Median Donor Age Research Articles

Prevalence and Factors Associated with transfusion-transmissible infections among blood donors in Arua regional blood bank, Uganda

BackgroundBlood transfusion services play a very key role in modern health care service delivery. About 118.5 million blood donations were collected globally in 2022. However, about 1.6 million units of blood are destroyed annually due to transfusion-transmissible infections (TTIs). There is a very high risk of TTIs through donated blood to recipients if safe transfusion practices are not observed. This study determined the prevalence and factors associated with TTIs among blood donors in Arua regional blood bank, Uganda.MethodsThis study was a retrospective cross-sectional design that involved a review of a random sample of 1370 blood donors registered between January 1st, 2018 and December 31st, 2019 at Arua regional blood bank, Uganda. Descriptive statistics were used to describe the characteristics of the blood donors. The binary logistic regression was used to determine the factors associated with TTIs.ResultsThe majority of the blood donors were male (80.1%), and the median donor age was 23 years (IQR = 8 years). The overall prevalence of TTIs was found to be 13.8% (95%CI: 12.0-15.6%), with specific prevalences of 1.9% for HIV, 4.1% for HBV, 6.6% for HCV and 2.8% for treponema pallidum. Male sex (AOR = 2.10, 95%CI: 1.32–3.36, p-value = 0.002) and lapsed donor type compared to new donor type (AOR = 0.34, 95%CI: 0.13–0.87, p-value = 0.025) were found to be associated with TTIs.ConclusionThe prevalence of TTIs among blood donors of West Nile region, Uganda was found to be significantly high, which implies a high burden of TTIs in the general population. Hence, there is need to implement a more stringent donor screening process to ensure selection of risk-free donors, with extra emphasis on male and new blood donors. Additionally, sensitization of blood donors on risky behaviors and self-deferral will reduce the risk of donating infected blood to the recipients.

Deceased Donor Uterus Transplantation: A Narrative Review of the First 24 Published Cases.

Uterus transplantation is the surgical treatment for absolute uterine factor infertility (AUFI), a congenital or acquired condition characterized by the absence of a uterus. More than 80 transplants have been performed worldwide, resulting in more than 30 live births, originating both from living and deceased donors. The collection of published articles on deceased donor uterus transplantations was performed in PubMed and SCOPUS by searching for the terms "Uterus transplantation" AND "deceased donor"; from the 107 articles obtained, only case reports and systematic reviews of deceased donor uterus transplantations and the resulting live births were considered for the present manuscript. The extracted data included the date of surgery (year), country, recipient (age and cause of AUFI) and donor (age and parity) details, outcome of recipient surgery (hysterectomy), and live births (date and gestational age). The search of peer-reviewed publications showed 24 deceased donor uterus transplantations and 12 live births (a birth rate of 66%) with a 25% occurrence of graft loss during follow-up (6 of 24). Among this series, twelve transplants were performed in the USA (seven births), five in the Czech Republic (one birth), three in Italy (one birth), two in Turkey (two births), and two in Brazil (one birth). The median recipient age was 29.8 years (range 21-36), while the median donor age was 36.1 years (range 20-57). Of 24 recipients, 100% were affected by MRKH (Mayer-Rokitanski-Kuster-Hauser) syndrome. Two live births were reported from nulliparous donors. Deceased donor uterus transplantation birth rates are very similar to the living donor rates reported in the literature, but ethical implications could be less important in the first group. It is necessary to register every case in the International Registry for Uterus Transplantation in order to perform a systematic review and comparison with living donor rates.

Allogeneic blood or marrow transplantation using haploidentical grandchildren donors and post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis.

High-dose post-transplant cyclophosphamide allows safe and effective use of allografts from haploidentical relatives (siblings, parents and children) in patients undergoing allogeneic blood or marrow transplant (alloBMT). More recently, second- and third-degree relatives have also been shown to be safe allograft donors. An increasing number of older patients undergoing alloBMT have been receiving allografts from haploidentical donors. However, older patients are more likely to have older siblings and children, and older donor age is associated with worse outcomes. In the current study, we report the safety and utility of grandchildren as haploidentical donors and compared with children as donors in patients undergoing alloBMT. We compared characteristics and outcomes of alloBMT patients aged 55 years and older with children older than 30 years as donors (C group; n = 276) and those with grandchildren as donors (GC group; n = 40). Because many important baseline characteristics predict outcomes after alloBMT, we performed propensity score matched analysis based on recipient age, alloBMT year, disease, graft source and haematopoietic cell transplantation comorbidity index (HCT-CI). The median age of recipients was 67 years (range 55-79) in the C group and 73 years (range 57-78) in the GC group. More than 70% of recipients in the GC group were older than 70 years, compared with 27% in the C group. The median donor age was 37 years (range 31-52) in the C group and 20 years (range 14-34) in the GC group. More patients in the GC group had HCT-CI scores ≥3 than in the C group (32.5% vs. 23%, p = 0.27). Two-year overall survival did not differ between the two groups (GC 62% vs. C 60%, hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.53-1.75, p = 0.90) despite recipients of allografts from grandchildren being older. The 2-year RFS was 55% in the C group compared with 50% in the GC group (HR 1.05, 95% CI 0.62-1.77, p = 0.85). Non-relapse mortality subdistribution [SD] (SDHR 1.36, 95% 0.70-2.63, p = 0.36), relapse (SDHR 0.72, 95% CI 0.33-1.58, p = 0.42) or relapse-free survival (HR 1.05, 95% CI 0.62-1.77, p = 0.85). Propensity score matching analysis showed no significant differences in 2-year overall survival (GC 64% vs. C 53%; HR 0.77, 95% CI 0.42-1.42, p = 0.40), non-relapse mortality (SDHR 1.26, 95% 0.66-2.41, p = 0.48), relapse (SDHR 0.57, 95% CI 0.21-1.52, p = 0.26) or relapse-free survival (HR 0.94, 95% CI 0.57-1.54, p = 0.81). Our results indicate that outcomes of alloBMT patients with grandchild donors are similar to those with child donors, despite recipients' older age and higher comorbidities in the GC group. Grandchildren should be considered when selecting a donor for older alloBMT recipients.

