1 Introduction

  • Umbilical cord blood transplant (UCBT) from unrelated donors (UD) was developed to overcome the limitations of HLA-matched bone marrow (BM)/peripheral blood (PB) UDs and improve access to allogeneic transplant (allo-HCT) both by increasing the donor pool and fasten time to HCT.

  • UCBT activity has sharply decreased in favor of partially HLA-matched related donor transplants (haplo-HCT) using posttransplant cyclophosphamide (Passweg et al. 2021). This procedure shares most of the advantages of UCBT. It has expanded its use worldwide due to its effectiveness, lower financial impact, and relative simplicity. Two randomized trials have shown superiority of haplo-HCT over UCBT (Fuchs et al. 2020; Sanz et al. 2020). However, it is still a clinical option for some patients lacking other alternatives, due to either the absence of relative donors at due time or the presence of donor-specific antibodies. Whether or not it could be prioritized over haplo donors with negative characteristics like older age or gender mismatch should be the focus of future research.

  • Recent advances in conditioning, graft manipulation, and supportive care have improved UCBT outcomes. These advances reflect in very encouraging outcomes after UCBT for adults and children with high-risk leukemias and some genetic diseases.

2 Potential Advantages and Disadvantages of UCBT

UCBT versus BMT/PBHCT

Advantages

Disadvantages

• Expanded access to transplant*

 – Higher availability of donor*

 – Faster search and shorter time to transplant*

 – Greater HLA disparity allowed with low incidence of GVHD*

• Lower risk of transmission of viral infections

• More versatile transplant planning*

• No risk of donor refusal

• No risk to the donor

• Slower engraftment

• Higher risk of non-immunological rejection (graft failure)

• Remote possibility of transmission of a genetic disease*

• Greater delay in immune reconstitution

• No possibility of donor lymphocyte infusion*

*Advantages shared with partially matched related (haploidentical) HCT

*Disadvantages not shared with haploidentical HCT

Similar to UCBT, haploidentical HCT can also be used on an urgent basis and extends donor availability to the vast majority of patients. In addition, haploidentical HCT allows a DLI if necessary.

3 Indications

Except for some patients with severe bone marrow failure, such as aplastic anemia and paroxysmal nocturnal hemoglobinuria, UCBT in adults is performed almost exclusively in patients with malignant hematological diseases. However, UCBT in children has been used for many other nonmalignant diseases, including primary immunodeficiency diseases and inherited metabolic disorders.

The American Society for Blood and Marrow Transplantation (ASBMT) (Kanate et al. 2020) and the European Society for Blood and Marrow Transplantation (EBMT) (Snowden et al. 2022) have recently published their respective guidelines that include recommendations for transplant indications in children and adults. It should be noted that the ASBMT did not differentiate recommendations for transplant indications based on donor or graft source and EBMT grouped the same indications for all HLA-mismatched alternative donors (UCB, haplo, and mismatched unrelated donors).

Allo-HCT indications should not defer according to donor or graft source but rather the expertise of the transplant center along with patient- and/or disease-related factors, and availability should determine the donor/graft source for the individual patient. More recent data shows that UCBT is probably a preferred donor choice for patients with very high-risk leukemias and some genetic and metabolic disorders in children; however, comparative studies with other alternative donors are lacking in the literature.

4 Approaches to Improve Outcomes After UCBT

Strategies have been developed aiming to shorten the time to engraftment, improve immune reconstitution, and decrease NRM.

Approaches to improve outcomes after UCBT

Expert point of view

1. Refining criteria for UCB unit selection

Selection of the most appropriate UCB unit is key to transplant success. Recent comprehensive consensus guidelines have been recently published (Politikos et al. 2020; Ruggeri 2019). Selection of double cord blood units including high-resolution HLA typing for adults have been recently published (Fatobene et al. 2020; Fatobene et al. 2023). See chapter of banking, processing, and procurement of cord blood cells

2. Optimization of conditioning regimens

Specific conditioning regimen can influence transplant outcomes. See Sect. 64.5

3. Strategies aiming to shorten the time to engraftment:

 

 (a) Double UCBT

In children, two randomized trials have demonstrated no benefit and increased risk of GVHD (Wagner et al. 2014; Michel et al. 2016)

In adults, retrospective studies showed no advantage when single-unit with TNC dose >2.5 × 107/kg available (Scaradavou et al. 2013)

