Outcome Of Transplantation Research Articles

Outcomes of Liver Transplantation with Incidental Intrahepatic Cholangiocarcinoma-Own Experience and a Systematic Review.

Background: Cholangiocarcinoma, the second most common primary liver cancer, is still a contraindication for performing liver transplantation in most patients. Despite various trials being performed in large clinical centers, the results are still not satisfactory. The aim of this study was to present cases from our own cohort and perform a systematic review of the results of liver transplantation in patients with incidental intrahepatic cholangiocarcinoma. Materials and methods: We retrospectively reviewed the records of all patients who underwent liver transplantation and identified two patients with incidental intrahepatic cholangiocarcinoma via histopathological examination of the explanted liver. The results of radiological and biochemical screening performed during liver transplantation, standardized histopathological examination and follow-up data are presented. Additionally, a systematic review of PubMed and Cochrane Reviews based on the PRISMA protocol was performed, yielding 413 similar cases. Results: We present two cases of incidental intrahepatic cholangiocarcinoma found after liver transplantation. The patients were managed according to a standard protocol with no consecutive modification of immunosuppression or chemotherapy. There was no recurrence or mortality. In this systematic review, the mean reported number of lesions ranged between 1 and 2 per patient. A total of 42 recurrences were reported. The percentage of recurrences ranged between 28.6% and 80%. Conclusions: Despite not being a frequent finding, follow-up and further treatment of patients with incidental iCCA should be reported and analyzed. Extra carefulness in screening is advised in patients who are already diagnosed with oncological disease of the liver. In long-term follow-up, recurrence of the disease is rather probable.

Normothermic regional perfusion in controlled DCD liver procurement: Outcomes of the Swedish national implementation protocol.

Liver transplantation (LTX) using donors after controlled circulatory death (cDCD) is associated with poorer graft survival and increased incidence of nonanastomotic biliary strictures (NASs) compared to livers procured from brain-dead donors (DBD). The use of normothermic regional perfusion (NRP) during cDCD procurement may improve posttransplant outcomes and reduce the incidence of NAS. In Sweden, cDCD LTX was introduced through a national pilot protocol with mandatory NRP. This study aims to evaluate the outcome of cDCD LTX during the pilot period. Donor and recipient data were collected on all cDCD liver transplants during the pilot period between January 2020 to December 2022. Outcome on NAS, patient and graft survival, early allograft dysfunction, acute kidney injury, and comprehensive complication index was compared to a matched cohort of 28 patients transplanted with a DBD liver between 2018 and 2022. Eighteen patients were transplanted with a liver from a cDCD donor after using NRP. The mean functional warm ischemia time was 29 ± 6 minutes. The mean lactate reduction during NRP was 8.7 ± 2.4mmol/L, and the end NRP perfusate alanine aminotransferase was 1.4 ± 1µkat/L. When comparing recipients of cDCD liver transplant to DBD, no significant differences were observed in the incidence of NAS, patient and graft survival, comprehensive complication index, early allograft dysfunction, or acute kidney injury. Study protocol magnetic resonance cholangiopancreatography in cDCD patients showed no signs of subclinical biliary strictures. Evaluation of the Swedish national pilot of cDCD LTX with mandatory NRP shows comparable outcomes to a matched DBD cohort with 94.4% 1-year patient and graft survival and no incidence of NAS within the first year.

Open Renal Transplantation in Obese Patients: A Correlation Study between BMI and Early and Late Complications with Implementation of a Prognostic Risk Score.

Obesity is a global epidemic that affects millions worldwide and can be a deterrent to surgical procedures in the population waiting for kidney transplantation. However, the literature on the topic is controversial. This study evaluates the impact of body mass index (BMI) on complications after renal transplantation, and identifies factors associated with major complications to develop a prognostic risk score. A correlation analysis between BMI and early and late complications was first performed, followed by a univariate and multivariate logistic regression analysis. The 302 included patients were divided into obese (BMI ≥ 30 kg/m2) and non-obese (BMI ≤ 30 kg/m2) groups. Correlation analysis showed that delayed graft function (DGF) was the only obesity-associated complication (p = 0.044). Logistic regression analysis identified female sex, age ≥ 57 years, BMI ≥ 25 and ≥30 kg/m2, previous abdominal and/or urinary system surgery, and Charlson morbidity Score ≥ 3 as risk factors for significant complications. Based on the analyzed data, we developed a nomogram and a prognostic risk score. The model's area (AUC) was 0.6457 (95% IC: 0.57; 0.72). The percentage of cases correctly identified by this model retrospectively applied to the entire cohort was 73.61%. A high BMI seems to be associated with an increased risk of DGF, but it does not appear to be a risk factor for other complications. Using an easy-to-use model, identification, and stratification of individualized risk factors could help to identify the need for interventions and, thus, improve patient eligibility and transplant outcomes. This could also contribute to maintaining an approach with high ethical standards.

