Donor Selection Strategies Research Articles

Convalescent plasma therapy for COVID-19 – Donor selection strategies and establishment of a plasma bank

BackgroundEarly in the COVID-19 pandemic, convalescent plasma (CP) emerged as a potentially effective treatment neutralising SARS-CoV-2. Early CP therapy with high neutralising antibody (NAb) titre may benefit COVID-19 outpatients and, in sufficient quantities even some hospitalised patients. This study details the process of setting up a CP bank, containing high- and low-titre CP for a clinical trial. Study design and methodsWe identified 18–65-year-old convalescents with SARS-CoV-2 NAb titres of ≥1:40 in microneutralisation test (MNT). Following eligibility pre-screening, the Finnish Red Cross Blood Service (FRCBS) determined suitability as CP donors. ResultsOf the 6466 COVID-19 convalescents contacted, 1481 provided serum, with 851 (57.5 %) exhibiting NAb titres ≥1:40. Participation barriers included reluctance, advanced age and, for women, insufficient body size. Of the volunteers, 125 were evaluated at FRCBS, with major exclusions for HLA antibodies (42 women), interferon antibodies (five men), and NAb titres waning below 1:20 (16 participants). Finally, 70 underwent plasmapheresis, resulting in 50 suitable CP donors (0.8 % of initial contacts and 3.4 % of those tested for NAb). DiscussionThe process of setting up a CP bank proved challenging. Excessive laboratory workloads during a pandemic hamper their ability to conduct MNT, underscoring the need for rapid screening tests. Only a small proportion of our convalescents exhibited high-titre CP, this fraction declining over time because of waning immunity. Strict plasmapheresis criteria further constrained donor eligibility. Establishing a plasma bank requires meticulous planning to maximize efficiency. Detailed insights from current experiences may prove critical in future pandemics before other remedies and vaccines become available.

Unveiling ancestral threads: Exploring CCR5 ∆32 mutation frequencies in Colombian populations for HIV/AIDS therapeutics

AIDS remains a significant global health challenge since its emergence in 1981, with millions of deaths and new cases every year. The CCR5 ∆32 genetic deletion confers immunity to HIV infection by altering a cell membrane protein crucial for viral entry. Stem cell transplants from homozygous carriers of this mutation to HIV-infected individuals have resulted in viral load reduction and disease remission, suggesting a potential therapeutic avenue. This study aims to investigate the relationship between genetic ancestry and the frequency of the CCR5 ∆32 mutation in Colombian populations, exploring the feasibility of targeted donor searches based on ancestry composition. Utilizing genomic data from the CÓDIGO-Colombia consortium, comprising 532 individuals, the study assessed the presence of the CCR5 ∆32 mutation and examined if the population was on Hardy-Weinberg equilibrium. Individuals were stratified into clusters based on African, American, and European ancestry percentages, with logistic regression analysis performed to evaluate the association between ancestry and mutation frequency. Additionally, global genomic databases were utilized to visualize the worldwide distribution of the mutation. The findings revealed a significant positive association between European ancestry and the CCR5 ∆32 mutation frequency, underscoring its relevance in donor selection. African and American ancestry showed negative but non-significant associations with CCR5 ∆32 frequency, which may be attributed to the study's limitations. These results emphasize the potential importance of considering ancestry in donor selection strategies, reveal the scarcity of potential donors in Colombia, and underscore the need to consider donors from other populations with mainly European ancestry if the CCR5 ∆32 stem cell transplant becomes a routine treatment for HIV/AIDS in Colombia.

Sero Prevalence of Transfusion Transmissible Infection in Blood Donors: North Goa District Hospital Based Study

Transfusion transmissible infections (TTIs) have emerged as one of the significant public health problems globallyin blood transfusion . The morbidity and mortality associated with TTIs have highlighted the need for improvingblood safety. The present study aims to investigate the sero prevalence of various TTIs among blood donors in theNorth Goa District Hospital.This study was a retrospective cross sectional study conducted from January 2021 upto September 2023. A totalof 5,426 blood donors were included in this study. Relevant demographic and clinical data were obtained fromthe donors. Enzyme-linked immunosorbent assay (ELISA) was used to detect the presence of various TTIs such asHIV, HBV, HCV, and Syphilis.The mean age of the donors was 32 years, with the majority being males (87.4%). Out of the 5,426 donors, 11 testedpositive for HIV, 32 for HBV, 30 for HCV, and 1 for Syphilis. The overall sero prevalence of TTIs was found to be1.36%.This study highlights the importance of regular screening of blood donors to ensure blood safety. The resultsof this study can be utilized to develop and implement effective donor selection strategies, which will help inreducing the transmission of TTIs through blood transfusion.So far no such study has been published from Goa.

Establish a Graded Method to Avoid HLA Class I Antibodies Corresponding Antigen and Combining HLAMatchmaker Application in Improving the CCI Value after Platelet Transfusion for Patients with IPTR