 (b) Co-infusion with third-party cells

Has consistently demonstrated benefit to accelerate hematopoietic recovery. No proved benefit on NRM or survival (Sanz et al. 2017)

 (c) Ex vivo expansion of UCB cells

Omidubicel, the first FDA-approved UCB ex vivo-expanded cellular therapy product, has demonstrated faster engraftment, fewer infections, and decreased NRM compared with unmanipulated UCB that was confirmed in long-term follow-up (Horwitz et al. 2021). Should be considered the standard of care. However, logistical issues and costs may hamper real-life use. Other compounds to expand CB cells such as UM171 are currently being explored in phase 2 clinical trials with encouraging results (Cohen et al. 2020)

4. Improvement of supportive measures

Supportive care to prevent or treat opportunistic infections until neutrophil and immune recovery has occurred is critical in UCBT. See Sect. 64.7

5 Conditioning Regimens

The selection of conditioning regimen for HCT, including UCBT, should take into account the risk of toxicity and the risk of graft failure and relapse in malignant diseases. In UCBT, given the relatively lower cell dose (T cells and CD34+ cells) and the use of HLA-mismatched grafts, graft failure is of particular concern, especially in adults. It usually combines agents with additive immunosuppressive properties. The choice of the conditioning regimen is of primary importance and can influence transplant outcomes. A comprehensive and exhaustive review of myeloablative and nonmyeloblative/reduced intensity conditioning regimens in the UCBT setting has been published (Cord blood transplantations 2017). The American Society for Transplantation and Cellular Therapy Cord Blood Special Interest Group has also recently published their recommendations (Metheny et al. 2021).

The use of in vivo T-cell depletion with ATG in the conditioning regimen has been used to enhance myeloid engraftment as well as to prevent GVHD. Its use has been associated with reduced rates of GVHD but also with increased mortality due to delayed T-cell recovery in hematologic malignancies and is generally not recommended in this setting. Some data suggest that safety of ATG can be improved by adjusting timing or dose with ATG pharmacokinetics (Admiraal et al. 2016) to avoid posttransplantation exposure.

Some conditioning regimens options of varying intensities to be considered are as follows:

Myeloablative conditioning regimens (MAC)

Chemotherapy-based

• TBF regimen (Sanz et al. 2012)

TT 10 mg/kg + BU IV 9.6 mg/kg + Flu 150 mg/m2

TBI-based

• TBI-Flu-Cy regimen (Barker et al. 2015)

TBI 13.2 Gy + CY 120 mg/kg + Flu 75 mg/m2

TT thiotepa, BU busulfan, Flu fludarabine, TBI total body irradiation, CY cyclophosphamide

Intermediate intensity conditioning regimens (IIC)

• TBI-TT-flu-Cy regimen (Barker et al. 2020)

TT 10 mg/kg + CY 50 mg/kg + Flu 150 mg/m2 + TBI 4 Gy

TT thiotepa, Flu fludarabine, CY cyclophosphamide, TBI total body irradiation, CY cyclophosphamide

Reduced intensity conditioning regimens (RIC)

• rTBI-Ffu-Cy regimen (Fuchs et al. 2020)

TBI 2 Gy + CY 50 mg/kg + Flu 200 mg/m2

TBI total body irradiation, CY cyclophosphamide, Flu fludarabine

6 GVHD Prophylaxis

The most important advantage of UCB over unrelated donor grafts is the capability to tolerate HLA disparities and facilitate a low incidence of chronic GVHD. However, acute GVHD is still one of the most important contributors to morbidity and mortality. Different GVHD prophylaxis regimens have been explored with no evidence of benefit of any specific strategy. Methotrexate is generally not recommended to avoid myelotoxicity and delayed neutrophil recovery although it is widely used in Asia. The most frequently used regimen worldwide is the combination of calcineurin inhibitors for 6–9 months with mycophenolate mofetil for 2–6 months.

7 Supportive Care

The supportive measures described below are not intended to be recommendations but only to be taken into account and to consider their use in the context of each institution’s own experience and epidemiology. The most common measures are described merely as a guide since they have a very variable level of evidence.

Prophylaxis, monitoring, and treatment options to be considered for infections.

