Human Leukocyte Antigen Matching Research Articles

Grasping time - longevity of vascularized composite allografts.

Despite significant advancements in the field of vascularized composite allotransplantation, challenges, particularly regarding the long-term viability and functionality of vascularized composite allotransplantation (VCA) grafts, persist. This paper provides a review of the current literature on the longevity of VCA grafts, focusing on factors influencing graft survival, immunological considerations and clinical outcomes. Longevity of VCA grafts is influenced by a variety of peri- and postoperative factors including cold ischemia time, human leukocyte antigen matching, environmental exposure, psychosocial factors, adherence, immunosuppression, and complications. Due to the limited number of VCA transplants performed and heterogenous reporting, direct correlation of single factors with VCA outcomes remains inconclusive. Indirect evidence, however, supports their importance. High immunosuppressive burden, frequent occurrence of acute and accumulating cases of chronic rejection remain a significant challenge of the field. Insights gained from this review aim to inform clinical practice and guide future research endeavors with the goal of ameliorating outcomes after VCA transplantation and facilitate wider use of VCA grafts for restoration of tissue defects.

Basiliximab induction alone vs a dual ATG-basiliximab approach in first live-donor non-sensitized kidney transplant recipients with low HLA matching.

Individualizing induction therapy based on immunological risk is crucial for optimizing outcomes in kidney transplantation. A retrospective analysis included 157 first live-donor non-sensitized kidney transplant recipients (KTRs). Within this cohort, 96 individuals exhibited low human leukocyte antigen (HLA) matching (5-6 HLA mismatches). The low HLA match subgroup was categorized into 52 KTRs receiving basiliximab alone and 44 recipients treated with a combined single ATG dose of 1.5mg/kg and basiliximab. The primary endpoint was early acute cellular rejection (ACR) within 6months post-transplant while secondary outcomes encompassed infection rates, renal allograft function, length of stay (LOS) and readmissions post-transplant. The incidence of early ACR was decreased for low HLA match KTRs, who received ATG-basiliximab, when compared with low HLA-matched KTRs who received basiliximab alone (9.1% vs 23.9%, P=.067). Age was a predictor for rejection, and subgroup analysis showed consistent rejection reduction across age groups. No significant differences were observed in admission for transplant LOS or in peri-operative complications, nor in infections rate including BK and cytomegalovirus viremia, allograft function and number of readmissions post-transplant up to 6months post-transplant. In non-sensitized first live-donor KTRs with low HLA matching, a dual ATG-basiliximab induction approach significantly reduced early ACR without compromising safety.

Human Leukocyte Antigen Mismatching and Survival in Contemporary Hematopoietic Cell Transplantation for Hematologic Malignancies.

PURPOSEHuman leukocyte antigen (HLA) mismatching can reduce survival of patients with blood cancer after hematopoietic cell transplantation (HCT). How recent advances in HCT practice, in particular graft-versus-host disease (GVHD) prophylaxis by post-transplantation cyclophosphamide (PTCy), influence HLA risk associations is unknown.PATIENTS AND METHODSThe study included 17,292 unrelated HCTs with 6-locus high-resolution HLA typing, performed mainly for acute leukemia or related myeloid neoplasms between 2016 and 2020, including 1,523 transplants with PTCy. HLA risk associations were evaluated by multivariable Cox regression models, with overall survival (OS) as primary end point.RESULTSOS was lower in HLA mismatched compared with fully matched transplants (hazard ratio [HR], 1.23 [99% CI, 1.14 to 1.33]; P < .001). This was driven by class I HLA-A, HLA-B, HLA-C (HR, 1.29 [99% CI, 1.19 to 1.41]; P < .001) but not class II HLA-DRB1 and HLA-DQB1 (HR, 1.07 [99% CI, 0.93 to 1.23]; P = .19). Class I antigen-level mismatches were associated with worse OS than allele-level mismatches (HR, 1.36 [99% CI, 1.24 to 1.49]; P < .001), as were class I graft-versus-host peptide-binding motif (PBM) mismatches compared with matches (HR, 1.42 [99% CI, 1.28 to 1.59]; P < .001). The use of PTCy improved GVHD, relapse-free survival compared with conventional prophylaxis in HLA-matched transplants (HR, 0.77 [0.66 to 0.9]; P < .001). HLA mismatching increased mortality in PTCy transplants (HR, 1.32 [1.04 to 1.68]; P = .003) similarly as in non-PTCy transplants (interaction P = .43).CONCLUSIONClass I but not class II HLA mismatches, especially at the antigen and PBM level, are associated with inferior survival in contemporary unrelated HCT. These effects are not significantly different between non-PTCy compared with PTCy transplants. Optimized HLA matching should still be considered in modern HCT.