Pretransplant Cognitive Function and Kidney Transplant Outcomes: A Prospective Cohort Study

Background and hypothesisCognitive impairment is common in patients being evaluated for a kidney transplant (KT). The association between pre-transplant cognitive function and post-transplant outcomes is unclear. Study DesignWe performed a prospective cohort study to assess the association between pre-transplant cognitive function and clinically relevant post-transplant outcomes. Setting and PopulationIn this single center study, participants from the transplant clinic were evaluated during their pre-transplant clinic visits and followed prospectively. OutcomesOur primary outcome measure was allograft function. Secondary outcomes were length of hospitalization for KT, hospital readmission within 30 and 90 days, graft loss, graft rejection within 90 days and one year, and mortality. Analytic approachWe measured cognitive function with the Montreal Cognitive Assessment (MoCA) test. We assessed the association of pre-transplant MoCA score with post-transplant outcomes; we used linear mixed effects models to assess the association with the change in estimated glomerular filtration rate (eGFR), Poisson regression for length of hospitalization, Cox proportional hazard model for graft loss and mortality, and a logistic regression model for readmission and rejection. ResultsWe followed 501 participants for 2.7±1.5 years. The mean age of the patients was 53±14 years and the mean pre-transplant MoCA score was 25±3. Lower pre-transplant MoCA scores did not adversely affect the primary outcome of allograft function or the secondary outcomes. Although higher MoCA scores predicted a higher decline in graft function (β -0.28, 95% CI -0.55, -0.01, p= 0.04), the effect was small and not clinically significant. Older age was associated with longer hospitalization, lower likelihood of rejection, and higher mortality. Deceased donor KT (vs. living donor KT) was associated with longer hospitalization but better graft function. Longer time on dialysis prior to KT was associated with longer hospitalization. A history of diabetes mellitus was associated with higher mortality. LimitationsSingle center study limiting generalizability. ConclusionsPre-transplant MoCA scores were not associated with the primary outcome of allograft function or the secondary outcomes.

Impact of Race and Ethnicity on Outcomes After Umbilical Cord Blood Transplantation