Hernia Correction After Liver Transplantation Using Nonvascularized Fascia.

Liver transplantation is an increasingly frequent surgical procedure, with elevated rates of postoperative incisional hernias ranging from 5% to 46%. There are numerous known risk factors for incisional hernia, including the type of incision, patient sex, and presence of comorbidities such as diabetes, ascites, older age, and the use of steroids. Most studies on the treatment of incisional hernias in patients who have undergone liver transplantation have shown consistently high rates of complications. Consequently, we propose the use of nonvascular fascia for the symptomatic treatment of incisional hernias in patients with concomitant liver transplantation. We performed our new technique on 8 patients, who had previously undergone liver transplantation, between January 2019 and January 2023. The patients were examined using imaging techniques during the follow-up period. Of the 8 patients, 7 were liver transplant recipients and 1 was a combined liver-kidney transplant patient. The median donor age was 57 y (5-66 y), whereas the mean recipient age was 58 y (31-66 y). The median patient height and weight were 163 cm (117-185 cm) and 76 kg (17-104 kg), respectively. Immunosuppression did not change in fascia recipients. The median time between transplantation and hernia repair surgery was 41 mo (5-116 mo). The sizes of the aponeurotic defects varied from 6 × 6 to 25 × 20 cm. Two patients experienced complications: one experienced bulging that required reintervention and the other experienced surgical site seroma. There was no mortality related to the use of the technique, and none were reported during follow-up. With its promising results, nonvascularized fascial transplantation can be a successful treatment for incisional hernias in patients who had previously received a liver transplant.

Is an earlier strategy for harvesting peripheral blood stem cells in healthy allogeneic donors feasible?

IntroductionPeripheral blood stem cells (PBSC) mobilization with granulocyte colony stimulating factor (G-CSF) for healthy donors is generally performed at 5th day. However, earlier collection is sometimes feasible, raising the question of whether to initiate apheresis early to limit further G-CSF exposure, while considering the risk of mobilization failure. In the current study, we examined the factors predicting successful 4th day collection and developed a model that can be used practically. Patients and methodsThe study was carried out by obtaining the data of PBSC mobilizations performed between January 2009 and September 2022 in our transplantation center. ResultsA total of 141 healthy donors with a median donor age of 32 (18–64) were included. Adequate mobilization was achieved in 115 (81.6 %) patients. Median peripheral CD34 + cell count was 69.4/μL in the adequate mobilization group and 46/μL in the mobilization failure group (p < 0001). Multivariate analysis revealed that donor/recipient weight ratio and the 4th day peripheral CD34 + cell count≥ 50/μL were independent markers for 4th day collection success. A predictive model of our center including these parameters was available with 0.765 sensitivity and 0.968 specificity [(AUC):0.948 (95 % CI, 0.90–0.99), p < 0.001]. ConclusionThe result of the current study shows that peripheral 4th day collection can be performed in selected donors, taking into account peripheral CD34+ cell count and donor/recipient weight ratio. In addition, using these indicators, new predictive models can be created that may assist clinicians in daily practice.

#2741 The interplay between donor &amp; recipient factors, outcomes, and transplant artery flow volume as measured by phase-contrast magnetic resonance imaging

Abstract Background and Aims Cardiovascular health and kidney transplant health are inter-connected [1]. Phase-contrast magnetic resonance imaging (PC-MRI) is a non-invasive means of quantifying blood flow volume within vasculature. Its utility for the assessment of blood flow volumes within the transplant renal artery has not been explored. The aims of this study were to determine if: (A) flow in the transplant artery is influenced by donor and recipients factors, (B) flow in the transplant artery is related to or influences clinical outcomes for transplant recipients. Method Analysis of PC-MRI sequences obtained during 218 kidney transplant magnetic resonance angiograms (MRA) performed at a single centre between 2019 and 2021 was undertaken. All scans were clinically indicated and requested by clinicians to investigate for transplant renal artery stenosis (TRAS). Baseline clinical and demographic data and subsequent clinical outcome data were collected for all study participants. Median follow up was 49 (IQR 40–54) months. For Kaplan-Meier survival analyses, comparison of clinical outcomes by interquartile range of flow volumes was performed, whereby quartile one comprised subjects with the lowest transplant artery blood flow volumes. Statistical analysis was performed using MedCalc Statistical Software version 22.013. Results In this study of 218 subjects, 49 (22.4%) had features of possible TRAS identified on initial MRA. TRAS was subsequently confirmed via intra-arterial digital subtraction angiography in 19 (8.7%) cases. The majority of participants were male 150/218 (68.8%). The commonest cause of ESKD was diabetic kidney disease at 71/218 (32.6%). Living donor transplant recipients were 35/218 (11.5%) of the study population. The median donor age was 55 (IQR 44–65) years. The median time from ESKD to transplantation was 25 (IQR 9–53) months. The median time from transplantation to PC-MRI for all participants was 322 (IQR 81–1744) days; for participants who were ultimately diagnosed with TRAS it was 169 (IQR 76–262) days. The median age of recipients at time of PC-MRI was 56 (IQR 45–64) years. Overall, the mean transplant artery flow volume was 0.41 L/min (95% CI 0.39–0.45 L/min). Rank correlation between age of donor and flow in the transplant artery (L/min) showed r = −0.25 (95% CI −0.37 - −0.12) P = 0.0002. Rank correlation between age of recipient at time of PC-MRI and flow in the transplant artery (L/min) showed r = −0.37 (95% CI −0.48 to −0.25) P ≤ 0.0001. Rank correlation between flow in the transplant artery (L/min) and estimated glomerular filtration rate (mL/min/1.73 m2) showed r = 0.43 (95% CI 0.31–0.53) P &amp;lt; 0.0001. Univariable linear regression analysis of flow in the transplant artery (L/min) and estimated glomerular filtration rate (mL/min/1.73 m2) was R2 0.14, DF regression = 1 DF residual = 214, F = 34.7, P &amp;lt; 0.0001 (Fig. 1). Overall, 35 (16.1%) participants experienced kidney transplant failure and 42 (19.3%) participants died within the study follow up period. Kaplan-Meier analysis showed no significant difference in kidney transplant survival between four groups categorized according to transplant artery flow volumes, logrank test P = 0.93 (Fig. 2A). Subjects in the first quartile were at greater risk of death, logrank test P = 0.01, HR 4.36 (95% CI 1.77–10.74) compared with fourth quartile (Fig. 2B) Conclusion This study has demonstrated that both older donor age and older recipient age negatively correlate with transplant artery flow, and that transplant artery flow is positively correlated and predicts estimated glomerular filtration rate. Finally, recipients with low transplant artery flow volume are at greater risk of death. Neither cause nor effect of low blood flow volume have been elucidated in this study. However, improving transplant blood flow by optimising cardiovascular health may have a positive impact on outcomes for people with kidney transplants and warrants further study.

