BACKGROUND:Subsequent neoplasms (SN) are serious late complications after umbilical cord blood transplantation (UCBT). However, population-based comparisons of the incidence and outcomes of SN between Japan and Europe are lacking. OBJECTIVES:To compare the incidence, types, and outcomes of subsequent neoplasms after unrelated UCBT between Japan and Europe. METHODS:We conducted a retrospective registry-based study using data from the Japanese Society for Transplantation and Cellular Therapy/Japanese Data Center for Hematopoietic Cell Transplantation and Eurocord/European Society for Blood and Marrow Transplantation. Patients who underwent unrelated UCBT between 1998 and 2018 and later developed SN were included in this study. Patients with Fanconi anemia, Diamond-Blackfan anemia, solid tumors as the primary disease, or those who received combined grafts were excluded. Overall survival (OS) was assessed using the Kaplan-Meier method. RESULTS:Among 16,241 (Japan) and 10,358 (Europe) UCBT recipients, 527 (3.2%) and 232 (2.2%) developed SN. The incidence of donor-derived acute leukemia/myelodysplastic syndrome (AL/MDS) was higher in Japan (58%) than in Europe (13%). Solid tumor types differed, with upper gastrointestinal cancers being more frequently observed in Japan (20% versus 5%), while skin (14% versus 8%), thyroid (14% versus 4%), and soft tissue tumors (9% versus 1%) were more common in Europe. Five-year OS after post-transplant lymphoproliferative disorder was significantly higher in Japan than in Europe (48% versus 23%, P < .001), whereas after solid tumors and AL/MDS, it was comparable between the two groups. CONCLUSIONS:Marked regional differences exist in SN type and prognosis after UCBT. The observed variations in donor-derived leukemia and solid tumor types underscore the importance of tailored region-specific surveillance strategies for long-term post-transplant care.

Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by macrocytic anemia and physical malformations. The only available curative treatment for patients with DBA is hematopoietic cell transplantation (HCT). Previous studies have included umbilical cord blood transplantation (UCBT) alongside other graft sources. We conducted a retrospective analysis of 41 pediatric patients with DBA who underwent related or unrelated UCBT between 1994 and 2023, using data from the Eurocord/EBMT registry. Twenty patients received related and 21 received unrelated single UCBT. Most patients received myeloablative conditioning and were transplanted after 1999. In related UCBT, median follow-up was 144.8 months, neutrophil engraftment at day +42 was 100% and 5-year overall survival (OS) was also 100%. In unrelated UCBT, median follow-up was 34 months, neutrophil engraftment at day +42 was 90%, and 5-year OS was 66%. The incidence of acute graft-versus-host disease (GvHD) was considerably higher among unrelated UCBT recipients. The incidence of chronic GvHD was similar between the two cohorts; however, extensive disease was more common after unrelated UCBT. UCBT from an HLA-identical sibling should be considered for DBA patients given the favorable short- and long-term outcomes. For the remaining patients, unrelated UCBT could be considered after individualized risk-benefit assessement.

ABSTRACT:During double umbilical cord blood transplant (DUCBT), the winning unit (WU) rejects the losing unit (LU) because of WU T cells directed against the LU mismatched HLA. This immune response might protect against relapse, especially when the patient and LU (PT-LU) share the same mismatch with the WU. To validate this hypothesis, a retrospective Eurocord study, conducted on 383 DUCBTs, focused on posttransplant relapse and HLA mismatches between PT-LU and the WU. A PT-LU HLA-A mismatch shared with the WU was associated with a lower 7-year relapse incidence (16% vs 28%; P = .048). In addition, multiple PT-LU shared HLA mismatches were also associated with a lower relapse risk (7% vs 29%; P = .003). In DUCBT with ≥2 HLA mismatches between patient and WU, the number of HLA mismatches between those did not significantly affect relapse incidence, whereas multiple PT-LU shared HLA mismatches remained associated with a lower relapse risk (7% vs 29%; P = .0038). Finally, considering patients who did not develop either grade 2 to 4 acute graft-versus-host disease or chronic graft-versus-host disease, a PT-LU shared HLA-A mismatch as well as multiple PT-LU HLA mismatches shared with the WU remained associated with a significantly lower 7-year relapse incidence. In multivariate adjusted analyses multiple PT-LU shared HLA mismatches remained associated with a significantly reduced 7-year posttransplant relapse risk. Our analysis indicates that, during DUCBT, PT-LU shared HLA mismatches prime an immune response of the WU against leukemia, reducing the long-term risk of posttransplant relapse, and that DCBT has particular utility in those with high-risk leukemia.