The Impact of Donor-Recipient Human Leukocyte Antigen Matching on Bronchiolitis Obliterans-Free Survival Among Lung Transplant Recipients With Connective Tissue Diseases.

The development of connective tissue disease-associated lung diseases (CTD-LD) occurs in association with specific human leukocyte antigens (HLA). For CTD-LD patients who require lung transplant, it is unknown whether utilization of donor organs expressing these same HLA impacts posttransplant outcomes. Using the Scientific Registry of Transplant Recipients, we assessed whether CTD-LD lung transplant recipients in the United States have worse bronchiolitis obliterans (BOS)-free survival based on the degree of donor HLA matching. This included overall degree of donor-recipient HLA matching, donor-recipient matching at DR loci, and recipient matching with specific donor HLA antigens associated with the development of pulmonary disease in their condition. Among 1413 patients with CTD-ILD, highly HLA-matched donor-recipients did not have worse adjusted survival (hazard ratio [HR]=0.93, 95% confidence interval [CI]=0.58-1.51, p=0.77). Recipients who were fully matched at HLA DR did not have worse survival (HR=0.82, 95% CI=0.56-1.19, p=0.29). Finally, among individual CTD-LD, including rheumatoid arthritis, systemic sclerosis, the idiopathic inflammatory myopathies, and systemic lupus erythematous, transplant with a donor expressing HLA antigens associated with lung manifestations in these conditions was not associated with worse BOS-free survival. Among transplant recipients with CTD-LD, HLA donor-recipient matching, including at the DR loci, does not result in worse BOS-free survival. Based on these findings, there is no reason to treat these as unacceptable antigens when considering donor offers for CTD-LD candidates.

Orchestrating the Impact of KIR/HLA Interactions on Kidney Transplant.

This study examines the interplay between human leukocyte antigen (HLA) compatibility and killer-cell immunoglobulin-like receptor (KIR) genotypes in influencing kidney transplantation outcomes. Understanding these interactions is crucial for improving graft survival and minimizing rejection risks. We evaluated 84 kidney transplant recipients, dividing them into two groups based on post-transplant outcomes: there were 68 with stable graft function (SGF) and 16 who experienced chronic rejection (CR). Patients were selected based on specific inclusion criteria. HLA mismatches (Class I: HLA-A, -B; Class II: HLA-DR) and KIR genotypes were determined using standard genotyping techniques. Statistical analyses, including logistic regression, were performed to correlate these factors with transplant outcomes. Significant age differences were observed, with younger patients more likely to experience graft rejection, while no significant gender-based differences were noted. A significant correlation was found between Class II mismatches and increased rejection rates, highlighting the importance of HLA-DR compatibility. Further analysis revealed that certain inhibitory KIRs, such as KIR3DL1, were associated with favorable outcomes, suggesting a protective role against graft rejection. These findings were corroborated by evaluating serum creatinine levels over multiple years, serving as a biomarker for renal function post transplant. This study underscores the critical need for meticulous HLA matching and the consideration of KIR genotypes in pre-transplant evaluations to enhance graft survival and minimize rejection risks. Integrating these genetic factors into routine clinical assessments could significantly improve personalized transplant medicine strategies, ultimately enhancing patient outcomes. Further research is needed to explore the underlying mechanisms and validate these findings in larger, diverse populations.

Improved outcomes of ABO-incompatible living donor liver transplant with biologically related donors.

Liver transplantation is considered to be the only curative treatment for decompensated liver disease. Shortage of liver allografts is a major impediment to the widespread application of this procedure. ABO-incompatible (ABO-I) grafts have been used successfully, thereby increasing the living donor liver transplantation (LDLT) donor pool. However, ABO-I liver transplantation is associated with complications like acute liver rejection, hepatic artery thrombosis, and higher biliary stricture rates, leading to transplant failure, retransplantations, or sepsis-related complications. Various desensitization strategies have been adopted to improve outcomes. Biologically related donor-recipient pairs have the theoretical advantage of favorable HLA (human leukocyte antigen) match. We have analyzed the outcomes of ABO-I LDLT and compared the results of HLA-matched (biologically related) and HLA-unmatched (biologically unrelated) donor-recipient pairs. Retrospective data of 90 cases of ABO-I liver transplant recipients: HLA-matched (n = 35) and HLA-unmatched (n = 55) for comparison of preoperative and postoperative data. Peak bilirubin levels in HLA-unmatched recipients were higher. Platelet count was lower than HLA-matched recipients (7.3 vs. 8.9mg/dL). No significant difference in days-to-normal bilirubin, peak International Normalised Ratio, hospital stay, and discharge-day from transplant between both groups. Postoperatively, HLA-unmatched recipients required more pulse-steroids therapy than HLA-matched: 21/55 (38.2%) versus 11/35 (31.4%). Biliary complications and interventions were more prevalent in the HLA-unmatched group (12/55, 21.8%) than in the HLA-matched group (4/35, 11.4%). Renal complications requiring postoperative hemodialysis were more prevalent in the HLA-unmatched group than the HLA-matched group (9/55 [16.4%] vs. 3/35 [8.6%]). The incidence of vascular complications was similar. ABO-I LDLT is an effective and safe method for increasing the donor pool in the absence of an ABO-compatible liver donor. Long-term outcomes of recipients with biologically related donors are marginally better than biologically unrelated ABO-I LDLT recipients. However, the incidence of antibody-mediated graft rejection and biliary complications is higher in biologically unrelated ABO-I liver recipients.

Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis Attenuates Disparity in Outcomes Between Use of Matched or Mismatched Unrelated Donors.

PURPOSEAccess to allogeneic hematopoietic cell transplantation (HCT) remains limited among persons of non-European ancestry if human leukocyte antigen (HLA) matching is required. We evaluated whether post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis improved HCT outcomes with HLA-matched unrelated donor (MUD) and mismatched unrelated donor (MMUD) HCT when compared with calcineurin inhibitor (CNI)-based prophylaxis.METHODSThree-year overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were compared between adult recipients undergoing initial MUD or single HLA locus MMUD HCT with either PTCy- or CNI-based prophylaxis who were reported to the Center for International Blood and Marrow Transplant Research between 2017 and 2021.RESULTSIncluded were 10,025 HCT recipients (7,272 recipients of MUD with CNI, 1,681 MUD with PTCy, 613 MMUD with CNI, and 459 MMUD with PTCy) who underwent HCT for acute leukemia (70.9%) or myelodysplastic syndromes (29.2%). Median patient age was 60.7 years (range, 18.0-82.7) and median follow-up was 36.6 (range, 3.0-77.8) months. When compared with MUD HCT with PTCy, MMUD HCT with PTCy had similar OS (hazard ratio [HR], 0.96 [95% CI, 0.823 to 1.11]; P = .60) and GRFS (HR, 0.90 [0.79 to 1.02]; P = .1). When compared with MUD HCT with CNI, OS was improved after MUD HCT with PTCy (HR, 0.88 [0.80 to 0.96]; P = .004) and GRFS was improved with PTCy after either MUD (HR, 0.61 [0.57 to 0.66]; P < .0001) or MMUD (HR, 0.68 [0.60 to 0.76]; P < .0001) HCT. Benefit from PTCy was independent of patient ancestry. Global registry level analysis demonstrated that inclusion of MMUD increased donor availability regardless of recipient ancestry.CONCLUSIONUse of PTCy results in comparable OS and GRFS using either MUD or MMUD HCT, expanding access to HCT for patients from all racial and ethnic ancestry groups.

Preimplantation Genetic Testing for HLA Matching (PGT-HLA) When Only Partial Embryo Matches are Identified

Introduction: Preimplantation Genetic Testing (PGT) is an option for couples to select embryos that have a matching Human Leukocyte Antigen (HLA) type to a child that is in need of hematopoietic stem cell transplant (HSCT). Families in search of HLA-matched donors for HSCT may have a difficult time finding publicly available optimal donors or donors within their families. The likelihood of a family finding an optimal donor can vary from 16% to 75%, depending on ethnic and racial groups. Previously, PGT-HLA has been used to identify potential future siblings who would be an HLA match to an affected child through embryo testing as early as 2001 for conditions like Fanconi Anemia. PGT-HLA can be complicated by the presence of recombination within the HLA complex on chromosome 6 in the affected individual. If an affected child is found to be recombinant within the HLA complex (6-7% of PGT-HLA cases), the chances of finding a full sibling-matched donor can be extremely low. PGT for partial HLA matching can be used when the affected child is found to be recombinant or if a full parental match is not possible. When a child is identified as recombinant in the HLA region, consultation with their transplant team can determine whether a partial sibling match would be a good therapeutic candidate. PGT-HLA is performed by linkage analysis which requires DNA samples from the oocyte source, sperm source, and the affected child. These results will determine shared parental regions of the HLA complex genes so that partial matches can be identified. Case Reviews: We present two cases of PGT-HLA where only partial matches were identified during embryo testing. Of these 2 cases, both families completed one testing cycle for PGT-M and PGT-HLA and both had partial matches that were recommended for transfer per patient consent. One family had 3 partial match embryos, but they did not have a successful pregnancy following frozen embryo transfer. However, during the period of their transfers, they were able to find an adequate publicly-matched donor for HSCT therapy for their child. In one family, only a paternal HLA match was sought due to advanced maternal age of the mother. Consultation with the family’s transplant team indicated that a paternal-only match would be sufficient for a therapeutic effect. Conclusions: Despite the complexity of testing for PGT-HLA matching for a child where a full sibling match is not available embryo testing can still provide a therapeutic benefit. Interdisciplinary consultation in these cases would optimally include the couple, the affected child’s transplant team, the couple’s reproductive endocrinologist, and genetic counseling available at the PGT laboratory or the REI office. As accessibility to PGT continues to grow and as guidelines for PGT acceptability continue to be written, PGT-HLA should similarly find more usage. Inevitably, partial embryo matches will be seen and we will continue to learn how these can be used in clinical practice.

