (overall survival (OS); relapse-free survival (RFS); relapse incidence (RI); nonrelapse mortality (NRM); acute graft-versus-host disease (aGVHD); cGVHD) in patients with nonmalignant hematological disorders undergoing allo-HCT.Patients and MethodsA total of 2,355 allo-HCTs performed between 1997 and 2016 for acquired bone marrow failure or hemoglobinopathies were included in this retrospective Registry megafile Infectious Diseases Working Party of the European Society of Blood and Marrow Transplantation (IDWP-EBMT) study.ResultsDemographics: The median age of recipient was 17.7 years (range: 0–77), and 50.8% were children. 79.0% of recipients and 75.4% of donors were EBV-seropositive. 67.8% had HCT from a matched family donor, 4.6% from a mismatched family donor, and 27.6% from an unrelated donor (UD). T-cell depletion was performed in vivo and ex vivo in 82.2% and 6.6% of patients, respectively. Conditioning regimen was myeloablative in 63.7% and reduced intensity conditioning (RIC) in 36.3% of patients. The median follow-up was 4.7 years. Transplant outcomes: EBV-seropositive recipients in comparison with EBV-seronegative recipients had lower OS (85.4% vs. 88.4%, p = 0.035) and higher NRM (10.0% vs. 6.4%, p = 0.018). No other significant differences were found for: RI, RFS, and aGVHD or cGVHD with respect to EBV pretransplant serostatus donor and/or recipient. Multivariate analysis: A trend toward higher risk of development of cGVHD (HR = 1.31; p = 0.081) and better survival (HR = 0.78; p = 0.087) in allo-HCT from EBV-seropositive donors was found. Allo-HCT in EBV-seropositive recipients had a trend toward lower risk of development of cGVHD (HR = 0.75; p = 0.065). When four subgroups (R−/D−, R−/D+, R+/D−, R+/D+ EBV serology) were analyzed, the EBV serostatus had no significant impact on OS, RFS, RI, NRM and development of aGVHD or cGVHD.ConclusionsAllo-HCT from EBV-seropositive versus EBV-seronegative donors are at 31% higher risk of cGVHD in patients with nonmalignant hematological disorders undergoing allo-HCT; however this difference is nonsignificant in multivariate analysis.

The Impact of Gastroesophageal Reflux and Esophageal Motility on Spirometry Following Lung Transplantation

Although lung transplant recipients (LTR) with uncorrected gastroesophageal reflux disease (GERD) have been shown to have increased allograft complications, including lower early lung function and chronic lung allograft dysfunction development, the impact of esophageal dysmotility ( EsD) on lung function remains incompletely understood. This study examines the interaction of GERD and EsD on spirometry in LTRs. 46 esophageal manometry, and pH impedance studies were available for review within 54 sequential lung transplant recipients at Johns Hopkins Hospital between July 2015 and June 2018. GERD was defined by either an abnormal DeMeester (>14) and/or abnormal impedance, and EsD was defined per any abnormal Chicago classification 3.0 diagnosis. Recipient, donor demographics and spirometry (FEV1) were captured up to post -op month nine, prior to any post-transplant fundoplication procedures. Categorical variables were compared using Kruskal Wallis test, and continuous variables with Rank Sum or Kruskal Wallis tests. Demographics and findings are displayed in table 1. There were no significant differences in pre transplant recipient and donor characteristics. Both LTR's with EsD and LTR's with any GERD had significantly lower median FEV1 values when compared to LTR without EsD or without GERD, respectively, at 6 months post-transplant. (1.82 vs 2.32, p<0.007, and 1.57 vs 2.13 <0.04). These differences persisted at month 9. LTR's with combined GERD and EsD had significantly lower median FEV1 compared to LTR's without either at both 6 months (1.52 vs 2.2 p< .03 ) and at 9 months 1.59 vs 2.18, p <0.02 ) and a trend towards worse FEV1 than with GERD or EsD alone. Our findings suggest that LTR's with combined EsD and GERD may be at highest risk of post- transplant allograft dysfunction. Further multivariate analysis of covariates, along with assessment of the impact of corrective procedures in LTR's with combined GERD/EsD may be helpful in guiding management.

