Don't Cut the Cord: Why Umbilical Cord Blood Still Deserves a Place in Transplantation.

Introduction

Umbilical cord blood (UCB) first emerged as a possible stem cell source in the 1980s, when Broxmeyer et al. ( 1989 ) demonstrated in pre‐clinical studies that UCB contained sufficient haemopoietic stem cells (HSCs) to enable successful haematopoietic stem cell transplant (HSCT) and that these cells could be safely cryopreserved. From there, the first UCB transplant (UCB) was successfully performed in 1989 in a child with Fanconi anaemia (Gluckman et al. 1989 ). This landmark case demonstrated that UCB stem cells could achieve durable engraftment and established UCB as an alternate stem cell source for HSCT. Through international collaborative efforts, cord blood banks were established, enabling safe storage and rapid availability of stem cells for transplant, with an estimated 800,000 UCB units stored world‐wide in public banks and over 4 million in private banks (Dessels et al. 2018 ; Gluckman 2009 ). In general, UCB units stored in public banks are provided altruistically, in comparison to private banks which offer preservation of UCB stem cell products for future progeny (Roura et al. 2015 ).

UCB transplantation (UCBT) has been used as a source of HSCs for transplanting both adults and children for both malignant and non‐malignant disorders. Although a matched sibling donor (MSD) is the usual first choice of HSCT, only 30% of patients have this as an option, and so the role of alternate donors became important (Yao et al. 2013 ). UCB has unique practical and biologic properties that provide advantages over adult stem‐cell sources. From a practical perspective, as UCB is available off the shelf with details of human leukocyte antigen (HLA) typing ready to use in comparison to adult donors, the time between decision to transplant and the transplant itself is shorter (Gupta and Wagner 2020 ). This offers an advantage in patients with high‐risk leukaemia, where time to transplant is important. UCB also increases the donor diversity, making HSCT an option for patients who may not have a suitably matched unrelated donor (MUD) or MSD (Gupta and Wagner 2020 ). The composition of UCB includes a relatively naïve immune system, with lower levels of alloreactive T‐cells present within the graft. As a result, UCB enables greater tolerance of HLA mismatch and is associated with lower rates of chronic graft‐versus‐host disease (cGVHD) (Admiraal et al. 2016 ; Gupta and Wagner 2020 ). In addition, outcomes of UCBT in haematological malignancies have been shown to be comparable to those of related or unrelated donors.

Despite these benefits, the clinical use of UCB as a stem cell source has declined in recent years, largely because of the increased preference for mismatched unrelated donors (MMUDs) and haploidentical donors, together with post‐transplant cyclophosphamide (PTCy) as GVHD prophylaxis for patients without a related or unrelated fully matched donor (Auletta et al. 2024 ; Bolaños‐Meade et al. 2023 ; Shaw et al. 2021 ). The challenges with UCB are predominantly those related to cost and cell dose (Kelly et al. 2010 ). It is well documented that the total nucleated cell (TNC) dose transplanted per kilogram (kg) of body weight correlates with outcomes post‐transplant (Aldenhoven et al. 2015 ; Gluckman et al. 2004 ; Migliaccio et al. 2000 ). As a result, UCBT has been more successful in the paediatric population. Even within the paediatric population, there is a delay in engraftment compared with traditional stem cell sources (Chakrabarty et al. 2022 ; Kelly et al. 2010 ; Thomson et al. 2000 ). Increased costs of UCBT are largely attributed to prolonged admissions and supportive care requirements for delayed engraftment and engraftment failure (Kelly et al. 2010 ). However, these costs are likely offset by the reduced total treatment costs secondary to lower rates of cGVHD seen with UCB, which has been shown to increase healthcare costs by 1.5–2.0 times that of a patient without cGVHD (Avenoso et al. 2024 ; Michonneau et al. 2023 ). In addition, collection and banking of UCB have historically been higher than those associated with harvesting stem cells from alternate stem cell sources (Bart 2010 ; Roura et al. 2015 ).