#856 Performance of ex vivo confocal microscopy in the assessment of Remuzzi score in preimplantation biopsies

Abstract Background and Aims Confocal microscopy (CM) is a technique that generates digital images from fresh tissue samples with resolution comparable to that obtained with conventional stains. These images are digitally stained with Hematoxylin/Eosin-like. The clear advantage of this technique with respect to conventional staining is the speed in obtaining results which is of great importance in the donation process, as well as their digitalization. The aims of the present study were two: 1) to assess reproducibility for CM between two nephropathologist in preimplantation biopsies and 2) to describe the correlation between gold standard for preimplantation biopsies in our institution performed in frozen block and CM. Method Donor biopsies were reviewed according to Remuzzi score (RS) by on-call pathologist for frozen block and two nephropathologist for CM, blinded to the original frozen block report. The intraclass correlation coefficient (ICC) for every variable in RS was calculated for the two nephropathologists. Later, concordance between the techniques was evaluated by the κ index. Results We included 50 preimplantation biopsies between January and October 2023. Median donor age was 74 years (IQR 62-77.3), 56% were male, 74% had arterial hypertension and 24% had diabetes mellitus. Number of glomeruli were 23 (IQR 14.25-30.25). ICC was excellent for glomerulosclerosis (0.755) and total RS (0.787) and good for interstitial fibrosis (0.536), while fair for tubular atrophy (0.412) and poor for vascular narrowing (0.14). There was excellent agreement between frozen block and CM for interstitial fibrosis (κ 0.898) and global RS (κ 0.898) and substantial for glomerulosclerosis (κ 0.694) while it failed to moderate for vascular narrowing (κ 0.522) and fair for tubular atrophy (κ 0.37). Conclusion CM proved to have reproducibility between nephropathologists and comparability to our gold standard technique in evaluating preimplantation biopsies. The ease of acquisition of CM images suggests that it may be useful for rapid evaluation of graft histology.

The Potential for Heart Donation After Death Determination by Circulatory Criteria in the Province of Québec

BackgroundHeart donation (HD) by those with death determination by circulatory criteria (DDCC) has been proposed as a method to increase the heart donor pool in response to the growing need for heart transplantation (HT). However, the potential level of HD after DDCC in the province of Québec has not yet been reported. This study aims to assess the suitability for HD among donors with DDCC, and to estimate its impact on HT activity. MethodsDonation records by those with DDCC in the province of Québec, from January 2016 to December 2020, were retrospectively reviewed for donor and predonation characteristics. Predetermined exclusion criteria were used to evaluate eligibility for HD. ResultsOf the 122 patients with DDCC who were included, 42 (34%) were identified as potentially-eligible heart donors. The median age of potentially-eligible donors was 52 years; 60% were female; and the most prevalent causes leading to organ donation in this group were medical aid in dying (26%), traumatic brain injury (26%), and anoxia (24%). A 19% increase (42 of 225) in potential HT activity was estimated using strict criteria. In only one case did functional warm ischemia time exceed the 30-minute limit. ConclusionsUsing those with DDCC as a new source of heart donors can significantly increase the volume of heart donation in the province of Québec. Implementing an HD program for those with DDCC in Québec may reduce waiting time and increase the number of heart recipients.

Factors influencing overall survival and GvHD development after allogeneic hematopoietic stem cell transplantation - single centre experience.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a substantial therapeutic procedure for the treatment of a wide spectrum of severe diseases. Despite advancements in treatment and supportive care, alloHSCT still carries a considerable mortality risk, primarily caused by graft-versus-host disease (GvHD). Our retrospective analysis aimed to identify the factors influencing overall survival and GvHD development in HLA-identical sibling alloHSCT. We have analyzed patients' and donors' age, AB0 compatibility, recipient-donor gender match, stem cell source, time from the diagnosis to alloHSCT, conditioning regimen type, GvHD prophylaxis, and relapse. Our study included 96 patients (54 male, 42 female) who underwent HLA-identical sibling alloHSCT. The median follow-up was 64.5 months (range 1-218 months), and the median age of both recipients and donors was 34 years. Malignant hematological diseases were the most common indications for alloHSCT. GvHD and its complications accounted for the highest number of deaths (N = 24; 46.2%), followed by relapse (N = 18; 34.6%). Acute GvHD developed in 30 patients (31.3%), while chronic GvHD occurred in 25 patients (26.0%), resulting in a total of 45 patients (46.9%) experiencing GvHD. Male recipients with female donors had significantly worse overall survival compared to other patients (P = 0.01; HR = 2.33). Overall survival was better in patients transplanted within 1 year from the diagnosis compared to those transplanted after 1 year (P = 0.03; HR = 1.93). No factor reached statistical significance regarding the impact on acute GvHD, chronic GvHD, or overall GvHD. We confirmed that sex mismatch, specifically in the case of a female donor and a male recipient, significantly negatively affects overall survival after alloHSCT. Additionally, overall survival is significantly shorter when the interval between the diagnosis and alloHSCT exceeds one year.