Spectrum of Chronic Lung Allograft Pathology in Human Lung Transplantation

The long-term survival after a lung transplantation remains limited by Chronic Lung Allograft Dysfunction (CLAD), which includes two main phenotypes: bronchiolitis obliterans syndrome (BOS), characterized by airway fibrosis and obliteration, and restrictive allograft syndrome (RAS), presenting with parenchymal fibrosis (PF) and restriction (2019 ISHLT consensus). It has been noted that there can be overlap between these phenotypes. We aimed to detail and quantify pathological features of human CLAD sub-types. Peripheral and central paraffin-embedded explanted left upper lobe lung samples were obtained from 20 consecutive patients undergoing second lung transplantation for CLAD (phenotyped clinically at retransplant). Sections were stained with Hematoxylin & Eosin and Elastic-Trichrome. Blinded semi-quantitative grading was performed: percentage of evaluable lung tissue area affected by PF was estimated; Peri-airway fibrosis (P-AF) and bronchiolitis obliterans (BO) were graded 0-4 for each airway. Pleural fibrosis (PLF), epithelial flattening (EF) and hyperplasia (EH) were graded on a scale 0-4 (fig 1A-C). There was notable overlap in pathological scores between BOS (n=11) and RAS/Mixed (RAS n=8, Mixed n=1), although there was a trend towards higher PF, P-AF and EH scores in RAS (fig 1D, E). Samples with BO grades >=2 had higher EH grades (p=0.003) and tended to have lower EF grades (p=0.11). Samples with P-AF >=2 had higher EH grades (p=0.002) and lower EF grades (p=0.01). Also, 9 patients had a respiratory infection at the time of retransplantation (1 BO, 8 RAS): PF scores were higher in RAS infected patients (p=0.02). Our results confirm that BO and PF can coexist to different degrees of severity in both patients with RAS and BOS. Divergent epithelial changes are seen and may be important in CLAD phenotype evolution. Sampling heterogeneity may be confounding these results and we plan to confirm these by grading multiple samples across 4 lobes.

Chest X-ray Sizing for Lung Transplants Reflects Pulmonary Diagnosis and Body Composition and Is Associated With Primary Graft Dysfunction Risk.

Donor-recipient oversizing based on predicted total lung capacity (pTLC) is associated with a reduced risk of primary graft dysfunction (PGD) following lung transplant but the effect varies with the recipient's diagnosis. Chest x-ray (CXR) measurements to estimate actual total lung capacity (TLC) could account for disease-related lung volume changes, but their role in size matching is unknown. We reviewed adult double lung transplant recipients 2007-2016 and measured apex-to-costophrenic-angle distance (=lung height) on pretransplant donor and recipient CXRs (oversized donor-recipient ratio >1; undersized ≤1]. We tested the relationship between recipient lung height to actual TLC; between lung height ratio and donor/recipient characteristics; and between both lung height ratio or pTLC ratio and grade 3 PGD with logistic regression. Two hundred six patients were included and 32 (16%) developed grade 3 PGD at 48 or 72 hours. Recipient lung height was related to TLC (r2=0.7297). Pulmonary diagnosis, donor BMI, and recipient BMI were the major determinants of lung height ratio (AUC 0.9036). Lung height ratio oversizing was associated with increased risk of grade 3 PGD (odds ratio, 2.51; 95% confidence interval, 1.17-5.47; P = 0.0182) in this cohort, while pTLC ratio oversizing was not. CXR lung height estimates actual TLC and reflects pulmonary diagnosis and body composition. Oversizing via CXR lung height ratio increased PGD risk moreso than pTLC-based oversizing in our cohort.

Early postoperative mortality in liver transplant recipients involving indications other than hepatocellular carcinoma. A retrospective cohort study

To analyze the perioperative differences in a consecutive cohort of liver transplant recipients (LTRs) classified according to the indication of transplantation, and assess their impact upon early mortality 90 days after transplantation. A retrospective cohort study was carried out. A single university hospital. A total of 892 consecutive adult LTRs were included from January 1995 to December 2017. Recipients with acute liver failure, retransplantation or with grafts from non-brain death donors were excluded. Two cohorts were analyzed according to transplant indication: hepatocellular carcinoma (HCC-LTR) versus non-carcinoma (non-HCC-LTR). Recipient early mortality was the primary endpoint. The pretransplant recipient and donor characteristics, surgical time data and postoperative complications were analyzed as independent predictors. The crude early postoperative mortality rate related to transplant indication was 13.3% in non-HCC-LTR and 6.6% in HCC-LTR (non-adjusted HR=2.12, 95%CI=1.25-3.60; p=0.005). Comparison of the perioperative features between the cohorts revealed multiple differences. Multivariate analysis showed postoperative shock (HR=2.02, 95%CI=1.26-3.24; p=0.003), early graft vascular complications (HR=4.01, 95%CI=2.45-6.56; p<0.001) and multiorgan dysfunction syndrome (HR=18.09, 95%CI=10.70-30.58; p<0.001) to be independent predictors of mortality. There were no differences in early mortality related to transplant indication (adjusted HR=1.60, 95%CI=0.93-2.76; p=0.086). The crude early postoperative mortality rate in non-HCC-LTR was higher than in HCC-LTR, due to a greater incidence of postoperative complications with an impact upon mortality (shock at admission to intensive care and the development of multiorgan dysfunction syndrome).

