Recipient Weight Research Articles

Effect of ABO Mismatch and RBC Alloimmunization on the Outcome of Hematopoietic Cell Transplantation for Sickle Cell Disease

BackgroundHematopoietic cell transplantation (HCT) remains the only well-established curative option for sickle cell disease (SCD) patients. Nonmyeloablative (NMA) conditioning has been used to improve the outcomes and reduce toxicities in adult SCD patients. However, Recipient/Donor (R/D) ABO incompatibility and alloimmunization could be significant impediments to successful outcomes when transplanting SCD patients due to risks of hemolysis, delayed engraftment, poor graft function and graft failure (GF). Herein, we report our experience with allogeneic HSCT for SCD and the effects of RBC groups mismatch and alloimmunization on the outcome of transplanted patients. MethodsWe conducted a retrospective analysis of all SCD patients (age >14 year) that underwent HSCT from January 2015 to February 2022 at our center. All patients received Intravenous alemtuzumab (1 mg/kg divided over 5 days on days -7 to -3) and 300 cGy TBI on day -2 or -1 for conditioning. Pre-transplant preparation consisted of hydroxyurea at maximum tolerated dose for 2-3 months and one session of exchange transfusion. Peripherally mobilized CD34 stem cells targeting 10 × 106 /kg of recipient weight were used. For graft versus host disease (GVHD) prophylaxis sirolimus was started on day -1 and continued for one year with tapering if lymphoid chimerism was > 50%. For Patients with major ABO incompatibility, we administered 2 doses of rituximab (375 mg/m2) and 3 sessions of plasmapheresis before starting the conditioning regimen targeting an isoheamagglutinin titer < 1/32. The primary objective was to determine the impact of RBC groups mismatch and alloimmunization on the outcome of transplanted patients. The secondary objective was to assess the impact of GF on overall survival (OS). Logistic regression was done to evaluate predictors for GF. Kaplan-Meier method was used for survival analysis. ResultsA total of 194 patients were included with a median age of 26 years. The median baseline Hgb and HbS were 93 g/L and 71.3%, respectively. Indications of stem cell transplantations were most commonly due to recurrent vaso-occlusive crisis in 52.5% of patients, CNS events in 19.6%, and acute chest syndrome in 17%. After a median follow up of 28.8 months (5-83), sixteen patients (8%) experienced graft failure (3 with primary GF and 13 with secondary GF). On univariate analysis, ABO minor incompatibility and RBC alloantibodies against donor non-ABO antigens were predictive for GF.On multivariate analysis RBC alloantibodies against donor non-ABO antigens (OR, 8.29; 95% CI, 2.01 to 34.05, P=0.0033) was the only factor predictive of GF. None of the 16 patients with major ABO incompatibility developed GF. Two-years OS for all patients was 95%. The 2 years OS for patients without GF was 98% compared to 74% in patients with GF, (P<0.0001). ConclusionIn our SCD transplanted patients, RBC alloantibodies against donor non- ABO antigens were an independent risk factor for GF. Patients with GF had an inferior survival and strategies for decreasing GF risk are needed.

Splenectomy Before Recipient Hepatectomy for Inflow Modulation Using a Very Small Modified Right Hemiliver Graft: A Case Report

Portal inflow modulation has become standard practice in many transplant centers performing living donor liver transplantation. This is believed to counteract the deleterious effects of excess portal flow into a small-for-size graft. A splenectomy negates the contribution of the splenic vein flow completely and thereby substantially reduces portal inflow. Although it has been adopted as a standard strategy by many Japanese centers for inflow modulation, especially while using left hemiliver grafts, there is justifiable apprehension about its usage due to potential increases in morbidity. Described here is a splenectomy performed while using a modified right hemiliver graft with a graft to recipient weight ratio of 0.49. The challenges in decision making and reasons regarding how such a small graft might have worked without manifestations of small-for-size/flow syndrome are discussed.

Cumulative rabbit anti-human thymocyte globulin dose to recipient weight during the peri-operative period is an independent risk factor for early postoperative urinary tract infection after kidney transplantation

Anti-human thymocyte globulin-Fresenius (ATG-F) is frequently utilized to achieve successful induction for kidney transplantation recipients. This study aimed to examine the association between the ATG-F dose-to-recipient-weight ratio (ADR) and the risk of developing urinary tract infections (UTIs) following kidney transplantation. Data of kidney transplant recipients who underwent ATG-F-induction peri-operatively in a medical center were retrospectively collected, and the incidence of UTIs during the first postoperative year was also recorded. The risk of UTI associated with ADR was analyzed, and receiver operating characteristic curves were drawn to determine the optimal ADR, followed by Cox regression models. In total, 131 recipients were included, with an UTI incidence of 19.08% and a mean interval of 3.08 months. The optimal ADR was 6.34, involving 41 and 90 patients in the low ADR and high ADR groups, respectively. The UTI-free rate in the low ADR group was significantly higher than that in the high ADR group (p = 0.007). Cox regression analysis indicated that a high ADR independently increased the risk of UTI following kidney transplantation (hazard ratio: 5.306, 95% confidence interval: 1.243–22.660, p = 0.024). There was no significant difference in rejection rate between the high ADR and low ADR groups. In conclusion, a high ADR increased the incidence of early postoperative UTI among kidney transplant recipients.