To establish a graded method to avoid mean fluorescence intensity (MFI) threshold of HLA Class I antibodies corresponding antigen, and the HLAMatchmaker program has been used to select the minimum mismatch value of donor-patient epitopes. Evaluate the application value of combining both methods in selecting HLA compatible platelets (PTL) for patients with immune platelet transfusion failure (IPTR) in improving platelet the corrected count increment (CCI). A total 7 807 PLT cross-matching compatible were performed by the solid-phase red cell adherence (SPRCA) method for 51 IPTR patients. The Luminex single antigen flow cytometry was used to detect HLA Class I antibodies in patients, and detected the MFI value for different specificity antigens of HLA Class I antibodies, was graded into strong positive group (MFI>4 000, level 1), medium positive group (1 000< MFI≤4 000, 2), weak positive group (500< MFI≤1 000, 3), and one negative control group (MFI≤500). The results of 7 807 SPRCA their negative/positive reaction wells were enrolled and statistically analyzed in different grades and the four groups, the statistical differences between the four groups were compared. Multiple applications for the select HLA Class I compatible donor events were made for patients in two cases, and HLAMatchmaker program was used to calculate the number of HLA Class I epitopes mismatches between the donors and patients. The donor with the minimum number of epitopes mismatches was selected, while avoiding the corresponding antigens of HLA Class I antibodies in levels 1 and 2, the provision of HLA compatible platelets for IPTR. After the transfusions, the CCI value of the platelet transfusion efficacy evaluation index was calculated, and the clinical evaluation of the transfusion effect was obtained through statistical analysis. There were statistically significant differences in the positive results of SPRCA immunoassay among the strong positive group, medium positive group, and weak positive group of 51 IPTR patients with different specific of HLA -I class antibodies and corresponding antigens(all P <0.001). The positive results showed a range from high to low, with strong positive group>medium positive group>weak positive group. There were a statistical difference among between the strongly positive or moderately positive groups and the negative control group(P <0.001). There was no statistical difference between the weakly positive group and the negative control group(P >0.05). The strong positive group was set as the corresponding specific HLA Class I site corresponding antigen grade 1 avoidance threshold, the medium positive group as the grade 2 avoidance thresholds, and the weak positive group as the grade 3 avoidance threshold. In the case of donor platelet shortage, it is not necessary to avoid the weak positive group. Avoiding the strategy of donor antigens and HLAMatchmaker program scores ≤7 corresponding to HLA Class I antibodies of levels 1 and 2, with CCI values>4.5×109/L within 24 hours, can obtain effective clinical platelet transfusion conclusions. When selecting HLA Class I compatible donors for IPTR patients, the grading avoids HLA Class I antibodies corresponding to donor antigens, and the donor selection strategy with the minimum scores of HLAMatchmaker program is comprehensively selected. The negative result confirmed by platelet cross-matching experiments has certain practical application value for improving platelet count in IPTR patients.

Donor Search and Selection Strategy to Facilitate Comparable Transplant Rates across Donor Search Prognosis Groups: A Report from the BMT CTN 1702 Trial

Donor Search and Selection Strategy to Facilitate Comparable Transplant Rates across Donor Search Prognosis Groups: A Report from the BMT CTN 1702 Trial

Outcomes after Hematopoietic Cell Transplantation for T-Lineage Acute Lymphoblastic Leukemia and Lymphoma: A Cooperative Study from the Adult Acute Lymphoblastic Leukemia Working Group and the Adult Malignant Lymphoma Working Group of the Japanese Society for Transplantation and Cellular Therapy

Background: T-lineage acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LBL) arise from immature precursor T cells and are currently considered a single disease entity according to the World Health Organization Classification. Patients with T-ALL or T-LBL typically receive ALL-type intensive chemotherapy if applicable, and those with high-risk features or relapsed disease undergo hematopoietic cell transplantation (HCT). Although autologous HCT for T-ALL is uncommon, it remains a choice in the general practice of T-LBL, resulting in different donor selection strategies for these diseases. However, there is limited data on outcomes for these patients. Methods: We analyzed nationwide registry data (Transplant Registry of Unified Management Program Japan, TRUMP) from 2000 to 2017 to evaluate outcomes after the first HCT and identify prognostic factors among p with T-ALL/T-LBL. Five patients who underwent autologous HCT for T-ALL were excluded from the analysis. Overall and disease-free survival (OS and DFS) were assessed using the Kaplan-Meier method with the log-rank test. Univariate and multivariate analyses were performed to identify the potential prognostic factors. The Cox proportional hazards method was used for the multivariate analysis to assess OS, whereas Gray's test and the Fine-Gray model were used to determine the cumulative incidence of relapse (CIR) considering competing risks such as relapse and non-relapse mortality (NRM). Results: A total of 1345 patients (T-ALL, n=808; T-LBL, n=537) were included in the database. The median follow-up period of survivors was 4.5 (interquartile range, 2.0-7.7) years. The median age at HCT was 32 (range, 16-70) years. The OS and DFS at 4 years after HCT were comparable between T-ALL and T-LBL (OS 51.7% vs. 52.0%, p = 0.494; DFS 48.3% vs. 45.4%, p = 0.066). However, higher NRM and lower CIR were observed in T-ALL compared with T-LBL (4-year NRM 21.8% vs. 14.5%, p = 0.002; 4-year CIR 29.9% vs. 40.1%, p &amp;lt; 0.001). In T-LBL, patients who received allogeneic HCT (allogeneic LBL, n = 402) had significantly worse survival than those who received autologous HCT (autologous LBL, n = 135) (4-year OS 47.4% vs. 66.2%, p &amp;lt; 0.001; 4-year DFS 47.4% vs. 66.2%, p &amp;lt; 0.001), with significantly worse NRM and comparable CIR (4-year NRM 18.0 vs 3.8%, p &amp;lt; 0.001; 4-year CIR 39.6% vs. 41.6%, p = 0.875). Compared with the allogeneic ALL or allogeneic LBL groups, the autologous LBL group had a significantly older age at HCT (the respective median age was 31 years [range, 16-70], 33 [16-86], and 49 [16-76]; p &amp;lt; 0.001). The allogeneic LBL group had a lower rate of first complete remission (CR1) and a higher rate of non-CR at SCT (CR1/non-CR: allogeneic ALL, 57.1%/30.4%; allogeneic LBL, 37.6%/47.0%; autologous LBL, 57.8%/31.1%; p &amp;lt; 0.001). Among patients in CR1 at HCT, OS and DFS were comparable among the allogeneic ALL (n = 461), allogeneic LBL (n = 151), and autologous LBL (n = 78) groups (Fig. 1, 4-year OS 69.3% vs. 72.6% vs. 76.7%, respectively, p = 0.389; 4-year DFS 64.9% vs. 65.5% vs. 67.1%, respectively, p = 0.830). However, the NRM was lower in the autologous LBL group (4-year NRM 16.6% vs. 8.3% vs. 0.0%, respectively, p &amp;lt; 0.001), and the CIR was lower in the allogeneic ALL group (4-year CIR 18.9% vs. 26.3% vs. 32.9%, respectively, p = 0.004). Among patients without CR at SCT, outcomes were comparable between allogeneic ALL (n = 246), allogeneic LBL (n = 189), and autologous LBL groups (n = 42) (4-year OS 18.4%, 24.6%, vs 36.9%, respectively, p = 0.347; 4-year DFS 17.4%, 21.9%, vs 23.6%, respectively, p = 0.818; 4-year NRM 29.8%, 28.0%, vs 12.7%, respectively, p = 0.107; 4-year CIR 52.8%, 50.2%, vs 63.7%, respectively, p = 0.347). In T-ALL, multivariate analysis identified age ≥ 41 years, male sex, PS ≥ 2, disease status other than CR1, HLA disparity ≥ 2 loci, myeloablative conditioning (MAC) without total body irradiation (TBI), and HCT before 2010 as factors associated with poor OS (Table 1, Upper). In T-LBL, PS ≥ 2, non-CR at HCT, MAC without TBI, use of anti-thymocyte globulin, and multiple treatment regimens before HCT were significant factors for poor OS (Table 1, Lower). Donor type did not affect OS. Conclusion: This largest-ever retrospective study shows comparable OS after HCT for T-ALL or T-LBL. Active disease, PS ≥ 2, and non-TBI MAC were potent poor prognostic factors. In T-LBL, autologous HCT can be a suitable option, which should be confirmed in further prospective studies.