Association of HLA B- and T-cell molecular mismatches with HLA antibodies, rejection, and graft survival in pediatric kidney transplantation.

Optimizing graft survival and diminishing human leukocyte antigen (HLA) sensitization are essential for pediatric kidney transplant recipients. More precise HLA matching predicting epitope mismatches could reduce alloreactivity. We investigated the association of predicted HLA B- and T-cell molecular mismatches with the formation of de novo donor-specific antibodies, HLA antibodies, rejection, and graft survival. Forty-nine pediatric kidney transplant recipients transplanted from 2009 to 2020 were retrospectively studied. Donors and recipients were high-resolution HLA typed, and recipients were screened for HLA antibodies posttransplant. HLA-EMMA (HLA Epitope MisMatch Algorithm) and PIRCHE-II (Predicted Indirectly ReCognizable HLA Epitopes) predicted the molecular mismatches. The association of molecular mismatches and the end-points was explored with logistic regression. Five recipients (11%) developed de novo donor-specific antibodies. All five had de novo donor-specific antibodies against HLA class II, with four having HLA-DQ antibodies. We found no associations between PIRCHE-II or HLA-EMMA with de novo donor-specific antibodies, HLA sensitization, graft loss, or rejection. However, we did see a tendency towards an increased odds ratio in PIRCHE-II predicting de novo donor-specific antibodies formation, with an odds ratio of 1.12 (95% CI: 0.99; 1.28) on HLA class II. While the study revealed no significant associations between the number of molecular mismatches and outcomes, a notable trend was observed - indicating a reduced risk of dnDSA formation with improved molecular match. It is important to acknowledge, however, that the modest population size and limited observed outcomes preclude us from making definitive conclusions.

O236: The Impact of HLA Matching on Pancreas and Simultaneous Pancreas-Kidney (SPK) Transplantation Outcomes

Abstract Background This study evaluates the controversial impact of human leukocyte antigen (HLA) matching on pancreas graft survival and acute rejection. Methods Utilizing a large-scale multi-center database (UNOS/OPTN), we identified 8,005 pancreas and 7,850 simultaneous pancreas-kidney (SPK) transplant patients. Patients were classified into HLA matched (0-3 mismatches) and mismatched (4-6 mismatches) groups. Subsequently, utilizing multivariate Cox analysis, we evaluated risk-adjusted outcomes, represented through Kaplan-Meier survival curves. We also examined differences in graft survival and acute rejection based on transplant type (SPK or pancreas alone) within the same HLA mismatch group. Findings There were no significant differences in pancreas graft survival or acute rejection observed between HLA matched and mismatched groups for both pancreas and SPK transplant recipients (P &amp;gt; 0.05). However, among HLA mismatched patients, pancreas patients exhibited a 629-day lower pancreas graft survival than SPK patients (3774 vs. 4403 days, P &amp;lt; 0.001) and had a higher likelihood of experiencing acute rejection post-transplant (P &amp;lt; 0.001). Similarly, within the HLA matched groups, pancreas patients showed lower graft survival compared to SPK patients (3774 vs. 4403 days, P &amp;lt; 0.001); however, their acute rejection rates did not significantly differ (P &amp;gt; 0.05). Interpretation Although HLA matching was not associated with improved pancreas graft survival or a reduction in acute rejection, the results suggest a potential protective effect of the kidney in SPK transplants against the consequences of HLA mismatching. This underscores the clinical significance of considering the kidney component in donor-recipient matching for pancreas transplantation.