Study of related factors to vascular complications after pediatric liver transplantation

Objective: To explore the related factors of vascular complications after liver transplantation in children. Methods: This is a retrospective case-series research. The clinical data of 89 pediatric liver transplant patients admitted to the Organ Transplantation Center, the Affiliated Hospital of Qingdao University from January 2016 to March 2024 were collected retrospectively. This study included 44 males and 45 females,aged from 4 months to 17 years. The ratio of graft to recipient weight was 0.6% to 7.7%. The primary diseases included 48 cases of biliary atresia and 41 cases of non-biliary atresia. The t-test, Wilcoxon rank sum test, χ2 test, and Fisher's exact probability method were used for data analysis. Multivariate Logistic regression was used to analyze the related factors of vascular complications. Results: All 89 children with liver transplantation completed surgery successfully. There were 8 cases of arterial complications after surgery, including 6 cases of hepatic artery thrombosis and 2 cases of hepatic artery stenosis. There were 16 cases of portal vein complications after surgery, including 9 cases of portal vein stenosis and 7 cases of portal vein thrombosis. The results of univariate analysis showed that the age of the recipient ≤1 year was the relevant factor for hepatic arterial complications(χ2=4.772,P=0.029). The age of the recipient ≤1 year, the age of the donor, the hepatic phase, and the time of cold ischemia were the relevant factors for the occurrence of portal vein complications(χ2=7.270,Z=388.500,Z=838.000, Z=594.500;all P<0.05). The results of multivariate analysis showed that age(≤1 year vs. >1 year) and duration of cold ischemia(every additional 1 hour) were independent related factors for portal vein complications after liver transplantation in children(both P<0.05). Conclusion: Children aged ≤1 year and with prolonged cold ischemia are more likely to develop portal vein complications after liver transplantation.

Association Between Liver Graft to Recipient Weight Ratio and Acute Kidney Injury Following Liver Transplantation: A Historical Cohort Study.

Acute kidney injury (AKI) is a frequent complication following liver transplantation (LT) that has a multifactorial etiology. While some perioperative risk factors have been associated with postoperative AKI, the impact of liver graft weight to recipient body weight ratio (GW/RBW) has been poorly explored. We hypothesized that a high GW/RBW ratio would be associated with AKI after LT. This single-center historical cohort study included all consecutive adults who had LT at Paul Brousse Hospital between 2018 and 2022. Patients requiring preoperative renal replacement therapy, combined solid organ transplantation, retransplantation, split or domino graft were excluded, as well as those with missing graft weight and creatinine values during the first postoperative week. The primary exposure was GW/RBW ratio expressed as a proportion. The primary outcome was the incidence of postoperative AKI within 7 days after surgery, defined using the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. The secondary outcome was the AKI severity (KDIGO grades). We estimated logistic and ordinal regression models adjusted for potential confounding factors and explored nonlinear associations. Of 467 patients analyzed, 211 (45%) developed AKI. A high GW/RBW ratio was associated with both the risk of postoperative AKI and the severity of AKI (KDIGO grades), especially above a threshold of 2.5% (non-linear effect). A high GW/RBW ratio was associated with an exponential increase in the risk of AKI after LT. A high GW/RBW ratio was also associated with an increased AKI severity. Our findings may help improve graft allocation in patients undergoing LT.

Comparison of Long-Term Outcomes Achieved With Live Donor and Split Deceased Donor Liver Grafts in Pediatric Liver Transplantation.

The aim of the present study was to compare the outcomes of pediatric LT with left liver grafts, obtained either from a living donor (LD) or a split deceased donor (sDD). Retrospective single-center study from 2002 to 2022. All pediatric LT with left liver grafts (not including middle hepatic vein) from LD or sDD were included. Reduced grafts were not included. A total of 112 pediatric LT were performed: 58 with LD grafts and 54 with sDD grafts (17 split ex situ and 37 insitu). Donor characteristics were similar, apart from donor age (33 years in LD vs. 30 years in sDD, p = 0.03). Indications were similar with 55% biliary atresia in each group. Retransplantation was more frequently performed in the sDD group (2% vs. 15%, p = 0.01). Recipient age, weight, and PELD score at transplant were not significantly different between groups. Cold ischemia time was longer for sDD (158 min in LD vs. 390 min in sDD; p < 0.0001). Posttransplant peak ALT was higher with sDD grafts (1470 vs. 1063, p = 0.018), and hospital stay was longer with sDD grafts (27 vs. 21 days, p = 0.005). However, there was no difference between groups in terms of major morbidity (Dindo-Clavien grade ≥3), vascular and biliary complications, and 90-day mortality. Patient survival at 10 years was 93.1% for LD and 92.8% for sDD (p = 0.807). Graft survival at 10 years was 89.7% for LD and 83.1% for sDD (p = 0.813). Technically similar LD and sDD grafts achieve very similar postoperative and long-term outcomes with excellent patient and graft survival.

