Risk Of Primary Graft Failure Research Articles

Coronary Angiography During Ex-Situ Heart Perfusion in a Porcine Model.

Heart transplantation is the gold standard treatment for advanced heart failure. The procurement of extended criteria donors (ECD) increases due to the current organ shortage. Coronary angiography is recommended in ECD at risk for coronary artery disease but is not systematically performed. These hearts are, therefore, either declined for transplant or procured without screening for coronary artery disease. Coronary angiography during normothermic ex-situ heart perfusion (NESP) could be an interesting approach to enhance the rate of ECD procurement and to reduce the risk of primary graft failure in the absence of coronary angiography in ECD. The present protocol aims to provide material details along with optimal imaging views for coronary angiography during NESP. Reproducible angiographic views were observed, including one dedicated to the right coronary artery, two for the left anterior descending artery, two for the circumflex artery, and a spider view. Continuous lactate extraction was observed in all procedures with a final median concentration of 1.10 mmol/L (0.61-1.75 mmol/L) two hours after coronary angiography, consistent with myocardial viability. The median contrast agent volume used for ex-situ imaging of the isolated perfused heart was 48 mL (38-108 mL). This protocol was reproducible for coronary artery imaging and did not impair myocardial viability during NESP.

Association between Storage Time of Corneal Grafts and Primary Graft Failure in Penetrating Keratoplasty

Purpose: To determine association between storage time of corneal grafts and primary graft failure in Penetrating Keratoplasty (PK). Study Design: Quasi experimental study. Place and Duration of Study: Institute of Ophthalmology, Eye Unit-III, King Edward Medical University, Mayo Hospital, Lahore from June, 2019 to December, 2019. Methods: In this study, 120 patients (between 11 and 30 years of age) diagnosed with keratoconus were enrolled and divided into two groups. Group A comprised individuals who underwent PK with donor tissues stored for 8 to 14 days, while Group B consisted of patients whose donor tissues were stored for a duration not exceeding 7 days. Patients were followed up for three weeks post-operatively. The data was analyzed using SPSS version 19 and stratified for age, gender and primary graft failure. Post stratification RR was calculated with p-value ≤ 0.05 as significant. Results: The mean age of patients in Group A was 21.38 ± 6.29 years and in Group B was19.80 ± 5.81 years. In Group A there were 32 male and 28 female while in Group B there were 29 male and 31 female. In Group A 16(26.7%) patients and in group B, 4 (6.7%) patients had primary graft failure. The risk of primary graft failure was higher in Group A, with RR = 4, p-value < 0.05. Conclusion: The risk of primary graft failure in PK is higher when the storage time of corneal grafts is longer. Hence, minimization of storage time may ensure better success rate of corneal grafting.

The impact of the OPTN policy change on patients with a durable left ventricular assist device and chronic kidney disease: Analysis of the UNOS database.

The Organ Procurement and Transplantation Network (OPTN) implemented modifications in 2018 to the adult heart transplant allocation system to better stratify the most medically urgent transplant candidates. We evaluated the impact of these changes on patients supported by a durable left ventricular assist device (LVAD) with chronic kidney disease (CKD). To evaluate the impact of the OPTN policy change on patients supported by durable left ventricular assist devices (LVAD) with chronic kidney disease (CKD). We performed an analysis of patients from the United Network of Organ Sharing Database supported by durable LVAD listed for a heart transplant (HT) between October 17, 2016 and September 30, 2021. Patients were divided into two groups: pre- and postpolicy, depending on whether they were listed on or prior to October 17, 2018. Patients who were on dialysis prior to surgery or discharge were excluded from the analysis. Patients with simultaneous heart and kidney transplants were excluded. Patients who were listed for transplant prepolicy change but transplanted postpolicy change were excluded. This cohort was then subdivided into degrees of CKD based on estimated glomerular filtration rate (eGFR), which resulted in 678 patients (23.7%) in Stage 1 (GFR ≥89.499) (Prepolicy: 345, Postpolicy: 333), 1233 (43.1%) in Stage 2 (89.499 > GFR ≥ 59.499) (Prepolicy: 618, Postpolicy: 615), 613 (21.4%) in Stage 3a (59.499 > GFR ≥ 44.499) (Prepolicy: 291, Postpolicy: 322), 294 (10.3%) in Stage 3b (44.499 > GFR ≥ 29.499) (Prepolicy: 143, Postpolicy: 151), 36 (1.3%) in Stage 4 (29.499 > GFR ≥ 15) (Prepolicy: 21, Postpolicy: 15), and 9 (0.3%) in Stage 5 (15 > GFR) (Prepolicy: 4, Postpolicy: 5). The primary outcome was 1-year and 2-year post-HT survival. There were 2863 patients who met the study criteria (1422 prepolicy, 1441 postpolicy). Overall survival, regardless of CKD stage, was lower following the policy change (p < 0.01). There was a similar risk of primary graft failure (PGF) in the pre- and postpolicy period (1.8% vs. 1.2%, p = 0.26). 1-year overall survival was 93% (91, 94) and 89% (87, 91) in the pre- and postpolicy periods, respectively. 2-year overall survival was 89% (88, 91) and 85% (82, 87) in the pre- and postpolicy periods, respectively. For CKD Stages 1, 2, 3a, 3b, 4, and 5, 1 -year survival was 93% (91, 95), 92% (90,93), 89% (86, 91), 89% (86, 93), 80% (68, 94), and 100% (100, 100), respectively. For CKD Stages 1, 2, 3a, 3b, 4, and 5, 2-year survival was 91% (88, 93), 88% (86, 90), 84% (81, 88), 84% (80, 89), 73% (59, 90), and 100% (100, 100), respectively. Patients with CKD 1 and 2 had better survival compared to those with CKD 3 (p < 0.01) and CKD 4 and 5 (p = 0.03) in the pre- and postpolicy periods. Patients with CKD 3 did not have a survival advantage over those with CKD 4 and 5 (p = 0.25). On cox regression analysis, advancing degrees of CKD were associated with an increased risk of mortality. Patients with LVAD support had decreased overall survival after the OPTN policy change. Patients with more advanced CKD had lower survival than patients without advanced CKD, though they were not impacted by the OPTN policy change.

