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Chapter 107 Unrelated Donor Cord Blood Transplantation for Hematologic Malignancies 1637

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demonstrated that all evaluable patients achieved donor-derived CD34 cell doses have not predicted which unit will win. Current
neutrophil engraftment at a median of 23 days. The striking finding evidence suggests that unit dominance is predominantly immune-
of this report was the high level of engraftment despite sustained mediated, although unit hematopoietic potential can also play a role
hematopoiesis being mediated by a single donor in nearly all patients (Table 107.2).
and the high 1-year overall survival (OS) of 72%. The RIC series
demonstrated that it was possible to engraft CB after conditioning
with cyclophosphamide 50 mg/kg, fludarabine 200 mg/m2, and 200 Host Factors as Determinants of Unit Dominance
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cGy of total body irradiation. In 2007, Brunstein et al updated the
RIC experience in 110 adults (17 single-unit CBT and 93 DCBT) Based on earlier studies using DCBT murine models and correlating
and demonstrated neutrophil engraftment in 92% but a higher prob- findings that the dominant unit in mice correlated clinically in 18 of
ability of 3-year event-free survival of 39% in DCBT recipients 21 patients, it was suggested that unit dominance is not related to
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compared with 24% in single-unit recipients (p = .05). The high host-versus-graft factors. Later studies showed that there was no
incidences of donor-derived neutrophil engraftment have been sub- effect of donor-specific anti-HLA antibodies in on the speed of
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sequently replicated at other centers. 37–41 engraftment or unit dominance in recipients of DCBT, providing
further evidence that host factors do not play a major role in unit
dominance.
Determinants of Unit Dominance
Hematopoietic Potency as a Determinant of Unit
After DCBT single cord provides long-term engraftment while the
second unit is lost in a majority of cases usually within 30–60 days Dominance
and evidently within 1 year. 34,36,38,40,42,43 Myeloablative conditioning
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regimens lead to an early dominance of single unit, while nonmy- Although the infused CD34 cell or colony-forming unit dose has
eloablative conditioning regimens are associated delayed emergence not been associated with unit dominance, studies suggest that high
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of single dominant unit. Less than 5% of patients may have evi- CD34 cell viability, which correlates with colony-forming unit
dence of stable persistent mixed-unit chimerism, 41,44–49 defined as potential, predicts unit dominance. 41,53,59,60 Thus, damage to the unit
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detection of both CB units at varying proportions for at least 1 year as reflected by a low percentage of viable CD34 cells likely impairs
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posttransplantation. This is more common after nonmyeloablative engraftment potential.
conditioning regimens and if two CB units are closely HLA-
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matched to each other. Moreover, a review of studies with persis-
tent mixed-unit chimerism suggests that HLA-C matching between Immune Factors as Determinants of Unit Dominance
the cords may be associated with a higher likelihood of mixed-unit
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chimerism through intercord tolerance induction. The determi- The role of graft T-cells in predicting unit dominance is supported
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nants of DCBT unit dominance remain to be fully elucidated. by the studies showing that higher infused CD3 cell dose correlates
Better HLA match, ABO group, and higher infused TNC or with the engrafting unit. 41,61 Murine models have also suggested
TABLE Potential Determinants of Unit Dominance After Double-Unit Cord Blood Transplantation
107.2
Potential Mechanism Reference Finding Implications
Host factors Eldjerou et al 51 Unit dominance in mice correlated with clinical Host factors do not influence unit
engraftment. dominance.
Brunstein et al 52 Donor specific anti-HLA antibodies had no influence on
unit dominance.
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Unit factors Scaradavou et al 53 Infused TNC/kg, CD34 /kg, and CFU doses were not Infused CD34 cell dose and CFU, CFC,
Hematopoietic associated with unit engraftment. However, units with or CAFC content do not directly
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potential low CD34 viability were very unlikely to engraft. influence unit dominance, but
Eldjerou et al 51 In vitro CFC and CAFC content did not correlate with poor-quality units are very unlikely to
unit dominance. engraft in humans.
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Immune factors Barker et al 34 Higher infused CD3 cell dose is associated with unit Graft-versus-graft interactions dictate
Scaradavou et al 53 dominance. unit dominance.
Avery et al 41
Kim et al 54 DCBT with MNC associated with unit dominance
whereas coengraftment achieved with lineage
depletion or MSC infusion.
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Yahata et al 55 Mixed chimerism achieved by CD34 selection.
Eldjerou et al 51 Loss of unit dominance with CD34 DCBT restored with
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addition of CD34 cells.
Delaney et al 56 Unmanipulated unit is dominant when coinfused with
T-cell depleted expanded CB.
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Gutman et al 57 Dominant unit CD8 T cells directed against the
nondominant unit detected in patients with single
unit dominance.
Avery et al 41 High level of unit–unit match associated with increased
likelihood of coengraftment.
Brunstein et al 58 Higher prevalence of dual chimerism after Treg infusion.
CAFC, 5 Cobblestone area-forming cell; CB, cord blood; CFC, colony forming cell; CFU, colony forming unit; DCBT, double-unit cord blood transplantation; HLA, human
leukocyte antigen; MNC, mononuclear cell; MSC, mesenchymal stromal cell; TNC, total nucleated cell dose; Treg, regulatory T cell.