Effect of an intensive nutrition intervention of a high protein and low glycemic load diet on weight of kidney transplant recipients: a randomized clinical trial.

The purpose of this study is to evaluate the effect of a high protein and low glycemic load diet in preventing weight gain after kidney transplantation. We designed a prospective, single-center, open-label, randomized controlled study to compare the efficacy of a high protein (1.3-1.4 g/kg/day) and low glycemic load diet versus a conventional diet (0.8-1.0 g/kg/day of protein and no recommendations on glycemic load) in preventing weight gain (ClinicalTrials.gov identifier: NCT02883777). A total of 120 patients were evaluated. Patients were followed for 12 months, and the primary outcome was weight maintenance or weight gain lower than 5%. There were no differences in total energy intake, carbohydrates, and total fats between groups. Intervention group (IG) increased protein intake to 1.38 ± 0.56 g/kg/day and decreased the glycemic load to 87.27 ± 4.54 g/day, while control group (CG) had a dietary protein intake of 1.19 ± 0.43 g/kg/day and a glycemic load of 115.60 ± 7.01 g/day. Total fiber intake was greater and trans-fat was lower in IG. Dietetic cholesterol increased in IG over time and was significantly different between groups. Overall, patients had an increase in body weight over time, with a mean increment of 4.1 ± 5.5 kg (5.75%). The percentage of patients who achieved the primary outcome was 50% of sample size, without differences between groups. The glomerular filtration rate improved over time in both groups. Considering 24-h proteinuria and albuminuria, a similar rise was observed in both groups. The present dietary intervention was safe, but had no effect on weight gain in kidney transplant subjects. Our findings suggest that other strategies, including alternative dietary and/or pharmacological and psychological interventions might be tested in randomized control trials in order to improve patients' body weight outcomes after transplant.

Does body weight below 6 kg modify survival of infants after liver transplant? Complete National Transplant Registry Data.

To determine the impact of infant recipient body weight at primary liver transplantation (LT) on both recipient and graft survival rates in complete national data from Poland. We conducted a single-center, retrospective cohort study including 142 LT recipients below 1 year of age with body weights below 10 kg who received primary and isolated LT between 2001 and 2017. Patients were divided into two study groups according to body weight at the time of LT: (1) Group I (≤6.0 kg, 32 patients) and (2) Group II (6.1-9.9 kg, 110 patients). Independent impact of body weight on patient and graft survival were assessed using survival curves and a multivariable Cox regression analysis. The univariate predictors of mortality or retransplantation at 1 year post-LT were recipient body weight of ≤6 kg at transplantation, pediatric end-stage liver disease score, urgent LT, graft from deceased donor, cold ischemia time, post-LT hepatic artery thrombosis, and post-LT dialysis. No statistically significant impact of body weight ≤6 kg on 1-year failure-free survival was found based on the multivariable analysis (p = 0.063). Body weight ≤6 kg was associated with longer post-LT intensive care unit and post-LT hospital stays (p = 0.013 and 0.025, respectively). Since no evidence of independent negative impact of recipient body weight ≤6 kg on failure-free survival 1 year post-LT was found, LT in infants with end-stage liver disease in Poland should be performed according to medical indications and urgency when an appropriate donor is available.

Differential effects of donor factors on post-transplant survival in lung transplantation

BackgroundPredicting post-transplant (PT) survival in lung allocation remains an elusive goal. We analyzed the impact of donor factors on PT survival and how these relationships vary among transplant recipients. MethodsWe studied primary bilateral lung transplant recipients (n=7,609) from the US Scientific Registry of Transplant Recipients (19 February 2015 - 1 February 2020). Main and interaction effects were evaluated and adjusted across candidate age, sex, and diagnosis. Models predicting PT survival were compared to the PT composite allocation score model (PT-CAS): 1. Cox regression donor multivariable model (COX), 2. COX + PT-CAS, 3. random forest model (RF), 4. RF + PT-CAS. Model discrimination and calibration measures were compared. ResultsInteractions between donor and recipient factors emerged by – age: lower survival for DCD organs for recipients aged 55-69 years, donor smoking for recipients aged 30-54 and 70+, Hispanic donor for recipients < 30, non-Hispanic Black (NHB) donor for recipients aged 30+; sex: CMV mismatch for males; diagnosis: higher donor recipient weight ratio for diagnosis Group C (e.g.CF), donor diabetes for diagnosis Group D (e.g. IPF). COX and RF models performed similarly to PT-CAS; however, the combined COX PT-CAS model had improved discrimination (1y AUC PT-CAS 0.609 vs. 1y AUC COX + PT-CAS 0.626) and improved calibration across a broader range of predicted risk. ConclusionThe influence of donor factors on recipient post-transplant survival differed by age, sex, and diagnosis. The addition of donor factors to existing models predicting posttransplant survival led to only modest improvement in prediction accuracy. Future efforts may focus on optimizing matching strategies to improve donor utilization.