HLA matching is a critical factor in allogeneic unrelated hematopoietic cell transplantation (HCT) because of its impact on post-transplantation survival and quality of life. Umbilical cord blood transplantation (UCBT) offers unique advantages, but determining the optimal approach to graft selection and immunosuppression remains challenging. Unsupervised clustering, a machine learning technique, has potential for analyzing transplantation outcomes, but its application in investigating leukemia outcomes has been limited. This study aimed to identify optimal combinations of HLA/ killer immunoglobulin receptor (KIR) donor-patient pairing, conditioning, and immunosuppressive regimens in pediatric patients with acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML) undergoing UCBT. Outcome data for single, unmanipulated UCBT in pediatric AML (n = 708) and ALL (n = 1034) patients from the Eurocord/EBMT registry were analyzed using unsupervised clustering. Resulting clusters were used to inform post hoc competing risks and Kaplan- Meier analyses. In AML, single HLA-C mismatches with other loci fully matched (7/8) were associated with poorer relapse-free survival (RFS) (P = .039), but a second mismatch at any other locus counteracted this effect. In ALL, total body irradiation (TBI) effectively prevented relapse mortality (P = .007). KIR/HLA-C match status affected RFS in AML (P = .039) but not in ALL (P = .8). Administration of antithymocyte globulin (ATG) substantially increased relapse, with no relapses occurring in the 85 patients who did not receive ATG. Our unsupervised clustering analyses generate several key statistical and mechanistic hypotheses regarding the relationships between HLA matching, conditioning regimens, immunosuppressive therapies, and transplantation outcomes in pediatric AML and ALL patients. HLA-C and KIR combinations significantly impact RFS in pediatric AML but not in ALL. ATG use in fully matched pediatric patients is associated with late-stage relapse. TBI regimens appear to be beneficial in ALL, with efficacy largely independent of histocompatibility variables. These findings reflect the distinct genetic and biological profiles of AML and ALL.

Background HLA mismatches adversely impact transplant outcomes by increasing the risk of graft-versus-host disease (GVHD) and rejection. In leukemic relapse after haplo-identical transplant, the mismatched HLA-haplotype is deleted, indicating that HLA might be involved in graft-versus-leukemia (GVL) responses. In adult cord blood transplants (CBT), relapse is reduced after HLA-mismatched compared to matched grafts. During double CBT, one cord emerges as the “winning unit” (WU). ) Based on earlier translational observations (Lamers CH et al BLOOD 2011 (117) and Cornelissen JJ et al Stem Cell Investigation 2017 (26), we hypothesised that unit predominance may be HLA-restricted and if the losing unit (LU) and recipient share the same HLA mismatch with the WU, the same T-cell response that mediates the rejection of the LU will also be directed at the leukemic clone, reducing the relapse risk. Methods Retrospective study by Eurocord, Royal Manchester Children's Hospital and the Cellular Therapy & Immunobiology Working Party of EBMT. Eligibility: Patients (children and adults) with acute leukemia or myelodysplastic