Predicting Clinical Outcome in Expanded Criteria Donor Kidney Transplantation: A Retrospective Cohort Study.

Background:The gaps in organ supply and demand necessitate the use of expanded criteria donor (ECD) kidneys.Objective:To identify which pre-transplant and post-transplant predictors are most informative regarding short- and long-term ECD transplant outcomes.Design:Retrospective cohort study.Setting:Single center, Quebec, Canada.Patients:The patients were 163 consecutive first-time ECD kidney only transplant recipients who underwent transplantation at McGill University Health Centre (MUHC) between January 1, 2008 and December 31, 2014 and had frozen section wedge procurement biopsies.Measurements:Short-term graft outcomes, including delayed graft function and 1-year estimated glomerular filtration rate (eGFR), as well as long-term outcomes including all-cause graft loss (defined as return to dialysis, retransplantation, and death with function).Methods:Pre-transplant donor, recipient, and transplant characteristics were assessed as predictors of transplant outcomes. The added value of post-transplant predictors, including longitudinal eGFR, was also assessed using time-varying Cox proportional hazards models.Results:In univariate analyses, among the pre-transplant donor characteristics, histopathologic variables did not show evidence of association with delayed graft function, 1-year post-transplant eGFR or all cause graft loss. Recipient age was associated with all-cause graft loss (hazard ratio: 1.038 [95% confidence interval: 1.002-1.075] and the model produced only modest discrimination (C-index: 0.590; standard error [SE]: 0.045). Inclusion of time-dependent post-transplant eGFR improved the model’s prediction accuracy (C-index: 0.711; SE = 0.047). Pre-transplant ECD characteristics were not associated with long-term survival, whereas post-transplant characteristics allowed better model discrimination.Limitations:Single-center study, small sample size, and potential incomplete capture of all covariate data.Conclusions:Incorporation of dynamic prediction models into electronic health records may enable timely mitigation of ECD graft failure risk and/or facilitate planning for renal replacement therapies. Histopathologic findings on preimplantation biopsies have a limited role in predicting long-term ECD outcomes.Trial registration:Not applicable.

Comparison of cell based and solid phase assays in detecting pre transplant donor specific antibody and impact of its results on graft outcome

Background: The clinical significance of positive results on more sensitive platforms available for antibody screening has been a matter of contention. This study explores the relationship of test results of Complement Dependent Cytotoxicity (CDC) crossmatch, ELISA anti HLA antibody test and Donor Specific Antibody (DSA) assay using donor lysate on the Luminex platform and their impact on graft outcome. Materials and Methods: Participants included patients who underwent renal transplant over four years, in whom pre transplant screening included an initial CDC cross match, followed by final CDC cross match, ELISA and DSA screening by the Luminex on the final pre transplant serum. Relevant clinical data and results of supportive laboratory investigations were taken from HLA laboratory and computerised records.Results: 126 recipients were included in the study. Pre transplant CDC positivity correlated with overall rejection episodes (P=0.03) and the historical crossmatch Ig M/G positivity with biopsy proven rejections (P=0.029). There was no significant correlation between pre-transplant DSA and ELISA results and rejection episodes.A comparison between DSA, ELISA and CDC showed a low association (Kappa value for DSA and CDC: -0.42; ELISA and CDC: - 0.63; DSA and ELISA: + 0.159).Conclusion: CDC continues to have relevance in pre transplant screening. In spite of their technical advantages and superior sensitivity, the ELISA pooled antigen assay and the Luminex crossmatch do not appear to show any significant clinical advantage when used with conventional CDC.