BackgroundUmbilical cord blood transplant (UCBT) improves access to transplant for patients lacking a fully matched donor. Previous Center for International Blood and Marrow Transplant Research (CIBMTR) showed that Black patients had a lower overall survival (OS) than White patients following single UCBT. The current study draws on a larger modern cohort and compares outcomes among White, Latinx, Black, and Asian patients. ObjectiveTo compare outcomes by social determinants of health. Study DesignWe designed a retrospective study using CIBMTR data. US patients were between ages 1 and 80; 983 received single and 1529 double UCBT as reported to CIBMTR, following either a myeloablative (N = 1752) or reduced intensity conditioning (N = 759) for acute myeloid leukemia, acute lymphoid leukemia, or myelodysplasia. The primary outcome was 2-year OS. Secondary outcomes included disease free survival, transplant related mortality (TRM), acute and chronic graft vs host disease (GVHD), and GVHD free, relapse free survival (GRFS). ResultsFor 1705 adults, in univariate analysis, 2-year OS was 41.5% (99% CI, 37.6 to 45.3) for Whites, 36.1% (99% CI, 28.2 to 44.5) for Latinx, 45.8% (99% CI, 36.7 to 55.1) for Blacks, and 44.5% (99% CI, 33.6 to 55.6) for Asians. In multivariate analysis of adults, Latinx patients had inferior OS compared to black patients (p = .0005, HR 1.45, 99% CI 1.18 to 1.79). OS improved over time for all racial/ethnic groups. GVHD rates were comparable among the different racial/ethnic groups. In the 807 children, the 2-year OS in univariate analysis was 66.1% (99% CI, 59.7 to 72.2) for Whites, 57.1% (99%CI, 49 to 64.9) for Latinx, 46.8% (99%CI, 35.3 to 58.4) for Blacks, and 53.8% (99%CI, 32.7 to 74.2) for Asians. In multivariate analysis, no difference in OS was observed among racial/ethnic groups (p = .051). Grade III/IV acute GVHD was higher in Blacks compared with Whites (p = .0016, HR 2.25, 99% CI 1.36 to 3.74) and Latinx (p = .0016, HR 2.17, 99% CI 1.43 to 3.30). There was no survival advantage to receiving a UCB unit from a donor of similar race and ethnicity, for any racial/ethnic groups, for both children and adults.Black and Latinx adult patients were more likely to live in areas defined as high poverty. Patients from high poverty level areas had worse OS (p = .03), due to a higher rate of TRM (p=0.04). Educational level, and type of insurance did not impact overall survival, GVHD, TRM or other transplant outcomes. Children from areas with a higher poverty level had higher TRM, regardless of race and ethnicity (p = .02). Public health insurance, such as Medicaid, was also associated with a higher TRM (p = .02). However, poverty did not impact pediatric OS, DFS, or other post-transplant outcomes. ConclusionsOS for UCBT has improved over time. In adults, OS is comparable among Whites, Blacks, and Asians and lower for Latinx patients. In children, OS is comparable among Whites, Blacks, Latinx, and Asians, but Grade III/IV acute GVHD was higher in Black patients. There was no survival benefit to matching UCB unit and patient by race and ethnicity for adults and children.

Normothermic Machine Perfusion and Normothermic Regional Perfusion of DCD Kidneys Before Transplantation: A Systematic Review.

To overcome organ shortages, donation after circulatory death (DCD) kidneys are being increasingly used for transplantation. Prior research suggests that DCD kidneys have inferior outcomes compared with kidneys donated after brain death. Normothermic machine perfusion (NMP) and normothermic regional perfusion (NRP) may enhance the preservation of DCD kidneys and improve transplant outcomes. This study aimed to review the evidence surrounding NMP and NRP in DCD kidney transplantation. Two independent reviewers conducted searches for all publications reporting outcomes for NMP and NRP-controlled DCD kidneys, focusing on delayed graft function, primary nonfunction, graft function, graft survival, and graft utilization. Weighted means were calculated for all relevant outcomes and controls. Formal meta-analyses could not be conducted because of significant heterogeneity. Twenty studies were included for review (6 NMP studies and 14 NRP studies). Delayed graft function rates seemed to be lower for NRP kidneys (24.6%) compared with NMP kidneys (54.3%). Both modalities yielded similar outcomes with respect to primary nonfunction (NMP 3.3% and NRP 5.6%), graft function (12-mo creatinine 149.3 μmol/L for NMP and 129.9 μmol/L for NRP), and graft utilization (NMP 83.3% and NRP 89%). Although no direct comparisons exist, our evidence suggests that both modalities have good short- and medium-term graft outcomes and high graft survival rates. Current literature demonstrates that both NMP and NRP are feasible strategies that may increase donor organ utilization while maintaining acceptable transplant outcomes and likely improved outcomes compared with cold-stored DCD kidneys. Further research is needed to directly compare NRP and NMP outcomes.

Knockdown of swine leukocyte antigen expression in porcine lung transplants enables graft survival without immunosuppression.

Immune rejection remains the major obstacle to long-term survival of allogeneic lung transplants. The expression of major histocompatibility complex molecules and minor histocompatibility antigens triggers allogeneic immune responses that can lead to allograft rejection. Transplant outcomes therefore depend on long-term immunosuppression, which is associated with severe side effects. To address this problem, we investigated the effect of genetically engineered transplants with permanently down-regulated swine leukocyte antigen (SLA) expression to prevent rejection in a porcine allogeneic lung transplantation (LTx) model. Minipig donor lungs with unmodified SLA expression (control group, n = 7) or with modified SLA expression (treatment group, n = 7) were used to evaluate the effects of SLA knockdown on allograft survival and on the nature and strength of immune responses after terminating an initial 4-week period of immunosuppression after LTx. Genetic engineering to down-regulate SLA expression was achieved during ex vivo lung perfusion by lentiviral transduction of short hairpin RNAs targeting mRNAs encoding β2-microglobulin and class II transactivator. Whereas all grafts in the control group were rejected within 3 months, five of seven animals in the treatment group maintained graft survival without immunosuppression during the 2-year monitoring period. Compared with controls, SLA-silenced lung recipients had lower donor-specific antibodies and proinflammatory cytokine concentrations in the serum. Together, these data demonstrate a survival benefit of SLA-down-regulated lung transplants in the absence of immunosuppression.