syndrome (MDS) who engrafted after unrelated double CBT transplant at EBMT centers between 2005 and 2022, with no in-vivoT cell depletion, available HLA data and known WU. We analysed the impact of disease, patient and CBT characteristics on relapse and other CBT outcomes. The influence of HLA-mismatch on CBT outcomes considered classical typing (HLA-A,-B and -DRB1), with HLA-C, and whether the recipient and LU shared an HLA mismatch not present in the WU. HLA typing was compared at low resolution for class I HLA and high resolution for HLA-DRB1. Results In 383 eligible CBTs, median follow-up of surviving patients was 71.5 months and median year of CBT was 2012. Median age at CBT was 42.9 years, 59.8% of patients were male; most had acute leukemia (n=344; AML n=102; ALL n=232), 57.5% and 30.4% were in CR1 or CR2, respectively. Most received reduced intensity conditioning (RIC) regimens (56.5%) and total body irradiation (90%). Considering the most mismatched unit, 64% transplants were 4/6, 3% were 5/6 and only 1% were 6/6 (HLA-A, -B and -DRB1). Including HLA-C, 41% were 6/8, 32% were 5/8, 12.5% were 7/8 and 0.5% were 8/8. In 49% cases there was an HLA-mismatch in the WU to a specificity shared between the LU and the patient. This mismatch was at HLA-A in 17.8% transplants, at -B in 15.1%, at -C in 20.1% and at -DRB1 in 12.3%, and possibly at multiple loci simultaneously. Relapse was increased in multivariate analysis (MVA) in those with leukemia rather than MDS, in those with AML rather than ALL, in those with RIC regimen, and in those transplanted before 2013. In univariate analysis (UVA), relapse was reduced where the recipient and LU shared the same mismatch with the WU at HLA-A (16% vs 28%, p=0.08) or HLA-B (15% vs 28%, p=0.07), but not HLA-C (22% vs 27%, p=0.48) or -DRB1 (28% vs 26%, p=0.82). If the mismatch was at either HLA-A or -B (combined in the same variable) relapse was reduced compared to other mismatches (16% vs 30%; p=0.027). The same effect (not statistically significant), was observed in MVA with a 35.5% decrease in risk where there was a shared mismatch in HLA-A or -B between patient and LU. In MVA, HLA-mismatches showed no effect in acute GVHD which was only increased in those receiving myeloablative conditioning or were cytomegalovirus (CMV) positive. A shared mismatch between LU and recipient did not influence GVHD risk. For chronic GVHD, there was no influence of HLA mismatch, but a decreased risk was observed in older subjects and those transplanted before 2013. Of note, UVA showed decreased incidence of chronic GVHD where the recipient and LU shared an HLA-DRB1 mismatch against the WU. Discussion CBT is associated with reduced relapse in those with acute leukaemia compared to other cell sources, likely mediated by an augmented GVL response in a transplant that is more often HLA-mismatched and is performed T-cell replete. In this series of double CBT, we provide data that support an HLA-restricted response directed at the LU by the WU, mediated by either HLA-A or HLA-B. This will reduce relapse if the disease bears the same mismatch (LU primes the immune response against the disease). There is no increase in GVHD with HLA mismatching in CBT, but there is a tendency for decreased chronic GVHD if the LU and patient share the same HLA-DRB1 mismatch against the WU.