Identification of New Polymorphisms in Genes of the Immune System Associated with Acute Graft Versus Host Disease after Identical HLA-Allogeneic Stem-Cell Transplantation

INTRODUCTION Allogeneic haematopoietic stem cell transplant (allo-HSCT) could be the only curative therapy for patients with hematological malignancies due to graft effect against tumor. However, approximately 40% of patients develop post-transplantation complications such as acute graft-versus-host disease (aGVHD). Cytokines and their receptors are involved in regulatory and inflammatory processes that occur during GVHD. Therefore, the analysis of polymorphisms (SNPs) that affect the expression or activity of these genes could be used as biomarkers to predict the development of these complication. The aim of this study was to select new polymorphisms in cytokine genes (interleukins, chemokines and their receptors) to build models to predict the development of aGVHD after allo-HSCT from an HLA-identical sibling donor. METHODS We retrospectively selected 88 patients with hematological malignancies who received an allo-HSCT from an HLA-identical sibling donor from 2000 to 2015. A total of 176 pre-transplant recipient (R) and donor (D) peripheral blood samples were collected. The genotyping was performed using an enrichment-capture gene panels (include 132 genes (73 interleukins, 59 chemokines) in a HiSeq platform (Illumina, USA). The bioinformatic analysis was carried out with the GeneSystemssoftware (Sistemas Genómicos, Spain). Variants located in coding region, splicing sites, and UTR, 5'upstream and 3'downstream zones (+ 200pb) were analyzed. We selected polymorphisms corresponding to non-synonymous variants, represented in at least 5% of our cohort, with readings ≥30X in the canonical isoformwith an allele frequency ≥ 0.4. Fisher test was used to compare the differences among groups. Multiple logistic regression models were performed using combination of interleukins and chemokines polymorphisms selected previously that could be applied to clinical practice to predict aGVHD. The models with the highest AUC value, sensitivity and specificity value and the lowest number of genetic variants used were selected.Statistical Package for the Social Sciences (SPSS, Chicago, USA) was used for statistical test. RESULTS The cumulative incidence rates for aGVHD of grades II-IV and III-IV at 100 days after transplantation were 48.93% and 18.08%, respectively. The clinical variables (age, gender, pathology, stem cell source and previous transplantation) were not correlated with II-IV or III-IV aGVHD. However, patients who received ablative conditioning regimen presented a lower incidence of III-IV aGVHD (p= 0.041). Using filters defined previously, we detected 481 polymorphisms (350 coincident, 68 specific R and 63 for D) in the interleukins group. On the other hand, we detected 339 polymorphisms (267 coincident, 29 specific R and 43 for D) in the group of chemokines. Finally, 17 polymorphisms were selected in the interleukin group and 10 in the chemokine group for its correlation with the aGVHD (p &lt;0.05). Specifically, 14 SNPs were correlated with II-IV aGVHD (Table 1) and 12 SNPs with III-IV aGVHD (Table 2). Most polymorphisms found are located in regulatory regions, which until have been little studied, but these regions are involved in the expression genes, therefore could be affecting the function of these genes. We developed multiple logistic regression models for II-IV and III-IV aGVHD in interleukins and chemokines genes (Table 3). The identification of these 15 polymorphisms could help us to prevent the developing II-IV and III-IV aGVHD. CONCLUSIONS We have identified new genetic polymorphisms correlate with the risk of developing aGVHD after allo-HSCT from an HLA-identical sibling donor. Based on these data, we have developed a genetic score that encompasses polymorphisms of greater relevance. In this way, patients at greatest risk for developing this type of post-transplantation complication who could benefit from personalized management through immunosuppression and other drugs. Disclosures No relevant conflicts of interest to declare.

Pediatric Intensive Care Resource Utilization Following Hematopoietic Cell Transplantation in Children with Acute Leukemia