Type II innate lymphoid cell plasticity contributes to impaired reconstitution after allogeneic hematopoietic stem cell transplantation

Type II innate lymphoid cells (ILC2s) maintain homeostasis and barrier integrity in mucosal tissues. In both mice and humans, ILC2s poorly reconstitute after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Determining the mechanisms involved in their impaired reconstitution could improve transplant outcomes. By integrating single-cell chromatin and transcriptomic analyses of transplanted ILC2s, we identify a previously unreported population of converted ILC1-like cells in the mouse small intestine post-transplant. Exposure of ILC2s to proinflammatory cytokines resulted in a mixed ILC1-ILC2 phenotype but was able to convert only a small population of ILC2s to ILC1s, which were found post-transplant. Whereas ILC2s protected against acute graft-versus-host disease (aGVHD) mediated mortality, infusion of proinflammatory cytokine-exposed ILC2s accelerated aGvHD. Interestingly, murine ILC2 reconstitution post-HSCT is decreased in the presence of alloreactive T cells. Finally, peripheral blood cells from human patients with aGvHD have an altered ILC2-associated chromatin landscape compared to transplanted controls. These data demonstrate that following transplantation ILC2s convert to a pro-pathogenic population with an ILC1-like chromatin state and provide insights into the contribution of ILC plasticity to the impaired reconstitution of ILC2 cells, which is one of several potential mechanisms for the poor reconstitution of these important cells after allo-HSCT.

Etiology-Specific Effects of Impaired Functional Status on Liver Transplant Outcomes.

Pre-liver transplant (LT) functional status is an important determinant of prognosis post LT. There is insufficient data on how functional status affects outcomes of transplant recipients based on the specific etiology of liver disease. We stratified LT recipients by etiology of liver disease to evaluate the effects of functional status on post-LT prognosis in each subgroup. 2005-2019 United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research (STAR) was used to select patients with liver transplant. A total of 14,290 patients were included in the analysis. These patients were stratified by functional status according to Karnofsky Performance Scale (KPS) score: no assistance, some assistance, or total assistance. They were then further divided into six diagnosis categories: metabolic dysfunction-associated steatotic liver disease (MASLD), hereditary disorders, hepatitis C, hepatitis B, autoimmune disease (AID), and alcoholic liver disease (ALD). Primary endpoints included all-cause mortality and graft failure, while secondary endpoints included organ-specific causes of death. Those under the age of 18 and those with non-whole liver or prior liver transplantation were excluded. Patients with MASLD requiring some assistance (aHR: 1.57, 95% CI 1.03-2.39, p = 0.04) and those requiring total assistance (aHR: 2.32, 95% CI 1.48-3.64, p < 0.001) had higher incidences of graft failure compared to those requiring no assistance. Those with MASLD requiring total assistance had a higher all-cause mortality rate than those needing no assistance (aHR: 1.62, 95% CI 1.38-1.89, p < 0.001). Patients with hereditary causes of liver disease showed a lower incidence of all-cause mortality in recipients needing some assistance compared with those needing no assistance (aHR: 0.52, 95% CI 0.34-0.80, p = 0.003). LT recipients with hepatitis C, AID, and ALD all showed higher incidences of all-cause mortality in the total assistance cohort when compared to the no assistance cohort. For the secondary endpoints of specific cause of death, transplant recipients with MASLD needing total assistance had higher rates of death due to general cardiac causes, graft rejection, general infectious causes, sepsis, general renal causes, and general respiratory causes. Patients with MASLD cirrhosis demonstrated the worst overall outcomes, suggesting that this population may be particularly vulnerable. Poor functional status in patients with end-stage liver disease from hepatitis B or hereditary disease was not associated with a significantly increased rate of adverse outcomes, suggesting that the KPS score may not be broadly applicable to all patients awaiting LT.