Effects of donor-specific antibodies on engraftment and long-term survival after allogeneic hematopoietic stem cell transplantation-A systematic review and meta-analysis.

The presence of donor-specific antibodies (DSAs) have been reported to be associated with an increased risk of primary graft failure following allogeneic hematopoietic stem cell transplantation (allo-HSCT), but its effects on the time to engraftment and long-term outcomes remain unclear. We performed a systematic review and meta-analysis of studies investigating the impact of DSAs on engraftment and long-term survival of patients undergoing allo-HSCT. We systematically searched PubMed, Embase, the Cochrane Library, and CBM. Data were analyzed using RevMan5.4. Pooled hazard ratio (HR), standard mean difference (SMD) or odds ratio (OR) and corresponding 95% confidence interval (CI) are calculated for time-to-event data, continuous data, discontinuous data respectively. 17 eligible studies were included, involving 2169 patients main receiving haploidentical SCT (haplo-SCT) or umbilical cord blood transplantation (UCBT). Meta-analysis showed that DSAs-positive patients are associated with significantly higher risk of GF(OR = 12.87, 95%CI, 6.45-25.70; P < 0.00001; OR = 4.76, 95%CI, 2.88-7.87), poorer neutrophil engraftment (HR = 2.20, 95%CI, 1.02-4.73; P = 0.04; HR = 1.83, 95%CI, 1.46-2.30; P < 0.00001), worse OS (HR = 3.19, 95%CI, 1.85-5.50; P < 0.0001; HR = 1.68, 95%CI, 1.04-2.71; P = 0.03), and inferior PFS (HR = 4.25, 95%CI, 1.59-11.40; P = 0.004; HR = 4.83, 95%CI, 1.65-14.12; P = 0.004) in haplo-SCT and UCBT, respectively.

Cryopreservation Impairs Engraftment in Bone Marrow Transplantation

Introduction: Due to the covid-19 pandemic, a recommendation was made, especially for non-related allogeneic hematopoietic stem cell transplantation (allo-HSCT), to cryopreserve hematopoietic stem cells products and start the conditioning regimen only after the product be received at the receptor service. There are conflicting data on how the procedure of cryopreservation (and thaw) of bone marrow affects outcomes. In this study we evaluated the primary graft failure incidence using cryopreserved bone marrow grafts compared to non-cryopreserved bone marrow grafts. We also evaluated transfusion needs during the first 30 days after transplant and the occurrence of severe adverse events (AEs) related to the product infusion, during covid-19 pandemic in a single Brazilian center. Methods: From January 2020 to 30 June 2022, we retrospectively analyzed clinical and laboratory data from 9 cryopreserved (cryo) (all of them unrelated) and 15 non-cryopreserved (non-cryo) bone marrow grafts (2 of them unrelated), here defined as control group. Haploidentical transplants were excluded due to a higher risk of primary graft failure reported on this type of transplant. Children and adults with malignant and non-malignant disorders were included. We evaluated engraftment, red blood cells (RBC) and platelets (Pl) units transfused during the first 30 days, and adverse effects associated with product infusion. Neutrophil engraftment was defined as the first of 3 consecutive days with absolute neutrophil counts of ≥ 500/µL and primary graft failure was defined as failure to achieve a neutrophil engraftment by day 28 after bone marrow infusion. Results were given as median (range) and comparison between the groups was performed employing the Mann-Whitney U test. Percentages were compared with the chi-square or the Fisher exact test. Results: Only two cryopreserved grafts have not been used (one patient died before the start of the conditioning regimen and the other did not receive the graft yet). Baseline characteristics were similar in both groups. The median (range) age was 21 (1-37) and 20 (6-32) years, with 42.86% and 40% under 18 years of age in the cryo and non-cryo groups, respectively. Also, 85.7% and 53.3% were male, and 14.3% and 13.3% had malignant disease (acute leukemia) in the cryo and non-cryo groups, respectively (Table 1). The numbers of infused total nuclear and CD34+ cells/kg in the cryo and non-cryo groups were not significantly different (p= 0.14, and p= 0.41, respectively) (Table 1). Three (42.8%) patients from the cryo group, all of them children (with osteopetrosis, aplastic anemia, and acute leukemia) did not achieve neutrophil engraftment by day 28, whereas all 15 patients from non-cryo group had hematologic recovery (RR= 4.75, 95% CI: 1.61-11.75; p= 0.02). Furthermore, there was a slight tendency toward delayed neutrophil engraftment in the cryo group: 21.5 (19-23) and 19.0 (15-28) days (p= 0.20). The numbers of RBC and Pl units transfused during the first 30 days after product infusion were higher in the cryo than non-cryo group: RBC 5.0 (3-9) and 1.0 (0-4) (p< 0.0001); Pl 15.0 (7-18) and 5.0 (1-20) (p= 0.0014), respectively (Figure 1). Three patients (42.8%) had severe AEs (seizure, hypertension urgency associated with second-degree atrioventricular block: Mobitz type 1, and acute renal failure) during or right after bone marrow infusion, all of them in the cryo group (relative risk= 4.75, 95% CI: 1.61-8.43, p= 0.02). All of them recovered completely from AE. Conclusions: Transplantation of cryopreserved bone marrow grafts seems to be associated with a higher risk of primary engraftment failure and, consequently, a higher transfusion needs, and with more severe adverse events related to the product infusion. Because of these findings and in spite of the ongoing pandemic, we recommend a careful evaluation of the necessity to adopt this practice. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Functional Assessment of the Donor Heart During Ex Situ Perfusion: Insights from Pressure-Volume Loops and Surface Echocardiography.