O204: The influence of HLA matching on graft survival in lung transplant recipients is indication specific: An UNOS database analysis

Abstract Background and aims The importance of human leukocyte antigen (HLA) matching in lung transplantation remains unclear, and the influence of indication in HLA compatibility is unknown. This study aimed to determine the relationship between HLA matching and lung graft survival using a large-scale multi-center database (UNOS/OPTN) and multivariate logistic analysis. The secondary aim was to determine whether this relationship was influenced by transplant indication. Methods This retrospective observational analysis was performed using 26,312 lung transplant recipients from the UNOS/OPTN database. Patients were divided into two groups based on number of HLA mismatches (0-3 mismatches vs 4-6 mismatches) and then subcategorized by indication. Risk-adjusted outcomes were assessed by multivariate Cox analysis adjusting for donor and recipient characteristics and visualized using Kaplan-Meier survival curves. Results Increased HLA mismatch was associated with reduced allograft survival. Adjusted models found that the total HLA mismatch &amp;gt;3 increased the mortality hazard at 15 years (HR 1·05, p &amp;lt;0·05) and 20 years (HR 1·05, p&amp;lt;0·01). Pulmonary hypertension was the only indication with a statistically significant association between HLA mismatch and graft survival. Allografts in patients with 0-3 mismatches survived for 401 days longer than those with 4-6 mismatches (p=0·02). Conclusion Increased HLA mismatch reduced graft survival. When stratified by indication, this association was preserved exclusively in pulmonary hypertension. This finding is of potential clinical relevance to the management of this subsection of lung transplant recipients, impacting organ allocation, transplant surveillance and use of desensitisation and immunosuppression protocols.

O203: HLA Matching Between Donors and Recipients Improves Clinical Liver Transplant Graft Survival

Abstract Background and Aims The importance of human leukocyte antigen (HLA) matching between liver transplant donors and recipients on graft survival remains unclear and is not a clinical consideration in liver transplantation. This study aimed to determine the relationship between HLA matching and liver graft survival using a large-scale multi-center database (UNOS/OPTN) and multivariate logistic analysis. The secondary aim was to determine whether this relationship was influenced by transplant indication and donor status. Methods This retrospective observational analysis was performed using 22,702 liver transplant recipients from the UNOS/OPTN database. Patients were divided into two groups based on number of HLA mismatches (0-3 mismatches vs 4-6 mismatches), and then subcategorized by indication and donor status. Risk-adjusted outcomes were assessed by multivariate Cox analysis adjusting for donor and recipient characteristics and visualized using Kaplan-Meier survival curves. Results Allograft survival and risk of acute rejection were associated with degree of HLA mismatch. This association between HLA mismatch and graft survival persisted in individuals who underwent transplant for hepatitis, metabolic, drug toxicity and congenital indications. Donor status influenced the relationship between HLA mismatch and graft survival. Graft survival in DBD recipients was longer than in DCD in the 4-6 HLA mismatch group, whereas no significant difference was found in the 0-3 HLA mismatch group. Conclusion HLA mismatch significantly reduced graft survival and increased risk of acute rejection. This association was noted only in specific indications. These findings are of potential clinical relevance to organ allocation, allograft matching algorithms, immunosuppression protocols and transplant surveillance.

Expression of Rejection-Associated Transcripts in Early Protocol Renal Transplant Biopsies Is Associated with Tacrolimus Exposure and Graft Outcome.

Subclinical inflammation in protocol biopsies relates to tacrolimus exposure and human leukocyte antigen (HLA) matching. We aimed to characterize transcripts associated with rejection and tacrolimus exposure and the latter's association with transplant outcomes. We tested whether gene expression is associated with rejection using strictly normal protocol biopsies (n = 17) and biopsies with T cell-mediated rejection (TCMR) or antibody-mediated rejection (ABMR) according to Banff criteria (n = 12). Subsequently, we analyzed these transcripts in a set of 4-month protocol biopsies (n = 137) to assess their association with donor and recipient characteristics, the intensity of immunosuppression, and the graft outcome. Differential expression (false discovery rate (FDR) < 0.01, fold (change (FC) > 3) between normal and rejection biopsies yielded a set of 111 genes. In the protocol biopsy cohort (n = 137), 19 out of these 111 genes correlated with tacrolimus trough levels at the time of biopsy (TAC-C0), and unsupervised analysis split this cohort into two clusters. The two clusters differed in donor age and tacrolimus trough levels. Subclinical rejection, including borderline lesions, tended to occur in the same cluster. Logistic regression analysis indicated that TAC-C0 at the time of biopsy (OR: 0.83, 95%CI:0.72-0.06, p = 0.0117) was associated with cluster 2. In a follow-up averaging 70 ± 30 months, this patient group displayed a significant decline in renal function (p = 0.0135). The expression of rejection-associated transcripts in early protocol biopsies is associated with tacrolimus exposure and a faster decline in renal function.