Hematopoietic cell transplantation (HCT) remains the sole available curative treatment for Fanconi anemia (FA), with particularly favorable outcomes reported after matched sibling donor (MSD) HCT. This study aimed to describe outcomes, with a special focus on late complications, of FA patients who underwent umbilical cord blood transplantation (UCBT). In this retrospective analysis of allogeneic UCBT for FA performed between 1988 and 2021 in European Society for Blood and Marrow Transplantation (EBMT)-affiliated centers, a total of 205 FA patients underwent UCBT (55 related and 150 unrelated) across 77 transplant centers. Indications for UCBT were bone marrow failure in 190 patients and acute leukemia/myelodysplasia in 15 patients. The median age at transplantation was 9 years (range, 1.2 to 43 years), with only 20 patients aged >18 years. Among the donor-recipient pairs, 56% (n = 116) had a 0 to 1/6 HLA mismatch. Limited-field radiotherapy was administered to 28% (n = 58) and 78% (n = 160) received a fludarabine (Flu)-based conditioning regimen. Serotherapy consisted of antithymocyte globulin (n = 159; 78%) or alemtuzumab (n = 12; 6%). The median follow-up was 10 years for related UCBT and 7 years for unrelated UCBT. Excellent outcomes were observed in the setting of related UCBT, including a 60-day cumulative incidence (CuI) of neutrophil recovery of 98.1% (95% confidence interval [CI], 93.9% to 100%), a 100-day CuI of grade II-IV acute graft-versus-host disease (GVHD) of 17.3% (95% CI, 9.5% to 31.6%), and a 5-year CuI of chronic GVHD (cGVHD) of 22.7% (95% CI, 13.3% to 38.7%; 13% extensive). Five-year overall survival (OS) was 88%. In multivariate analysis, none of the factors included in the model predicted a better OS. In unrelated UCBT, the 60-day CuI of neutrophil recovery was 78.7% (95% CI, 71.9% to 86.3%), the 100-day CuI of grade II-IV aGVHD was 31.4% (95% CI, 24.6% to 40.2%), and the 5-year CuI of cGVHD was 24.3% (95% CI, 17.8% to 32.2%; 12% extensive). Five-year OS was 44%. In multivariate analysis, negative recipient cytomegalovirus serology, Flu-based conditioning, age <9 years at UCBT, and 0 to 1/6 HLA mismatch were associated with improved OS. A total of 106 patients, including 5 with acute leukemia/myelodysplasia, survived for >2 years after UCBT. Nine of these patients developed subsequent neoplasms (SNs), including 1 donor-derived acute myelogenous leukemia and 8 solid tumors, at a median of 9.7 years (range, 2.3 to 21.8 years) post-UCBT (1 related and 8 unrelated UCBT). In a subset of 49 patients with available data, late nonmalignant complications affecting various organ systems were observed at a median of 8.7 years (range, 2.7 to 28.8 years) post-UCBT. UCB is a valid source of stem cells for transplantation in patients with FA, with the best results observed after related UCBT. After unrelated UCBT, improved survival was observed in patients who underwent transplantation at a younger age, with Flu-based conditioning, and with better HLA parity. The incidence of organ-specific complications and SNs was relatively low. The incidence of SNs, mostly squamous cell carcinoma, increases with time. Rigorous follow-up and lifelong screening are crucial in survivors of UCBT for FA. (c) 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Pocket motifs and their amino acid positions of HLA molecules are known to govern antigen presentation to effector cells. Our objective was to analyse their influence on the risk of graft-versus-host disease (GVHD) and relapse after umbilical cord blood transplant (UCBT). The transplant characteristics of 849 patients with acute leukaemia were obtained from the Eurocord/EBMT database. Higher acute (a) GVHD was associated with homozygosity of UCB HLA-C amino acid positions 77 and 80 (NN/KK) (p = 0.008). Severe aGVHD was associated with HLA-A pocket B YSAVMENVHY motif (p = 0.002) and NN and RR genotypes of the HLA-C amino acid positions 77 and 156 (p = 0.006 and p = 0.002). Such risk was also increased in case of recipient and UCB mismatches in P4 (p < 0.0001) and P9 (p = 0.003) pockets of HLA-DQB1 alleles. For chronic GVHD, the pocket B YYAVMEISNY motif of the HLA-B*15:01 allele and the absence of mismatch between recipient and UCB in the P6 pocket of HLA-DRB1 were associated with a lower risk (p = 0.0007 and p = 0.0004). In relapse, both UCB pocket B YFAVMENVHY belonging to HLA-A*32:01 and recipient pocket B YDSVGENYQY motif of the HLA-C*07:01 allele were associated with higher risk (p = 0.0026 and p = 0.015). We provide clues on HLA-mediated cellular interactions and their role in the development of GVHD and relapse.