Heart transplantation remains the gold standard treatment for advanced heart failure. However, the current critical organ shortage has resulted in the allocation of a growing number of donor hearts with extended criteria. These marginal grafts are associated with a high risk of primary graft failure and may benefit from ex situ perfusion before transplant. This technology allows for extended organ preservation using warm oxygenated blood perfusion with continuous metabolic monitoring. The only NESP device currently available for clinical practice perfuses the organ in an unloaded non-working state, which does not allow for functional assessment of the beating heart. We therefore developed an original platform of NESP in working mode conditions with adjustment of left ventricular preload and afterload. This protocol was applied in porcine hearts. Ex situ functional assessment of the heart was achieved with intracardiac conductance catheterization and surface echocardiography. Along with a description of the experimental protocol, we herein report the main results, as well as pearls and pitfalls associated with the acquisition of pressure-volume loops and myocardial power during NESP. Correlations between hemodynamic findings and ultrasound variables are of major interest, especially for further rehabilitation of donor hearts before transplantation. This protocol aims to improve the assessment of donor hearts to both increase the donor pool and reduce the incidence of primary graft failure.

Functional Assessment of the Donor Heart During &lt;em&gt;Ex Situ&lt;/em&gt; Perfusion: Insights from Pressure-Volume Loops and Surface Echocardiography

Heart transplantation remains the gold standard treatment for advanced heart failure. However, the current critical organ shortage has resulted in the allocation of a growing number of donor hearts with extended criteria. These marginal grafts are associated with a high risk of primary graft failure and may benefit from ex situ perfusion before transplant. This technology allows for extended organ preservation using warm oxygenated blood perfusion with continuous metabolic monitoring. The only NESP device currently available for clinical practice perfuses the organ in an unloaded non-working state, which does not allow for functional assessment of the beating heart. We therefore developed an original platform of NESP in working mode conditions with adjustment of left ventricular preload and afterload. This protocol was applied in porcine hearts. Ex situ functional assessment of the heart was achieved with intracardiac conductance catheterization and surface echocardiography. Along with a description of the experimental protocol, we herein report the main results, as well as pearls and pitfalls associated with the acquisition of pressure-volume loops and myocardial power during NESP. Correlations between hemodynamic findings and ultrasound variables are of major interest, especially for further rehabilitation of donor hearts before transplantation. This protocol aims to improve the assessment of donor hearts to both increase the donor pool and reduce the incidence of primary graft failure.

Natural Killer Cell Alloreactivity Predicted By Killer Cell Immunoglobulin-Like Receptor Ligand Mismatch Does Not Impact Engraftment in Umbilical Cord Blood and Haploidentical Stem Cell Transplantation

Natural killer cell alloreactivity is determined by killer cell immunoglobulin-like receptor (KIR) ligands in donor and recipient pairs. A small, single institution study suggested that the risk of primary graft failure after cord blood hematopoietic cell transplantation (CBT) can be predicted by host-versus-graft (HvG)–directed natural killer cell alloreactivity. In the haploidentical transplantation (Haplo HCT) cohort, graft failures were observed only in graft-versus-host (GvH) KIR ligand mismatched pairs. A subsequent study was designed to explore the association between HvG and GvH KIR ligand mismatching and engraftment in both CBT and Haplo HCT using the large, multicenter transplant population of the Center for International Blood and Transplant Research database. Nine hundred single CBT (sCBT), 954 double CBT (dCBT), and 671 Haplo HCT performed between 2008 and 2017 for acute leukemias and myelodysplastic syndrome were examined. Several models of KIR-L interactions were analyzed by multiple regression analyses for their association with engraftment, overall survival (OS), and transplant-related mortality (TRM). In sCBT, although HvG or bidirectional KIR ligand mismatch (KIR-L-MM) was initially associated with higher TRM in the first 6 months after transplantation, this effect was nullified after 6 months such that long-term survival was not different compared to GvH KIR-L-MM or KIR-L matched (KIR-L-M) pairs. There was no significant difference in neutrophil and platelet engraftment. In dCBT, no significant differences were seen in engraftment, OS and TRM. In the Haplo cohort there was faster platelet recovery in the GvH KIR-L-MM/KIR-L-M pairs versus HvG KIR-L-MM or bidirectional mismatch (HR 1.23, P= .0116). There was no significant association with OS, TRM, or neutrophil engraftment. In this large registry study, KIR-L mismatching did not significantly impact engraftment, TRM, or survival in CBT and Haplo HCT, although an association with platelet engraftment in Haplo HCT was demonstrated.