This review will discuss the intrinsic properties of UCB that make it both a practical and advantageous stem cell source in patients with relapsed/refractory haematological malignancies. The greatest risk to survival in haematological malignancy remains relapse. In an era where MMUDs and haploidentical donors dominate practice, we will re‐examine the evidence to support the continued use of UCB, particularly for high‐risk or relapsed/refractory malignancies where time to transplant is critical and in whom current treatment outcomes are unacceptable.

UCBT Reduces Relapse in Patients With Malignant Disease

Although the literature exhibits significant heterogeneity in study characteristics, there have been many single‐institution and registry studies which have demonstrated improved relapse‐free survival in patients with malignant disease, compared with alternative donor transplants, including MMUD transplant; these are summarised in Table 1 .

Milano et al. ( 2016 ) retrospectively compared transplant outcomes in a cohort of 582 adult patients, in whom 140 received a UCBT, 344 received an MUD transplant and 98 received a transplant from an MMUD. Although the percentage of patients with minimal residual disease (MRD) at time of transplant was similar across the groups, the UCB group had a higher proportion of patients with high‐risk or very‐high‐risk disease. The 4‐year adjusted risk of relapse was significantly higher in the MUD and MMUD groups compared with the UCB group, and this risk was higher in those with MRD positivity pre‐HSCT. The study also demonstrated that among those with MRD, the UCB group had a significantly higher probability of survival compared to the MMUD group and at least as good as those of MUD.

Eapen et al. ( 2007 ) analysed HSCT data in paediatric patients with leukaemia from the Centre for International Blood and Marrow Transplant Research (CIBMTR). This registry study analysed data from 503 children with acute leukaemia who underwent UCBT in comparison with 282 children undergoing bone marrow MUD or MMUD transplants. Their data demonstrated that relapse rates were similar across all groups, except in two‐antigen mismatched UCBT group, for which relapse rates were significantly lower, suggesting a greater graft‐versus‐leukaemia (GVL) effect. Transplant‐related mortality (TRM) was similar across groups.

Takahashi et al. ( 2025 ) evaluated CIBMTR data on paediatric patients with acute myeloid leukaemia (AML) with a particular focus on relapse reduction by UCB. The study reported data on 1148 patients with AML who underwent first‐HSCT, including 388 undergoing UCBT, 233 MSD transplants, 84 mismatched‐related donor (MMRD) transplant, 323 MUD transplants and 120 MMUD transplants. Use of T‐cell depletion was not reported. Overall disease‐free survival (DFS) and overall survival (OS) between alternative donor sources for all levels of MRD were comparable; however, relapse rates were lower in < 5/8 UCBT compared with MUD. This benefit was offset by higher non‐relapse mortality (NRM). This again highlights the benefit of greater HLA disparity in UCBT as being beneficial secondary to its GVL effect. There is a close relationship in these studies between mismatch, GVHD, mortality and relapse reduction.

Keating et al. ( 2019 ) reported retrospective multicentre data on paediatric patients undergoing HSCT in complete remission. This study included 317 patients in which 61 had an MSD, transplant 73 received an MUD transplant, 122 received single unit UCBT and 61 received a double unit UCBT (DUCBT). Keating et al. ( 2019 ) reported the trend of a nearly 2‐fold relapse reduction with UCBT versus MUD.

Horgan et al. ( 2023 ) collected data from consecutive patients undergoing T‐replete UCBT for paediatric AML or myelodysplastic syndrome (MDS) across multiple centres and compared outcomes of patients undergoing T‐deplete UCBT with those undergoing transplant using any other cell source. A total of 112 patients undergoing T‐replete UCBT were compared with 136 MUDs, 63 MSDs, 36 MMUDs, 9 T‐deplete UCBT and 11 haploidentical donors. Multivariable analysis showed increased event‐free survival (EFS) and improved OS in the T‐replete UCBT group in those with AML at the highest risk of relapse, because of a massive reduction in relapse risk. When stratified by disease status, T‐replete UCBT had a significant reduction in relapse compared with other donor sources.

In contrast to the mentioned studies, Fuchs et al. ( 2021 ) reported results of the BMT CTN 1101 trial, which compared 368 adult patients with lymphoma or leukaemia in remission, who were randomly assigned to undergo UCBT or haploidentical transplant. Although the primary end point of 2‐year PFS was lower in the UCBT group compared with the haploidentical transplants (35% and 41%, respectively), the trial did not demonstrate a statistically significant difference between donor sources ( p = 0.41). It did demonstrate a lower 2‐year OS after UCB compared with haploidentical transplantation, 46% (95% CI, 38–53) and 57% (95% CI, 49%–64%), respectively ( p = 0.04).