Pediatric Intensive Care Resource Utilization following Hematopoietic Cell Transplantation in Children with Acute Leukemia Baldes C1, Wetzel M3, McCraken C3, Saber W4, Arnold SD2. Introduction: Hematopoietic cell transplantation (HCT) is one of the mainstays of treatment of acute leukemia in children. While previous studies have calculated the overall healthcare resource utilization following this treatment, to date there is limited analysis regarding intensive care resource utilization specifically. The goal of this research is to investigate the costs associated with and potential patient drivers of intensive care resource utilization following hematopoietic cell transplantation in children with acute leukemia. Methods: Retrospective study of U.S. patients aged 1-20 years who received HCT for acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) from 2004-2011 using data merged from the Pediatric Health Information System (PHIS) and the Center for International Blood and Marrow Transplant Research (CIBMTR). We investigated the primary outcome of total intensive care unit (ICU) cost and total ICU cost per day survived from initial HCT through 100-day post-transplant as well as through two-year follow-up using paired comparisons with Wilcoxon rank sums tests for differences in costs between groups. Results: We identified 202 patients with at least one ICU admission in the first 100 days and 292 in the two years following HCT. At day 100, ICU cost per day survived and total ICU cost were lower for secondary AML (P=0.019; P=0.022, respectively) when compared to AML but no significant difference was identified for ALL patients (P=0.186 ;P=0.064, respectively) compared to AML. Cytomegalovirus (CMV) seropositivity compared to seronegativity (P=0.027; P=0.027, respectively) had higher ICU cost per day survived and total ICU cost at day 100 and at 2-years post-HCT (P=0.026; P=0.045, respectively) (Table 1). At 2-years post-HCT, disease status also showed a statistically significant relationship between ICU cost per day survived and total ICU cost for intermediate disease status at transplant (p&amp;lt;0.001; P=0.018) and ICU cost per day survived for advanced disease (P=0.042) compared to early disease status. Females transplant recipients (P=0.042) and, when compared to matched unrelated donor, unrelated cord blood transplants (P=0.029) also had significantly higher ICU cost per day but not total ICU cost (Table 2). Conclusion: Among patients with at least one ICU visit, patients who are CMV negative generate less ICU costs and costs per day survived at both time intervals. While disease status, donor type, and gender become significant at two-years post HCT. This analysis may help identify patient specific risks that could be mitigated by surveillance or supportive care measures. Ultimately, further investigation of pre-transplant diagnosis, donor type, gender, and disease status at transplant is needed to better determine specific factors influencing these cost outcomes. 1. Department of Pediatrics, Emory University, Atlanta, Georgia. 2. Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia. 3. Pediatric Biostatistics Core, Emory University, Atlanta, Georgia. 4. CIBMTR (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI. Disclosures No relevant conflicts of interest to declare.

118.6: Oncologic outcomes of ABO-incompatible living donor liver transplantation for HCC patients.

Background: ABO incompatible living donor liver transplantation (ABOi LDLT) could be one of the treatment options for hepatocellular carcinoma (HCC) to overcome organ scarcity. However, desensitization protocol including B cell depletion besides traditional T cell suppression could be a risk factor for HCC recurrence that is a major cause of graft failure and patient death. We analyzed oncologic outcomes of ABOi LDLT comparing to ABO compatible LDLT. Methods: The data of 101 recipients who underwent LDLT for HCC were prospectively collected and reviewed. Of the patients, 21 patients underwent ABOi LT. We compared the pre- and post-transplant tumor factors, HCC recurrence and survival between ABOi and ABOc LT. Results: There was no significant difference in pre-transplant tumor staging, recipient and donor demographics between the groups. One and 3-year recurrence-free survival rates were 89.8% and 86.9% for the ABOc LT group and 85.4% and 80.1% for the ABOi LT, respectively (P=0.439; Fig 1). One and 3-year overall survival rates were 96.3% and 88.1% for the ABOc LT group and 90.5% and 85.2% for the ABOi LT, respectively (P=0.651; Fig 2). In multivariate analysis, a pre-transplant AFP level over 400 ng/mL was the only independent risk factor for HCC recurrence and poor patient survival. Conclusions: The HCC recurrence survival and overall survival of ABOi LT were comparable to those of ABOc LT. ABOi LT is safe and feasible option for HCC patients.

What Stimulates the Development of De Novo Donor Specific Antibodies in Cardiac Transplant Recipients?

Introduction The formation of de novo donor specific antibodies (dDSAs) has been implicated in the development of antibody-mediated rejection (AMR) and coronary allograft vasculopathy (CAV) after cardiac transplantation. dDSAs can develop at any time following transplantation and are associated with a poor prognosis, but the reason dDSAs develop after the initial injury of the transplant surgery is unknown. Since the detection of dDSAs often triggers the use of potentially toxic therapies to reduce these antibodies, it is important to understand whether dDSAs are a mediator of poor outcomes or a marker of a harmful underlying process. Hypothesis In some cases, the development of dDSAs is precipitated by the development of CAV or other myocardial injury which can expose myocardial cell epitopes. Methods We reviewed the medical record of 217 patients followed at our institution who underwent heart transplantation between 2014 and 2017, were not desensitized prior to transplant and did not have pre-transplant donor specific antibodies. Of these, we identified 36 patients with dDSAs, 16 of whom did not develop dDSAs until ≥ 6 months post-transplant, as detected by the modern bead-based multiplex assay on routine measurement every 3 months. Results Major findings are shown in Figure 1. In 10 of 16 patients with dDSAs but without evidence of AMR, CAV diagnosis or significant elevation in BNP suggestive of myocardial injury preceded dDSA development. Conclusions These findings suggest that CAV or other myocardial injury may precede the development of dDSAs in some cardiac transplant recipients and would explain why dDSAs signal a poor prognosis. These findings may shift the therapeutic focus from direct suppression of dDSAs to earlier detection, prevention and therapy of CAV or other injury that may trigger these antibodies' delayed appearance.