Prognostic Significance of Elevated Troponin in Adult Heart Transplant Recipients: A Systematic Review and Meta-Analysis.

Cardiac troponin is a highly specific biomarker of myocardial injury that is of prognostic significance in a range of cardiovascular diseases. However, the prognostic value of elevated troponin in cardiac transplant recipients is uncertain. We aimed to evaluate the prognostic value of elevated cardiac troponin in predicting adverse recipient outcomes following heart transplant. We searched MEDLINE (Ovid), Embase (Ovid), and the Cochrane Library from inception until December 2020 and included studies reporting associations between elevated recipient troponin and outcomes after cardiac transplant. We generated summary odds ratios for associations with short- and long-term adverse events and used descriptive analyses where meta-analyses were inappropriate. We included 15 studies involving 1830 patients undergoing cardiac transplant. The risk of primary graft failure was greater in recipients with elevated troponin than in those without (odds ratio = 3.09; 95% CI, 1.08-8.87). Considerable interstudy heterogeneity (I2 statistic 98%) was partially explained by variations in study design, troponin subtype, and overall risk of bias. Descriptive analyses suggested associations between elevated recipient troponin and long-term adverse cardiac events, coronary artery disease, and mortality. Elevated cardiac troponin in cardiac transplant recipients may be prognostic for primary graft failure, adverse cardiac events, coronary artery disease, and mortality. Further high-quality, prospective, and multicenter research is needed to demonstrate the clinical applicability of these findings.

НЕИНВАЗИВНЫЕ МЕТОДЫ ОЦЕНКИ СТЕАТОЗА ПЕЧЁНОЧНОГО ГРАФТА У ДОНОРА С УСТАНОВЛЕННОЙ СМЕРТЬЮ ГОЛОВНОГО МОЗГА

The increase in the number of patients requiring liver transplantation raises the question of expanding and clarifying the criteria of hepatic grafts suitability for transplantation, and also shows the need to develop new, fast and noninvasive methods for assessing the functional state of the liver at the stage of donor examination and treatment. Hepatic grafts with severe steatosis, previously considered unsuitable for transplantation due to the higher risk of primary graft failure, are now referred to as potential for transplantation. There are several ways to diagnose and determine the stage of steatosis, but, unfortunately, today none of them can give an accurate and rapid assessment of its grade in a hepatic graft. Currently, the "gold standard" for determining liver steatosis is a biopsy with subsequent examination of samples by a pathomorphologist. There are also prognostic models, non-invasive tests and instrumental methods, the effectiveness of which has been proven - these are ultrasound elastography, contrast computed tomography and contrast computed tomography with liver density measurement. The decision on the suitability of a hepatic graft for transplantation depends on many factors, both on the part of the donor and on the part of the recipient, and it would be correct to assume that these data should be taken into account in aggregate. The review covers all the approaches currently used to quantify and qualitatively assess steatosis in liver transplants from a brain-dead donor.

Cryopreservation of Allogeneic Hematopoietic Cell Grafts Did Not Adversely Affect Early Post-Transplant Survival during the First Six Months of the COVID-19 Pandemic

▪Introduction: During the COVID-19 pandemic, concerns regarding travel logistics and donor safety necessitated a substantial increase in the use of cryopreserved hematopoietic stem cell (HSC) grafts from both related (RD) and unrelated donors (URD) to ensure patients have a graft available prior to the start of conditioning for hematopoietic cell transplantation (HCT). However, pre-pandemic data beyond single center or small multi-center reports are lacking to reassure clinicians that cryopreservation of allogeneic grafts does not adversely impact post-HCT outcomes including hematopoietic engraftment and overall survival (OS). The Center for International Blood and Marrow Transplant Research (CIBMTR) has recently published three retrospective analyses of outcomes in recipients of cryopreserved compared to fresh grafts administered prior to the pandemic. Results have been conflicting and reasons for receipt of cryopreserved grafts were not routinely collected, rendering interpretation of the impact of cryopreservation on clinical outcomes problematic. Since the pandemic provided a unifying rationale (including mandatory cryopreservation required by the National Marrow Donor Program (NMDP) and other major registries) for the majority of patients to receive cryopreserved allografts, we sought to evaluate early post-HCT clinical outcomes in patients reported to the CIBMTR database who received a first allogeneic HCT using cryopreserved grafts from March through August 2020.Methods: Key study endpoints were hematopoietic engraftment and overall survival (OS). We compared these outcomes to those in patients allografted using fresh products transplanted between March through August 2019. Additional patient selection criteria included: 1) recipients in US only, 2) peripheral blood stem cell (PBSC) or bone marrow (BM) grafts, 3) consented to research, and 4) availability of both CIBMTR product infusion and post-HCT day 100 (D100) follow-up form. The Pearson chi-square test was used for comparing discrete variables; the Kruskal-Wallis test was used for comparing continuous variables. Multivariate analysis (MVA) using a Cox proportional hazards model was performed for OS after adjusting for confounders and testing the proportional hazards assumption. Neutrophil engraftment by D28 and platelet engraftment by D100 were analyzed using multivariate logistic regression.Results: This study included 959 and 2,499 recipients of cryopreserved and fresh products, respectively. Patient characteristics are presented in Table 1. Recipients of cryopreserved grafts were older, more likely to receive URD grafts, PBSC as the graft source and post-transplant cyclophosphamide (PTCy) for graft versus host disease (GVHD) prophylaxis. They received lower infused PBSC and BM cell doses. Due to differences in duration of follow-up between the cohorts, follow up for the OS analysis was censored at Days 100 and 180. MVA results are presented in Table 2. No impact of cryopreservation on OS at either D100 (HR 0.93, p=0.72) or D180 (HR 1.10, p=0.34) post HCT was detected (see also Figure 1). When we performed the MVA for OS limiting the analysis to URD recipients only, the results were unchanged. Median time to neutrophil and platelet engraftment were both delayed by 1 day in recipients of cryopreserved grafts (16 vs. 15 days and 21 vs. 20 days, respectively) but there was no difference in the risk of primary graft failure by D28 (OR 1.38, p=0.96). Some delay in D100 platelet engraftment was observed in recipients of cryopreserved grafts (OR 0.67, p<0.005). There were no interactions identified between donor or graft type for OS or engraftment. Other important clinical outcomes such as secondary graft failure, acute GVHD, and early relapse are being analyzed and will be included at the time of abstract presentation.Conclusion: The shift in clinical practice to cryopreserved products necessitated during the pandemic did not adversely impact early post HCT OS or risk of primary graft failure. We caution that follow up is short and it will be critical to follow this cohort and subsequent recipients of cryopreserved grafts for much longer periods to determine the ultimate impact of cryopreservation on outcomes. Nevertheless, this large multi-center study will be useful to inform clinical decision making both during and following the pandemic. [Display omitted] DisclosuresDevine: Sanofi: Consultancy, Research Funding; Magenta Therapeutics: Current Employment, Research Funding; Tmunity: Current Employment, Research Funding; Vor Bio: Research Funding; Kiadis: Consultancy, Research Funding; Johnsonand Johnson: Consultancy, Research Funding; Orca Bio: Consultancy, Research Funding; Be the Match: Current Employment. Stefanski: Novartis: Honoraria. Shaw: mallinkrodt: Other: payments; Orca bio: Consultancy.