Constructing a Machine Learning-Based Rating Model to Predict the Outcome of GCSF Mobilization of Hematopoietic Stem Cells in Peripheral Blood

Objective Peripheral blood stem cells serve as the primary source of hematopoietic stem cells for both autologous and allogeneic stem cell transplantation. Granulocyte colony-stimulating factor (G-CSF) stands as the most commonly employed mobilizing agent in clinical practice. While the majority of donors receiving G-CSF mobilization demonstrate high mobilization efficiency, there remains a subset of donors who fail to yield a sufficient quantity of hematopoietic stem cells. Inefficient mobilization not only leads to wastage of valuable resources but also significantly impacts transplant outcomes for recipients. Therefore, addressing the challenges associated with predicting mobilization outcomes, optimizing donor selection strategies, and further enhancing mobilization approaches is of paramount importance. Methods In this study, we conducted a retrospective analysis of mobilization data from 1008 donors who underwent hematopoietic stem cell mobilization using G-CSF at the Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University School of Medicine, over the past 5 years. We meticulously examined the correlation between mobilization outcomes (quantified by the quantity of collected CD34+ cells) and various factors, including mobilizing agent usage, demographic data, complete blood count, and blood biochemistry. Furthermore, we harnessed the power of machine learning algorithms, such as linear regression, decision tree, and AdaBoost, to develop a robust scoring model capable of predicting mobilization outcomes. The primary objective of this model is to furnish a predictive tool for assessing mobilization outcomes with accuracy and precision. Results (1) Prior to receiving G-CSF, several factors exhibited a significant positive correlation with the quantity of CD34+ cells in the collection: donor's body weight (R=0.37, p&amp;lt;0.001), peripheral blood leukocytes (R=0.24, p&amp;lt;0.001), hemoglobin (R=0.23, p&amp;lt;0.001), monocytes (R=0.22, p&amp;lt;0.001), lymphocytes (R=0.18, p&amp;lt;0.001), platelets (R=0.18, p&amp;lt;0.001), red blood cells (R=0.12, p&amp;lt;0.001), neutrophils (R=0.15, p&amp;lt;0.001), hematocrit (R=0.21, p&amp;lt;0.001), mean corpuscular-hemoglobin concentration (R=0.15, p&amp;lt;0.001), low-density lipoprotein (R=0.11, p&amp;lt;0.01), albumin (R=0.09, p&amp;lt;0.05), ferritin (R=0.19, p&amp;lt;0.001), triglycerides (R=0.17, p&amp;lt;0.001), creatinine (R=0.17, p&amp;lt;0.001), and uric acid (R=0.29, p&amp;lt;0.001). (2) Age exhibited a significant negative correlation with the quantity of collected CD34+ cells in the collection (R=-0.11, p&amp;lt;0.001). (3) When the total dose of G-CSF administration was fixed, mobilization with twice-daily dosing yielded superior results compared to once-daily dosing (collected CD34+ cell count: 1268/μl vs. 1044/μl, p&amp;lt;0.001). (4) The ratio of G-CSF dosage to body weight demonstrated a significant negative correlation with the quantity of CD34+ cells (R=-0.09, p&amp;lt;0.01). Mobilization with a ratio of 6-7 μg/kg/day showed better results compared to a ratio of 7-12 μg/kg/day (p=0.07). (5) A scoring model was developed using machine learning methods to predict the mobilization outcomes of donors. Validation on the test dataset exhibited a high predictive ability of the model (AUC&amp;gt;0.7). Conclusion This study provides valuable insights for selecting hematopoietic stem cell donors and serves as a reference for future strategies aimed at improving mobilization outcomes. The identified factors, such as donor weight, peripheral blood parameters, G-CSF dosing regimen, and the ratio of dosage to body weight, can be considered when selecting donors and optimizing mobilization protocols. By incorporating machine learning techniques, a scoring model was developed, demonstrating a high predictive ability that can assist in forecasting mobilization outcomes for potential donors. These findings contribute to the optimization of donor selection and mobilization strategies.