The impact of the donors' COVID-19 status on the outcomes of allogeneic hematopoietic stem cell transplantation: a multi-center retrospective study.

To explore the impact of donors' COVID-19 status on allogeneic stem cell transplantation (allo-HSCT), we compared the transplant outcomes of 74 participants. This multi-center retrospective study included nine participants receiving grafts from COVID-19 positive donors (CPD), 45 from COVID-19 experienced donors (CED), and 20 from COVID-19 naive donors (CND). We evaluated engraftment, complications, and survival rates among the three groups. All apheresis procedures were successful with no significant differences in CD34+ cells or lymphocytes in grafts among the three groups. All patients achieved engraftment by day 30 post-HSCT. The incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 55.6%, 20%, and 10% in the CPD, CED, and CND groups, respectively (p = 0.024). Multivariate analysis indicated that COVID-19 positivity in donors at the time of apheresis was an independent risk factor for II-IV aGVHD (p = 0.020, OR = 12.159, 95% CI 1.783 -135.760). No differences were observed among the groups in terms of chronic GVHD, viral infection, or sinusoidal obstruction syndrome. The 6-month overall survival and disease-free survival rates were also similar among the three groups. Our results suggest that the COVID-19-positive status of donors might not impact graft collection, engraftment, or short-term survival of allo-HSCT recipients but might increase the risk of aGVHD. Further research is needed to explore the influence of donors' COVID-19 status on long-term complications and survival in allo-HSCT recipients.

Fresh osteochondral allograft transplantation for knee full-thickness articular cartilage lesions using femoral head of living donors: short-term results.

Fresh osteochondral allograft transplantation is a good treatment option of cartilage defects. However, this treatment option is not available in all countries due to limited graft availability and tissue banks limitations. The purpose of this study is to assess the short term functional and imaging outcomes of fresh osteochondral allograft transplantation in the knee using the femoral head of living donors. Fresh osteochondral allografts from the femoral heads of living donors is a valid graft source for management of distal Femur cartilage defects. This technique can improve functional knee scores with good radiological outcomes. Prospective case series. Fifteen patients with full thickness cartilage defects of the distal femur underwent osteochondral allograft transplantation from the femoral heads of living donors. Grafts were transplanted by both shell and multiple dowels techniques. The average follow up duration was 18.3 months (range, 12-25 months). Patients were evaluated by Lysholm and International Knee Documentation Committee (IKDC) scores, radiography and MR imaging using Osteochondral Allograft MRI Scoring System (OCAMRISS). There was a statistically significant improvement (P < 0.001) in both Lysholm and IKDC average scores at 6 months and 12 months postoperative. Postoperative MRI was done at an average 6.8 months (range, 5-11 months) postoperative. The mean total OCAMRISS score was 3.4 (range, 1-7). A second look arthroscopy was done in four patients and showed intact articular cartilage in all three patients. Femoral head of living donors is a valid new source for fresh osteochondral allograft transplantation of knee osteochondral lesions. Short term results showed improvement in clinical assessment scores. Follow up imaging showed graft incorporation and good MRI scores.

Primary hyperoxaluria: Long-term outcomes of isolated kidney versus simultaneous liver/kidney transplant.

To compare long-term transplant outcomes (organ rejection and retransplant) of simultaneous liver/kidney transplant (SLK) versus isolated kidney transplant (IK) for patients with primary hyperoxaluria (PH). The Rare Kidney Stone Consortium PH registry was queried to identify patients with PH who underwent SLK or IK from 1999 to 2021. Patient characteristics and long-term transplant outcomes were abstracted and analyzed. Statistical comparisons were performed with Kaplan-Meier plots and Cox proportional hazards models. We identified 250 patients with PH, of whom 35 received care at Mayo Clinic and underwent SLK or IK. Patients who underwent SLK as their index transplant had lower odds of kidney rejection than did those who underwent IK (hazard ratio [HR], 0.29; 95% confidence interval [CI], 0.08-0.99; p = .048). The immunoprotective effect of concomitant liver and kidney transplant appeared to enhance outcomes for patients with PH. Additionally, the odds of retransplant were significantly lower for patients who underwent SLK as their index transplant than for those who underwent IK (HR, 0.08; 95% CI, 0.02-0.42; p = .003). Of five patients who underwent IK and had maintained graft function for at least 5 years after transplant, three (60%) had documented vitamin B6 responsiveness. Patients with PH who underwent SLK had a lower risk of kidney rejection and retransplant than those who underwent IK. Accurate genetic assessment for vitamin B6 responsiveness may optimize IK allocation. Novel therapeutics, such as lumasiran, have been introduced as promising agents for the management of PH.