DQB1 antigen matching improves rejection-free survival in pediatric heart transplant recipients

IntroductionPresence of donor-specific antibodies (DSAs), particularly to class II antigens, remains a major challenge in pediatric heart transplantation. Donor-recipient human leukocyte antigen (HLA) matching is a potential strategy to mitigate poor outcomes associated with DSAs. We evaluated the hypothesis that antigen mismatching at the DQB1 locus is associated with worse rejection-free survival. MethodsData was collected from Scientific Registry of Transplant Recipients for all pediatric heart transplant recipients 2010-2021. Only transplants with complete HLA typing at the DQB1 locus for recipient and donor were included. Primary outcome was rejection-free graft survival through 5 years. ResultsOf 5,115 children, 4,135 had complete DQB1 typing and were included. Of those, 503 (12%) had 0 DQB1 donor-recipient mismatches, 2,203 (53%) had 1, and 1,429 (35%) had 2. Rejection-free survival through 5 years trended higher for children with 0 DQB1 mismatches (68%), compared to those with 1 (62%) or 2 (63%) mismatches (pairwise p=0.08 for both). In multivariable analysis, 0 DQB1 mismatches remained significantly associated with improved rejection-free graft survival compared to 2 mismatches, while 1 DQB1 mismatch was not. Subgroup analysis showed the strongest effect in non-Hispanic Black children and those undergoing retransplant. ConclusionMatching at the DQB1 locus is associated with improved rejection-free survival after pediatric heart transplant, particularly in Black children, and those undergoing retransplant. Assessing high-resolution donor typing at the time of allocation may further corroborate and refine this association. DQB1 matching may improve long-term outcomes in children stabilized either with optimal pharmacotherapy or supported with durable devices able to await ideal donors.

Reduced human leukocyte antigen mismatching is associated with more favourable outcomes after unrelated donor haematopoietic stem cell transplantation.

The patient-donor human leukocyte antigen (HLA) match remains the most important prognostic factor for successful unrelated donor haematopoietic stem cell transplantation (UD-HSCT). This single-centre study comprised 125 adult patients with malignant haematological diseases undergoing their first UD-HSCT. The primary goal of this study was to validate the impact of HLA matching on HSCT outcomes, specifically at the HLA-DPB1 and HLA-DRB3/4/5 loci. A multivariable Cox regression analysis with a backward selection algorithm was employed to assess the associations of selected prognostic factors with outcomes after UD-HSCT. Any HLA locus mismatch was found to be associated with an increased incidence of grade II-IV acute graft versus host disease (aGvHD) at 100 days (p=.031; hazard ratio [HR] 1.935) and 6 months (p=.004; HR 2.284) after HSCT. The results of the following analyses also confirmed the strong impact of HLA-DPB1-only mismatch on the incidence of grade II-IV aGvHD at 100-day (p=.006; HR 2.642) as well as at 6-month (p=.007; HR 2.401) time periods. The HLA-DPB1-only mismatch was also shown to be statistically significantly associated with lower relapse incidence (p=.034; HR 0.333). The impact of the HLA-DRB3/4/5 mismatch on outcomes was inconclusive, though the two and more HLA-DPB1+DRB3/4/5-only mismatches showed a trend towards worse outcomes than a single mismatch. Based on our findings and those of more comprehensive studies, the extended HLA loci typing of patients and donors is suggested to avoid unexpected HLA mismatches during the UD selection.

Program Report: Expanding the Deceased Donor Pool in Manitoba With an Age-Targeted Kidney Transplant Program.

The ongoing shortage of organs for transplant combined with the highest prevalence of end-stage kidney disease (ESKD) in Canada has resulted in long wait times for a deceased donor transplant in Manitoba. Therefore, the Transplant Manitoba Adult Kidney Program has ongoing quality improvement initiatives to expand the deceased donor pool. This clinical transplant protocol describes an age-targeted program intended to increase the use of transplants with a kidney donor profile index (KDPI) >85 by allocating them to suitable pre-consented recipients age ≥65 with low wait times. The goal is to improve survival and quality of life for older recipients by maximizing a previously under-utilized donor pool. Scoping literature review; Transplant Manitoba deceased donor audit; and key stakeholder engagement with patient partners, inter-disciplinary health care providers, and health system leaders. The alternative donor pool criteria include deceased donor kidneys with KDPI 86-100 or another concern for graft longevity but are otherwise suitable for transplantation. Patients with no living donor, age ≥65, low wait times and otherwise eligible for transplant listing will be educated, and if suitable, pre-consented for the age-targeted program. All patients remain eligible for a standard criteria donor according to the local allocation criteria. The age-targeted program waitlist follows the same provincial allocation rules using wait time, panel reactive antibody (PRA), and human leukocyte antigen (HLA) match points for determining rank order. If an age-targeted recipient experiences early graft loss from a KDPI 86-100 kidney within 12 months from transplant, their cumulative wait time, including time with the transplant, will be reinstated upon relisting. Transplant Manitoba's provincial allocation rules do not permit bypassing top of the list recipients for kidney offers; therefore, transplant providers were previously reluctant to utilize KDPI 86-100 donor kidneys to top of the list recipients eligible for higher quality kidneys. This age-targeted program facilitates allocation of KDPI 86-100 kidneys to suitable older pre-consented recipients with low wait times, who may obtain a survival and quality of life benefit from these transplants. This approach expands the utilized deceased donor pool to benefit all Manitobans awaiting a deceased donor kidney transplant. This program was launched in January 2023, and there are no data reported on outcomes given the small numbers and abbreviated follow-up. The goal of this quality improvement project is to improve access to deceased donor kidney transplantation for Manitobans with ESKD. This program was developed with patient and provider feedback, including multimedia patient education materials which may be helpful for other programs. We anticipate this program is a safe and effective way to expand access to deceased donor kidney transplantation using a previously under-utilized donor pool.