Objectives NKG2D is an activating receptor expressed by natural killer (NK) and CD8+ T cells and activation intensity varies by NKG2D expression level or nature of its ligand. An NKG2D gene polymorphism determines high (HNK1) or low (LNK1) expression. MICA is the most polymorphic NKG2D ligand and stronger effector cell activation associates with methionine rather than valine at residue 129. We investigated correlation between cord blood (CB) NKG2D and MICA genotypes and haematopoietic stem cell (HSC) transplant outcome. Methods We retrospectively studied 267 CB HSC recipients (178 adult and 87 paediatric) who underwent transplant for malignant disease between 2007 and 2018, analysing CB graft DNA for NKG2D and MICA polymorphisms using Sanger sequencing. Multivariate analysis was used to correlate these results with transplant outcomes. Results In adult patients, LNK1 homozygous CB significantly improved 60-day neutrophil engraftment (hazard ratio (HR) 0.6; 95% confidence interval (CI) 0.4-0.9; p = .003). In paediatrics, HNK1 homozygous CB improved 60-day engraftment (HR 0.4; 95% CI 0.2-0.7; p = .003), as did MICA-129 methionine+ CB grafts (HR 1.7 95% CI 1.1-2.6; p = .02). Conclusion CB NKG2D and MICA genotypes potentially improve CB HSC engraftment. However, results contrast between adult and paediatric recipients and may reflect transplant procedure disparities between cohorts.

Fanconi Anemia (FA) remains a disease with poor prognosis for which hematopoïetic cell transplantation (HCT) offers the only available curative option, with particular good results observed after matched sibling donor transplants. This study aimed to assess transplant outcomes and describe late complications in a large cohort of patients with FA who underwent umbilical cord blood transplantation (UCBT) in the European Society for Blood and Marrow Transplantation (EBMT) affiliated centres. Methods: We retrospectively reviewed all cases of FA whoreceived UCBT as first allogeneic transplant between 1988 and 2021. Data on late effects were collected with a questionnaire completed by transplant centres for patients who survived >2 years (y) after UCBT. Results: A total of 205 patients with FA received UCBT (55 related and 150 unrelated) in 77 transplant centres. Indications for UCBT were bone marrow failure in 191 patients (BMF, 93%) and acute leukemia/myelodysplasia in 14 patients (AL/MDS, 7%). Median age at transplant was 8.8 y (1.2-43) and 90% (n=185) were children <18y old. Graft sources included single (n=164), double (n=23) or UCB co-infused with other cell sources (n=18). Recipients and UCB pairs had 0-1/6 HLA mismatches in 48% (n=99). Most patients (n=196, 97%) received reduced intensity conditioning. Flu Cy-based (n=116; 57%) and Bu Cy ± Flu (n=48, 23%) were the most frequently used regimens. Total body irradiation (TBI) or total lymphoid irradiation (TLI) were administered to 28% (n=58) of patients at doses < 8 Gy. Serotherapy consisted of anti-thymocyte globulin (ATG, n=159; 78%) or alemtuzumab (n=8; 4%). Graft- vs-host disease (GVHD) prophylaxis was mainly based on CSA ± steroids (65%) or MMF ± steroids (32%). Median follow-up was 88 months (3-345). The cumulative incidence (CI) of neutrophil recovery was 79% (67-79) at day 60,with a median time of 20 (7-62) days (d). The 100d CI of grades II-IV acute GVHD (aGVHD) was 29.8% (24-37). The 5y CI of chronic GVHD (cGVHD) was 30.4% (24-38) with 12% extensive forms. The 1y-CI of non-relapse mortality (NRM) was 37.4% (31-45). At 5y follow-up, event-free survival (EFS) was54% ± 3 and overall survival (OS) was 55% ± 3. In multivariate analysis, HLA matching 0-1/6 (HR 2.0, p=0.01) and related UCBT (HR 2.4; p=0.001) were predictive of better engraftment. None of the tested factors had statistical significant impact on incidence of aGVHD or cGVHD. Negative recipient CMV serology (HR 0.29, p=0.003) and transplant year ≥2013 (HR 0.29; p=0.004) were the only factors associated with improved OS. Both factors were also predictive of better NRM and EFS. Fifty-one recipients of UCBT (3 related and 48 unrelated) experienced primary graft failure (GF). Twenty-six patients underwent subsequent allogeneic HCT within a median of 1.8 months (0.8 -6.8) after first UCBT. Seven subsequent HCT recipients (1 related bone marrow (BM), 1 related peripheral blood, 1 unrelated BM, and 4 unrelated UCB) were alive at last follow-up. Second neoplasms developed in 8 patients (4%) within a median