The reduction in relapse rate in UCBT is likely due to an enhanced GVL effect that reflects that it is performed T‐cell replete and more often mismatched and T‐cells mediate GVL, and major mismatch is an important antigen in GVL. During haploidentical transplant, genomic loss of the mismatched HLA is found in greater than 30% of relapses (Vago et al. 2009 ). Use of in vivo T‐cell depletion risks losing this GVL effect and might be detrimental in curing patients with high‐risk disease, accounting for some of the differences described in this group of patients (Zheng et al. 2015 ). UCBT is often performed T‐cell replete and comprises a relatively naïve immune system, with lower levels of alloreactive T‐cells within the graft, permitting a greater tolerance of HLA mismatch than other cell sources (Gupta and Wagner 2020 ).

Rates of Acute GVHD Are Comparable With Other Donor Sources, But cGVHD Is Reduced in UCBT

The long‐term goal for all patients undergoing HSCT is disease‐free, GVHD‐free survival. GVHD can be either acute (aGVHD) or cGVHD, and both have significant impacts on morbidity and NRM (Lueck et al. 2023 ; Wynn et al. 2022 ). Literature regarding the incidence of aGVHD in UCBT compared with other donor sources is varied. aGVHD is higher in UCB compared with MSDs, with literature reporting rates of Grades II–IV aGVHD of between 35% and 50% (Ando et al. 2020 ; Keating et al. 2019 ; Konuma et al. 2016 ). aGVHD is similar between UCBT and MUD transplants in setting of bone marrow as cell source but reduced if peripheral blood stem cells (PBSCs) are used (Ando et al. 2020 ; Eapen et al. 2007 ; Rocha et al. 2001 ; Weisdorf et al. 2014 ). In comparison to MMUDs, UCBT is consistently reported as having a lower incidence of aGVHD (Mehta et al. 2019 ; Milano et al. 2016 ; Takahashi et al. 2025 ; Weisdorf et al. 2014 ). The literature comparing UCBT with haploidentical transplants is varied, with some evidence to support increased aGVHD in UCBT (Konuma et al. 2021 ; Wagner et al. 2021 ) and some data to suggest aGVHD rates are similar between the two (Ruggeri et al. 2015 ). Although aGVHD is seen frequently in UCBT, this does not translate into increased cGVHD.

cGVHD is a long‐term complication of HSCT that results in increased morbidity, mortality and reduced long‐term quality of life. The literature consistently reports lower rates of cGVHD in UCBT, even in the absence of the use of serotherapy, use of double UCB unit and in HLA‐mismatched settings. cGVHD in UCBT is also more likely to be corticosteroid responsive (Barker et al. 2017 ). Paediatric and adult data support lower rates of cGVHD compared with MSDs across both PBSC and bone marrow cell sources (Ando et al. 2020 ; Horgan et al. 2023 ; Konuma et al. 2021 ). Similarly, in comparison to MUD transplants, UCBT is consistently reported to have a lower incidence of cGVHD, with incidence ranging from 44%–53% to 5%–28%, respectively (Ando et al. 2020 ; Horgan et al. 2023 ; Keating et al. 2019 ; Rocha et al. 2001 ; Weisdorf et al. 2014 ). Even in the MMUD and haploidentical donor settings, rates of cGVHD are lower in UCBT (Horgan et al. 2023 ; Konuma et al. 2021 ; Mehta et al. 2019 ; Ruggeri et al. 2015 ; Takahashi et al. 2025 ; Weisdorf et al. 2014 ). These clinical findings have been replicated in xenograft models where the anti‐tumour or GVL effect of UCB T‐cells appears to be independent of xenoreactivity (Hiwarkar et al. 2015 ). The mechanism for which cGVHD is lower in UCBT compared with other donor sources is not well understood but suggests significant differences in the immunologic features of UCB, particularly of T‐cells.