Graft Inflow Modulation by Splenic Artery Ligation for Portal Hyper Perfusion does not Decrease Rates of Early Allograft Dysfunction in Adult Live Donor Liver Transplantation: A Randomized Control Trial.

The primary objective was to compare the rates of early allograft dysfunction (EAD) in patients undergoing elective adult live donor liver transplantation (ALDLT) with and without graft portal inflow modulation (GIM) for portal hyper-perfusion. The secondary objectives were to compare time to normalization of bilirubin and International Normalized Ratio (INR), day 14 ascitic output more than 1liter, small-for-size syndrome (SFSS), intensive care unit / high dependency unit and total hospital stay, and 90 day morbidity and mortality. GIM can prevent EAD in ALDLT patients with portal hyper-perfusion. A single-center randomized trial with and without GIM for portal hyper-perfusion by splenic artery ligation (SAL) in ALDLT was performed. After reperfusion, patients with portal venous pressure (PVP)>15mm Hg with a gradient (PVP - central venous pressure) of ≥ 7mm Hg and/or portal venous flow (PVF)>250mL/min/100 grams of liver were randomized into two groups: GIM and No GIM. 75 of 209 patients satisfied the inclusion criteria, and 38 underwent GIM. Baseline PVF and PVP were comparable between the GIM and no GIM groups. SAL significantly reduced the PVF and PVP (P<0.001). There were no differences in the primary and secondary outcomes between the two groups. In the subgroup analysis, with a Graft to Recipient Weight Ratio (GRWR)≤0.8, there were no significant differences in the primary and secondary outcomes. SAL significantly decreased PVP and PVF, but did not decrease rates of EAD in adult LDLT.

Graft reduction in adult liver transplantation: indications, techniques, and outcomes

PurposeGraft reduction can be a patients and graft-saving option to avoid large-for-size syndrome. The aim of this article was to summarize the literature on graft reduction in adult liver transplantation and to show the technique of H 6/7 graft hepatectomy. MethodsThe technique, showed in a didactical video, entails an ex-situ posterior sectionectomy under hypothermic perfusion. The right hepatic vein is identified, and the transection line follows the right hepatic fissure. The Glissonean pedicles are ligated during parenchymal transection. ResultsA narrative review of the literature yielded seven studies. A total of 15 liver grafts were reduced in adult liver transplantations. Most of the reduction were ex situ (11/15; 73.3%); graft reduction entailed an H6,7 sectionectomy in 10 cases and one H2, 3 in one case. In-situ reduction included one right hepatectomy (H5, 6, 7,8), two H6, 7 sectionectomy, and one H2, 3 left lateral sectionectomy. The duration of ex-situ reduction averaged 56minutes (median 40.5minutes, range 33-130minutes), and the graft weight to recipient weight ratio (GWRW) decreased from 3.57±0.4 to 2.70±0.5% after graft reduction. The average cold ischemia time was 390minutes (range 230-570minutes). There were no liver retransplantations. ConclusionGraft reduction in adult liver transplantation can become necessary to avoid large-for-size syndrome. Ex-situ H6, 7 sectionectomy represents the easiest “graft reduction hepatectomy” and is able to minimize the occurrence of graft compression while leaving enough functional liver parenchyma.

Sustained cross-talk between donor T cells and IL-33+ stromal cells maintains CD4 T cell differentiation and determines GVHD outcomes

Abstract Conditioning before allogeneic hematopoietic stem cell transplantation (AlloHSCT) increases the tissue injury signal IL-33 in fibroblastic reticular cells (FRC). Released IL-33 directly stimulates donor CD4 T cells to prime IL-12-independent Type 1 T helper cell (Th1) differentiation and expansion. Tissue stroma upregulates IL-33, but a role for IL-33 in sustaining the pathogenic donor Th1 responses causing GVHD is unclear. We compared B6 mice with inducible ST2 deletion (R26-CreERT2xSt2fl/fl) to wildtype (WT) R26-CreERT2 as T cell donors in a lethal GVHD model (B6 to BALB/c). Donor ST2 deletion at days 10-14 post AlloHSCT increased CD4 T cells Foxp3 expression with reciprocal decreases in Tbet expression in both the lymphoid organs and target tissues. Sustained IL-33 signaling also maintained donor T cell TCF1 expression. Ablating ST2 after GVHD development improved clinical scores and promoted recipient weight gain. How bioactive IL-33 is released from nuclear sequestration remains undefined. RNAseq analysis suggested that IL-33 stimulates T cell granzyme B (GzmB) expression and B6 GzmB deficient (Gzmb-/-) donor T cells displayed reduced activation and expansion similar to ST2 deficient CD4 T cells. In contrast to GzmBWT, anti-IL-33 antibodies had no impact on GzmBKO T cell responses. Thus, cross-talk between donor T cells and IL-33+ stroma orchestrates the T cell identities that are critical to sustain the pathogenic CD4 T cell responses causing GVHD.