interval of 9.7 y post-UCBT (3.6-13.5) and included one donor derived-AML and 7 solidtumors (1 skin, 2 upper GI, 4 oral cavity) . A totalof93 patients (45%) died from transplant related toxicity (n=85, including 42 who died after GF), second neoplasms (n=6) or unknown cause (n=2). Survival >2y was observed in 106 patients, but comprehensive data for late transplant complications were available only in 45 long-term survivors. For these 45, median post transplant follow-up was 8.7y (2.7-28.8). Late organ impairments ( table 1) included: endocrine disorders (32%), lung (24%), eyes (20%), kidneys (20%), immune system (18%), liver (16%), musculoskeletal, and bone (16%) diseases. Other dysfunctions involved: oral mucosa (11%), neurologic system (7%), gastrointestinal (4%), genital (13%) and urinary tracts (4%). Cardiovascular complications were rare (1 case of chronic pericarditis). Conclusion: Improved outcomes have been observed in recent years in FA patients receiving unrelated UCBT likely due to improved conditioning regimens, effective post-transplant care and better HLA parity. With longer survival, late multi-organ complications are observed. Identification of risk factors and life-long screening for early management of organ impairments and second neoplasms are mandatory to improve quality of life of transplant survivors and decrease late mortality.

Four decades ago, Broxmeyer et al. demonstrated that umbilical cord blood (CB) contained hematopoietic stem cells (HSC) and hypothesized that CB could be used as a source of donor HSC for rescue of myeloablated bone marrow. In 1988, Gluckman et al. reported the first successful matched sibling cord blood transplant (CBT) in a child with Fanconi Anemia. In 1991, Rubinstein et al. established an unrelated donor CB bank, and in 1993, the first unrelated CBT used a unit from this bank. Since that time, >40 000 CBTs have been performed worldwide. Early outcomes of CBT were mixed and demonstrated the importance of cell dose from the CB donor. We hypothesized that improvements in CB banking and transplantation favorably impacted outcomes of CBT today and performed a retrospective study combining data from Eurocord and Duke University in 4834 children transplanted with a single unrelated CB unit (CBU) from 1993 to 2019. Changes in standard transplant outcomes (overall survival [OS], disease free survival [DFS], acute and chronic graft-versus-host disease [GvHD], treatment related mortality [TRM], and relapse) over 3 time periods (1: <2005; 2: 2005 to <2010; and 3: >2010 to 2019) were studied. Increased cell dose and degree of HLA matching were observed over time. OS, times to engraftment, and DFS improved over time. The incidence of TRM and GvHD decreased while the incidence of relapse remained unchanged. Relative contributions of cell dose and HLA matching to transplant outcomes were also assessed and showed that HLA matching was more important than cell dose in this pediatric cohort.

Abstract The genetic diversity of the human leukocyte antigen (HLA) system was shaped by evolutionary constraints exerted by environmental factors. Analyzing HLA diversity may allow understanding of the underlying pathways and offer useful tools in transplant setting. The aim of this study was to investigate the HLA haplotype diversity in patients with sickle cell disease (SCD, N = 282) or β‐thalassemia (β‐Thal, N = 60), who received hematopoietic cell transplantation (HCT) reported to Eurocord and the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM‐TC). We identified 405 different HLA‐A‐B‐DRB1 haplotypes in SCD and 108 in β‐Thal patients. Using data from African and European populations of the “1000 Genomes Project” for comparison with SCD and β‐Thal, respectively, we found that the haplotypes HLA‐A*30‐B*14‐DRB1*15 (OR 7.87, 95% CI: 1.66–37.3, pb = 0.035), HLA‐A*23‐B*08 (OR 6.59, 95% CI: 1.8–24.13, pb = 0.023), and HLA‐B*14‐DRB1*15 (OR 10.74, 95% CI: 3.66–31.57, pb = 0.000) were associated with SCD, and the partial haplotypes HLA‐A*30‐B*13 and HLA‐A*68‐B*53 were associated with β‐Thal (OR 4.810, 95% CI: 1.55–14.91, pb = 0.033, and OR 17.52, 95% CI: 2.81–184.95, pb = 0.011). Our results confirm the extreme HLA genetic diversity in SCD patients likely due to their African ancestry. This diversity seems less accentuated in patients with β‐Thal. Our findings emphasize the need to expand inclusion of donors of African descent in HCT donor registries and cord blood banks.