UCB T‐Cells Mediate Enhanced Tumour Cytotoxicity

We contend that UCB decreases the risk of relapse in patients with high‐risk disease. We further propose that this positive outcome reflects that such transplants are performed T‐cell replete, they are frequently HLA mismatched and that UCB T‐cells are intrinsically different from adult T‐cells.

Hiwarkar et al. ( 2015 ) utilised xenograft models to compare UCB T‐cell activity with adult T‐cell activity in eliminating B‐cell lymphoma. UCB T‐cells demonstrated enhanced anti‐tumour responses compared with adult T‐cells, with increased CD8+ T‐cell recruitment to the tumour. Analysis of tumour‐infiltrating lymphocytes (TILs) demonstrated the predominant T‐cells recruited to the tumour were CCR7 + CD8+ T‐cells. The chemokine receptor CCR7 is a homing receptor for naïve T‐cells, and high levels of expression may provide CD8+ T‐cells with enhanced tumour‐homing abilities (Hiwarkar et al. 2015 ). UCB TILs were also shown to rapidly differentiate from naïve T‐cells to central memory and memory effector T‐cells. These UCB TILs also demonstrated a gain of cytotoxic effector function, with increased TNF‐a production and perforin expression. Interestingly, the anti‐tumour effect of UCB T‐cells was independent of xenoreactivity, as opposed to adult T‐cells, which was associated with xenoreactivity. This correlates with clinical observations that UCB has powerful GVL effects without an increase in cGVHD. HLA mismatching between UCB and adult T‐cells was comparable, suggesting there is an ontogeny difference in UCB T‐cells which enables them to not only rapidly reconstitute in the lymphopenic host post‐HSCT but also to rapidly infiltrate the tumour. UCBTs are more likely to have greater degrees of mismatch and be T‐replete, which may amplify this phenomenon. In summary, CD8+ T‐cells appear vital for the GVL effect observed post HSCT, and UCB possesses properties which enable enhanced recruitment of CD8+ T‐cells to the tumour, with prompt differentiation into memory effector cells and gain of cytotoxic functions at the tumour site. These antigen‐specific T‐cell responses are occurring early after transplant and despite intensive immunosuppression. Although many aspects of GVL are yet to be understood, it does highlight that UCB stem cells may be preferred over other stem cell sources for patients with high‐risk and/or relapsed/refractory disease.

UCB T‐Cells Have Different Reconstitution Kinetics Which Can Be Harnessed to Exaggerate the GVL Effect

There is accumulating evidence that UCB‐derived T‐cells display different functional properties to their adult counterparts. UCB without serotherapy (typically comprising agents such as anti‐thymocyte globulin and the anti‐CD52 monoclonal antibody alemtuzumab) results in rapid thymus‐independent T‐cell reconstitution, which is predominantly CD4+, as opposed to adult T‐cell‐replete HSCT which is CD8+ T‐cell‐biased (Chiesa et al. 2012 ; Hiwarkar et al. 2017 ). As discussed above, xenograft models have demonstrated rapid expansion and differentiation of UCB T‐cells from naïve cells to effector memory and CD8+ T‐cells, which appears important for GVL.

We serendipitously noted an early, massive CD8+ T‐cell expansion in patients receiving a pooled granulocyte product in the setting of significant infection (Hiwarkar et al. 2020 ). This observation was expanded in a Phase I/II clinical trial which aimed to investigate the reproducibility of this CD8+ T‐cell expansion and its ability to control disease through administration of granulocytes to paediatric patients undergoing T‐replete UCBT for very high‐risk leukaemia (Borrill et al. 2023 ). Following granulocyte administration, patients experienced rapid T‐cell expansion, which, in contrast to usual immune reconstitution post CBT, was predominantly CD8+. The CD8+ expansion was associated with increased expression of cytotoxic markers, including granzyme B, perforin and IFN‐γ, which correlates with observations in xenograft studies (Hiwarkar et al. 2015 ). Importantly, this CD8+ expansion was associated with induction of and sustained remission in patients with otherwise incurable leukaemia. Within this cohort, 90% of patients achieved haematological remission, 80% became MRD negative, and 50% remain alive and disease‐free over 1 year post‐follow‐up. It is potentially due to the pooled nature of these granulocytes from multiple donors that the exposure to a large number of Class‐I and Class‐II HLA molecules and the associated antigen is the stimulus for this T‐cell response.