Interindividual HLA Evolutionary Divergence in Single HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation for Malignant Hematological Disorders: A Report on Behalf of the Cellular Therapy and Immunobiology Working Party of the EBMT

In allogeneic hematopoietic cell transplantation (allo-HCT), alloreactive T-cell responses (graft versus leukemia - GvL and graft versus host disease - GvHD) are mediated by the interaction between recipient antigens and donor lymphocytes via human leukocyte antigen (HLA) molecules. HLA evolutionary divergence (HED) is a metric recently implemented as a functional proxy for the structural variability between two homologous HLA alleles at their peptide binding sites, mirroring quantitative differences in pathogen and cancer-related immunopeptidomes ( A). 1 Here, we hypothesize that differences in and between donor and recipient HEDs at given loci may modulate the direction and the intensity of alloreactivity, informing on post-transplant outcomes. We tested this hypothesis in onco-hematologic patients undergoing allo-HCT from a single HLA-A, -B, -C, -DRB1, or -DQB1 (9/10) mismatched unrelated donor (MMUD) at EBMT centers. We included patients with selected hematological malignancies, receiving a thymoglobulin-based T cell depletion, for whom complete clinical and HLA information was available in the EBMT database. We deployed individual locus-specific recipient/donor HED (HED-R, HED-D) metrics as previously described 1, and conceptualized two novel interindividual HED scores accounting for functional differences at the mismatched HLA loci ( A). The latter were considered as: 1) DeltaHED, quantifying the relative directional difference between HED-D and HED-R and informing on differences in immunopeptidome sizes, potentially capturing the direction and the intensity of the alloreactive response (GvH or HvG); 2) HEDmismatch, describing the HED of the mismatched locus as a proxy for the qualitative differences in immunopeptidomes between donor and recipient ( B). Using multivariable Cox regression (cause-specific) models adjusted for relevant clinical variables, we investigated the associations of HED-R, DeltaHED and HEDmismatch, analyzed as continuous variables, with relapse free survival (RFS), overall survival (OS), non-relapse mortality (NRM), relapse and grade II-IV acute and chronic GvHD. For each outcome and in each mismatched subgroup, we built separate models for these immunogenetic parameters and checked for proportional hazards assumption (PHA). To account for multiple comparisons, only p-values &amp;lt;0.01 were considered significant. Overall, 4639 adult patients, with available HLA data, received a 9/10 MMUD allo-HCT between 2010 and 2019 for acute leukemia (N=3853, 83%), myelodysplastic syndromes or myeloproliferative neoplasms (N=786, 17%). Median recipient age was 53.5 (IQR 40.2-61.9) with a male/female ratio of 1.28, whilst median donor age was 33.1 (IQR 24.5-40). Majority of patients (90%) received peripheral blood stem cells and were mismatched with their donors for locus A (33%), followed by C (21%), B (15%), DQB1 (14%) and DRB1 (6%). When analyzing the impact of HED-related parameters in each model, we observed that most recurrent associations with outcomes occurred with DRB1-related metrics. In the DRB1-mismatched subgroup (N=276), a time-varying association was found for HEDmismatch of DRB1 locus with higher HEDmismatch leading to worse RFS [HR:1.25 at t=0, (95% CI 1.1-1.42), p&amp;lt;0.001] and lower OS [HR:1.23 at t=0, (95%CI 1.08-1.41), p=0.002]. The strength of this associations declined over time for both endpoints (respectively RFS: HR:0.91, 95% CI 0.86-0.97, p=0.005 and OS: HR:0.93, 95% CI 0.88-0.98, p=0.013). The (directional) DeltaHED DRB1 measure instead did not display any impact on outcomes. In the same subgroup, higher HED-R in the locus C showed also a time-varying association with NRM at transplant [HR:1.89, (95% CI 1.29-2.85), p=0.002], progressively declining over time (HR:0.77, 95% CI 0.65-0.92, p=0.003). Furthermore, DRB1 HED-R modulated the probability of survival in B-mismatched subgroup, being higher scores associated with reduced OS [HR:1.03, (95%CI 1.01-1.06), p=0.009]. Here, we provide an immunogenetic benchmark to explore donor-recipient interactions in MMUD allo-HCT, demonstrating how different HLA configurations within the mismatched loci, in particular for DRB1 genes, can influence post-transplant outcomes. Given the peculiar associations observed, HED may have a role in driving early GvL effects, informing on future donor selection strategies in high-risk patients.

Donor Selection for Allogeneic Hematopoietic Cell Transplantation.