Major ABO Incompatibility Significantly Influences the Survival and Outcomes after Allogeneic Hematopoietic Cell Transplantation in Leukemia - CIBMTR Analysis

Background: Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). While many factors influence the outcomes of allo-HCT in these leukemias, the independent impact of ABO mismatching between the patient and donor remains unclear.Methods: Using the CIBMTR database, we identified adults aged ≥18 years with AML or ALL who underwent allo-HCT from HLA-matched sibling donor (MSD) or 8/8 matched unrelated donor (MUD) between 2008-2018. We excluded patients who underwent transplant from a mismatched donor source or who received an ex-vivo T-cell depleted graft. Patients were stratified into cohorts based on ABO status (match, minor mismatch, major mismatch, bidirectional mismatch). Outcomes such as overall survival (OS), disease free survival (DFS), non-relapse mortality (NRM), relapse, incidence of acute graft versus host disease (GVHD), chronic GVHD, neutrophil engraftment, platelet engraftment and graft failure were evaluated. Survival analysis was done using Kaplan-Meier method and significant predictors were evaluated using Cox-proportional hazard regression method. Multivariate regression model included main effect (ABO status) and covariates (patient age, gender match, disease type, disease status, HCT-CI, Karnofsky performance status, donor type, conditioning intensity/use of TBI, stem cell source, GVHD prophylaxis, ATG/alemtuzumab use, transplant year).Results: Of 4946 patients who met the study criteria, 2741 patients (55.4%) were ABO matched, 1030 patients (20.8%) had minor ABO mismatch, 899 patients (18.1%) had major ABO mismatch and 276 patients (5.6%) had bidirectional ABO mismatch. Graft manipulation for ABO incompatibility was performed in 900 patients (minor ABO mismatch=532; major ABO mismatch=226; bidirectional mismatch=142), however, the information on individual graft manipulation techniques was limited. In multivariable analysis (table 1), major ABO mismatch significantly affected the OS, platelet engraftment and primary graft failure. Compared to ABO matched allo-HCT, major ABO mismatched allo-HCT was associated with worse OS (major mismatch - HR 1.16, 95% CI 1.05-1.29; p=0.005), inferior platelet engraftment (HR 0.83, 95% CI 0.77-0.90; p=<0.001), and higher risk of primary graft failure [4.5% (major mismatch) vs. 3.2% (ABO matched) - HR 1.60, 95% CI 1.12-2.30, p=0.01]. There was a significant interaction between the ABO status and graft type (peripheral blood vs. bone marrow) for the acute GVHD grades 2-4 model, and they are presented separately (table 1). Bidirectional ABO mismatch also significantly impacted the outcomes such as acute GVHD grades 2-4 (in bone marrow stem cell subgroup, HR 0.50, 95%CI 0.27-0.93, p=0.02) in addition to a trend towards inferior survival and NRM (p-value not significant). Other outcomes such as relapse (p=0.41), acute GVHD grades 3-4 (p=0.13), and chronic GVHD (p=0.30) were not significantly influenced by the ABO status.Conclusions: Our study demonstrates that pre-transplant ABO status is an independent predictor of survival and other post-transplant outcomes in a large cohort of patients with AML and ALL undergoing allo-HCT in the recent era. This demonstrates the importance of considering ABO status in the donor selection algorithms and potential strategies to mitigate its adverse impact. Due to the limited information available on graft manipulation strategies, the impact of graft manipulation techniques on the outcomes could not be evaluated and needs to be investigated in future studies. [Display omitted] DisclosuresGuru Murthy: Techspert: Consultancy; Guidepoint: Consultancy; Cancerexpertnow: Honoraria; Qessential: Consultancy; TG therapeutics: Other: Advisory board; Cardinal Health Inc.: Honoraria. Devine: Magenta Therapeutics: Current Employment, Research Funding; Tmunity: Current Employment, Research Funding; Sanofi: Consultancy, Research Funding; Johnsonand Johnson: Consultancy, Research Funding; Orca Bio: Consultancy, Research Funding; Be the Match: Current Employment; Vor Bio: Research Funding; Kiadis: Consultancy, Research Funding. Farhadfar: Incyte: Consultancy. Sharma: Vertex Pharmaceuticals/CRISPR Therapeutics: Other: Salary support paid to institution; Novartis: Other: Salary support paid to institution; Spotlight Therapeutics: Consultancy; Medexus Inc: Consultancy; CRISPR Therapeutics: Other, Research Funding; Vindico Medical Education: Honoraria. Stefanski: Novartis: Honoraria. Pulsipher: Equillium: Membership on an entity's Board of Directors or advisory committees; Adaptive: Research Funding; Jasper Therapeutics: Honoraria. Shaw: mallinkrodt: Other: payments; Orca bio: Consultancy.