Similarly, a current Phase II trial has been conducted in Seattle using a T‐cell‐depleted, ex vivo expanded and pooled cord product after an unmanipulated UCB unit. Similarly, there was an early surge of cytotoxic CD8+ T‐cells, with exceptionally low relapse rates and without any cGVHD, suggesting that in such UCB transplants there may be separation of GVL from GVHD (Milano et al. 2024 ).

UCB T‐Cell Responses Are Antigen‐Specific and These Responses Can Be Targeted to Increase GVL Effect and Induce Deeper Remission Post‐Transplant

The benefits of using a UCB unit that is T‐cell replete are that T‐cell responses can be induced early (as discussed above) and we may be able to direct those antigen‐specific responses through different strategies. Previous studies have demonstrated that in the case of DUCBT, 1 U predominantly engrafts (referred to as the ‘winning unit’ [WU]), and the other unit is lost (referred to as the losing unit [LU]) (Gutman et al. 2010 ; Purtill et al. 2014 ). It has been demonstrated that in such cases, the WU results in increased effector CD8+ (CD45RO +/− CCR7 − ) T‐cells with associated increased IFN‐γ production which results in failure of the LU graft (Gutman et al. 2010 ). These results support the theory that engraftment of the WU after double UCBT is due to immune‐mediated rejection of the LU driven by mismatch at one or more HLA alleles (Brunstein et al. 2016 ; Gutman et al. 2010 ; Verneris et al. 2009 ). We recently explored this concept further through a registry‐based study on DUCBT in patients with acute leukaemia or MDS by analysing post‐transplant relapse and HLA mismatches between the patient, the LU and the WU (Wynn et al. 2025 ). We found the risk of relapse was reduced only when the HLA mismatch was shared between the patient and the LU and with the WU. When the patient and the LU share multiple HLA mismatches with the WU, the relapse risk was significantly reduced (7% vs. 29%, p = 0.003). This suggests that when the patient and the LU share HLA mismatches against the WU, the WU's immune‐mediated rejection of the LU also promotes leukaemic rejection. The data from this study suggest that Class‐I mismatches, particularly HLA‐A is important for this GVL effect. Though previous studies have demonstrated a role for Class‐II mismatches in LU rejection (Lamers et al. 2016 ), it is likely that both may play a role, but their roles require further investigation. In relation to GVHD, there was no increase in aGVHD seen in association with the number of HLA mismatches between the patient‐LU and the WU. In conjunction with clinical observations, this GVL effect is not associated with increased cGVHD and was not associated with increased TRM. This has enormous potential for patients with high‐risk leukaemia, where if the WU unit can be selected for/predicted prior to transplant, an LU sharing host antigens not present on the WU may then be selected to enhance this GVL effect and improve RFS.

UCBT May Reduce Risk of Clonal Haematopoiesis Compared With Alternate Stem Cell Sources

Clonal haematopoiesis (CH) is the acquisition of somatic leukaemia‐associated mutations in haematopoietic stem cells (HSCs), without overt haematological malignancy (Nawas et al. 2021 ). CH has become increasingly studied as it has been shown to confer increased risk for development of haematologic cancer and cardiovascular disease (Abelson et al. 2018 ; Desai et al. 2018 ; Genovese et al. 2014 ). Genetic drivers of CH mutations have been demonstrated to involve genes encoding epigenetic regulators (DNMT3A, TET2, AXL1), DNA damage response proteins (TP53, PPM1D) and signalling proteins (JAK2) (Nawas et al. 2021 ). Emerging research on CH in post‐HSCT recipients has shown that CH mutations can be present in HSCT donors (even at young age); these CH mutations can engraft in the recipient, and the forced proliferation of HSCs causes DNA damage and telomere shortening which may further contribute to the evolution of CH (Boettcher et al. 2020 ; Gibson et al. 2022 ; Nawas et al. 2021 ; Wong et al. 2020 ). CH can affect any HSCT recipient but is of particular relevance in the paediatric population given their long life‐expectancy beyond the time of transplant.