Challenges faced in establishing a pediatric liver transplant program in a lower-middle-income country with free healthcare service.

Liver transplant is the cure for children with liver failure. Sri Lanka is a lower-middle-income country with a predominant free, state health system. Pediatric liver transplant program in Sri Lanka is still in the budding state where the initial experience of the program is yet to be documented. A retrospective review was performed including the clinical characteristics of all pediatric liver transplant recipients of Colombo North Centre for Liver Diseases since the inception of the program from June 2020 to May 2023. There were 14 PLT performed in 3 years. The median recipient age and weight were 8 years (6 months-15 years) and 23.3 kg (6.4-49.2), respectively. The majority were boys (64%). All were from low-income backgrounds. Indications for LT were acute liver failure (5/14), decompensated chronic liver disease (5/14), and acute on chronic liver failure (4/14). Underlying liver diseases were Wilson disease (6/14), autoimmune liver disease (3/14), biliary atresia (2/14) and progressive familial intrahepatic cholestasis type 3 (1/14), and unknown etiology (2/14). The majority were living donor liver transplants (86%). Of the living donors, 42% (5/12) were Buddhist priests. There were three immediate deaths and two late deaths. The 3-month survival was 78%, and overall survival was 64%. Living donor transplants carried a higher success rate (92%) compared to diseased donor transplants (0%; 2/2). Initial experience of pediatric liver transplant program of Sri Lanka is promising despite being established in a free healthcare system amidst the crisis circumstances.

Safety and efficacy of peripheral blood stem cells collection in healthy children and pediatric patients with thalassemia major weighing 20 kg or less.

Peripheral blood stem cell (PBSC) collection in children poses challenges due to their small size, low body weight (BW), and unique pediatric physiology, especially among children weighing 20 kg (kg) or less. PBSC collection data of both healthy children and patients with thalassemia major (TM) weighing 20 kg or less between January 2013 and December 2020 were reviewed. Moreover, PBSCs characteristics along with various aspects of efficiency and safety between healthy donors and patients with TM were compared. A total of 262 PBSC procedures were performed on 255 children. Of these, 91 procedures were carried out on 85 allogeneic healthy donors, and 171 auto-backup collections were performed on 170 patients with TM to ensure PBSC availability and prevent transplantation failure. A minimum pre-apheresis hemoglobin (HGB) level of 60 g/L was discovered to be safe and feasible in patients with TM. The median CD34+ cell dose in the PBSC product during the initial apheresis procedure was higher in healthy donors compared to patients with TM (7.29 ± 5.28 × 106 cells/kg vs5.88 ± 4.23 × 106 cells/kg, P = .043). The total CD34+ cells/kg recipient weight exhibited a positive correlation with pre-apheresis monocyte counts, but a negative correlation with donor weight. Apheresis significantly reduced hematocrit and platelet counts in the allogeneic group compared to the autologous group. Patients with TM experienced a higher occurrence of bone pain related to granulocyte colony-stimulating factor treatment. Notably, no serious complications related to PBSCs mobilization, central venous catheter placement, or the apheresis procedure were observed in either group. PBSCs collection was both safe and effective in healthy children and pediatric patients with TM weighing 20 kg or less.

Factors associated with operational tolerance after liver transplantation: a single center retrospective study.

Liver transplantation has adverse effects from life-long immunosuppression that limit the improvement of long-term outcomes. Achieving clinical operational tolerance is a major goal in organ transplantation. This study analyzed liver transplantation patients at a single institution from 1998 to 2020, excluding those who died within 1-year posttransplant. Operational tolerance was defined as normal liver function even after immunosuppressive drugs were discontinued. Propensity score matching was implemented at a 1:2 ratio for the tolerant group (TG) and the nontolerant group (NTG). Out of 2,300 recipients, 99 achieved operational tolerance without rejection. No significant differences in sex or body mass index (BMI) were found between the TG and NTG. There was a significantly higher percentage of children in the TG (24.0%) than in the NTG (10.1%). The NTG had more living donor liver transplants. Among 2,054 adult recipients, no significant differences in age, sex, or BMI were found between the TG and the NTG. However, the rate of living donor liver transplantation was 40.3% (29/75) in the TG and 84.8% in the NTG (P<0.001). The propensity score-matched analysis showed higher chronic renal failure rates and a higher graft recipient weight ratio in the TG, along with shorter warm ischemic times during surgery. After immunosuppressant withdrawal, a significant increase in the ratio of CD4+CD25+ T cells to total CD4+ T cells was observed in the TG. These findings suggest that larger, healthier grafts are more conducive to inducing tolerance, and regulatory T cells are crucial in achieving tolerance.

