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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., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Graft failure (GF) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HCT). In the absence of autologous recovery, a second HCT is necessary to attempt to prevent death due to prolonged pancytopenia. Previous studies describing outcomes of second HCT performed after GF with different types of donor sources report wide ranges of overall survival (OS) and transplantation-related mortality (TRM); however, studies including a large number of patients undergoing a second HCT with umbilical cord blood (UCB) as the graft source are scarce. This retrospective registry-based study examined data extracted from Eurocord and the European Society for Blood and Marrow Transplantation (EBMT) databases to evaluate outcomes of 247 UCBTs performed in EBMT transplant centers after GF following a previous HCT. Data were analyzed separately for patients with malignant diseases (n = 141) and those with nonmalignant diseases (n = 106). The most frequent HCT that resulted in GF was also UCBT (65.0% for patients with malignant diseases and 68.9% for those with nonmalignant diseases), and most GFs occurred within 100 days after transplantation (92.3% and 85.9%, respectively). The median follow-up was 47 months for surviving patients with malignant diseases and 38 months for those with nonmalignant diseases. We observed a similar cumulative incidence of neutrophil engraftment of 59.1% (95% confidence interval [CI], 51.4% to 67.9%) and 60.4% (95% CI, 51.7%-70.6%), respectively, at a median time of 23 days and 24 days, correspondingly. The 3-year OS was 28.9% (95% CI, 21.8% to 37.3%) in the malignant disease group and 49.1% (95% CI, 39.5%-58.8%) in the nonmalignant disease group. In patients with malignancies, TRM was 39.9% (95% CI, 32.5% to 49.1%) at 100 days and 57.5% (95% CI, 49.4%-66.8%) at 3 years. In multivariate analyses, none of the characteristics studied was statistically significantly associated with engraftment or OS. Although survival is not optimal in patients requiring a second HCT, UCBT remains a valid life-saving option for patients with GF., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to report., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)