A recent study by Müskens et al. ( 2025 ) in paediatric HSCT recipients demonstrated that older haematopoietic age and the HSCT procedure itself independently increased the risk of CH. The prevalence of CH was significantly increased as haematopoietic age increased. Though, of note, a single UCB was noted to have CH 15 years post‐transplant, suggesting that CH mutations may already be present at birth and then increase in an environment that favours their expansion, such as in HSCT. In relation to the transplant procedure itself, use of serotherapy with accompanying inflammation at time of graft infusion was associated with increased CH. Interestingly, there was no relationship observed between aGVHD and CH. Beyond the reasons already discussed in this review, UCB may confer additional benefit as a stem cell source by reducing haematopoietic age and often being performed without serotherapy, thus reducing risk of CH, which is particularly important for paediatric patients.

UCB Expansion Technologies Make UCB a Potential Stem Cell Source to All Patients Regardless of Weight or Age

One of the major historical limitations with UCB as a stem cell source is the low cell dose. Even in those with adequate cell dose, UCB is associated with delayed engraftment, prolonged cytopenia, increased viral infections and increased NRM (Wynn et al. 2022 ). If these issues could be resolved, then UCB could be the best stem cell source because of its low risk of relapse and reduced cGVHD.

Several studies have looked at overcoming the obstacle of low TNC cell dose through ex vivo expansion of UCB units (Meaker and Wilkinson 2024 ). The first expanded HSC product was Omisirge, which was approved by the United States (US) Food and Drug Administration (FDA) in 2023 (Meaker and Wilkinson 2024 ). Omisirge uses nicotinamide riboside, a form of B3 known to support HSC expansion through inhibition of deacetylase sirtuin, to expand UCB (Peled et al. 2012 ). In Phase I/II trials comparing Omisirge with unmanipulated UCB, Omisirge was shown to reduce time to neutrophil engraftment from 22 days to 12 days (Horwitz et al. 2019 ). Omisirge (omidubicel) was approved in the US for use in adults and children > 12 years for haematological malignancies undergoing UCBT to reduce incidence of infection and time to neutrophil recovery (Gandhi et al. 2023 ; Heo 2023 ). There are ongoing clinical trials exploring its role in other disease indications, including severe aplastic anaemia and MDS ( NCT03173937 ).

A second product, known as UM171, has also been shown to increase HSC renewal through degradation of histone deacetylase 1/2 and lysine‐specific demethylase 1 which prevent cell differentiation in culture (Chagraoui et al. 2021 ). In a Phase I/II clinical trial of patients with high‐risk haematological malignancies, 22 patients received a single UM171‐expanded UCB unit (Cohen et al. 2020 ). The study found that a UCB unit as small as 0.52 × 10 5 /kg could result in successful and prompt engraftment, with no incidence of graft failure, 100% donor chimerism in all cell lineages, improved immune reconstitution and reduced risk of moderate–severe infections (Cohen et al. 2020 ; Dumont‐Lagacé et al. 2021 ). The trial also showed that patients were able to receive more closely HLA‐matched CB as a result of expansion. Current clinical trials for UM171 are exploring dose optimisation ( NCT07301866 ) and its anti‐leukaemic effect in high‐risk and very high‐risk haematological malignancies ( NCT03913026 ) and high‐risk multiple myeloma ( NCT03441958 ).

Cohen et al. ( 2025 ) and Roura et al. ( 2015 ) performed a retrospective cohort study where they performed a matched‐pair analysis comparing outcomes of UM171‐expanded UCB units with 6 different stem cell sources through the EBMT registry (unmanipulated UCB, PBSC from 10/10 MUD, BM from a 10/10 MUD, 9/10 MUD, T‐replete haploidentical and MSD). Time to neutrophil engraftment was similar across all groups, and UM171‐expanded UCB units demonstrated similar or improved short‐ and long‐term outcomes compared with other stem cell sources. Across all groups, Grades II–IV aGVHD was higher in UM171, but the incidence of severe aGVHD (Grades III and IV) was similar. There was no moderate–severe cGVHD observed in the UM171 cohort. GVHD‐free relapse‐free survival was higher in UM171‐expanded UCB units compared with all other donor sources. NRM, PFS and OS were similar between UM171‐expanded UCB and 10/10 PBSC MUD, 10/10 BM MUD and MSD but improved compared with 9/10 MUD and haploidentical donors. These expansion technologies could not only improve the safety of UCBT but also improve access to HSCT by removing TNC cell dose as a barrier and improving access to a suitably HLA‐matched donor.