Changes in graft outcomes in recipients

Kidney transplant (KT) was initially associated with poor outcomes, especially in smaller recipients. However, pediatric transplantation has evolved considerably over time. We investigated the impact of weight at the time of transplant and whether outcomes changed over 25 years for <10 kg recipients. Using the UNOS database, pediatric recipient outcomes were analyzed between 1/1/99 and 12/31/14. KT weight was stratified: <8.6 kg (mean weight of recipients <10 kg), 8.6-9.9 kg, 10-14.9 kg, 15-29.9 kg, and ≥30 kg. Outcomes in recipients <10 kg were then compared between 1990-1999 and 2000-2014. 17 314 pediatric KT recipients were included; 518 (3%) had a transplant weight <10 kg. The highest rates of allograft loss and death were in recipients <8.6 kg and ≥30 kg. Recipients <8.6 kg also had higher rates of delayed graft function, rejection, and longer hospital length of stay. In the multivariable Cox regression model, transplant weight was not a predictor of allograft loss. When compared with recipients <8.6 kg, patient survival hazard ratios associated with recipient weight of 10-14.9 kg, 15-29.9 kg, and ≥30 kg were 0.61 (95%CI: 0.4, 1), 0.42 (95%CI: 0.3, 0.7) and 0.32 (95%CI: 0.2, 0.6), respectively. In the later era of transplant, recipients <10 kg had improved outcomes on univariate analysis; however, the era of transplantation was not an independent predictor of allograft loss or patient survival in Cox regression models. Outcomes in children weighing 8.6-9.9 kg at the time of KT were similar to higher weight groups and improved over time; however, special precautions should be taken for recipients <8.6 kg at the time of transplant.

Tailoring allocation policies and improving access to paediatric liver transplantation over a 16-year period

Mortality on the paediatric liver transplantation (pLT) waiting list (WL) is still an issue. We analysed the Italian pLT WL to evaluate the intention-to-treat (ITT) success rate and to identify factors influencing success. All children (<18 years) listed for pLT in Italy between 2002-2018 were included (Era 1 [2002-2007]: centre-based allocation; Era 2 [2008-2014]: national allocation; Era 3 [2015-2018]: national allocation+mandatory-split policy). A total of 1,424 patients (median age: 2.0 [IQR 1.0-9.0] years; median weight: 12.0kg [IQR 7-27]) were listed for pLT. Median WL time was 2 days (IQR 1-5) for Status 1 and 44 days (IQR 15-120) for non-Status 1 patients; 1,302 children (91.4%) were transplanted (67.3% with split grafts), while 50 children (3.5%) dropped off the WL (2.5% death, 1.0% clinical deterioration). Predictive factors for receiving LT included Status 1 (hazard ratio [HR] 1.66, p= 0.001), Status 1B (HR 1.96, p= 0.016), Status 2A (HR 2.15, p= 0.024) and each 1-point increase in PELD/MELD score. Children with recipient's weight >25kg, blood group O or awaiting pLT combined with other organs had less chance of being transplanted. ITT patient survival rates were 90.5% at 1 year and 87.5% at 5 years, remaining stable across eras. Risk factors for ITT survival were re-transplantation (HR 5.83, p <0.001), Status 1 (HR 2.28, p= 0.006), Status 1B (HR 2.90, p= 0.014), Status 2A (HR 9.12, p <0.001), recipient weight <6kg (HR 4.53, p <0.001) and low-volume activity (HR 4.38, p= 0.001). In Italy, continuous adaption of paediatric organ allocation policies via the introduction of national allocation, paediatric prioritisation rules and a mandatory-split policy have helped maximise the use of donors for paediatric candidates and to minimise WL mortality without compromising outcomes. Globally, paediatric liver transplant candidates still suffer from high mortality. Over recent decades, the continuous adaption of organ allocation policies in Italy has led to excellent outcomes for children awaiting liver transplantation. The mortality rate of paediatric liver transplant candidates has been minimised to almost zero, mainly using grafts from deceased donors. Paediatric prioritisation rules, national organ exchange organisation and a mandatory-split liver policy have resulted in a unique allocation model for paediatric liver transplant candidates and represent a landmark for the paediatric transplant community.

Immediate extubation after pediatric liver transplantation: Update on a single-center experience.

Immediate extubation (IE) following liver transplantation (LT) is increasingly common in adult patients. This study reviews our center's experience with IE in children following LT to determine characteristics predictive of successful IE and its effects on post-operative outcomes. We performed a retrospective chart review of all patients who underwent LT at our institution between January 2005 and November 2022. Patients with concomitant lung transplants and chronic ventilator requirements were excluded. Overall, 235 patients met study criteria. IE was achieved in 164 (69.8%) patients across all diagnoses and graft types. Of IE patients, only two required re-intubation within 3 days post-transplant. IE patients exhibited significantly shorter ICU (2 [1, 3 IQR] vs. 4 [2, 4 IQR] days, p < .001) and hospital lengths of stay (17 [12, 24 IQR] vs. 22 [14, 42 IQR] days, p = .001). Pre-transplant ICU requirement, high PELD/MELD score, intraoperative transfusion, cold ischemia time, and pressor requirements were risk factors against IE. There was no association between IE and recipient age or weight. The proportion of patients undergoing IE post-transplant increased significantly over time from 2005 to 2022 (p < .001), underscoring the role of clinical experience and transplant team learning curve. Spanning 18 years and 235 patients, we report the largest cohort of children undergoing IE following LT. Our findings support that IE is safe across ages and clinical scenarios. As our center gained experience, the rate of IE increased from 40% to 83%. These trends were associated with lower ICU and LOS, the benefits of which include earlier patient mobility and improved resource utilization.