Liver Transplant From Increased-Risk Donors in the Era of Direct-Acting Antivirals for Hepatitis C.

The opioid epidemic and the associated deaths have increased the availability of increased-risk donor organs. Here, we assessed factors associated with increased-risk donor liver transplant and determined their impact on survival and response to direct-acting antivirals. We analyzed anti-hepatitis C virus-positive deceased-donor liver transplant recipients from August 2013 through December 2017. We compared recipient and donor clinical and virologic features, response to direct-acting antivirals, and graft and patient survival rates in increased-risk versus tradi-tional or non-increased risk donor organ transplants. Of 153 transplant recipients, 89 (58%) were anti-hepatitis C virus positive, with 42/89 receiving increased-risk donor livers (mean age 62 years, 1 female, 80% white, and 60% with hepatoma). On univariable analysis, receipt of increased-risk donor liver was associated with simultaneous liver-kidney transplant, lower Model for End-Stage Liver Disease score, hepatitis C virus RNA positivity, pretransplant direct-acting antiviral nonresponse, and younger donor age. On multivariable analysis, only donor age and Model for End-Stage Liver Disease score were associated with increased-risk donor transplant. Among increased-risk donors, 12 (29%) were hepatitis C virus RNA positive, including one who was anti-hepatitis C virus antibody negative. Among recipients, 62 were hepatitis C virus RNA positive (35 with increased-risk livers), with 50 recipients (81%) having genotype 1. Posttransplant, recipient genotype changed in 6 and was mixed in 4 recipients. Of 55 recipients treated with direct-acting antivirals, 54 (98%) achieved viral clearance. Overall 1-year graft and patient survival was 93%. Increased-risk donor organs provided high levels of utility in liver transplant recipients who were anti-HCV positive, showing optimal graft and patient survival. Increased-risk donors were younger and preferably transplanted in hepatitis C virus RNA-positive recipients with lower Model for End-Stage Liver Disease score. Posttransplant direct-acting antiviral therapy was highly efficacious irrespective of pretransplant recipient and donor virologic status.

Abstract LB-052: Detection of rare, deleterious clonal mutations during unrelated allogeneic hematopoietic stem cell transplants using an error correction pipeline for NGS

Abstract While next-generation sequencing (NGS) has transformed our ability to characterize the genome, it is limited in detection of rare mutations due to a high error rate of ~0.5-2.0%. We have developed an error correction pipeline and previously demonstrated that our process is capable of detecting variants as rare as 1:10,000 or 0.0001 VAF. Using our error correction pipeline, we have recently identified leukemia-related hematopoietic clones in a cohort of young healthy bone marrow donors (median age 26). In the context of allogeneic hematopoietic stem cell transplantation (HSCT), we sought to determine whether these detected leukemia-related clones of donor origin selectively engraft and correlate with transplant-related morbidities in recipients post-HSCT. Genomic profiles of pre-transplant donor samples were compared to the genomic profiles of corresponding recipient samples post-HSCT. Results show that two-thirds of the healthy donor samples harbor deleterious hematopoietic clones and that these specific clones are significantly more likely to engraft compared to benign clones. We also found that 75% of recipients who had at least one persistently engrafted, deleterious mutation developed chronic GvHD versus 50% of those without persistently engrafted clones with deleterious mutations. In comparing the results from our error correction pipeline and conventional short tandem repeat (STR) testing for donor-patient chimerism, we showed that our method provides a highly sensitive approach to both screening for donors without deleterious clones and monitoring residual disease in recipients following hematopoietic stem cell transplants (HSCT). Furthermore, the clinical implications of these results warrant a large-scale study using our error correction pipeline to detect rare variants in HSCT. Citation Format: Wing Hing Wong, Andrew Young, Todd Druley. Detection of rare, deleterious clonal mutations during unrelated allogeneic hematopoietic stem cell transplants using an error correction pipeline for NGS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-052.

PB1700 LOSS OF CHROMOSOME 9 AND/OR 1 HETEROZYGOSITY IN TUMOR CELLS GENOME COME UP WITH ABO AND/OR RH CHANGE IN RELAPSED AML BUT NOT ALL PATIENTS.