HLA Matching for UCBT and Selection of Potential UCB Donors

Traditionally, stem cell donor selection has focussed upon identifying the best HLA match available for any given recipient, regardless of their primary disease. Although there is an understanding of the greater immunological tolerance in terms of HLA mismatching when using UCB compared with adult stem cells (Brunstein et al. 2016 ), it could be suggested that the widespread use of PTCy in MMUD and haplotype transplants outweighs this advantage. Donor selection guidelines (Little et al. 2021 ) focus mainly on HLA matching, and algorithms for donor selection employed are mostly applied universally to all recipients, regardless of their clinical diagnosis.

As technologies used in HLA typing improved, matching at higher resolution, and ultimately allele‐level resolution correlated with improved outcomes in adult unrelated HSCT, with shared ethnicity also contributing as a favourable prognostic factor in GVHD (Picardi et al. 2021 ). In histocompatibility and immunogenetics, our view of quantifying HLA matching considers the classical HLA loci (HLA‐A, B, C and DRB1), giving a score out of a possible maximum of 8 alleles matched, extending this score to include HLA‐DQB1 and DPB1 to give a score out of 10 or 12 potential alleles matched, with the highest scores reflecting the best potential match. HLA matching at this level is recommended best practice and is applied to all sources of donors in the selection process to identify the most appropriate donor for each recipient. Although there is substantial evidence from large registry studies that as the degree of HLA matching between donor and recipient increases, TRM and OS improve regardless of donor cell source (Brunstein et al. 2016 ), a closer scrutiny of HLA matching in relation to primary disease shows the correlation to be less predictable (Orvain et al. 2025 ). It remains the case that if the indication for stem cell transplant is non‐malignant, the identification of the closest HLA‐matched donor is imperative and will give the best long‐term prospects of survival. This is also a requirement when using cord blood as a stem cell source.

HLA‐mismatched donors are generally avoided and are selected only after a failure to identify a fully matched donor option. For these individuals, an understanding of the most effective alternative HLA mismatch to select in a donor is essential. Some HLA mismatches have been described as ‘permissive’, having little or no impact, for example, at HLA‐DP (Arrieta‐Bolaños et al. 2024 ; Fleischhauer and Shaw 2017 ; Oran et al. 2018 ), or non‐inherited maternal antigens which were encountered by the recipient in utero (Rocha et al. 2012 ), and these are therefore good options to substitute if an exact HLA match cannot be identified. Similarly, if an HLA‐B mismatch is present in the donor, a lower NRM is seen after transplant if the leader peptide for the mismatched HLA‐B allele is not only mismatched with the recipient but if it also carries a methionine variant (M) rather than threonine (T) (Petersdorf et al. 2021 ). The HLA‐B leader peptides can be defined by association with specific alleles, with M leader alleles belonging to HLA‐B7, B8, B14, B38, B39, B42, B48, B64, B65, B67, B73 and B81 allelic families, whereas all other HLA‐B alleles carry T leader alleles. It is possible that the HLA‐B leader could influence the risk of relapse following cord blood transplantation and that selecting an HLA‐B mismatch from any donor expressing an M leader antigen could offer an advantage in cases where the recipient's relapse risk is high (Petersdorf et al. 2021 ).