Pre-Transplantation Suppression of Haemopoiesis Is Associated with a High Rate of Macrophage Activation Syndrome in Ptcy Haploidentical Transplantation for Haemoglobinopathies

▪Post infusion of stem cell cyclosphosphamide (PTCy) has enable transplantation across the HLA barrier and with the use of reduced intensity conditioning protocols. This constitutes a very important development for conditions affecting populations poorly represented in the donor registries, like haemoglobinopathies. However, PTCy in haemoglobinopathies is associated with a high risk of primary graft failure using standard regimens unless additional interventions are applied: suppression of haemopoiesis pre-transplantation with hydroxycarbamide and azathioprine, and the addition of thiotepa. We report for the first time an unexpected high rate of macrophage activation syndrome with this approach.Three centres (two in India and one in London, UK) used a common protocol to undertake 87 haploidentical bone marrow transplants for patients with haemoglobinopathies. The backbone of the conditioning regimen was provided by the reduced intensity PTCy approach developed by John Hopkins University for haploidentical transplantation in SCD (Bolaños-Meade, Blood 2012). This included the use of ATG 0.5 mg/kg day -9 and 2 mg/kg days -8 and -7 (total dose 4.5 mg/kg), fludarabine 30 mg/m2 days -6 to -2 (total dose 150 mg/m2), cyclophosphamide 14.5 mg/kg days -6 and -5 (total dose 29 mg/kg) and TBI 200 cGy days -1. Post-transplantation patients received two doses of cyclophosphamide 50 mg/kg on days +3 and +4 to delete alloreactive T cells whilst preserving haempoietic stem cells, and GvHD prophylaxis was provided from day +5 with MMF until day +35 and sirolimus targeting 10 - 15 ng/mL. The source of stem cells was bone marrow harvested following priming with filgrastim 10 mg/kg/day for five days and aiming to obtain a cell dose of >8 x 108 TNC/kg. Supportive care recommendations included granulocyte colony-stimulating factor commenced on day +7 and continued until neutrophils maintained independently >1 x 109/L. The additional components added to the backbone to reduce graft failure included strategies previously found effective in achieving such aim in transplantation for thalassaemia major: (1) suppression of the expanded endogenous haemopoiesis with hypertransfusions, hydroxycarbamide 30 mg/kg and azathioprine 3 mg/kg and for a minimum of 42 days pre-transplantation (Sodani, Blood 2004; Shen Eur Radiol 2008; Capelli, Br J Haematol. 2009) and (2) addition of thiotepa 10 mg/kg on day -7 to the conditioning regimen (Bernardo, Blood 2012).Eleven patients (12.6%) suffered from macrophage activation syndrome, resulting in death in seven of the patients. Six patients had sickle cell disease and five thalassaemia. Patients presented with persistent fever not responding to broad spectrum antibiotics and antifungals in 6 cases, unexplained cytopenias in three cases and both persistent fever and cytopenias in two cases. The majority of the patients developed haemophacytosis with cytopenias, elevated ferritin (median 54,200 mg/L, range 2,026 - 128,844), triglycerides (median 3 mmol/L, range 1.78 - 7.92) and all but two had organomegaly. The presence of rash was a rare feature, only found in two patients and fever was not found in three patients. HHV6 infection in the bone marrow was found in 6 patients in whom it was specifically looked for, the other five had concomitant infection with CMV in three patients, adenovirus in one patient and JC was found in a case presenting with ataxia. Those surviving presented later (median 80 days, range 22- 143 days) with preservation of the bone marrow cellularity (>50% with no further reduction) and responded to treatment with dexamethasone 10 mg/m2 and antivirals and had resolution within 50 days of presentation; whereas those who did not survive presented early (median 42 days, range 17 - 258 days) with a bone marrow cellularity <50% eventually leading to secondary graft failure (<5% of hematopoietic cells in the bone marrow), and only had a partial response to dexamethasone, antivirals and targeted monoclonal antibodies, which was not sustained.In conclusion, PTCy transplants for haemoglobinopathies receiving pre-transplantation strategies to reduce graft failure have a high risk of macrophage activation syndrome. This has not been previously recognized and has a high risk of death (two third of the cases) despite targetted treatment. We postulate that the pre-transplantation treatment allows alloreactive T cells escape the use of PTCy. Disclosuresde la Fuente:Jazz Pharmaceuticals: Honoraria; bluebird bio: Consultancy; HCA: Consultancy.