Randomized controlled trial of pre-transplant zoledronate versus observation for prevention of bone loss in allogeneic hematopoietic cell transplantation.

Approximately half of allogeneic hematopoietic cell transplantation (HCT) recipients experience significant bone loss in the early post-HCT period. Only recently have international guidelines started recommending early screening. However, the guidance for intervention remains conservative. In this study, we sought to evaluate the efficacy of pre-transplant prophylactic zoledronate in preventing early bone loss in allogeneic HCT recipients. This was an open-label, investigator-initiated, phase 2 randomized controlled trial (RCT) of prophylactic zoledronate versus observation to prevent bone loss in allogeneic HCT recipients. Recipients aged ≥ 18 years of age were included after informed consent and randomized to prophylactic zoledronate 4 mg pre-HCT or observation in a 1:1 ratio. The primary outcome of the study was bone mineral density (BMD) loss at the femoral neck (FN), total hip (TH), and lumbar spine (LS), as assessed using dual-energy X-ray absorptiometry (DXA) on day+100 post-HCT. The secondary outcomes included BMD loss on day+365 and Z scores on day+100 and day+365 at the FN, TH, and LS sites. The trial was terminated because the interim analysis showed a significant benefit in the intervention arm, with 50% planned recruitment. A total of 40 patients were randomized to the zoledronate and control arms. Both arms were matched for age, sex, diagnosis, pre-HCT steroid exposure, body mass index, human leukocyte antigen (HLA) match, and conditioning intensity. The grade 2-4 acute graft versus host disease (GVHD) incidences were comparable. The primary endpoint of BMD loss at FN and TH at day+100 was significant (5.62% vs. -6.78%, p = 0.009, -1.59 vs. -3.98, p = 0.016, respectively). There was no difference in the secondary endpoint of BMD loss on day+365 compared to that on day+100 or baseline at any BMD site. There was no difference in the Z-scores at any site on day+100 or day+365. Prophylactic zoledronate prevented early bone loss on day+100. The indicated preemptive zoledronate beyond day+100 in recipients prevented further bone loss. Patients receiving prophylactic zoledronate may benefit from a supplementary dose of the indicated preemptive zoledronate.

Abstract A081: Patient-derived xenograft models from hematological malignancies for preclinical drug development and biomarker research

Abstract Background: Acute leukemias and lymphomas encompass a diverse group of hematologic malignancies, posing significant challenges in clinical practice. They often exhibit resistance to standard-of-care (SoC) treatments and have a high recurrence rate. Recent advancements in molecular profiling have identified potential drivers for various leukemia and lymphoma subtypes, offering new therapeutic targets. However, the validation of these targets and the development of drugs rely heavily on preclinical models that faithfully represent the different clinical subtypes. These models play a crucial role in refining target selection and facilitating drug development projects. Methods: AML- and ALL-PDX were derived from bone marrow aspirates or peripheral blood samples, from primary or relapsed acute leukemia patients. Purified cells were transplanted either intravenously (i.v.) and/or subcutaneously (s.c.) into immunodeficient mice. Some mice developed a systemic AML, which was monitored by flow cytometric analysis of blood samples. Non-Hodgkin (NHL) - or Hodgkin lymphoma (HL)-PDX were derived from peripheral blood, lymph node extirpations or core needle biopsies, and were usually transplanted subcutaneously into immunodeficient mice. Results: More than 45 PDX models from AML, ALL, NHL and HL have been successfully established and characterized. Highly individual response rates to SoC and investigational drugs were observed and correlated with mutation and gene expression data. An individual Human Leucocyte Antigen (HLA) profile of each PDX was determined by RNA-seq and a comprehensive HLA matching analysis of the models and peripheral blood mononuclear cell (PBMC) donors was performed to enable personalized, preclinical immuno-oncology studies. Conclusions: Our extensively characterized PDX models derived from hematologic malignancies serve as valuable tools for evaluating novel targeted and immunological therapies. These models provide an exceptional platform for identifying and validating new targets, as well as preclinical screening of compounds and combinations for translational research projects in this field. Citation Format: Antje Siegert, Bernadette Brzezicha, Stephan Fuhrmann, Martin Janz, Clemens Schmitt, Ulrich Keller, Christian Rupp, Wolfgang Walther, Jens Hoffmann. Patient-derived xenograft models from hematological malignancies for preclinical drug development and biomarker research [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A081.