National Trends in Utilization of Normothermic Machine Perfusion in DCD Liver Transplantation.

In liver transplantation, advances in ex situ normothermic machine perfusion (NMP) have improved outcomes compared with traditional static cold storage (SCS) in donation after circulatory death (DCD) organs. We aimed to characterize trends in the utilization of NMP versus SCS in DCD liver transplantation in the United States. This retrospective cohort study used data from the United Network for Organ Sharing database to identify recipient-donor adult liver transplant pairs from DCD donors from January 2016 to June 2022. Utilization of NMP and changes in donor risk index (DRI) and components between NMP and SCS were assessed across transplant year eras (2016-2018, 2019-2020, and 2021-2022). Statistical comparisons were made using the Kruskal-Wallis test or the chi-square test. A total of 3937 SCS and 127 NMP DCD donor transplants were included. Utilization of NMP ranged from ~0.4% to 3.5% from 2016 to 2021 and rose significantly to 11.2% in early 2022. Across transplant eras, median DRI increased significantly for SCS and NMP, but the magnitude of the increase was larger for NMP. With NMP DCDs, there were significant increases in median donor age, national share proportion, and "cold ischemic time" over time. Finally, there was a shift toward including higher DRI donors and higher model for end-stage liver disease score transplant recipients with NMP in later transplant eras. In recent years, NMP utilization has increased and expanded to donors with higher DRI and recipients with higher model for end-stage liver disease score at transplant, suggesting increasing familiarity and risk tolerance with NMP technology. As NMP remains a relatively new technique, ongoing study of patient outcomes, organ allocation practices, and utilization patterns is critical.

Sequential Normothermic Regional Perfusion and End-ischemic Ex Situ Machine Perfusion Allow the Safe Use of Very Old DCD Donors in Liver Transplantation.

In Italy, 20 min of continuous, flat-line electrocardiogram are required for death declaration. Despite prolonged warm ischemia time, Italian centers reported good outcomes in controlled donation after circulatory death (cDCD) liver transplantation by combining normothermic regional and end-ischemic machine perfusion (MP). The aim of this study was to evaluate the safety and feasibility of the use of septuagenarian and octogenarian cDCD donors with this approach. All cDCD older than 70 y were evaluated during normothermic regional perfusion and then randomly assigned to dual hypothermic or normothermic MP. In the period from April 2021 to December 2022, 17 cDCD older than 70 y were considered. In 6 cases (35%), the graft was not considered suitable for liver transplantation, whereas 11 (65%) were evaluated and eventually transplanted. The median donor age was 82 y, being 8 (73%) older than 80. Median functional warm ischemia and no-flow time were 36 and 28 min, respectively. Grafts were randomly assigned to ex situ dual hypothermic oxygenated MP in 6 cases (55%) and normothermic MP in 5 (45%). None was discarded during MP. There were no cases of primary nonfunction, 1 case of postreperfusion syndrome (9%) and 2 cases (18%) of early allograft dysfunction. At a median follow-up of 8 mo, no vascular complications or ischemic cholangiopathy were reported. No major differences were found in terms of postoperative hospitalization or complications based on the type of MP. The implementation of sequential normothermic regional and end-ischemic MP allows the safe use of very old donation after circulatory death donors.

Haploidentical stem cell donor choice for patients with acute myeloid leukemia: a study from the ALWP of the EBMT

AbstractThere is a paucity of information to guide the selection of the most suitable donor in haploidentical (Haplo) hematopoietic stem cell transplantation (HSCT). For this reason, from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we conducted a retrospective analysis to evaluate the impact of Haplo donor characteristics on outcomes in patients with acute myeloid leukemia (AML) who received graft-versus-host disease prophylaxis with posttransplant cyclophosphamide (PTCy). The primary end point was graft-versus-host disease (GVHD)-free and relapse-free survival (GRFS). Overall, 2200 patients were included. The median age of donors was 37 years (range, 8-71); 820 (37%) were females, including 458 (21%) who were used for male recipients. In addition, 1631 donors (74%) donated peripheral blood (PB). Multivariable analysis identified certain donor-related risk factors with a detrimental impact on transplant outcomes. The use of PB, older donors’ ages (>37 years), and female donors to male recipients negatively affected GRFS. Donor’s age and female donor-to-male recipient combination also affected nonrelapse mortality, leukemia-free survival, and overall survival. In conclusion, donor-related variables significantly influence outcomes in patients with AML after Haplo-HSCT with PTCy. When possible, younger donors and male donors for male recipients should be prioritized. The use of bone marrow can additionally prevent GVHD.

Single center utilization and post-transplant outcomes of thoracoabdominal normothermic regional perfusion deceased cardiac donor organs.

Thoracoabdominal normothermic regional perfusion (TA-NRP) following cardiac death is an emerging multivisceral organ procurement technique. Recent national studies on outcomes of presumptive TA-NRP-procured organs are limited by potential misclassification since TA-NRP is not differentiated from donation after cardiac death (DCD) in registry data. We studied 22 donors whose designees consented to TA-NRP and organ procurement performed at our institution between January 20, 2020 and July 3, 2022. We identified these donors in SRTR to describe organ utilization and recipient outcomes and compared them to recipients of traditional DCD (tDCD) and donation after brain death (DBD) organs during the same timeframe. All 22 donors progressed to cardiac arrest and underwent TA-NRP followed by heart, lung, kidney, and/or liver procurement. Median donor age was 41 years, 55% had anoxic brain injury, 45% were hypertensive, 0% were diabetic, and median kidney donor profile index was 40%. TA-NRP utilization was high across all organ types (88%-100%), with a higher percentage of kidneys procured via TA-NRP compared to tDCD (88%vs. 72%, p=.02). Recipient and graft survival ranged from 89% to 100% and were comparable to tDCD and DBD recipients (p ≥ .2). Delayed graft function was lower for kidneys procured from TA-NRP compared to tDCD donors (27%vs. 44%, p=.045). Procurement from TA-NRP donors yielded high organ utilization, with outcomes comparable to tDCD and DBD recipients across organ types. Further large-scale study of TA-NRP donors, facilitated by its capture in the national registry, will be critical to fully understand its impact as an organ procurement technique.