Observations from centres with expertise in haploidentical transplantation have also extended our understanding of how grafts achieved using donors with a significant level of mismatching show excellent outcomes and that recipients in these cases are not disadvantaged by having an HLA‐mismatched transplant (Orvain et al. 2025 ). In recipients with high‐risk malignant disease an HLA‐mismatched transplant may improve the anti‐tumour effect observed as GVL and increase OS. This phenomenon has been reported in haploidentical transplants where survival analysis using the epitope‐matching informatics tools PIRCHE I and II demonstrated preferential outcomes for recipients with more HLA‐disparate donors (i.e., with higher PIRCHE scores) if stratified according to their pre‐transplant disease status and their GVHD prophylaxis (Iwasaki et al. 2025 ). The concept that HLA mismatching may promote a GVL response observed in recipients of double UCB grafts (Wynn et al. 2025 ) may, in time, enhance our understanding of promoting a GVL response by directing the selection of HLA‐mismatched donors. The disadvantage with this approach is that it is currently impossible to predict which unit will ‘win’ the battle for engraftment prior to the transplant, and a greater understanding of the dynamics between the two infused units is required.

Accumulating evidence supports a clinical advantage in using UCB as a donor cell source with less relapse, without cGvHD, and improved OS in very high‐risk leukaemia compared with SCT from an adult donation. For recipients with high‐risk haematological malignancies, the use of UCB as a donor cell source opens a potential survival advantage, compared with MMUD or haplotype donors, when recipients have multiple HLA mismatches against their donor. By extrapolation of this principle, it would mean that a patient with such a high‐risk malignancy would have a survival advantage if a deliberately HLA‐mismatched UCB donor were selected as the preferred donor stem cell source. Emerging evidence suggests that a mismatch at HLA‐A in combination with another HLA locus actively promotes a GVL effect in patients with a high‐risk haematological malignancy (Konuma et al. 2021 ).

Where the available cell dose of the donor unit is an issue (e.g., for an adult recipient), the deliberate selection of two donor UCB units which each carry a different HLA‐A mismatch with the recipient whilst being matched for their second HLA specificity would be a useful strategy to maximise the opportunity for a GVL effect. This would potentially recreate the ‘WU/LU’ situation noted by Wynn et al. ( 2025 ). In this way, if one specific (unknown) HLA‐A antigen in the recipient is compromised by the malignancy, it is possible to create a post‐transplant environment where both HLA‐A specificities in the recipient are mismatched, albeit that each donor carries a different mismatched antigen. This selective ‘double mismatch’ approach would enable the ‘WU’ to reject the ‘LU’ and, in doing so, would promote the GVL effect and enhance survival chances in recipients with the highest risk disease.

Emerging Non‐Haematopoietic Uses of Cord Blood‐Derived Products

Beyond their established role in haematopoietic transplantation, cord blood units (CBU) and CBU‐derived products are increasingly being explored for non‐haematological applications. Cord blood contains multiple cell populations beyond HSCs. Cord blood‐derived mesenchymal stem cells (MSCs) have potent immunomodulatory, anti‐inflammatory and regenerative properties and have been explored in a number of different settings, including osteoarthritis (Matas et al. 2019 ), inflammatory bowel disease (Zhang et al. 2018 ), auto‐immune disorders (Sun et al. 2010 ) and acute lung injury (Gorman et al. 2021 ). Evolving research has started to look at cell‐free approaches using extra‐cellular vesicles and exosomes derived from cord‐blood MSCs, which still retain the paracrine effects of CB cells, with potential improvements in safety and scalability (Dabrowska et al. 2020 ; Li et al. 2025 ). Although these applications remain experimental, it supports the concept that CB‐derived products represent a versatile therapeutic resource beyond traditional indications.

Conclusion

In the right patient cohort, UCB remains a valuable stem cell source owing to its unique immunological advantages and practical accessibility. The evidence demonstrates that UCBT offers comparable survival outcomes to other donor sources in haematological malignancy, lower rates of cGVHD and a strong GVL effect. These benefits seem to arise from the ontogeny of cord‐derived lymphocytes—particularly naïve, highly adaptable T‐cells, which are capable of rapid differentiation and tumour‐directed cytotoxicity without the sustained alloreactivity that drives cGVHD. There remain several ways we may continue to investigate how to interrogate these immune properties to drive a stronger GVL effect to induce sustained remission. Advances in ex vivo expansion technologies have also extended the feasibility of UCB to all paediatric and adult recipients. In an era where MMUDs and haploidentical donors dominate practice, the declining use of UCB warrants re‐evaluation, particularly in cases of high‐risk and relapsed/refractory malignancies where time to HSCT is critical.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

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Associated Data

Data Availability Statement

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.