In Germany, each year over 3000 patients with malignant and non-malignant hematologic and systemic diseases are treated by allogeneic hematopoietic cell transplantation (HCT). Genetic donor-recipient disparities, especially those concerning variable human leukocyte antigens (HLA), mediate both an immunotherapeutic effect and the risk of damage to healthy tissues ("graft-versus-host disease"). The adoption of evidence-based strategies for donor selection has been crucial for the continuous improvement of survival rates after allogeneic HCT, with over 50% of patients transplanted for standard indications-such as early-stage acute myeloid leukemia-alive at three years post-transplant. The PubMed database was selectively searched for literature on immunogenetic and clinical factors relevant to allogeneic HCT, as part of the process of establishing a German consensus statement on HCT donor selection. The most important factor in donor selection is a match for the five major HLA loci (HLA-A, -B, -C, -DR, -DQ), either in genetically HLA-identical siblings or in unrelated but fully HLA-compatible donors from international registries. Additional selection criteria for the latter include compatibility for the HLA-DP locus, donor age and sex, cytomegalovirus serostatus, and blood group. Related donors identical for only 50% of the HLA genes (haploidentical donors) as well as unrelated donors with a single HLA mismatch are both valid alternatives although they are associated with an up to 10% higher risk of mortality. The refinement of donor selection strategies has been instrumental for the continuous improvement of patient survival rates after allogeneic HCT witnessed over the past decades. An interdisciplinary approach to donor selection based on up-to-date scientific evidence is crucial for optimizing patient outcomes.

KIR genotype and haplotype repertoire in Kuwaiti healthy donors, hematopoietic cell transplant recipients and healthy family members.

The gene complex located on chromosome 19q13.4 encodes the Killer-cell Immunoglobulin-like Receptors (KIRs), which exhibit remarkable polymorphism in both gene content and sequences. Further, the repertoire of KIR genes varies within and between populations, creating a diverse pool of KIR genotypes. This study was carried out to characterize KIR genotypes and haplotypes among 379 Arab Kuwaiti individuals including 60 subjects from 20 trio families, 49 hematopoietic cell transplantation (HCT) recipients and 270 healthy Kuwaiti volunteer HCT donors. KIR Genotyping was performed by a combination of reverse sequence specific oligonucleotide probes (rSSO) and/or Real Time PCR. The frequencies of KIR genes in 270 healthy Kuwaiti volunteer donors were compared to previously reported frequencies in other populations. In addition, we compared the differences in KIR repertoire of patients and healthy donors to investigate the reproducibility of previously reported significant differences between patients with hematological malignancies and healthy donors. The observed frequencies in our cohort volunteer HCT donors was comparable to those reported in neighboring Arab populations. The activating genes KIR2DS1, KIR2DS5 and KIR3DS1 and the inhibitory gene KIR2DL5 were significantly more frequent in patients compared to healthy donors, however, none of the previously reported differences were reproducible in our Kuwaiti cohort. This report is the first description of KIR gene carrier frequency and haplotype characterization in a fairly large cohort of the Kuwaiti population, which may have implications in KIR based HCT donor selection strategies.

Association of iKIR-mismatch model and donor aKIRs with better outcome in haploidentical hematopoietic stem cell transplantation for acute myeloid leukemia.

Killer cell immunoglobulin like receptor (KIR) can trigger the alloreactivity of NK cells. However, there is no clear consensus as to their function. Here, we investigated the potential influence of KIR mismatch and KIR alleles on the outcome of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in acute myeloid leukemia (AML) patients. Data from 79 AML patients treated with haplo-HSCT were retrospectively analyzed. HLA-C genotyping was determined by the PCR-rSSO method. KIR, HLA-A and HLA-B genotyping was performed by the PCR-SSP method. Cox proportional hazards model and Kaplan-Meier survival curves were used for analysis. Both KIR ligand mismatch (KLM) group and KIR receptor-ligand mismatch (RLM) group were associated with a decreased risk in aGVHD and relapse rate (RR), and better overall survival (OS) compared to the KIR ligand matching and receptor-ligand matching groups, respectively (aGVHD: KLM: p=0.047, HR:0.235; RLM: p<0.001, HR:0.129; RR: KLM: p=0.049, HR:0.686, RLM: p=0.017, HR:0.200;OS:KLM: p=0.012, HR: 0.298, RLM: p=0.021, HR:0.301). RLM was more accurate at predicting relapse and aGVHD compared with KLM (aGVHD: p=0.009; RR: p=0.039). Patients with greater number of donor activating KIRs (aKIR) had a lower incidence of aGVHD and relapse, and the benefits correlated with the increase in the number of donor aKIRs (aGVHD: p=0.019, HR:0.156; RR: p=0.037, HR:0.211). Patients with RLM and the highest number of donor aKIRs had the lowest RR, lowest incidence of aGVHD and best OS. Both KLM and RLM reduced the risk of aGVHD and relapse after haplo-HSCT in AML patients, and RLM showed superiority in predicting HSCT outcome. The synergistic effects of RLM and donor aKIRs can provide a better donor selection strategy to improve haplo-HSCT outcome in AML patients.

A BAD IDEA OF USING MODE IMPUTATION METHOD

Missing data is a recurring issue in psychology questionnaire when a respondent does not respond to questions due to personal reasons. In general, two types of imputation techniques are used to replace missing data: single imputation and multiple imputation (MI). The single imputation technique generates a single value to impute each missing data. The simplest methods of single imputation are mean, mode and median. In contrast, the multiple imputation technique imputes each missing data several times resulting in multiple complete datasets. The most popular method in MI that can deal with numerical and categorical data type is the predictive mean matching (PMM). The aim of this article is to compare and visualize how the mode imputation method in the single imputation technique will lead to a biased data distribution and the PMM method in the MI techniques will reduce this issue. Both methods, mode imputation and PMM are often considered when dealing with categorical data types. The mode imputation replaces a missing data with the most frequent value of an item in a survey. Meanwhile, the predictive mean matching is an extension of regression model that apply donor selection strategy to replace a missing data. Results from bar charts visualize the multiple imputation shows less discrepancy between the original distribution and imputed distribution. Thus, in this research, it can be concluded that the PMM method in MI technique shows a less biased distribution than implementing the mode imputation method. A comparison of imputation methods with different missing rates on a survey dataset should be considered for future work.