Субпопуляционный состав T-хелперов у больных острыми лейкозами после трансплантации аллогенных гемопоэтических стволовых клеток

Aim. To identify the characteristics of T-helper subpopulations in healthy donors and to compare them with those reported in acute leukemia patients 6 months after allogeneic hematopoietic stem cell transplantation (allo-HSCT).&#x0D; Materials &amp; Methods. The study enrolled 41 blood donors and 49 patients after-HSCT. The median age of donors was 36 years (range 20–60 years), 29 of them were men and 12 were women. The median age of patients was 37 years (range 19–62 years), 18 of them were men and 31 were women. Acute myeloid leukemia was diagnosed in 27 (55 %) patients and acute lymphoblastic leukemia/lymphoma in 22 (45 %) patients. Myeloablative conditioning was administered to 4 (8 %) patients and reduced intensity conditioning to 45 (92 %) patients. T-helper subpopulations were studied in the blood of healthy donors vs. acute leukemia patients after allo-HSCT. The flow cytometry analysis was conducted to simultaneously assess the expression of markers CD3, CD4, CD8, CD25, CD45RA, CD197, CD28, CCR4, CCR6, CCR10, CXCR3, and CXCR5 in T-cells.&#x0D; Results. The study demonstrated that the count of T-helpers at different stages of differentiation (regulatory, naive T-cells, memory cells, and effector cells) comprehensively distinguishes healthy donors from patients. Moreover, the functional structure of each of these populations differ in donors vs. patients even on Month +6 after allo-HSCT. Donors appeared to have more polarized cells among the central memory T-helpers. The proportion of T-helpers type 1 among the effector cells was higher is patients.&#x0D; Conclusion. The results of the study indicate that the Т-cell parameter set can be analyzed to assess immunity and to describe its disorders in different pathologies or after drug chemotherapy.

HLA frequency distribution of the Portuguese bone marrow donor registry.

The Portuguese donor Registry of CEDACE was the fifth largest per capita bone marrow donor Registry of the WMDA as of 2019 and has yet to be thoroughly analyzed. We aimed to characterize its various aspects, including demographics and HLA allele and haplotype frequencies, to evaluate the genetic matching propensity score and ultimately further develop it. We described and compared characteristics of the donor population with census data and used an Expectation-Maximization algorithm and analyses of molecular variance to assess haplotype frequencies and establish phylogenetic distances between regions and districts within the country. We identified 396545 donors, corresponding to 3.85% of the Portuguese population; the median donor age was 39 years, with 60.4% of female donors. Most donors were Portuguese nationals, although 40 other nationalities were present, with a significant proportion of donors from Brazil and Portuguese-speaking African Countries; almost all donors self-reported as Western, with the second largest group reporting African ancestry. There was an asymmetric contribution of donors from different districts and regions, with most coming from coastal districts and few from the southern districts and autonomous regions; foreign and self-declared non-Western donors were mainly located in the Metropolitan Area of Lisbon and the South. Although most donors were typed in three loci (HLA-A, HLA-B and HLA-DRB1), only 44% were also typed in HLA-C, 1.28% in HLA-DQB1 and only 0.77% in all five loci and in high-resolution. There were varying allele and haplotype frequencies across districts and regions, with the most common three loci, low-resolution haplotypes, being HLA-A*01~B*08~DRB1*03, A*29~B*44~DRB1*07 and HLA-A*02~B*44~DRB1*04; some haplotypes were more prevalent in the South, others in the North and a few in the autonomous regions; African and foreign donors presented relevant differences in haplotype frequency distributions, including rare haplotypes of potential interest. We also report on four loci, low-resolution frequency distributions. Using AMOVA, we compared genetic distances between districts and regions, which recapitulated the country's geography. Our analysis showed potential paths to optimization of the Registry, including increasing the male donor pool and focusing on underrepresented districts and particular populations of interest, such as donors from Portuguese-speaking African countries.

Clonal Hematopoiesis Is Common in Unrelated Stem Cell Donors but Has No Impact on Patient Outcome after Hematopoietic Stem Cell Transplantation