Background:The rare phenomenon of splitting or alteration of ABO and/or RHD and RHCE phenotypes in the onset of the disease or in relapse, observed in a number of myeloproliferative, but not lymphoproliferative diseases, is probably caused by a loss of heterozygosity in blast cell genome.Aims:To correlate ABO, RHD, RHCE genotype and phenotype changes in remission and relapse with possible loss of heterozygosity in the regions 9q34.2 and 1p36.11 in AML and ALL patients.Methods:Study includes 62 patients that received allogeneic BMT in the National Research Center for Hematology, Moscow, between 2012 and 2018. Chimerism after BMT and loss of heterozygosity (LOH) in tumor cells genomes was evaluated by STR analysis with COrDIS Plus multiplex PCR kit for amplification of 19 polymorphic STR‐markers and amelogenin loci. The fragment analysis was performed on a 3130 Genetic Analyzer (Applied Biosystems, USA). Informative loci were chosen by comparison of pretransplant patient's and donor's DNAs. The percentage of donor chimerism was calculated using standard formula. High‐resolution chromosomal microarray (CMA) was performed using Affimetrix CytoscanTM HD array platform to verify the loss of heterozygosity. Data processing was carried out using Chromosome Analysis Suite v.4.0 software, genome assembly version hg19, GRCh37 Genome Reference Consortium Human Reference 37, https://genome.ucsc.edu/. The ABO and Rh phenotypes of RBC in posttransplant non‐transfused patients were detected by hemagglutination methods in plate and tube using monoclonal antibodies to ABO and Rhesus antigens (Hematolog, Russia). The ABO and Rh genotypes were evaluated by ABO‐Type and RH‐Type PCR‐SSP kits (BAG, Germany) and confirmed by direct Sanger sequencing.Results:Four patients (2 AML patients, 1 B‐ALL and 1 T‐ALL patient) from 17 LOH‐positive patients had LOH in 9 and/or 1 chromosomes (Table 1). Patient#1 with AML and heterozygous ABO∗B1O1 and homozygous RH∗D‐, RHCE∗ccee genotype received transplant from ABO∗A1O1 and RH∗D+, RHCE∗C w CDee donor. For this patient the LOH in 9q31.1‐34.3 area of 9 chromosome and heterozygous ABO∗B1O1genotype were established in blast cells in relapse. The O (I) Rh‐ ccdee phenotype of RBC was detected on +127 day after BMT, when the patient was in relapse, because of transfused O erythrocytes. In patient#2 with AML without relapse the loss of 9 chromosome was established cytogenetically in the onset of disease. The ABO∗A 1 B 1 and RH∗ CcDEe genotype was shown for this patient and ABO∗A2O1 RH∗CcDee for donor. Day +30 after BMT the ABO phenotype splitting in RBC was found: 90% of A1B (IV) Rh+ CcDEe and 10% of A1(II)Rh+ CcDee. The loss of 1p36.3‐1p35.3, 1p34.3‐1p32.3 and uniparental disomy of 9 chromosome was detected in tumor cells of patient#3 with T‐ALL. While patient had ABO∗O 1 O 1 RH∗C w cDEe genotype and donor was ABO∗B1O1 RH∗CcDee, homozygous genotype ABO∗O 1 O 1 RH∗C w C w Dee was detected on +160day after BMT, when the patient had relapse of disease. However RBC phenotype was B(III) CcDee fully compliant with donor's genotype. Patient#4 with B‐ALL had uniparental disomy of 1 and 9 chromosomes in tumor cells. Since patients phenotype was B(III) CCDee and donors – B(III) CcDee the allele loss in this case may not result into phenotype change.Summary/Conclusion:The data obtained confirms the impact of LOH on ABO and Rh phenotype splitting or alteration in onset or disease relapse of AML but not ALL. More research of extended samples of AML and ALL patients is required to confirm reported observations.image

Pretransplant Biopsy of Marginal Kidneys: Is It Necessary?

IntroductionPretransplant kidney biopsy from marginal donors is used to guide the decision of whether to accept or discard organs for transplantation; however, there is controversy about this procedure, and the need for a pretransplant biopsy is still a debate. We sought to determine if histologic evaluation before implantation of marginal kidneys would influence the outcome. Methods. A retrospective observational cohort study of marginal donor transplants at Centro Hospitalar e Universitário de Coimbra was done. From 2009 to 2016, 650 marginal kidney transplants were analyzed. We evaluated long-term graft survival in a cohort of patients who received marginal kidneys. The recipients were divided into 2 groups based on whether a pretransplant donor biopsy was performed. Continuous variables were summarized by mean and standard deviation or median and range, as applicable. Categorical variables were summarized by relative and absolute frequencies. The survival analysis was obtained and plotted using the Kaplan-Meier method and compared with the log-rank test. ResultsThe median age of recipients and donors were statistically different between both groups (P < .001), with the donors and the recipients being younger in the group without a pretransplant biopsy. The median cold ischemia time was higher in the biopsy group (P = .01). The survival analysis showed that graft survival didn't differ between the groups (P = .2). ConclusionsSelection of kidneys based on histological findings may not influence the graft survival and implies a higher cold ischemia time. More data are necessary to provide insight into which clinical, histologic, and biochemical parameters are necessary for decision making on kidney acceptance.