Intestinal Transplantation in a Country Without Home Parenteral Nutrition: The Largest Report from the Middle East.

Background:Many regions of the world, especially middle- and low-income countries, lack facilities for home parenteral nutrition and thus cannot follow existing guidelines for intestinal transplantation. Herein, we report our experiences with treatment protocols, intraoperative management, and early postoperative outcomes among patients undergoing either isolated intestinal transplantation or multivisceral transplantation in our center.Methods:During a 1-year period from March 2019 to March 2020, a total of 9 intestinal transplantations including 6 isolated intestinal transplantations and 3 multivisceral transplantations were performed in our center. We reported on donor selection strategies, surgical treatment, anesthesiology care and protocols for total parenteral nutrition, immunosuppression regimen, and pathology evaluation.Results:Mean (standard deviation) age of patients was 37.5 ± 12.5 years. The majority of patients were females (7/9). The median (interquartile range) waiting time for patients from diagnosis to transplantation was 79 (34, 164) days. Our 7-day survey of the amount of fluid therapy after transplantation revealed that the greatest need for fluid therapy was seen on the second postoperative day. After transplantation, 2 patients showed a total of 3 episodes of severe rejection, 1 of which was antibody-mediated. The 1-year survival was 66.6% and the 2-year survival was 44.5% in our study population. The median (interquartile range) time to death was 157 (26.5, 382) days. The most common cause of death was sepsis in our series (3/5).Conclusion:Acceptable outcomes can be obtained with intestinal transplantation in countries without home parenteral nutrition by application of specific treatment protocols.

Establishment of NGS-based HLA 9-locus haplotypes in the Eastern Han Chinese population highlights the role of HLA-DP in donor selection for transplantation.

We collected HLA typing data from 653 families in the Eastern Han Chinese population. HLA-A, B, C, DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, DPA1, and DPB1 (HLA-11 loci) typing of 1781 subjects was performed using a commercial next-generation sequencing (NGS) method in our laboratory. The phasing of haplotypes in each family was determined by Mendelian segregation. Haplotype analysis revealed 1634 different haplotypes among a total of 2230 haplotypes. The predominant haplotype was A*30:01-C*06:02-B*13:02-DRB1*07:01-DRB4*01:03-DQA1*02:01-DQB1*02:02-DPA1*02:01-DPB1*17:01 (HF=4.04%), followed by A*02:07-C*01:02-B*46:01-DRB1*09:01-DRB4*01:03-DQA1*03:02-DQB1*03:03-DPA1*02:02-DPB1*05:01 (HF=1.84%) and A*33:03-C*03:02-B*58:01-DRB1*03:01-DRB3*02:02-DQA1*05:01-DQB1*02:01-DPA1*01:03-DPB1*04:01 (HF = 1.48%), accounting for 7.35% of the total. Meanwhile 76.41% of all haplotypes were observed only once or twice (HF < 0.1%). Different from HLA-DRB3/4/5 and DQA1 loci, DP linkage markedly increased haplotype variation by 34.82% based on the 5-locus haplotype. The much weaker linkage disequilibrium (LD) of DQB1-DPB1 indicated the reason. We observed 10 analyzable recombination events, most of which occurred at DP loci. Even with the same common 5-locus haplotype, HLA-DP linkage alters the haplotype diversity and frequency. Analysis of related haplotype assignment and unrelated recipient-donor pairs matching at the 9-locus haplotype revealed that HLA-DP affects the donor selection strategy. Haplotype study of a large sample size using NGS identified linkage haplotypes beyond the 5 loci. LD, recombination events, and haplotype variation caused by DP loci emphasized that HLA 9-locus haplotype matching should be considered in donor selection, particularly the effect of DP loci. The finding lays the foundation for further studies on the effect of HLA-DP mismatch on transplantation.

Predictive Factors and Outcomes after Allogeneic Stem Cell Transplantation for Adults with Acute Lymphoblastic Leukemia in Brazil

Allogeneic stem cell transplantation (HSCT) remains a potentially curative approach for acute lymphoblastic leukemia (ALL), especially for high-risk patients and those with relapsed/refractory disease, although its efficacy is offset by a not-negligible toxicity. Adult patients with ALL fare worse in developing countries, with little data about the HSCT in this setting. In this study, we aimed to describe outcomes and examine risk factors for overall survival (OS), leukemia-free survival (LFS), cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), and graft-versus-host disease (GVHD) after HSCT for ALL in Brazilian centers. This retrospective registry study included patients with ALL or ambiguous lineage leukemia age >16 years who underwent a first HSCT at 5 Brazilian centers between January 2007 and December 2017. A total of 275 patients were included, with a median age of 31 years (range, 16 to 65 years). Thirty-five percent were Philadelphia chromosome-positive. A matched sibling donor was used in 53%, a matched unrelated donor (MUD) in 19%, a mismatched unrelated donor in 9%, a haploidentical donor in 19%, and umbilical cord blood in 5%. The engraftment failure rate was 1.5%. The 5-year cumulative incidence of acute grade II-IV was 54.2%, and that of chronic GVHD was 26.2%. Five-year CIR and NRM were 28.1% and 34.1%, respectively. Central nervous system involvement at diagnosis (hazard ratio [HR], 2.2) and disease status (HR, 1.8 for second or later complete response and 7.9 for refractory) were associated with increased relapse incidence, whereas the use of peripheral blood graft (HR, .51) and a haploidentical donor (HR, .4) significantly decreased relapse incidence. Five-year OS and LFS were 40.7% (95% confidence interval [CI], 35.1-47.1) and 37.8% (95% CI, 32.3-44.1), respectively. Patient age, donor age, and disease status were independently associated with OS and LFS. Pre-HSCT positivity of minimal residual disease (>.01%) was associated with worse LFS (HR, 1.47) in available cases. This is the largest series of adults with ALL undergoing HSCT from Brazil reported to date. Although OS and LFS were similar to data reported in the literature, NRM was higher. Patient age and donor age outweighed donor type or graft source in our analysis. Interestingly, haploidentical HSCT was associated with lower CIR, whereas the use of MUDs was associated with higher NRM and GVHD rates. These results impact donor selection strategy in Brazil with the aim of offering timely HSCT for high-risk ALL patients in our setting.