Subsequent neoplasms (SNs) compromise long-term survivors after hematopoietic cell transplantation. We performed a retrospective analysis of SNs in 10 358 recipients of umbilical cord blood transplantation (UCBT) from 1988 to 2018. SNs developed in 233 patients and 84 were of pediatric age. Indications for UCBT were malignant hematological diseases in 199 patients (85%). Three groups of SNs were observed. Posttransplant lymphoproliferative disorders (PTLD) were reported in 145 patients in a median of 4 months after UCBT. Of these, 9 patients died from relapse, 83 from PTLD, and 24 from transplant-related causes. At last follow-up, 29 were alive; 5-year overall survival (OS) after PTLD diagnosis was 21%. Acute leukemia/myelodysplasia (AL/MDS) was diagnosed in 23 patients in a median of 28 months after UCBT and included 3 donor-cell AL. Four of 23 patients died from relapse of primary disease, 8 from progression of SNs, and 4 from TRM. Seven patients remain alive; the 5-year OS after AL/MDS diagnosis was 36%. Solid tumors (ST) were reported in 65 patients in a median of 54 months after UCBT. Most common tumor sites were lung, thyroid, bone, and soft tissue. A total of 33 patients died (26 owing to ST, 6 to relapse of primary disease, and 1 cause missing). At last follow-up, 32 of 65 patients were alive; the 5-year OS after the diagnosis of ST was 51%. In conclusion, despite their poor outcomes, SNs that occur after UCBT are extremely rare. Identification of risk factors and early detection may help to improve OS.

To clarify the different characteristics and prognostic factors of cord blood transplantation (CBT) in adult patients with lymphoid neoplasms in Europe and Japan, we conducted a collaborative study. Patients aged 18-75 years receiving their first CBT (Europe: single CBT, n = 192; double CBT, n = 304; Japan: single CBT, n = 1150) in 2000-2017 were analyzed. Fewer patients with Hodgkin lymphoma (Europe vs Japan, 26% vs 5%), and older patients (>= 50 years) (39% vs 59%) with a higher refined disease risk index (rDRI) (high -very high: 49% vs 14%) were included in the Japanese registry. High -very high rDRI was associated with inferior overall survival (OS) (vs low rDRI, Europe: hazard ratio [HR], 1.87; P = .001; Japan: HR, 2.34; P < .001) with higher progression/relapse risks. Total body irradiation (TBI)-containing conditioning contributed to superior OS both in Europe (vs TBI-reduced-intensity conditioning [RIC], nonTBI-RIC: HR, 1.93; P < .001; non-TBI-Myeloablative conditioning [MAC]: HR, 1.90; P = .003) and Japan (non-TBI-RIC: HR, 1.71; P < .001; non-TBI-MAC: HR 1.50, P = .007). The impact of HLA mismatches (>= 2) on OS differed (Europe: HR, 1.52; P = .007; Japan: HR, 1.18; P = .107). CBT for lymphoid neoplasms, especially in those with high rDRI showed poor outcomes despite all the different characteristics in both registries. TBI should be considered in conditioning regimens to improve these outcomes. The different impacts of HLA mismatches call attention to the fundamental differences among these populations.

