Strategies for Success With Umbilical Cord Haematopoietic Stem Cell Transplantation in Children With Malignant and Non-Malignant Disease Indications

Abstract

Umbilical Cord blood is an intuitively attractive stem cell source, but its use has declined since it is associated with an increased procedure-related morbidity and transplant related mortality. Some of this reflects that cord blood transplants are more often HLA-mismatched compared to other unrelated donor transplants. The ability to transplant in such a setting, indeed without high rates of chronic Graft versus Host Disease (GVHD), constitutes an advantage compared to other unrelated donor cell sources and there are other advantages specifically associated with cord blood as a donor cell source. These advantages must be weighed against its disadvantage, and we have utilised cord blood preferentially as a donor cell source in certain clinical situations in paediatric medicine. In non-malignant diseases, outcomes in metabolic disease are critically dependent on age at transplant and the enzyme delivered by that transplant, and in cord blood transplantation then the time to transplant can be minimised and the engrafted recipients have higher chimerism that delivers higher enzyme levels. In malignant diseases, studies have described reduced relapse rate and better GVHD-free survival, and so we have prioritised cord as a donor cell source where the risk of relapse is highest, and the effects of higher transplant related mortality is most clearly offset by the reduced relapse rates.

T-cell replete cord transplants give superior outcomes in high-risk and relapsed/refractory pediatric myeloid malignancy

“…There is little doubt that other transplants, involving higher stem cell doses and graft T cell depletion, are more straightforward, but the superior EFS for T-replete cord recipients, particularly those with positive MRD, shows that the loss of a GVL effect associated with such strategies is disadvantageous for these patients. The higher TRM in the cord setting arises due to a combination of high rates of acute GVHD, increased graft failure, immune cytopenia and respiratory failure (31).…”

Granulocyte transfusion during cord blood transplant for relapsed, refractory AML is associated with massive CD8+ T‐cell expansion, significant cytokine release syndrome and induction of disease remission

“…All patients received a single, HLA‐mismatched T‐cell replete cord unit of adequate cell dose, according to institutional selection algorithms, as previously published 18 …”

“…All patients received a single, HLA-mismatched T-cell replete cord unit of adequate cell dose, according to institutional selection algorithms, as previously published. 18 Transplant conditioning was busulfan or treosulfan based and varied between patients after consideration of previous conditioning and comorbidities. GVHD prophylaxis included ciclosporin and mycophenolate mofetil (MMF).…”

Umbilical cord blood: an undervalued and underutilized resource in allogeneic hematopoietic stem cell transplant and novel cell therapy applications

“…Such considerations likely contribute to the continued demand for UCB units, particularly for pediatric patients and with inherited metabolic conditions, congenital leukodystrophies, and immune deficiency syndromes, where age at the time of transplant and time to transplant affect long-term outcomes. Furthermore, relatives may be carriers of the genetic disorder [28][29][30][31].…”

“…Second, dCBT predominated in the other studies and it must be recognized that single-donor CBT with adequate cell dose (e.g. !2.5 Â 10 7 total nucleated cells (TNC)/kg and !1.5-2.0 Â 10 5 CD34þ cells/kg [4]) remains the standard of care, with double-UCB transplantation only appropriate for patients who lack a single unit with adequate cell dose [5, 29,51]. This is due to higher rates of Grade III-IV aGVHD and Grade III-IV cGVHD and delayed platelet recovery with double vs. single CBT [52,53,54].…”