Aplastic anemia (AA) is a bone marrow failure syndrome caused by aberrant immune responses and is associated with high mortality and poor prognosis, particularly in patients with severe AA (SAA) or transfusion dependent non severe AA (TD-NSAA). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been increasingly adopted in the treatment of AA and has yielded encouraging results. However, fewer than 30% of patients requiring allo-HSCT are able to identify a suitable matched sibling donor (MSD), thereby limiting the broader application of MSD-HSCT. In such cases, alternative donor sources, including matched unrelated donor (MUD) and haploidentical donor (HID), are considered viable options. While there has been reported a higher frequency of chronic graft-versus-host disease (GVHD) with MUD-HSCT and increased rates of poor graft function in haploidentical HSCT (Haplo-HSCT). Additionally, specific human leukocyte antigen (HLA) mismatches in MUD-HSCT have been implicated in heightened risks of severe acute GVHD and mortality. Thus, further clinical practice is required to optimize the strategy. Umbilical cord blood (UCB) has been shown to decrease mixed chimerism (MC) and relapse rates, enhancing the success of combination transplantation strategies. Based on this rationale, our center implemented a novel approach combining UCB transfusion with MUD-HSCT (MUD-cord-HSCT), a strategy that has received limited investigation both domestically and internationally. In this retrospective analysis, we compared the outcomes of MUD-cord-HSCT, MSD-HSCT, and Haplo-HSCT to identify a more effective and safer strategy. This study was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang Chinese Medical University (2024-KLS-706-01) and was registered at chictr.org.cn under #ChiCTR2500097159.

The date of AA patients who received HSCT at the First Affiliated Hospital of Zhejiang Chinese Medical University from January 2014 to December 2023 were retrospectively reviewed. All MUD-cord-HSCT patients were included, and patients who underwent MSD-HSCT or Haplo-HSCT were matched in a 1:1:2 ratio. All patients in the study received the FCA conditioning regimen, consisting of fludarabine (total dose of 150 mg/m²), cyclophosphamide (total dose of 120–200 mg/kg), and rabbit anti-human thymocyte globulin (total dose of 8–10 mg/kg). In the MUD-cord-HSCT group, UCB stem cells were infused on day 01, and peripheral blood stem cells (PBSCs) were administered on days 02 and 03. Both bone marrow and PBSCs were collected and infused in patients receiving transplants from MSD and HID.

A total of 104 patients were assigned to three groups: MUD-cord-HSCT (n = 26), MSD-HSCT (n = 26), and Haplo-HSCT (n = 52). The cohort comprised 54 males and 50 females, with a median age of 29 (range 9–55) years. Of these, 86 patients were diagnosed with SAA and 18 with TD-NSAA. There were no significant differences in median engraftment time, engraftment rate, graft failure rate, or poor graft function among the groups. The 3-year overall survival (OS) rates were 88.0% ± 6.5%, 92.1% ± 5.3%, and 74.8% ± 6.0% (P = 0.10), and the event-free survival (EFS) rates were 77.3% ± 9.4%, 92.1% ± 5.3%, and 69.0% ± 6.4% (P = 0.13) for the MUD-cord-HSCT, MSD-HSCT, and Haplo-HSCT groups, respectively. Fully HLA-matched MUD-cord-HSCT (FM-MUD-cord-HSCT) demonstrated superior OS (100%) and EFS (85.7% ± 13.2%) compared to Haplo-HSCT (P = 0.046, P = 0.049) and single HLA allele-mismatched MUD-cord-HSCT (SM-MUD-cord-HSCT, P = 0.04, P = 0.04). The incidence of MC was significantly lower in the MUD-cord-HSCT group compared to the MSD-HSCT group (0% vs. 24.48%, P = 0.01). FM-MUD-cord-HSCT was associated with a significantly lower rate of grade II–IV acute GVHD compared to SM-MUD-cord-HSCT (P = 0.02) and Haplo-HSCT (P = 0.048), as well as a reduced incidence of bloodstream infections (P = 0.003). Moreover, multivariate Cox regression analysis identified failed or poor engraftment as a significant risk factor for OS, while pulmonary infection emerged as an independent risk factor for EFS.

Considering the low incidences of MC, GVHD, and infections, along with favorable survival outcomes, HLA fully matched MUD-cord-HSCT demonstrated comparable efficacy and safety to those of MSD-HSCT. Our study suggests a potential superiority of FM-MUD-cord-HSCT over MSD-HSCT, though this observation requires validation through further clinical investigations.

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2025
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