Long-term outcomes using uncontrolled donors after circulatory death (DCD) for liver transplantation. A 10-year single center experience

Introduction: Number of liver grafts is not enough to attend all patients who need an OLT. Many OLT teams have proposed to expand the number of available grafts using livers from donors after circulatory death (DCD). We aim to analyse the use of liver grafts from type 2 uDCD donors for OLT, comparing with a group of patients who received liver grafts from donors after brain death (DBD). Patients and methods: Between January 2006 and December 2016 we performed 783 OLT in adult recipients. 75 of these transplants were DCD (Maastricht type II). We compared thus 75 DCD with 265 optimal donors OLT. Results: We present 75 DCD with a mean age 58.8 ± 8 vs 54.7 ± 10; p = 0,000, no different has found according to gender, body mass index, Child, MELD neither OLT indication. Donor age was 41.7 ± 10 vs 47.8 ± 15;p = 0.001; No different has found in Esteatosis, neither preservation injury, or cold ischemia time. Warm ischemia time was faster in DCD 62 min ± 14 vs 70 ± 36 (p = 0,010). Transfusion rate was significally higer in DCD in RBC, FFP, platelets and fibrinogen. Primary graft failure was higher in DCD 8.1% vs 2.1% (p = 0,031), also retransplant rate 12% vs 4.6% (0,028) and ischemic cholangiopathy 31,1% vs 5,6% (p = 0,000). Patient survival at 1, 3 and 5 years was in DCD: 81,3%, 70,2% and 68,6% vs DBD 89%, 83,7% and 78,8% p = 0,070. Conclusion: Even with a higher risk of primary graft failure and ischemic cholangiopathy, DCD type II is a safe source of donor for liver transplantation.

Histopathological changes of bone marrow in patients with autosomal recessive osteopetrosis and mutation in TCIRG1 gene

Osteopetrosis is a group of rare hereditary diseases, the general structural manifestation of which is the excessive volume of bone tissue due to violation of osteoclastic resorption. The only way to treat this group of patients so far remains transplantation of hematopoietic stem cells, but the degree of its effectiveness largely depends on the severity of morphological changes in the hematopoietic microenvironment in the bone marrow. In this regard, a comprehensive clinical and morphological analysis, in conjunction with the results of transplantation can help in determining the prognosis of the disease depending on the genetic type of osteopetrosis. The material for the studies were biopsies and smears of bone marrow of patients with osteopetrosis, who were received at the R. Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology and Transplantation from the republics of Chuvashia and Mari El for carrying out transplantation of hematopoietic stem cells. The histological preparations were stained with hematoxylin and eosin, azur by Romanovsky and by Van Gieson. Bone marrow smears were stained by Romanovsky-Giemsa. The presence of the mutation c.807 + 5G&gt;A in the gene TCIRG1 in patients with autosomal recessive osteopetrosis causes a complete loss of osteoclastic resorption, which is accompanied by pronounced early structural changes in the hematopoietic microenvironment already at the time of diagnosis. This is manifested by an excessive amount of lamellar bone at the same time as the almost complete obliteration of the medullar lacunae, as well as fibrosis of the bone marrow stroma. A common morphological phenomenon among this group of patients is the presence in the bone marrow of an excessive number of osteoclast differentiation cells without the formation of resorption lacunae. This causes a complete suppression of hemopoiesis, which clinically manifests cytopenia and the formation of foci of extramedullary hematopoiesis. Such pronounced structural changes in the hematopoietic microenvironment result in a high risk of primary graft failure during after transplantation of bone marrow hematopoietic stem cells, the effectiveness of which decreases as the child's age increases. Early development of pronounced structural changes in the hematopoietic microenvironment in patients with TCIRG1-mediated osteopetrosis determines the need for diagnosis and transplantation as soon as possible after birth.

HLA donor-specific antibodies in allogeneic hematopoietic stem cell transplantation: challenges and opportunities.

Allogenic hematopoietic stem cell recipients may have preformed antibodies directed against foreign HLA antigens. The use of partially HLA-mismatched allogeneic hematopoietic stem cell donors allows for the possibility of the presence of circulating HLA donor-specific antibodies (DSAs) in the recipient. The presence of DSAs at the time of stem cell infusion increases the risk of primary graft failure. More recently developed technology using solid phase immunoassays (SPIs) with fluorochrome-conjugated beads has greatly improved the ability to detect and classify DSAs. When used in combination with the classic lymphocytotoxic complement-dependent and flow cytometric crossmatch tests, SPIs help provide DSA strength assessment. Parous females frequently harbor DSAs. DSAs tend to be of higher intensity when directed against haploidentical first-degree relatives. DSA assessment requires frequent monitoring as their relative strength can change over time. Although the criteria that constitutes a prohibitive DSA is unknown, desensitization techniques can result in engraftment rates as experienced in fully HLA-matched allogeneic blood or marrow transplantation recipients.

