Unrelated Donor Cord Blood Transplantation in Children: Lessons Learned Over 3 Decades

Abstract

Four decades ago, Broxmeyer et al. demonstrated that umbilical cord blood (CB) contained hematopoietic stem cells (HSC) and hypothesized that CB could be used as a source of donor HSC for rescue of myeloablated bone marrow. In 1988, Gluckman et al. reported the first successful matched sibling cord blood transplant (CBT) in a child with Fanconi Anemia. In 1991, Rubinstein et al. established an unrelated donor CB bank, and in 1993, the first unrelated CBT used a unit from this bank. Since that time, >40 000 CBTs have been performed worldwide. Early outcomes of CBT were mixed and demonstrated the importance of cell dose from the CB donor. We hypothesized that improvements in CB banking and transplantation favorably impacted outcomes of CBT today and performed a retrospective study combining data from Eurocord and Duke University in 4834 children transplanted with a single unrelated CB unit (CBU) from 1993 to 2019. Changes in standard transplant outcomes (overall survival [OS], disease free survival [DFS], acute and chronic graft-versus-host disease [GvHD], treatment related mortality [TRM], and relapse) over 3 time periods (1: <2005; 2: 2005 to <2010; and 3: >2010 to 2019) were studied. Increased cell dose and degree of HLA matching were observed over time. OS, times to engraftment, and DFS improved over time. The incidence of TRM and GvHD decreased while the incidence of relapse remained unchanged. Relative contributions of cell dose and HLA matching to transplant outcomes were also assessed and showed that HLA matching was more important than cell dose in this pediatric cohort.

HLA peptide‐binding pocket diversity modulates immunological complications after cord blood transplant in acute leukaemia

“…HLA diversity has consistently emerged as a major determinant of post-HCT outcomes, regardless of stem cell source, including unrelated UCB. [7][8][9][10] Indeed, despite the advantageous properties and unique characteristics of naive immune cell subsets, HLA remains a crucial factor influencing the outcomes of UCBT. This suggests that a comprehensive exploration of all facets of HLA diversity may improve our understanding of the immunology and immunogenetics of UCB, thereby facilitating a more accurate selection of the optimal UCB for each individual patient.…”

“…HLA diversity has consistently emerged as a major determinant of post‐HCT outcomes, regardless of stem cell source, including unrelated UCB 7–10 . Indeed, despite the advantageous properties and unique characteristics of naive immune cell subsets, HLA remains a crucial factor influencing the outcomes of UCBT.…”

“…7,8 Furthermore, a large retrospective study including children receiving single, unrelated UCBT showed that HLA matching influenced post-transplant outcomes, including graft-versus-host disease (GVHD). 7 Other studies showed a trend for lower DFS with increased UCB HLA disparity. 9,10 In addition to the classical HLA polymorphism, other aspects of HLA diversity have recently gained attention.…”

“…Nevertheless, the degree of HLA mismatch clearly affects outcomes after UCBT. UCB units with more than two HLA mismatches associate with low disease‐free survival (DFS) and high non‐relapse mortality (NRM) 7,8 . Furthermore, a large retrospective study including children receiving single, unrelated UCBT showed that HLA matching influenced post‐transplant outcomes, including graft‐versus‐host disease (GVHD) 7 .…”

“…UCB units with more than two HLA mismatches associate with low disease‐free survival (DFS) and high non‐relapse mortality (NRM) 7,8 . Furthermore, a large retrospective study including children receiving single, unrelated UCBT showed that HLA matching influenced post‐transplant outcomes, including graft‐versus‐host disease (GVHD) 7 . Other studies showed a trend for lower DFS with increased UCB HLA disparity 9,10 …”