Targeted isolation of diverse human protective broadly neutralizing antibodies against SARS-like viruses.

The emergence of current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) and potential future spillovers of SARS-like coronaviruses into humans pose a major threat to human health and the global economy. Development of broadly effective coronavirus vaccines that can mitigate these threats is needed. Here, we utilized a targeted donor selection strategy to isolate a large panel of human broadly neutralizing antibodies (bnAbs) to sarbecoviruses. Many of these bnAbs are remarkably effective in neutralizing a diversity of sarbecoviruses and against most SARS-CoV-2 VOCs, including the Omicron variant. Neutralization breadth is achieved by bnAb binding to epitopes on a relatively conserved face of the receptor-binding domain (RBD). Consistent with targeting of conserved sites, select RBD bnAbs exhibited protective efficacy against diverse SARS-like coronaviruses in a prophylaxis challenge model in vivo. These bnAbs provide new opportunities and choices for next-generation antibody prophylactic and therapeutic applications and provide a molecular basis for effective design of pan-sarbecovirus vaccines.

Association of Ikir-Mismatching and Donor Akirs with Better Outcomes in Haploidentical Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia

Objectives: Natural killer (NK) cells are the first donor-derived lymphocytes to be reconstituted after transplantation and play a critical role in improving transplantation outcomes. Their surface receptor, killer cell immunoglobulin like receptor (KIR), can trigger the alloreactivity of NK cells and have been shown to be protective for acute and chronic graft-versus-host disease (aGVHD, cGVHD) while retaining graft-versus-leukemia (GVL) effect. However, different results have been reported about KIR matching models and KIR alleles based on patient, donor and transplant characteristics, resulting in significant controversy about the best donor selection strategy. Here, we investigated the potential influence of KIR matching and KIR alleles on GVHD prophylaxis, overall survival (OS) and relapse rate (RR) of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in acute myeloid leukemia (AML) patients. Methods：Data from 79 patients with AML treated with haplo-HSCT between May 2015 and May 2021 in the transplantation unit of the Fujian Medical University Union Hospital were retrospectively analyzed. The cohort included 49 male patients (62.0%) and 30 female (38.0%), with a median age of 25 years (1-68 years). KIR genotyping was performed by the PCR-SSO method. The amplicons were quantified on the Luminex 200 flow analyzer and analyzed using the Quick-Type for Lifecodes software for generating KIR data. HLA-A and -B alleles were typed by polymerase chain reaction using sequence-specific primers (PCR-SSP) (TBG, Taipei, Taiwan). HLA-C genotyping was determined by reverse hybridization with sequence specific oligonucleotides probes (rSSO) Line probe assay. Cox proportional hazards model and Kaplan-Meier survival curves were used for analysis. Results：At the time of transplantation, 49 cases (62.0%) were at CR1, while 30 (38.0%) were not. aGVHD occurred in 16 patients (20.3%) and recurrence arose in 10 patients (12.7%), 4 (5.1%) cases cGVHD was observed. After adjusting for age, disease-risk, disease-status, HLA-match, donor gender, conditioning regimen intensity and type of post-grafting GVHD prophylaxis, Cox regression analysis revealed that both KIR ligand-ligand mismatching (KLM) and KIR receptor-ligand matching (RLM) was associated with an decreased risk of aGVHD and relapse compared to KIR ligand-ligand matching and receptor-ligand matching group, respectively (aGVHD: KLM: p=0.047, RLM: p＜0.001; RR: KLM: p=0.049, RLM: p=0.017). Furthermore, RLM shows more accurate in prediction of relapse and aGVHD compared with KLM in both aGVHD and relapse. (aGHVD: p=0.009; RR: p=0.039). After taking activating KIR (aKIR) into consideration to compensate the defect of only inhibitory KIR (iKIR) dominant model, we found that patients with more donor activating KIRs can reach the lower incidence of aGVHD and relapse, and the benefit can gradually increase parallel with the increase in donor activating KIRs. (aGVHD：p=0.019；RR：p=0.037). Patients with both receptor-ligand mismatch and the most donor aKIRs can reach the lowest relapse, lowest incidence of aGVHD and best overall survival (OS). Conclusions: KIR-mismatch, both KLM and RLM significantly reduced the risk of aGVHD and relapse after halpo-HSCT in AML patients and RLM show more superiority in the prediction of HSCT outcome. The synergistic effects of receptor-ligand mismatch and more donor aKIRs can provide a better clinically applicable donor selection strategy to improve haplo-HSCT outcome in AML patients. DisclosuresHu: Astellas Pharma, Inc.: Research Funding.