Renal Transplant Outcomes in Plasma Cell Dyscrasias and AL Amyloidosis after Treatment with Daratumumab.

Background: The morbidity and mortality from AL amyloidosis has significantly improved with the development of novel treatments. Daratumumab is a highly effective treatment for AL amyloidosis, but end-stage kidney disease is a common complication of this condition. Kidney transplantation is the ideal form of renal replacement therapy but has historically been contraindicated in this group of patients. Methods: Given the improved survival and better treatments of both conditions, we argue that it is time to reconsider transplanting these patients. Results: We report our experience of transplanting four patients with AL amyloidosis who had achieved stable remission through treatment with daratumumab. Conclusions: We highlight the key challenges involved and discuss important clinical issues for patients receiving daratumumab, particularly the difficulties with interpreting the crossmatch in light of daratumumab and immunoglobulin therapy interference. We also discuss the complexities involved in balancing the risks of infection, relapse, rejection, and immunosuppression in such patients.

High infection rates and risk‐adapted prevention strategies in contemporary pediatric allogeneic hematopoietic stem cell transplantation

AbstractWith recent changes in hematopoietic stem cell transplantation (HSCT) practices, such as the increasing use of alternative donors and ex vivo T‐cell depletion, how various risk factors interplay and affect the timeline of infections have not been well elucidated. We retrospectively reviewed the first 100 consecutive HSCT from April 2019 to October 2021 in the only pediatric HSCT center in Hong Kong. We found that the vast majority of the allogeneic transplant recipients (69/74, 93.2%) had infections after HSCT, amongst which bacterial, viral, and fungal infection rates were 35.1%, 90.5%, and 9.5%, respectively. In contrast, only 30.8% (8/26) of autologous transplant recipients had infections (rate of bacterial, viral, and fungal infection were 19.2%, 15.4%, and 3.8%, respectively). Human herpesvirus 6 (HHV‐6) and BK virus (BKV) typically occurred early after HSCT, adenovirus (ADV) and varicella zoster virus (VZV) thereafter, and cytomegalovirus (CMV) and Epstein–Barr virus (EBV) throughout the entire 2.5‐year observation period. Ex vivo T‐cell depletion was a general risk factor for viral infection with HHV‐6 (hazard ratio [HR] = 3.03), BKV (HR = 3.36), CMV (HR = 4.45), and EBV (HR = 7.15); all p &lt; 0.02. Cancer in second‐complete remission compared with first‐complete remission was a risk factor for bacterial infection (OR = 6.0, 95% CI = 1.12–32.2, and p = 0.037). Patients with gut graft‐versus‐host disease were at risk for fungal infections (OR = 12.3, 95% CI = 1.33–114.4, and p = 0.027). The infection‐related mortality rate was 10.0%, which occurred only in allogeneic HSCT patients with hematological malignancies receiving cord blood (n = 4) or haploidentical HSCT (n = 6). Collectively, our findings in pediatric patients after contemporary HSCT support both time‐dependent and risk‐adapted measures against infective complications to improve transplant outcome.

Permissible HLA mismatches in 9/10 unrelated donor pediatric stem cell transplants using HLA-EMMA: an EBMT Inborn Errors Working Party study