Prediction of Three-Year Mortality After Deceased Donor Kidney Transplantation in Adults with Pre-Transplant Donor and Recipient Variables.

BackgroundPrognostic models for 3-year mortality after kidney transplantation based on pre-transplant donor and recipient variables may avoid futility and thus improve donor organ allocation.Material/MethodsThere were 1546 consecutive deceased-donor kidney transplants in adults (January 1, 2000 to December 31, 2012) used to identify pre-transplant donor and recipient variables with significant independent influence on long-term survival (Cox regression modelling). Detected factors were used to develop a prognostic model for 3-year mortality in 1289 patients with follow-up of >3 years (multivariable logistic regression). The sensitivity and specificity of this model’s prognostic ability was assessed with the area under the receiver operating characteristic curve (AUROC).ResultsHighly immunized recipients [hazard ratio (HR: 2.579, 95% CI: 1.272–4.631], high urgency recipients (HR: 3.062, 95% CI: 1.294–6.082), recipients with diabetic nephropathy (HR: 3.471, 95% CI: 2.476–4.751), as well as 0, 1, or 2 HLA DR mismatches (HR: 1.349, 95% CI: 1.160–1.569) were independent and significant risk factors for patient survival. Younger recipient age ≤42.1 years (HR: 0.137, 95% CI: 0.090–0.203), recipient age 42.2–52.8 years (HR: 0.374, 95% CI: 0.278–0.498), recipient age 52.9–62.8 years (HR: 0.553, 95% CI: 0.421–0.723), short cold ischemic times ≤11.8 hours (HR: 0.602, 95% CI: 0.438–0.814) and cold ischemic times 11.9–15.3 hours (HR: 0.736, 95% CI: 0.557–0.962) reduced this risk independently and significantly. The AUROC of the derived model for 3-year post-transplant mortality with these variables was 0.748 (95% CI: 0.689–0.788).ConclusionsOlder, highly immunized or high urgency transplant candidates with anticipated longer cold ischemic times, who were transplanted with the indication of diabetic nephropathy should receive donor organs with no HLA DR mismatches to improve their mortality risk.

Post-transplant outcome in patients bridged to transplant with temporary mechanical circulatory support devices.

The new heart allocation system in the United States prioritizes patients supported by temporary mechanical circulatory support (TMCS) devices over those with uncomplicated durable continuous-flow left ventricular assist devices (CF-LVADs), which may increase the number of patients bridged to transplant with TMCS. Limited data are available in guiding post-transplant outcomes with various TMCS devices. We sought to describe post-transplant outcome and identify clinical variables associated with post-transplant outcome in patients bridged to transplant with TMCS. Using data from the International Society for Heart and Lung Transplantation Thoracic Transplant Registry, we included subjects who underwent transplantation between 2005 and 2016 with known use of mechanical circulatory support. Pre-transplant recipient, donor, and transplant-specific variables were abstracted. The primary outcome was patient survival at 1-year post-transplant. Outcomes of patients bridged to transplant with TMCS were compared with those of patients bridged with CF-LVADs. Cox regression analyses were performed to identify clinical variables associated with the outcomes. There were 6,528 patients bridged to transplant with the following types of mechanical circulatory support: durable CF-LVADs (n = 6,206), extracorporeal membrane oxygenation (ECMO, n = 134), percutaneous temporary CF-LVADs (n = 75), surgically implanted temporary CF-LVADs (n = 38) or surgically implanted temporary BiVAD (n = 75). Bridging with ECMO (hazard ratio 3.79, 95% confidence interval [CI] 2.69-5.34, p < 0.001) or percutaneous temporary CF-LVADs (hazard ratio 1.83, 95% CI 1.09-3.08, p = 0.02) was independently associated with higher risk of mortality. Additional risk factors included older donor age, female/male donor-recipient match, older recipient age, higher recipient body mass index, higher recipient creatinine, and prolonged ischemic time. This analysis of a large international cohort of patients bridged to transplant with mechanical circulatory support identified ECMO and percutaneous temporary CF-LVADs as predictors of mortality after transplant, along with additional donor and recipient clinical characteristics. These findings may provide guidance to clinicians in decisions on mechanical circulatory support device selection, transplant eligibility, and timing of transplant.