Textbook of Bone Marrow Failure, 26/03/2026
Introduction
Allogeneic Hematopoietic Cell Transplantation (HCT) is a cornerstone in the treatment of idiopathic and inherited Bone Marrow Failure (BMF) disorders. Post-transplant survival continues to improve across most disease groups, particularly in patients receiving grafts from alternative donors, due to advances in Human Leukocyte Antigen (HLA) matching techniques, reduced toxicity conditioning regimens, and improved prophylaxis for Graft versus Host Disease (GvHD).
The global availability of Umbilical Cord Blood (UCB) units has expanded transplant opportunities for patients lacking matched bone marrow or peripheral blood donors. Although its use has declined in recent years due to the rapid development of haploidentical transplantation, this graft source remains a valid option for both pediatric and adult patients with BMF.
For BMF and other non-malignant diseases, transplant strategies consistently aim to minimize transplant- and disease-related toxicities, limit harmful graft-versus-host reactions, and promote engraftment. This chapter provides an updated overview of cord blood transplantation in the context of BMF, including specific indications and disease-related considerations.
UCBT in BMF: History and Proof of Concept
BMF was the first indication for UCBT, with the first transplant performed in 1988 in a pediatric patient with Fanconi anemia using HLA-matched sibling cord blood, resulting in complete and sustained hematopoietic recovery.
This success demonstrated the capacity of a single UCB unit to achieve durable hematopoietic reconstitution, paving the way for the development of cord blood banking and expansion of transplant indications.
The main advantages of UCBT include: readily available source, rapid procurement, donor safety, and lower incidence of GvHD despite incomplete HLA matching. Since the late 1990s, numerous studies have reinforced the role of UCBT in BMF and other diseases.
Disease-Specific Aspects
Most evidence on UCBT in BMF comes from retrospective studies and registry data, making it difficult to establish standardized guidelines and resulting in significant variability between centers.
The best outcomes are achieved with HLA-matched related UCB donors, but this source is rare; unrelated transplants are less effective.
Therefore, unrelated UCBT is currently mainly reserved for selected patients after failure of other treatments.
Idiopathic Aplastic Anemia
Outcomes in SAA patients without matched related donors have improved with newer immunosuppressive regimens and transplantation from alternative donors.
UCBT is increasingly feasible, with survival rates of 30–70% (better with higher HLA matching, larger cell dose, use of Flu + low-dose TBI, and younger patients).
The main limitations are graft failure and infections. Some recent studies have shown very promising results (OS >80% at 1 year), and UCBT may surpass IST in certain cases. However, due to concerns about toxicity and lack of strong data, UCBT is currently mainly used for refractory SAA, and early indication remains investigational.
Unrelated UCBT in SAA: Practical Recommendations
Unrelated UCBT in SAA should only be considered when no suitable donor is available and after failure of IST (including eltrombopag in adults).
Donor-specific antibodies should be screened; use 1–2 UCB units with a maximum of 2/6 HLA mismatch, ensuring a dose ≥4 × 10⁷ nucleated cells/kg.
CMV status is important (seronegative status is more favorable), but the risk can now be reduced with prophylaxis using letermovir.
The main risks remain infection and graft failure → good supportive care is required at experienced centers. The risk of secondary myeloid neoplasms after allogeneic transplantation is generally very low, but long-term data for UCBT are still limited.
Recommended Conditioning Regimen for Unrelated UCBT in SAA (from APCORD Trial and SAAWP)
Flu 30 mg/m2/d (D-6 to D-3), Cy 30 mg/kg/d (D-6 to D-3), ATG 2.5 mg/kg/d (D-4 to D-3), and TBI 2 Gy (D-1); GvHD prophylaxis: CsA alone (from 3 mg/kg D-1)
Fanconi Anemia
The prognosis of patients with Fanconi anemia (FA) has improved due to better understanding of disease mechanisms and optimization of transplant procedures. Currently, allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment for hematopoietic disorders.
Unrelated UCBT is mainly supported by retrospective data, with previously limited outcomes (survival ~40%, high GvHD), but has improved with the use of fludarabine-based regimens, higher cell doses, and reduced-intensity conditioning (Flu/TBI). However, the risks of graft failure and complications remain significant, especially in advanced AML/MDS.
The most important factor is HLA matching: >1 mismatch is associated with poorer outcomes. Therefore, current recommendations suggest using a single UCB unit with ≤1 mismatch for patients without a suitable donor.