AbstractAllogeneic hematopoietic stem cell transplantation (HSCT) with mismatched unrelated donors (MMUD) is associated with inferior outcome compared with matched unrelated donors (MUDs). We aimed to identify permissible mismatches using HLA epitope mismatch algorithm, which determines permissibility by analyzing amino acid sequences, in a single-center cohort of 70 pediatric 9/10 MMUD HSCTs and 157 10/10 MUDs for comparison. Amino acid matching was evaluated for the whole HLA protein, the α-helices, and the β-sheets, in both host vs graft (HvG) and graft vs host (GvH) direction. Superior event-free survival (EFS) was found in 13 patients permissibly mismatched in the HvG direction (totalHvG, 92% vs 58% at 1 year; P = .009) and in 21 patients matched on the α-helices (αHvG, 90% vs 53%; P = .002). These rates were similar to EFS rates in patients with 10/10 MUDs (90% vs 80%; P = .60). EFS was not related to β-sheet amino acid matching, nor to matching in the GvH direction. Overall survival (OS) rates trended similarly to those of EFS for amino acid mismatches (totalHvG, 92% vs 74%; P = .075; αHvG, 90% vs 71%; P = .072). These findings were reproduced in an EBMT Registry inborn errors cohort of 271 pediatric 9/10 MMUD HSCTs and 929 10/10 MUD HSCTs, showing a significant effect of αHvG matching on both OS and EFS and similar OS and EFS between αHvG matched MMUDs and 10/10 MUDs. In summary, HvG amino acid matching on the α-helices identifies 9/10 MMUDs with permissible mismatches, which are correlated with favorable transplant outcomes similar to those of matched donors.

Histocompatibility assessment in hematopoietic stem cell transplantation: recommendations from the Italian Society for Immunogenetics and Transplantation Biology (Associazione Italiana di Immunogenetica e Biologia dei Trapianti - AIBT).

The outcome of allogeneic hematopoietic stem cell transplantation (HSCT) is significantly influenced by the degree of HLA histocompatibility between donor and recipient. To provide shared indications for required histocompatibility testing and interpretation before HSCT, the Italian Society for Immunogenetics and Transplantation Biology (Associazione Italiana di Immunogenetica e Biologia dei Trapianti [AIBT]) gathered members and created a working group to discuss and develop recommendations for histocompatibility assessment in HSCT.After a review of the literature and multiple panel discussions, AIBT developed up-to-date recommendations for the resolution levels of HLA typing, histocompatibility definitions of patients and donors, importance of anti-HLA antibodies, and significance of NK alloreactivity, which are reported in this document. These recommendations have been shared with the Italian Group for Bone Marrow Transplantation (Gruppo Italiano per il Trapianto di Midollo Osseo, cellule staminali emopoietiche e terapia cellulare [GITMO]) and the Italian National Center for Transplantation (Centro Nazionale Trapianti [CNT]). Notably, the increased use of HLA-mismatched transplantation (i.e., mismatched unrelated, haploidentical) in recent years has made these indications even more relevant for the standardization and improvement of quality of care.This document represents a useful instrument for health care workers involved in the field of HSCT, enhancing synergy with transplant physicians and enabling greater optimization of the available resources.

89Zr-immunoPET-guided selection of a CD33xIL15 fusion protein optimized for antitumor immune cell activation and in vivo tumour retention in acute myeloid leukaemia.

Immune cells are capable of eliminating leukemic cells, as evidenced by outcomes in hematopoietic cell transplantation (HCT). However, patients who fail induction therapy will not benefit from HCT due to their minimal residual disease (MRD) status. Thus, we aimed to develop an immunomodulatory agent to reduce MRD by activating immune effector cells in the presence of leukaemia cells via a novel fusion protein that chimerises two clinically tolerated biologics: a CD33 antibody and the IL15Ra/IL15 complex (CD33xIL15). We generated a set of CD33xIL15 fusion protein constructs with varying configurations and identified those with the best in vitro AML-binding, T cell activation, and NK cell potentiation. Using 89Zr-immunoPET imaging we then evaluated the biodistribution and in vivo tumour retention of the most favourable CD33xIL15 constructs in an AML xenograft model. Ex vivo biodistribution studies were used to confirm the pharmacokinetics of the constructs. Two of the generated fusion proteins, CD33xIL15 (N72D) and CD33xIL15wt, demonstrated optimal in vitro behaviour and were further evaluated in vivo. These studies revealed that the CD33xIL15wt candidate was capable of being retained in the tumour for as long as its parental CD33 antibody, Lintuzumab (13.9 ± 3.1%ID/g vs 18.6 ± 1.1%ID/g at 120 h). This work demonstrates that CD33xIL15 fusion proteins are capable of targeting leukemic cells and stimulating local T cells in vitro and of concentrating in the tumour in AML xenografts. It also highlights the importance of 89Zr-immunoPET to guide the development and selection of tumour-targeted antibody-cytokine fusion proteins.