Full CD34 Donor Chimerism Following CD34 Chimerism Directed Donor Lymphocyte Infusion Results in Reduced Relapse and Superior Overall Survival Compared with Mixed Chimerism Status in Allogeneic Haemopoietic Stem Cell Transplant Recipients

Introduction Peripheral blood CD34 donor chimerism (DC) is a clinically valuable method for detecting relapse of myeloid malignancies following allogeneic hematopoietic stem cell transplantation (alloHSCT). Our institution has recently shown that CD34 DC ≤80% was superior to CD3 DC for predicting relapse (1). While pre-emptive DLI has demonstrated efficacy in preventing relapse in the setting of falling whole unfractionated and CD3 DC, little has been reported about its utility in falling CD34 DC. Methods We conducted a retrospective analysis of consecutive patients who received DLI at the Alfred Hospital in Melbourne, Australia between January 2012 and January 2023. Peripheral blood CD34 DC was monitored in alloHSCT patients transplanted for myeloid malignancies or acute lymphoblastic leukaemia (ALL). CD34+ cells were enriched using magnetic beads and DC measured using an STR-PCR method, which had a sensitivity of 1%. DLI was administered to patients with CD34 ≤80% that did not respond to immunosuppression taper. DLI doses were based on donor type and recipient weight, with subsequent doses administered incrementally according to a predefined protocol. Starting doses were 3x10 6/kg for sibling donors, 1x10 6/kg for unrelated donors and 0.5x10 6/kg for haploidentical donors. DLI was discontinued upon achieving full DC (FDC) defined as CD34 DC &amp;gt; 95%, clinically significant graft-versus-host disease (GVHD), disease progression, or lack of available donor cells. Results One hundred and six patients received DLI between 2012 and 2023. Twenty-five of these patients received DLI for CD34 DC ≤80% without morphologic relapse. Eleven of 25 (44%) patients received DLI alone, while 14 (56%) patients received it in combination with other therapies, primarily a hypomethylating agent. At the time of DLI, 5 (20%) of the 25 patients had concurrent decreased CD3 DC ≤ 80%. The median follow-up period was 1.84 years (range 0.58 to 8.43 years). Sixteen of 25 (66.7%) patients achieved CD34 FDC while 8 (33.3%) had persistent CD34 mixed DC (CD34 MDC). One patient could not be assessed due to death from infection. Patient characteristics and outcomes according to response to DLI are presented in Table 1. The cumulative incidence of relapse was significantly lower in the CD34 FDC group (12.5% vs 75% at 2 years, p&amp;lt;0.001). Patients achieving CD34 FDC had improved progression-free survival (PFS) and overall survival (OS) compared to the CD34 MDC group (PFS median years not reached [95% CI 1.94-ND] vs 0.29 years [95% CI 0.09-ND], p&amp;lt;0.001; OS median years not reached vs 0.68 years [95% CI 0.58-ND], p=0.003; Figure 1). Rates of grade II-IV acute graft-versus-host-disease (aGVHD) post-DLI were 12.5% in those achieving FDC and MDC (Table 1). A significant proportion of patients (37.5%) achieving FDC developed moderate-severe cGVHD while the MDC group did not survive long enough to develop cGVHD (Table 1). The non-relapse mortality observed in the CD34 FDC group was 12.5% at 3 years post-DLI. Conclusion Our centre experience demonstrated that CD34-directed DLI reduced relapse risk and improved overall survival when FDC is restored in alloHSCT patients, with an acceptable toxicity profile. Only 20% of patients with CD34 MDC had concurrent CD3 MDC, highlighting the additional value of CD34 monitoring in guiding salvage DLI administration. In patients with CD34 MDC ≤80%, the target of DLI should be to achieve FDC (&amp;gt;95%) given the clear association with improved outcomes in this group. References 1/ Das TP, North D, Fleming SA, Tan JLC, Ivey A, Cummings NJ, Spencer A, Patil SS, Widjaja JML, Swain MI, Bourke C, O'Brien ME, Kliman DS, Curtis DJ. Peripheral Blood CD34 Donor Chimerism has Greater Clinical Utility Than CD3 for Detecting Relapse after Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia or Myelodysplastic Syndrome. Transplant Cell Ther. 2023 Jul;29(7):454.e1-454.e8. doi: 10.1016/j.jtct.2023.03.025.