Unrelated UCBT in FA: Practical Recommendations
Despite significant improvements, unrelated UCBT in Fanconi anemia (FA) still results in poorer outcomes and higher toxicity compared to other graft sources. However, when allogeneic transplantation is indicated and no HLA-matched bone marrow donor is available, it remains the only curative treatment option, especially in younger patients.
Key factors include HLA matching, donor-specific antibodies, and cell dose. In patients with bone marrow failure, reduced-intensity conditioning (Flu + low-dose Cy + TBI) with in vivo T-cell depletion is recommended. In FA patients with advanced AML/MDS, overly intensive regimens should be avoided due to high toxicity; sequential strategies have not yet been effectively applied in UCBT.
Post-transplant, close long-term follow-up is required due to delayed immune reconstitution and infection risk. FA patients have a high risk of post-transplant malignancies (≈30% solid cancers before age 50), particularly squamous cell carcinoma, with increased risk in the presence of chronic GvHD. Therefore, regular cancer screening (every 6 months), good oral hygiene, and avoidance of alcohol and tobacco are recommended. In addition, endocrine disorders (hypothyroidism, diabetes, metabolic syndrome, growth hormone deficiency) should be monitored as part of long-term care.
Recommended Conditioning Regimen for FA in Unrelated UCBT (Eurocord)
Flu 30 mg/m2/d (D-6 to D-3), Cy 10 mg/kg/d (D-6 to D-3), ATG 2.5 mg/kg/d (D-3 to D-2), and TBI 2 Gy (D-2); GvHD prophylaxis: CsA (3 mg/kg from D-1) and MMF (30 mg/kg from D+1)
Other Inherited BMF Disorders
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare disease caused by mutations in the MPL gene, leading to severe thrombocytopenia and potential progression to bone marrow failure or MDS. Due to the lack of effective long-term treatment and the high risk of bleeding, allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment.
Congenital neutropenia (CN) includes various forms such as Kostmann syndrome and cyclic neutropenia, often caused by ELANE mutations, leading to recurrent severe infections. The main treatment is G-CSF; HCT is considered in severe cases or those at risk of progression to leukemia/MDS. In summary, in both CAMT and CN, UCBT is only considered an alternative option when no other suitable graft source is available, as data remain limited and insufficient to establish standard guidelines.
Special Situations: Matched-Related UCBT for BMF
UCBT from fully HLA-matched siblings has been reported in multiple malignant and non-malignant diseases, particularly in children, with very favorable outcomes: low GvHD rates, high engraftment, and good long-term survival. In non-malignant diseases such as bone marrow failure (BMF), the benefits are even more evident, with high survival and low toxicity, although conditioning regimens and GvHD prophylaxis vary across studies.
A large Eurocord analysis in collaboration with EBMT (117 children and young patients, median age 6) showed: neutrophil engraftment rate of 89% (median 21 days), long-term survival ~88% (nearly 8 years follow-up), acute GvHD 15% and chronic GvHD 14%. Late complications were rare, mainly endocrine; only one case of secondary malignancy was reported.
These data confirm that HLA-matched related UCBT is a highly effective and safe option in BMF when no suitable bone marrow donor is available, with low risk of failure and favorable prognosis.
However, it is important to note that family-directed cord blood banking is not so promoted, and in contrast to the well-developed public banking systems for allogeneic use, only a few countries have centralized programs for family-directed UCB storage.
Conclusive Remarks
Umbilical cord blood (UCB) is an attractive stem cell source due to its availability, low risk of infection transmission, and less stringent HLA matching requirements, which help reduce the incidence and severity of GvHD compared to other sources.
In bone marrow failure (BMF) syndromes, UCBT may be considered when no suitable donor (related or unrelated) is available, after evaluation of alternative graft sources and failure of non-transplant therapies or in the presence of clonal evolution.
HLA-matched related UCBT yields very favorable outcomes and is increasingly used, sometimes in combination with bone marrow transplantation. In contrast, unrelated UCBT should be carefully considered, with appropriate patient selection, optimization of conditioning regimens, and effective complication management to improve outcomes and quality of life.
References
Pagliuca, S., Sterin, A. (2026). Umbilical Cord Blood Transplantation for Patients with Idiopathic and Inherited Bone Marrow Failure Disorders, Textbook of Bone Marrow Failure. Springer, 185–200.
Source: Textbook of Bone Marrow Failure
Link: https://link.springer.com/chapter/10.1007/978-3-032-02386-5_13
