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356 Part V: Therapeutic Principles Chapter 23: Hematopoietic Cell Transplantation 357

those of mixed ethnicity, and those with uncommon HLA haplotypes. recipients of PBPC or marrow allografts. Presumably the immunologic
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As a result, a substantial fraction of patients who would benefit from naïveté of UCB, which allows its use across HLA barriers, also contrib-
allogeneic HCT lack “conventional” related or unrelated donors. For utes to impaired antiviral immunity and immune reconstitution after
such patients, there are two widely used alternative sources of HSC for allogeneic HCT. CD8+ T-cell recovery is significantly delayed after
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allogeneic HCT: UCB and HLA-haploidentical family members. UCB compared to marrow allotransplantation (median time to reach
>0.25 × 10 CD8+ T cells/L, 7.7 months vs. 2.8 months, respectively),
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Umbilical Cord Blood whereas CD4+ T cell and NK cell recovery is similar with these two
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UCB, collected from the umbilical vessels in the placenta at the time graft sources. A novel syndrome of cord colitis has been described
of delivery, is a rich source of HSCs. Because these cells are immuno- in UCB recipients and tentatively linked to Bradyrhizobium enterica, a
logically naïve, it is feasible to cross major histocompatibility barriers, newly identified bacterium, 96,97 although other groups have questioned
thus extending the donor pool to individuals for whom finding suit- the existence of a distinct cord colitis syndrome and instead attributed
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ably HLA-matched adult donors can be difficult or impossible. The the findings in question to conventional GVHD. 98,99
first successful allogeneic HCT using UCB, in a child with Fanconi ane-
mia, was reported by Gluckman and colleagues in 1989. Since then, Human Leukocyte Antigen–Haploidentical Donors
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hundreds of thousands of UCB units have been collected and stored; Virtually all patients have HLA-haploidentical family members—
searchable registries have been established to facilitate identification including any parent, any child, and some siblings—available as donors.
of suitable UCB units for transplantation; and more than 20,000 allo- Haploidentical related donor HCT has been evaluated for more than
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geneic HCTs have been performed using UCB. Cord blood units are 2 decades as an alternative source of HSCs. However, as a result of the
fully HLA-typed before cryopreservation, and thus suitable units can be substantial HLA disparity involved, early attempts at haploidentical
rapidly identified (as compared to unrelated-donor searches, which can HCT were associated with severe GVHD in T-cell-replete transplants
take 2 to 6 months to complete). and with graft rejection in T-cell–depleted transplants. 100,101 Extensive ex
Most UCB units are HLA-typed as HLA-A and HLA-B using vivo depletion of CD3+ and CD19+ lymphocytes, coupled with mega-
low-resolution (serologic) methods, and as HLA-DRB1 using high- dose CD34+ cells and antithymocyte globulin, can successfully over-
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resolution (molecular) methods. UCB units matched at equal to or come the barriers to engraftment. The extensive T-cell depletion used
greater than 4/6 HLA loci are generally considered suitable for use, in these protocols to prevent GVHD would also be expected to result
although UCB units matched at 5/6 or 6/6 HLA loci should be used in weak or no graft-versus-malignancy effects. Yet despite the lack of
if available because they are associated with lower transplant-related T-cell–mediated alloreactivity and the unfavorable prognostic features
mortality. 84,85 The role of HLA matching between UCB units in dou- at the time of transplantation, relapse rates with this approach remained
ble UCB transplantation remains somewhat unclear, and unit-to-unit at 18 to 30 percent in patients with acute leukemia transplanted in first
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HLA matching does not appear to impact long-term engraftment rates complete remission (CR1). The low rate of relapse was attributed
or GVHD incidence. 85,86 to a strong antitumor effect mediated by donor NK cell alloreactivity.
A major limitation has been the relatively small number of HSC Transplantation from NK-cell-alloreactive donors was associated with
available in cord blood units relative to the size of the average adult a significantly lower leukemia relapse rate and improved overall sur-
recipient. As a result, most UCB transplants in adults use two UCB vival, leading some authorities to recommend selection of haploidenti-
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units rather than one. The minimum acceptable cell doses for single-unit cal donors based on NK cell alloreactivity. However, this approach to
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7
UCB transplantation are generally set at equal to or greater than 2.5 × 10 haploidentical HCT remains hampered by prolonged immune reconsti-
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total nucleated cells or equal to or greater than 2 × 10 CD34+ cells/kg tution and a high risk of serious infection. 105
of recipient weight. 84,88 It is difficult to locate units meeting these criteria More recently, the group at Johns Hopkins has pioneered the use
for average-sized adult recipients, and thus most adult UCB transplants of posttransplantation cyclophosphamide (CY) as GVHD prophy-
are performed using two UCB units. With double UCB transplantation, laxis in T-cell-replete haploidentical HCT. In this approach, unma-
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transient mixed donor chimerism from the two units is often observed, nipulated marrow from an HLA-haploidentical donor is infused after
but ultimately one UCB unit dominates, eradicates the other unit, and nonmyeloablative conditioning. A period of 48 to 72 hours elapses
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is responsible for establishment of long-term hematopoiesis. Despite after infusion, during which alloreactive donor T-cell clones become
extensive investigation, the factors determining which unit becomes activated and proliferate. CY is then administered on days +3 and +4
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dominant remain somewhat unclear, although CD8+ T-cell responses after allogeneic HCT, preferentially eradicating the activated alloreac-
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against the nonengrafting unit have been implicated. For recipients tive donor T-cell clones while leaving other, nonalloreactive clones rel-
with a single suitably sized UCB unit, single-unit UCB transplantation atively untouched. This approach has been remarkably well-tolerated
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is preferable to double UCB transplantation, because of better platelet and results in very low rates of GVHD and transplant-related mortality
recovery and a lower risk of GVHD. For the majority of adult recipi- (TRM). Additionally, because this approach avoids indiscriminate
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ents, who lack a suitable single UCB unit, double UCB transplantation is T-cell depletion, immune reconstitution is relatively robust, and the typ-
typically used and produces equivalent overall survival. For children, ical complications of T-cell-depleted allotransplantation (such as post-
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a single UCB unit appears superior to double UCB transplantation. A transplantation lymphoproliferative disorder [PTLD]) are not seen.
major area of active research in UCB transplantation is the expansion of The major limitation of this approach is a relatively high rate of relapse,
HSC or other hematopoietic progenitor cells in UCB products, with the perhaps driven by the eradication of the alloreactive donor T-cell clones
goal of improving engraftment rates, shortening the period of preen- which would mediate graft-versus-tumor (GVT) effects along with
graftment neutropenia, and reducing the need for double-unit UCB those mediating GVHD. 108
transplantation. Several approaches have been described in the litera- Retrospective studies have examined the question of selecting
ture, including Notch-mediated or prostaglandin-mediated expansion the optimal HLA-haploidentical donor when several such donors are
of progenitor cells and ex vivo mesenchymal cell coculture. 91–93 available. Early evidence suggested that lower TRM was seen with HLA-
Recipients of UCB allografts have a higher risk of opportunistic haploidentical sibling donors compared to parental donors, while
infections—particularly viral infection or reactivation—compared to maternal donors were associated with less chronic GVHD and better

Kaushansky_chapter 23_p0353-0382.indd 357 9/19/15 12:46 AM