Evaluating the Safety of HCAR19 (Now Actalycabtagene Autoleucel- Actaly-Cel™), a Novel Humanized CD19-Directed Chimeric Antigen Receptor T-Cells in Pediatric, Adolescents, and Young Adults with Relapsed/ Refractory B- Acute Lymphoblastic Leukemia (ESHA) - Report of Phase-1B

Background and aims Chimeric Antigen Receptor (CAR) T-cell therapies for relapsed-refractory Pediatric B-cell Acute Lymphoblastic Leukemia (r/r-B-ALL) show remarkable success but remain prohibitively expensive. We developed and reported a Humanized CD19-directed novel CAR T-cell- HCAR19 (now -Actalycabtagene autoleucel- Actaly-cel™) with robust activity and low toxicity in pre-clinical studies. This led to regulatory approval for the first CART-cell trial in India as a Pilot Phase-1 study (CTRI/2021/05/033348), and it's encouraging safety profile and responses led to approval for a roll-on Phase 1b/2 Trial (CTRI/2023/03/050689) to monitor safety, identify Phase-2 Dose (P2D) and assess efficacy. Trial design permitted pooling of data of both trials for all objectives. We report here the Phase-1b analysis of Actaly-cel in r/r-B-ALL in Pediatric, Adolescents and Young Adults 3-25 years of age. Methods Patients with r/r B-ALL not in remission after 2 or more lines of therapy ineligible for Allogenic-Stem Cell Transplant (Allo-SCT) were included if no CD19-negative blasts population were detected on flow-cytometry records. Those with isolated extra-medullary disease, active neurological involvement/ sequelae, genetic syndromes/prior malignancy, or prior CD19-directed therapy were excluded. Bridging therapy was at physician discretion. Lymphodepletion was with Fludarabine (30mg/m 2) x 3-days and cyclophosphamide (500 mg/m 2) x 2-days. There were 3 Target Doses, TD-1, 2 &amp; 3 CART-cells at 1 x10 6, 3-5 x10 6 and 10-15 x10 6/kg recipient weight respectively. Escalation and de-escalation followed 3+3 design with Coherence-guided dose-decision for bivariates- efficacy and toxicity, allowing all patients to be evaluable. Primary end-point was Overall Response Rates (ORR) at Day-30 on bone-marrow flow-cytometry. Patients were monitored for toxicities, in-vivo dynamics of Actaly-cel, and cytokine profiles. Results Of 12 patients enrolled Actaly-cel was infused in 9 at time of analysis as 2 were withdrawn prior to apheresis (1-progression, 1-withdrawl of consent) while 1 is awaiting infusion. Three patients were assigned TD-1 and 6, TD-2. In TD-2 group, 1 received lower dose (2.13x10 6/kg) due to obesity and weight gain from severe-Covid19 prior to infusion. Median age was 16-yrs (range:8-24), M:F-3:2, median prior lines of therapy were 3 (range:2-5), 6 had high-risk cytogenetics, and median pre-infusion bone-marrow blasts were 19.5%(range:0-88%). Eight patients were evaluable for response and toxicities. All had Grade 3 leukopenia and thrombocytopenia. Peak cytokine release syndrome (CRS) was Grade-3 in 1(12.5%), Grade-2 in 2(25%), and Grade-1 in 5(62.5%). Those with ≥ Grade-2 CRS received tocilizumab with full recovery. Only 1 patient had Immune effector cell associated neurotoxicity syndrome (ICANS) peak-Grade 3, and was also the only one with Grade-3 CRS and had severe-Covid19 prior to infusion. ICANS resolved with steroids in 4 weeks, but recurred in the second month post-infusion, this time associated with leukemia-progression. Toxicities corroborated with IL-6 (median peak: 25pg/ml, range:2.8-3604), but not with Ifn-γ, which remained low (median peak:6.25pg/ml, range:0-68.1) (Fig-1). ORR was 87.5% (1 no-response-NR), 3 Morphological Remission with MRD-positive (Partial Response-PR), and 4 MRD-negative (Complete Response-CR). Responses correlated with Actaly-cel expansion dynamics (Fig-2) the only non-response being in a patient with poor expansion. At median follow-up of 3 months (range:1-15) 3 patients with no or partial Day-30 response expired from progression within few weeks. All 4 with CR had B-cell aplasia needing intravenous immunoglobulin. Two of them underwent subsequent Allo-SCT, 1 relapsed post-transplant and died from disease progression 15 months later, while the other is alive in remission at 15 months. Two patients remain in CR at 3 and 12 months without further therapy, while 1 with PR is on follow-up. Patients receiving TD-2 had ORR of 100% (CR-3, PR-1) with peak toxicity of Grade-2 CRS in only 1. Conclusion In a Phase-1/1b trial, Actaly-cel had good safety profile with low toxicity and robust activity resulting in high ORR that improved at higher doses. In-vivo dynamics and toxicity profile of Actaly-cel showed robust activity and low cytokines corroborating with pre-clinical studies. A median dose of 5x10 6/kg Actaly-cel is proposed as the P2D.