Introduction. Clonal hematopoiesis (CH) has been associated with increased mortality mainly due to associations with cardiovascular diseases and hematologic cancer. Previous studies with predominantly related stem cell donors suggest that donor CH modulates graft-versus-host reactions and may augment graft-versus-leukemia effects after allogeneic hematopoietic cell transplantation (alloHCT). The impact of donor CH in the setting of unrelated alloHCT remains to be determined. To address this question, we initiated a joint study of the Transplant Complications Working Party of EBMT and DKMS. Patients and Methods. Donor samples from the time of stem cell donation were taken from the Collaborative Biobank. Patient baseline and outcome data were retrieved from the EBMT registry. Unrelated donor-recipient pairs were selected for a minimum donor age of 35 years. CH analysis was performed with an error-corrected ultra-deep NGS assay for 45 genes with a median sensitivity of 0.2% variant allele frequency (VAF). Accuracy of low frequency CH findings was checked by cross validation with an orthogonal assay. The primary objective was to assess the impact of donor CH on overall survival (OS). Major secondary endpoints were the risk of relapse/progression and non-relapse mortality (NRM), cumulative incidences of acute and chronic GVHD and event-free survival (EFS). All endpoints were evaluated with (cause-specific) multivariable Cox regression models. Adjustment factors were patient and donor age, diagnosis, disease risk index, Karnofsky performance status, conditioning intensity, GVHD-prophylaxis, graft source, HLA-match, sex match and CMV match. We did not adjust for multiple testing. Results. Data from 2584 unrelated donor-recipient pairs were analyzed. Median patient follow-up after alloHCT was 60 months. The median donor age was 46 years (range, 39-61 years). The median patient age was 54 years (range, 0-79 years). Indications for alloHCT were AML (44%), ALL (10%), MDS (10%), MPN (6%), B-cell lymphoma (6%), Multiple Myeloma (5%), CML 3%, inherited disorders (3%), CLL 2% and other (13%). Transplantations were performed between 2005 and 2018. In vivo or ex vivo T-cell depletion (TCD) was used in 81% of transplants, PTCY in 5% and no TCD in 14%. Mutations in DNMT3A, TET2, and ASXL1 defined CH most frequently. The distribution of donor CH across leukemia driver genes was comparable to previous reports (Panel A). With 0.2% (2%) VAF cutoffs, rates of DNMT3A-mutations were 19% (2%) among donors younger than 41 years compared to 37% (6%) among donors aged 55 years and higher. Corresponding rates for 0.2% (2%) VAF cutoffs for total CH were 38% (4%) among donors younger than 41 years compared to 67% (14%) among donors aged 55 years and higher. We tested systematically increasing VAF cutoffs (≥0.2% versus &amp;lt;0.2%, ≥1% versus &amp;lt;1%, ≥2% versus &amp;lt;2%, ≥5% versus &amp;lt;5%, and ≥5% versus &amp;lt;0.2%) for DNMT3A-CH and total CH for associations with clinical endpoints. Panel B shows results for multivariable regression analyses for total donor CH. Although we observed trends towards increased mortality and inferior EFS for some cutoffs, no incremental impact of donor CH with higher VAF was found and no systematic changes of the risk for GVHD and relapse/progression were observed. Conclusions. We conclude that donor CH has no significant impact on the risk for GVHD, relapse and survival in the context of HLA-compatible unrelated donor alloHCT with GVHD-prophylaxis based predominantly on T-cell depletion with ATG.

Clinical Determinants of Early Mortality Following Allotransplantation for Acute Lymphoblastic Leukemia in a Brazilian Multicenter Registry

Introduction: Allogeneic stem-cell transplantation (HSCT) continues to be a potentially curative approach for acute lymphoblastic leukemia (ALL). However, one of the primary challenges in HSCT remains the transplantation-related mortality (TRM), even though the overall complications and mortality rates have decreased over time. Notably, in developing countries, previous research on HSCT has highlighted that early mortality plays a significant role in their comparatively worse outcomes. Therefore, it is crucial to identify the factors involved in early mortality to enhance cure rates. Considering this, our study aims to investigate the risk factors associated with early mortality following HSCT for ALL in Brazilian centers. Methods: This is a retrospective registry study. Patients with ALL or ambiguous lineage leukemia above 16 years who underwent a first HSCT in 5 Brazilian centers between January 2007 and December 2017 were included. Early mortality (EM) was defined as death within 100 days from HSCT. A multivariable analysis (MVA) was performed using logistic regression, with the Akaike's information criteria used for model selection. A p-value&amp;lt;0.05 was considered statistically significant. Results: Overall, 275 patients were included in this study. Baseline characteristics are summarized in Table 1. The median age was 31y (range, 16-65) and 58.5% were male. The Philadelphia chromosome was reported in 35% and most patients were in first complete remission (CR1) (66%). Matched sibling donor (MSD), matched unrelated donor (MUD), mismatched unrelated donor (MMUD), haploidentical donor, and umbilical cord were reported in 53%, 19%, 9%, 19%, and 5%, respectively. The median donor age was 31y (range, 4-64) and 54.4% were male. EM rate was 24.4%. Univariate analysis pointed some factors statistically related to EM, as it follows: graft source (p&amp;lt;0.001), baseline KPS (p=0.03), gender (female vs. male, 16.7 vs 27.9%, p=0.03), Ph-positive status (p=0.03), refractory disease status (p=0.015), umbilical cord blood source (p=0.01), and donor age (p=0.08). There was no difference regarding EM rates between public and private centers (24.5 vs. 19%, p=0.463). The best multivariable model included gender, Ph-status, donor type and donor age as final variables for EM. In our cohort, Ph-positive status (OR = 2.83), donor age (OR = 1.05), and the use of MUD (OR = 3.68) were independently associated with early transplant-related mortality. Regarding the cause of EM, 69% were related to infection, and 19.5% were caused by acute GVHD. Interestingly, EM was higher in Ph-positive patients with no major molecular remission (BCR-ABL≥0.1%) - 40 vs. 3.6%, p=0.008). Cumulative incidence of acute GVHD at day 100 was 48.3% by competitive analysis. Only 3 out of 62 deaths in EM group were due to disease relapse. Remaining deaths were secondary to bacterial infection (52%), followed by acute GVHD (17.8%) and fungal infection (8.9%), mainly. Conclusions: This study represents the largest analysis in Brazil to assess early transplant-related mortality in ALL patients. Reducing EM rates is particularly important in resource-constrained settings to improve outcomes. While the overall patient characteristics were similar to other registry analyses, the EM rate in this study was higher than that reported in other cohorts worldwide. Notably, transplant-related factors such as donor age and type, in addition to Ph-positive status, were found to be associated with EM, outweighing previously known factors like conditioning intensity and the use of total body irradiation. These findings could aid in enhancing donor selection in Brazil and optimizing HSCT indications in specific subsets.