In single unrelated cord blood transplantation (UCBT), an increasing number of HLA allele mismatches (MM) has been associated with inferior overall survival (OS) and attributed to higher transplant-related mortality (TRM). Previous studies on the role of allele-level HLA matching after double UCBT (dUCBT) showed conflicting results. In this study, we report the impact of allele-level HLA matching on the outcomes of a large dUCBT cohort. We included 963 adults with hematologic malignancies, with available allele-level HLA matching at HLA-A, -B, -C, and -DRB1, receiving dUCBT between 2006 to 2019. Assignment of donor-recipient HLA match was performed considering the unit with the highest disparity with the recipient. Three hundred ninety-two patients received dUCBT with 0 to 3 MM and 571 with ≥4 allele MM. For recipients of dUCBT with 0 to 3 MM, day-100 and 4-year TRM were 10% and 23%, respectively, compared with 16% and 36% for those with ≥4 MM. A higher degree of allele MM was also associated with the worse neutrophil recovery and lower incidence of relapse; no significant effect on graft-versus-host disease was observed. Patients receiving units with 0 to 3 MM had a 4-year OS of 54% compared with 43% for those receiving units with ≥4 MM. The inferior OS associated with higher HLA disparity was only partially mitigated by increased total nucleated cell doses. Our results confirm that allele-level HLA typing is a significant factor for OS after dUCBT, and units with ≥4 MM (≤4/8 HLA-matched) should be avoided if possible.

Autism spectrum disorder (ASD) represents a set of heterogeneous neurodevelopmental conditions defined by impaired social interactions and repetitive behaviors. The number of reported cases has increased over the past decades, and ASD is now a major public health burden. So far, only treatments to alleviate symptoms are available, with still unmet need for an effective disease treatment to reduce ASD core symptoms. Genetic predisposition alone can only explain a small fraction of the ASD cases. It has been reported that environmental factors interacting with specific inter-individual genetic background may induce immune dysfunctions and contribute to the incidence of ASD. Such dysfunctions can be observed at the central level, with increased microglial cells and activation in ASD brains or in the peripheral blood, as reflected by high circulating levels of pro-inflammatory cytokines, abnormal activation of T-cell subsets, presence of auto-antibodies and of dysregulated microbiota profiles. Altogether, the dysfunction of immune processes may result from immunogenetically-determined inefficient immune responses against a given challenge followed by chronic inflammation and autoimmunity. In this context, immunomodulatory therapies might offer a valid therapeutic option. Mesenchymal stromal cells (MSC) immunoregulatory and immunosuppressive properties constitute a strong rationale for their use to improve ASD clinical symptoms. In vitro studies and pre-clinical models have shown that MSC can induce synapse formation and enhance synaptic function with consequent improvement of ASD-like symptoms in mice. In addition, two preliminary human trials based on the infusion of cord blood-derived MSC showed the safety and tolerability of the procedure in children with ASD and reported promising clinical improvement of core symptoms. We review herein the immune dysfunctions associated with ASD provided, the rationale for using MSC to treat patients with ASD and summarize the current available studies addressing this subject.

The association between acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) and the human leukocyte antigens (HLA) has rarely been studied in terms of diversity of peptide-binding pockets. The objective of this study was to analyse whether motifs of HLA class I and class II peptide-binding pockets and/or their amino acid positions were differentially associated with ALL and AML. We included 849 patients from the Eurocord/European Blood and Marrow Transplant registry. The HLA peptide-binding pockets whose amino acid variability was analysed were B and F for HLA class I, P4, P6, and P9 for HLA-DRB1, and P4 and P9 for HLA-DQB1. The motif RFDRAY in P4 of HLA-DRB1*16:01/02/03/05 alleles and the motif YYVSY in P9 of HLA-DQB1*05:02/04/05 alleles, were statistically associated with ALL (corrected p value [p(c)] = 0.001 and p(c) = 0.035 respectively). The frequency of serine 57 in the P9 of HLA-DQB1 was higher in ALL (odds ratio 2.09, 95% confidence interval: 1.27-3.44; p(c) = 0.037). Our analysis suggests that specific motifs in terms of HLA class II pockets and amino acids might be unique to ALL. The associations identified in this study encourage further investigation oF the role of HLA peptide-binding pockets and their amino acids in immune processes underpinning acute leukaemia and ultimately in immunotherapy settings.