Predictive Factors and Outcomes after Allogeneic Stem-Cell Transplantation for Adults with Acute Lymphoblastic Leukemia in Brazil

Introduction: Allogeneic stem-cell transplantation (HSCT) remains a potentially curative approach for acute lymphoblastic leukemia (ALL), especially for high-risk patients and those with relapsed/refractory disease, although its efficacy is offset by a not negligible toxicity. Adult patients with ALL fare worse in developing countries with low data about the HSCT in this setting. In this study, we aim to describe outcomes and examine risk factors for overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and graft-versus-host disease (GVHD) after 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. Kaplan-Meier method and competing risk analysis were used. Multivariable analysis (MVA) was performed using Cox regression and the Akaike's information criteria was used for model selection. Cut-offs for continuous variables were calculated through “findcut” R function. Center effect was evaluated by using frailty model.Results: Overall, 275 patients were included with a median age of 31y (range, 16-65). Philadelphia chromosome was found in 35%. Baseline characteristics are summarized in Table 1. 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. Total body irradiation (TBI) was used in 67% of myeloablative HSCT. Median time to HSCT in CR1 was 7.8 months. Engraftment failure rate was 1.5%. Median follow-up time was 6.4 y. Cumulative incidence of acute grade II-IV and chronic GVHD were 54.2% and 26.2%, respectively. In MVA, the use of MUD (HR=2.3) and increased donor age (HR=1.02) were associated with GVHD. Five-year CIR was 28.1% (95% CI 22.9-33.6) and 5-y NRM was 34.1% (95% CI 28.4-39.8). At D+100, NRM incidence was 22.6%. Central nervous system involvement at the diagnosis (HR=2.2), and disease status (HR 1.8 for CR2+, and HR 7.9 for refractory) increased relapse incidence, whereas the use of peripheral blood graft (HR=0.51) and haploidentical donor (HR=0.4) significantly decreased relapse incidence. In MVA, NRM was increased by patient's age (HR=1.04), refractory status (HR=4.2), MUD (HR=3.8) and donor age (HR=1.02). Center effect was significantly associated with relapse and NRM. Five-year OS and DFS were 40.7% (95% CI 35.1-47.1) and 37.8% (95% CI-32.3-44.1), respectively (Figure 1). Patient's age, donor age and disease status were independently associated with OS and DFS (Table 2). When GVHD (as a time-dependent variable) was introduced in the MVA for OS and DFS, it was associated with decreased OS (HR 4.2, p<0.001) but not with DFS. Pre-HSCT positivity of minimal residual disease (>0.01%) was associated with worse DFS in univariate analysis (HR=1.47) in available cases.Conclusions: This is the largest series of ALL adults receiving HSCT from Brazil. While OS and DFS were similar to published data, NRM was higher. Patient's age and donor age outweighed donor type or graft source in our analysis. Interestingly, haploidentical HSCT related to lower CIR, whereas the use of MUD was associated with higher NRM and GVHD rates. These results impact on donor selection strategy in our country, aiming to timely offer HSCT for high-risk ALL patients in our setting. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Abstract 2712: Donor selection strategies to optimize humanized mouse models for the evaluation of T cell engagers

Abstract The success of early cancer immunotherapies has led to the development of novel therapeutic approaches including multi-specific antibodies engaging innate and adaptive effector cells. To evaluate the antitumor potency of these multi-specific cell engagers, we have established a protocol to select human PBMCs from donors of a commercial frozen source by their potency to produce inflammatory cytokines and the capacity to engraft into NOD-Scid IL2Rgammanull (NSG)mice. The selected human PBMCs were used to reconstitute NSG mice, or as donors of effector cells that upon in vitro expansion were adoptively transferred to NSG mice for humanization. We have employed these humanization strategies to evaluate T cell engagers, which are typically multi-specific antibodies directed against the T cell and one or multiple tumor-associated antigen (TAA), whose therapeutic strategy is to 1) engage T cells, 2) activate the T cells and 3) engage tumor cells, and thus induce tumor cell killing. We will present representative data from several humanization approaches using liquid and solid orthotopic tumor models to assess the effectiveness of multi-specific T cell engagers in mediating antitumor responses. Thus, pre-clinical evaluations rely on the development of optimized tumor bearing humanized models that mirror key properties of a human setting, to assess the therapeutic potential of anti-tumor multi-specific biologics. Citation Format: Liqing Cheng, Jane Chen, Qunyan Yu, Natalia Malkova, Virna F. Cortez-Retamozo, Fangxian Sun, Sukhvinder Sidhu. Donor selection strategies to optimize humanized mouse models for the evaluation of T cell engagers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2712.

Safety and Threshold Analysis of Preoperative Platelets in Right Lobe Living Donors for Liver Transplantation

BackgroundLow perioperative platelet count is a powerful independent risk factor for posthepatectomy liver failure. Usually, categorical effect of thrombocytopenia was taken into account; upper thresholds were not studied in depth, exclusively in living liver donors. MethodsLiving liver donors who underwent right hepatectomy were included. Preoperative characteristics of donors were identified and examined to predict posthepatectomy liver failure. To eliminate selection bias, one-to-one propensity score matching was performed. ResultsThere were a total of 139 living donors and 40 (29%) donors developed posthepatectomy liver failure in the aftermath of the operation. Remnant liver volume ratio and preoperative platelet count were identified as adjustable independent risk factors (OR: 0.89 and 0.99, 95% CI: 0.79–0.99 and 0.98–0.99, respectively). After propensity score matching, odds ratio of preoperative platelet count was 0.99 (95% CI: 0.98–1.00). ConclusionsPreoperative platelet count, in addition to remnant liver volume ratio, can be used as a surrogate marker to predict the risk of posthepatectomy liver failure in living liver right lobe donors. Probability curves figured out from logistic regression analysis, in this regard, provided an explicit perspective of platelets having a decisive role on liver donor safety. Thus, remaining in safer remnant liver volume ratio limits with respect to preoperative platelet count should be addressed in safe donor selection strategies.