The Impact of Race and Socioeconomic Status on Transplant Accessibility and Outcomes: A Literature Review

Due to the high demand but low supply of donor organs, issues of organ allocation arise as patients on the waitlist are prioritized to determine who gets the next available organ. This literature review will review articles related to the racial and socioeconomic disparities in organ transplants and how they affect transplant access and outcomes. Patients of Black and minority (Hispanic and Native American) races had significantly lower rates of organ transplants as well as worse transplant outcomes including graft failure and post-operative complications (Bryce et al., 2009). Similarly, patients from lower socioeconomic status (SES) backgrounds (i.e. poverty or lack of private/commercial insurance) had lower rates of organ transplant surgeries but there has been no significant research done on the effect that SES specifically has on transplant outcomes. Further directions for future research should be investigating the role of SES on transplant outcomes. The findings of this literature review highlight the need for measures to make organ allocation more equitable; this can be done by factoring in the social determinants of health (SDOH) when prioritizing potential organ recipients to compensate for race and SES decreasing accessibility to transplants.

Effect of early post-hematopoietic stem cell transplant tacrolimus concentration on transplant outcomes in pediatric recipients: One facility’s ten-year experience of immunosuppression with tacrolimus

Acute graft-versus-host disease (GVHD) is a common life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), ranking as the second leading cause of death among recipients, surpassed only by disease relapse. Tacrolimus is commonly used for GVHD prophylaxis, but achieving therapeutic blood levels is challenging, particularly in pediatrics, due to the narrow therapeutic window and the high interindividual variability. The retrospective study conducted at IRCCS “Burlo Garofolo” in Italy aimed to assess the impact of early post-HSCT tacrolimus levels on transplant-related outcomes in pediatric recipients. The population pharmacokinetic model (POP/PK) was set up to describe tacrolimus pharmacokinetics. Elevated tacrolimus (>12–15 ng/ml) levels within the initial weeks post-HSCT are associated with reduced post-transplant infections (p < 0.0001) and decreased incidence of early transplant-related events (p < 0.01), including a lower incidence of acute GVHD (p < 0.05 on day 0). High tacrolimus exposure can lead to an increased risk of chronic GVHD (p < 0.0001) and reduced overall survival (p < 0.01). Personalized dosing and therapeutic monitoring of tacrolimus are crucial to ensure optimal outcomes. POP/PK could help achieve this goal, giving us a model by which we can balance immunosuppression while looking at the patient’s general well-being and providing the necessary treatment.

Outcomes of hematopoietic stem cell transplantation in 813 pediatric patients with Fanconi anemia

AbstractAllogeneic hematopoietic stem cell transplantation (HSCT) is the only established curative option for Fanconi anemia (FA)–associated bone marrow failure (BMF)/aplastic anemia (AA) and acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS). We performed a retrospective multicenter study on 813 children with FA undergoing first HSCT between 2010 and 2018. Median duration of follow-up was 3.7 years. Median age at transplant was 8.8 years (IQR, 6.5-18.1). Five-year overall survival (OS), event-free survival (EFS), and graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) were 83% (95% confidence interval [CI], 80-86), 78% (95% CI, 75-81), and 70% (95% CI, 67-74), respectively. OS was comparable between matched family donor (MFD; n = 441, 88%) and matched unrelated donor (MUD; n = 162, 86%) and was superior to that of mismatched family donor (MMFD) or mismatched unrelated donor (MMUD; n = 144, 72%) and haploidentical donor (HID; n = 66, 70%; P < .001). In multivariable analysis, a transplant indication of AML/MDS (vs AA/BMF), use of MMFD/MMUD and HID (vs MFD), and fludarabine-cyclophosphamide (FluCy) plus other conditioning (vs FluCy) independently predicted inferior OS, whereas alemtuzumab vs antithymocyte globulin was associated with better OS. Age ≥10 years was associated with worse EFS and GRFS. Cumulative incidences (CINs) of primary and secondary graft failure were 2% and 3% respectively. CINs of grade 3 to 4 acute GVHD and chronic GVHD were 12% and 8% respectively. The 5-year CIN of secondary malignancy was 2%. These data suggest that HSCT should be offered to patients with FA with AA/BMF at a younger age in the presence of a well-matched donor.