Chimeric antigen receptor natural killer cells: a promising antitumor immunotherapy.

Chimeric antigen receptor (CAR) T cells have been successfully used in adoptive cell therapy for malignancies. However, some obstacles, including side effects such as graft-versus-host disease and cytokine release syndrome, therapy resistance, limited sources, as well as high cost, limited the application of CAR T cells. Recently, CAR natural killer (NK) cells have been pursued as the effector cells for adoptive immunotherapy for their attractive merits of strong intrinsic antitumor activity and relatively mild side effects. Additionally, CAR NK cells can be available from various sources and do not require strict human leukocyte antigen matching, which suggests them as promising "off-the-shelf" products for clinical application. Although the use of CAR NK cells is restrained by the limited proliferation and impaired efficiency within the immunosuppressive tumor microenvironment, further investigation in optimizing CAR structure and combination therapies will overcome these challenges. This review will summarize the advancement of CAR NK cells, CAR NK cell manufacture, the clinical outcomes of CAR NK therapy, the challenges in the field, and prospective solutions. Besides, we will discuss the emerging application of other immune cells for CAR engineering. Collectively, this comprehensive review will provide a valuable and informative summary of current progress and evaluate challenges and future opportunities of CAR NK cells in tumor treatment.

Unsupervised Clustering Analysis of Regimen and HLA Characteristics Identifies Subgroups with Improved Relapse-Free Survival in Children with ALL and AML Undergoing Umbilical Cord Blood Transplantation

Introduction. Umbilical cord blood transplantation (UCBT) is an efficacious therapeutic intervention for pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). However, contention persists regarding how best to achieve long-term relapse-free survival (RFS). Differences in clinical practice can be attributed to an incompletely understood interplay between graft-versus-leukemia (GvL) effect and graft-versus-host disease (GvHD), as well as an incomplete understanding of how UCBTs differ from those of other stem cell sources. Human leukocyte antigen (HLA) matching is a critical determinant of post-transplant outcome, but factors such as GvHD prophylaxis and total body irradiation (TBI) usage also play a key role. Objective. To use unsupervised clustering algorithms to examine the interplay between HLA matching, immunosuppressive regimens, and conditioning factors with greater power than that conferred by conventional multivariate regression analyses. Methodology. Data pertaining to UCBTs performed for pediatric ALL (n = 908) and AML (n = 417) between 2004 and 2022 was obtained from the Eurocord/EBMT registry. ALL and AML UCBTs were separately subjected to a partitioning around medoids clustering algorithm, which identified k = 15 ALL clusters and k = 11 AML clusters. These clusters were used to form hypotheses for post-hoc testing, which were tested using Kaplan-Meier and competing risks analyses. Results. Clusters of both diseases were frequently divided by usage of ATG, which was administered in 77% of 8/8 ABCDR matched UCBTs. ALL and AML patients who did not receive ATG experienced greater RFS than recipients of ATG, and this appeared to be driven by elimination of relapse mortality in the late (≥5 year) post-transplant setting (Figs 1-2). ALL clusters were frequently divided by use of total body irradiation (TBI), and those featuring TBI regimens conferred RFS comparable or superior to non-TBI regimens; this appeared to be driven by a reduction in relapse mortality within the first three years post-UCBT (P = 0.007). In AML but not ALL, both HLA-C and KIR match levels appeared to be relevant (P = 0.04), despite typing only having been performed for 70% and 24% of AML UCBTs, respectively. Patients receiving a 7/8 ABCDR-matched graft with a single HLA-C mismatch experienced significantly poorer RFS than 8/8 matched UCBTs (P = 0.04), but a concomitant single co-mismatch at HLA-A or HLA-B appeared to restore RFS to levels comparable to 8/8 matched grafts. Conclusions. ATG is over-used in ALL and AML patient-graft pairings where risk of non-relapse mortality (NRM) is low, and this may be creating an avoidable risk of relapse. The conflicting results in published literature may be explained by follow-up time, as the effect does not become apparent until 5 years post-UCBT and many studies do not follow patients beyond this. Incorporation of TBI into ALL myeloablative regimens prevents relapse mortality in the early to mid-post UCBT setting, and this effect was independent of HLA matching. These findings align with the known genetic and biological determinants of these diseases and redouble the importance of typing at HLA-C in AML; administration of TBI in ALL; and a measured approach to the usage of ATG.