Donor-Specific Anti-HLA Antibodies in Allogeneic Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative treatment for a wide variety of hematological diseases. In 30% of the cases, a geno-identical donor is available. Any other situation displays some level of human leukocyte antigen (HLA) incompatibility between donor and recipient. Deleterious effects of anti-HLA immunization have long been recognized in solid organ transplant recipients. More recently, anti-HLA immunization was shown to increase the risk of primary graft failure (PGF), a severe complication of AHSCT that occurs in 3–4% of matched unrelated donor transplantation and up to 15% in cord blood transplantation and T-cell depleted haplo-identical stem cell transplantation. Rates of PGF in patients with DSA were reported to be between 24 and 83% with the highest rates in haplo-identical and cord blood transplantation recipients. This led to the recommendation of anti-HLA antibody screening to detect donor-specific antibodies (DSA) in recipients prior to AHSCT. In this review, we highlight the role of anti-HLA antibodies in AHSCT and the mechanisms that may lead to PGF in patients with DSA, and discuss current issues in the field.

Impact of Introducing 2 Simple Technique Modifications on the Descemet Membrane Endothelial Keratoplasty Learning Curve.

Purpose To analyze the impact of performing premarking of the Descemet roll and using SF6 20% on a surgeon's Descemet membrane endothelial keratoplasty (DMEK) learning process. Methods A total of 30 consecutive eyes with endothelial dysfunction undergoing DMEK during the learning curve of a surgeon were retrospectively analyzed. Prior to the study, the surgeon had already performed 10 DMEKs. The first 15 consecutive patients were included in group 1 (no premarking and air tamponade) and the other 15 consecutive patients were included in group 2 (premarking and SF6 tamponade). Main outcome parameters were best-corrected visual acuity (BCVA), endothelial cell density (ECD) loss at 6 months, and intraoperative and postoperative complications. Results Among the 2 groups, BCVA and ECD loss at 6 months were similar. However, there was a statistically significant reduction in primary graft failure (40% vs 0%) and need of rebubbling due to complete or partial graft detachment (40% vs 6%) when comparing group 1 versus group 2. In group 1, half of the patients needing rebubbling had primary graft failure. Conclusions Based on our personal experience, premarking the graft to assess orientation and using a SF6 gas tamponade dramatically reduces the risk of primary graft failure and the need for rebubbling even during the first stages of the learning curve. These findings should encourage surgeons to safely change from Descemet stripping automated endothelial keratoplasty to DMEK.

Lung transplantation: from the procedure to managing patients with lung transplantation.

The perioperative management of lung transplantation patients remains a challenge. The most important goal is the prevention or attenuation of primary graft failure due to ischemia and reperfusion, operative trauma, and activation of systemic inflammation; it significantly influences short-long and long-term outcome. This review focuses on different aspects regarding the management of these high-risk patients. The Lung Allocation Score was implemented to estimate the survival benefit from a lung transplant. As scarcity of lung grafts persists new techniques such as the ex-vivo lung perfusion might allow for expanding the criteria and distribution range of donor organs. Thoracic anesthesia for lung transplantation faces the challenge to manage impaired oxygenation, refractory hypercapnia, and severe pulmonary hypertension in order to attenuate the risk of primary graft failure. Further, lung protective ventilator strategies to prevent postoperative acute lung injury might have an impact on outcome. This includes extracorporeal circulation therapy as rapid advances in this field open up new possibilities. Recent findings suggest that particular attention should be paid to neurocognitive outcome. There is evidence that important key strategies improve outcome after lung transplantation. An update on the substantial challenges in anesthesia comprises ventilator strategy and the use of extracorporeal circulation to minimize inflammation associated with primary graft failure.

Complement-Binding Donor-Specific Anti-HLA Antibodies and Risk of Primary Graft Failure in Hematopoietic Stem Cell Transplantation

Detection of donor-specific anti-HLA antibodies (DSA) has been associated with graft rejection in all forms of transplantation. The mechanism by which DSA increase the risk of graft failure remains unclear. We hypothesized that complement-binding DSA are associated with engraftment failure in hematopoietic stem cell transplantation (HSCT) and analyzed 122 haploidentical transplant recipients tested prospectively for DSA. Retrospective analysis to detect C1q binding DSA (C1q+DSA) was performed on 22 allosensitized recipients. Twenty-two of 122 patients (18%) had DSA, 19 of which were women (86%). Seven patients with DSA (32%) rejected the graft. Median DSA level at transplant for patients who failed to engraft was 10,055 mean fluorescence intensity (MFI) versus 2065 MFI for those who engrafted (P = .007). Nine patients with DSA were C1q positive in the initial samples with median DSA levels of 15,279 MFI (range, 1554 to 28,615), compared with 7 C1q-negative patients with median DSA levels of 2471 MFI (range, 665 to 12,254) (P = .016). Of 9 patients who were C1q positive in the initial samples, 5 patients remained C1q positive at time of transplant (all with high DSA levels [median, 15,279; range, 6487 to 22,944]) and experienced engraftment failure, whereas 4 patients became C1q negative pretransplant and all engrafted the donor cells (P = .008). In conclusion, patients with high DSA levels (>5000 MFI) and complement-binding DSA antibodies (C1q positive) appear to be at much higher risk of primary graft failure. The presence of C1q+DSA should be assessed in allosensitized patients before HSCT. Reduction of C1q+DSA levels might prevent engraftment failure in HSCT.