Fractionated Total Body Irradiation and Fludarabine Based Conditioning Regimen with Post-Transplant Cyclophosphamide (PTCy) for Mismatched Related and Unrelated Donors HCT for Acute Leukemia and MDS

Background: Allogeneic hematopoietic cell transplantation (alloHCT) remains the only curable treatment option for several hematological malignancies. Preparative and graft-versus-host disease (GVHD) prophylactic regimens combined with graft-versus-leukemia effect (GVL) are important in preventing graft rejection, disease relapse and GVHD; and subsequently impact the success of this life saving procedure. Choice of regimen depends on patient, donor/graft source and disease characteristics. Objectives: Assess the outcomes of patients who underwent haploidentical (haplo) or mismatched unrelated donor (MMUD) HCT with myeloablative conditioning (MAC) regimen using radiation in combination with fludarabine (FLU) with PTCy as higher intensity GVHD prophylaxis and evaluate the feasibility of a fludarabine and fractionated total body irradiation (FLU/FTBI)-based regimen in both donors. Study Design: Retrospective analysis to study the outcomes of patients receiving FLU/FTBI as myeloablative conditioning for mismatched (related or unrelated) donor HCT combined with post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis. Results: One hundred and fifty-five consecutive patients undergoing HCT at City of Hope (COH) from January 2015 to December 2021 were included. Median age was 38 years (range 9-60) and 56.8% of patients were male and 97.5% had a Karnofsky performance status (KPS) ≥ 80. HCT comorbidity index was ≥ 3 in 36.1% cases and 29% with a disease risk index (DRI) of high/very high. Disease diagnosis included acute lymphoblastic leukemia (ALL) (46.5% of cases) and acute myeloid leukemia (AML) (36.1% of cases). The median donor age was 31-years with 67.1% haplo donors and 32.9% mismatched unrelated donors (MMUD). MMUD HCT led to faster neutrophil recovery (15 vs 16 days, p= 0.01) and platelet count recovery (18 vs 23 days, p= 0.029). Day 100 cumulative incidence of grade II-IV and III-IV acute GVHD had no statistical difference between the two cohorts. With a median follow-up of 24 months (range 3 to 81), 100-day and 1-year NRM was 1.9% and 8.5%, respectively. There was no difference in the NRM between MMUD and haplo (HR 0.92, CI (0.35,2.39), p=0.86). Two-year relapse rate and DFS were 11.8% and 76.9%, respectively. In this study, 7 out of 51 patients in the MMUD group and 17 out of 104 patients in the haplo group relapsed with no statistically significant difference between the groups (HR 0.82, CI: (0.35,1.97), p=0.67). At a median follow-up of 2 years, GRFS was 60% (95% CI 0.51- 0.67). There was no statistically significant difference in GRFS between the MMUD and haplo groups (HR 0.76, CI (0.44,1.32), p=0.33). Two-year OS was 80.1%. There were no DFS or OS differences between the MMUD and haplo groups. On multivariate analysis, age less than 40 and low to intermediate DRI showed a DFS benefit (p = 0.004 and 0.029 respectively). None of the demographic factors affected OS or GRFS. Disease risk index was the only factor on multivariate analysis affecting relapse rates with higher risk of relapse with higher DRI (p= 0.017) and extensive chronic GVHD risk (p= 0.014) with no impact on acute GVHD. Conclusions: FLU/FTBI followed by PTCy for GVHD prophylaxis is a well-tolerated myeloablative regimen in mismatched donors with acute leukemia or myelodysplastic syndrome (MDS) with low transplant related morbidity and mortality and has produced promising HCT outcomes.

MAIT Cell Frequencies within PBSC Grafts Are Associated with Donor CMV Serostatus and Age: An Initial Analysis from the DKMS and NMDP Graft Composition Study

Introduction We have established an international collaboration between the DKMS (Germany) and the National Marrow Donor Program (NMDP; USA) to characterize more than 2000 donor peripheral blood stem cell (PBSC) grafts. We aim to correlate graft immunophenotype with patient outcomes and perform additional analyses on biobanked aliquots of selected samples to deepen our understanding of the relationships between features of the donor graft and key patient outcomes, such as graft-versus-host disease, relapse, and overall survival. Here, we present an interim analysis, focused on the CD8 T cell compartment, describing relationships between donor characteristics and graft composition. We have developed a novel computational clustering method to integrate cytometry data from both the US and German analytical laboratories. Methods 300 donor PBSC graft samples were collected, processed, freshly stained (34-color panel for immunophenotyping of lymphocytes and hematopoietic stem cells), and analyzed using an Aurora Cytek instrument at the NMDP contract laboratory (Roswell Park, Buffalo, NY). 53 additional samples were processed in the DKMS laboratory in Dresden, Germany (equivalent antibody panel and instrument). We have developed a novel analytical pipeline for integrating these data. First, we group samples by facility, and by month run for computational convenience, to form “batches” for initial clustering. We perform Leiden clustering, and subclustering, to generate a large number of clusters per batch. To integrate data from all batches, we then cluster all subcluster centroids from all batch-specific clusterings. This gives a global clustering for each stream ( e.g. the CD8+ T cells). Cluster frequencies per sample provide features for quantifying links between immunophenotype and donor metadata ( e.g., CMV serostatus, age, and sex). Our approach offers an important complement to traditional gating and allows full exploration of the data in an unbiased fashion. Results 353 donor products were included in the analysis. The median donor age was 28 years (range 18 - 60), 59% were female and 65% were CMV positive. Initial metaclustering demonstrated that the 53 DKMS samples and the 300 NMDP samples are each well represented in all clusters, and that site-driven batch effects, while present, are mild. We initially focused on the CD8 T cell compartment (UMAP in Fig 1A) and discovered several phenotypic differences when we compared CMV seronegative and seropositive donors. CD8 T cell clusters 10 and 11 (both TCRαβ+ CD45RA+ CCR7+ HLA-DR+ CD57+; cluster 10 CCR9+; cluster 11 CCR9-) were present at higher frequency in CMV+ donors (n = 116) compared with CMV- donors (n = 220; p &amp;lt;0.0001; Fig 1B). Conversely, clusters 9 and 12, enriched for mucosal-associated invariant T (MAIT) cells, were significantly reduced in CMV+ donors (p &amp;lt;0.001). Of note, CMV serostatus was not significantly associated with age (median age in the CMV+ group was 29.4 years; vs 28.4 years in CMV- donors). We also observed an association between cluster 8 (TCRαβ+ CD45RA+ CCR7+ HLA-DR+ CD38+; consistent with an activated phenotype) and age (p = 0.0009; Fig1B). There was a trend toward decreased MAIT frequencies with age (Cluster 9; p = 0.058). When we analyzed the MAIT cell frequency as defined by traditional flow cytometry gating (CD3+ CD8+ CD161+ Vα7.2+), we observed a statistically significant relationship between younger donor age and increased MAIT cell frequency (p = 0.0002), consistent with the trend seen in cluster 9. Sex at birth was not linked with immunophenotype in our analyses thus far. Conclusions In this initial analysis of our multi-center observational study of PBSC graft products, we demonstrate the development and application of new computational tools for large-cohort flow cytometric data analysis. CMV-positive serostatus and younger donor age are both associated with an increased frequency of MAIT cells in the graft. We also found differences in CD8 T cell activation status in association with age and CMV. In the future, we will assess the relationships between these populations and patient outcomes, as well as explore cluster frequencies in association with key patient outcomes including GVHD, relapse, and overall survival. Sample collection and analysis are ongoing at both US and German sites as an ongoing collaborative effort between the NMDP and the DKMS.