Supportive measures for bacterial infections

Prophylaxis

Monitoring

Treatment

Levofloxacin or ciprofloxacin

Surveillance cultures to detect colonization with multidrug-resistant gram-negative bacteria

Empirical antibacterial therapy according to institutional epidemiologic patterns

Supportive measures for fungal infections

Prophylaxis

Monitoring

Treatment

Mold-covering azole

Galactomannan and beta-D-glucan assaysa

Liposomal amphotericin B, azoles, and/or echinocandins (according to previous prophylaxis)

Supportive measures for viral infections

Prophylaxis

Monitoring

(quantitative PCR)

Treatment

CMV: letermovir

Weekly on days 0–100 and then as clinically indicated

Ganciclovir, valganciclovir, foscarnet

HHV-6: none

As clinically indicated

Ganciclovir, valganciclovir, foscarnet

Adenovirus: none

Weekly on days 0–100 and then as clinically indicatedb

Cidofovir

EBV: none

Weekly on days 0–100 and then as clinically indicated

Preemptive rituximab

Supportive measures for protozoal infections

Prophylaxis

Monitoring

Treatment

Pneumocystis: cotrimoxazol, pentamidine, or atovaquone

–

Cotrimoxazol, pentamidine, or atovaquone

Toxoplasmosis: cotrimoxazol, atovaquone, or pyrimethamine

–

Cotrimoxazol, atovaquone, or pyrimethamine

  1. a Both have been included as microbiological criteria in the definitions of invasive fungal infections by the European Organization for Research and Treatment of Cancer (EORTC) and the Mycoses Study Group (MSG)
  2. b Specially in children
  3. c Reduced intensity conditioning and ATG are risk factors for EBV-PTLD

8 Results

UCBT outcomes are still improving in more recent years, probably explained by better patient and CBU selection, improved conditioning, and supported care. Registry data also showed important center effect with superior survival obtained in experienced centers. Eurocord recently updated clinical results.

Multiple retrospective studies have demonstrated that UCBT offers similar long-term outcomes compared with the gold standard of HLA-matched unrelated donor transplants in patients with hematologic malignancies, both in children and adults (Eapen et al. 2007; Brunstein et al. 2010; Atsuta et al. 2012). Interestingly, UCBT seems to offer a potent antileukemic efficacy, through yet unknown mechanisms. A markedly reduced relapse rate after UCBT as compared to URD transplantation in patients transplanted with minimal residual disease has been reported and needs to be validated (Milano et al, 2016). Moreover recently, the same observation has been reported in children with very high-risk leukemia transplanted with single CB units. Two-year EFS was 80% for CR 2, 67% for high risk (primary refractory or relapsed leukemia), and 61% for patients transplanted in CR1 (Horgan et al. 2023). In the same direction, very impressive results have been reported in children with genetic and metabolic disorders. Two-year overall survival was 91% with a median follow-up time of 4 years (Martinez et al. 2023).

9 Adults

 

2-year OS (%)

Outcomes according to DRI

 

 Low

55 ± 3

 Intermediate

47 ± 1

 High

27 ± 2

 Very high

19 ± 3

Disease-specific outcomes

 

 Acute leukemia

37 ± 1

 MDS/MPS

32 ± 2

 Lymphoproliferative disorders

45 ± 2

 Plasma cell disorder

37 ± 5

  1. OS overall survival, DRI disease risk index, MDS myelodysplastic syndrome, MPS myeloproliferative syndrome

10 Children

 

2-year OS (%)

Malignant disorders

49 ± 1

 Acute leukemia

52 ± 1

 MDS

55 ± 3

 Lymphoproliferative disorders

55 ± 3

Nonmalignant disorders

63 ± 1

 Inborn error of metabolism

70 ± 2

 Hemoglobinopathies

68 ± 9

 Primary immunodeficiency

68 ± 2

 Histiocytic disorders

60 ± 4

 Bone marrow failure syndrome

52 ± 3

  1. OS overall survival, MDS myelodysplastic syndrome

11 Conclusions

UCBT activity has drastically decreased in favor of other donor/stem cell options, specially haplo-HCT that shares the main advantage of UCB: high and rapid availability. However, UCB remains a valuable source of stem cells for HCT in selected patients that lack other options or in highly specialized units with preference of UCB. Important improvements in the field have taken place with a beneficial impact on NRM. Strategies to enhance engraftment with UCB ex vivo expansion have shown impressive success, although its widespread use and benefit in real-life clinical practice remain to be seen. There is still a room for improvement; however, clinical research in the field will be challenging in the future.