Regimen Intensity and Age Affect Transplant-Related Outcomes after Matched Related Donor Hematopoietic Cell Transplantation for Sickle Cell Disease: A STAR Registry Study

Background: Serotherapies such as anti-thymocyte globulin (ATG) and alemtuzumab (AL) are added to conditioning chemotherapy for matched related donor (MRD) hematopoietic cell transplantation (HCT) for sickle cell disease (SCD) to facilitate engraftment and prevent graft-vs-host disease (GVHD). Most reports show ATG added to myeloablative (MA) conditioning; however, the use of AL has increased with investigation of different intensity regimens. The aim of this study was to compare HCT-related outcomes across common conditioning approaches to determine superiority. Methods: Retrospective data on baseline patient and HCT characteristics, and HCT outcomes were collected on 352 SCD patients &amp;gt;1 yr post-HCT at 14 Sickle cell Transplant Advocacy and Research (STAR) Alliance centers. Patients with a non-MRD (n=117) or without serotherapy (n=26) were excluded, leaving 209. MA included busulfan (BU) cumulative dose (CD) &amp;gt;8mg/kg or TBI ≥800 cGy; other regimens were termed non-MA (nMA). Summary statistics were presented as median (IQR) for continuous variables and count (%) for categorical variables. Comparisons were made using two-sample hypothesis tests, with p-value of &amp;lt; 0.05 as significant. Time-to-event analyses followed out to 3 years (censored after) and considered 4 outcomes. The first 3 were estimated via the Kaplan-Meier method: (1) overall survival (OS); (2) rejection-free survival (RFS); with death and rejection as events; (3) severe GVHD-free, RFS (GRFS), with death, RFS and severe GVHD as events; and (4) GVHD was estimated by Fine-Gray competing risk analyses, considering death as a competing event and censoring for rejection. Results: 209 patients received MRD HCT with MA+AL (66, 32%), nMA+AL (49, 23%), MA+horse (hATG) (71, 34%), or MA+rabbit (rATG) (23, 11%). Median recipient and donor age at HCT were 8.4yr (IQR: 5.1, 13.0) and 9.3 (5.1, 15.0) and similar across cohorts. MA+AL had a less severe clinical phenotype and nMA+AL had decreased pulmonary function; other baseline characteristics were similar (data not included). Conditioning for MA+AL included bu/cyclophosphamide (cy) (64%) or bu/fludarabine (flu) (36%), for MA+hATG bu/cy (68%) or bu/cy/flu (32%), for MA+rATG bu/cy (83%) or bu/flu (17%), and for nMA+AL melphalan/flu (92%) plus thiotepa (TT) (8%). GVHD prophylaxis was primarily calcineurin inhibitor and methotrexate or mycophenolate mofetil (91.4%). In MA, serotherapy was proximal timed with AL starting day -5 or -6 at a median (IQR) CD of 1.05mg/kg (0.8, 1.5), hATG starting day -3 at 90mg/kg (90), or rATG starting day -5 at 10mg/kg (9.6, 10.1); in nMA, AL was distal timed starting day -22 at a CD of 1.98mg/kg (1.0, 2.8). Stem cells were bone marrow in all, and GCSF primed in 15.4% of MA+AL and 4% of nMA+AL. Total nucleated and CD3 cell doses were similar across cohorts. nMA+AL had shorter median follow up at 2y (1, 4) vs 3y (2, 6) overall. nMA+AL had earliest time to neutrophil engraftment, required less platelet infusions, and had a shorter hospital stay at median 13d (12, 15), 8 infusions (4,13), and 21d (18, 26), respectively. Readmissions were highest for MA+AL at 77% (vs 64% overall). Graft rejection occurred only in nMA+AL (4, 8.2%) and MA+rATG (2, 8.7%). Table 3-yr CI of grade III/IV aGVHD was highest in nMA at 12% (CI: 0.05, 0.23) vs 0-7%, p=0.130 and for any cGVHD was significantly higher in nMA+AL at 33% (0.19, 0.46) vs 9-19%, p=0.001. 3-year OS was excellent at 94.4% (91.3, 97.7) and comparable per cohort. 3-year RFS was lowest though not significantly in nMA+AL at 87% (0.78, 0.97) vs 91-97%, p=0.260. 3-year GRFS was significantly lower in nMA+AL at 69% (0.57, 0.83) vs 83-94%, p=0.001. When age controlled GRFS in nMA+AL ≥13y was significantly lower at 59% (0.40, 0.88) vs 74-100%, p=0.007. Figure Conclusions: Despite small cohort sizes and retrospective nature, this study allowed for direct comparison of common approaches to MRD HCT for SCD. Outcomes were collectively excellent. nMA had earlier engraftment, less transfusion needs, and shorter hospital stay, although significantly more cGVHD and lower 3-yr GRFS influenced by older age. Current clinical trials in nMA+AL include TT and abatacept to mitigate this difference. We previously reported an association between MA and cardiac dysfunction (Stenger et al. Transplant Cell Ther 2023). Potential benefit of nMA must be balanced against risk of rejection and GVHD, thus providers should carefully consider such when selecting conditioning.