Immune Reconstitution after Umbilical Cord Blood Versus Peripheral Blood Progenitor Cell Transplantation in Adults Following Myeloablative Conditioning
Authors: Mehta Rohtesh S. , Bejanyan Nelli , Cao Qing , Luo Xianghua , Brunstein Claudio , Cooley Sarah , Blazar Bruce R. , Weisdorf Daniel J. , Wagner John E. , Miller Jeffrey S. , Verneris Michael R. 
Published: October 2019

Abstract
Immune Reconstitution After Umbilical Cord Blood Versus Peripheral Blood Progenitor Cell Transplantation In Adults Following Myeloablative Conditioning
Introduction: We report on the tempo of immune reconstitution after myeloablative umbilical cord blood transplantation (UCBT, n=61) compared with allogeneic peripheral blood progenitor cells transplantation (PBPCT, n=59).
Methods: All patients 18 years or older who underwent first allogeneic transplantation after myeloablative conditioning for hematological malignancies between Jan, 2004 and Dec, 2013 and were alive at 1-year post transplant were included. Patients who received T-cell depletion or antithymocyte globulin were excluded.
Results: Overall, the most common diagnosis was acute (83.6% vs 61%) or chronic (3.3% vs. 10.2%) leukemia in UCBT and PBPCT groups, respectively, p=0.07. Median age of UCBT group was 37.2 years vs. 45 years in PBPCT group, p<0.01. The majority of UCBT group (92%) received two units. Almost all patients in PBPCT group (97%) had 6/6- or 8/8-HLA matched sibling donor. More than half of recipients of either UCBT (54%) or PBPCT (51%) were cytomegalovirus (CMV) seropositive. About 97% in both groups received total body irradiation (TBI) for conditioning. Graft-versus-host disease (GVHD) prophylaxis was provided with cyclosporine plus either mycophenolate (UCBT) or methotrexate (PBPCT).
The median time to neutrophil engraftment was notably faster in the PBPCT group (15 days, range 10-31) compared with the UCBT group (24 days, range 6-39), p<0.001. All subsets of cells analyzed were significantly lower in the UCBT group for at least first month post-transplant compared with PBPCT group [Figures 1-3]. Natural killer (NK) cells were the first cells to reconstitute in the UCBT group, especially the CD56bright subset, the absolute numbers of which were significantly higher in UCBT than in the PBPCT group from 2 months until at least one year. Similarly, although CD19+ B cells were lower in UCBT group for first month post- transplant, they reached comparable levels to that of PBPCT group at 2-3 months post-HCT and then surpassed the PBPCT group with UCB having significantly higher numbers at 6 and 12-months post-HCT (p<0.05). The absolute numbers of total T cells (CD3+CD56-), CD4+ and CD8+ T cells remain significantly lower in the UCBT group until 3 months, but were then comparable to that of PBPCT group at 6 and 12 months. "NKT" cells (CD3+CD56+) and the naïve T cells (CD4+CD45RO-CD27+) remain significantly lower in UCBT group at all time points tested. The numbers of effector memory (CD4+CD45RO+CD27-) and central memory T cells (CD4+CD45RO+CD27+) were lower for the first three months after transplant, but were then comparable to the PBPCT group thereafter. Regulatory T cells (Tregs; CD4+CD25brightCD127-) were lower in UCBT group for the first 6 months and then comparable to PBPCT group at 12 months.
Clinical correlates: Infection density at 1 year (number of infection events/1000 patient days at risk) of bacterial (6.3 vs. 3.7, p<0.01) and viral (5.4 vs 2.2, p<0.01), but not fungal infections (0.27 vs. 0.34, p=0.69) was significantly higher in the UCBT group than in the PBPCT group, respectively. UCBT group had a significantly higher incidence of acute grade II-IV GVHD (75%, 95% confidence interval (CI) 61- 90%, versus 51%, 95% CI 37-65%, p<0.01) and grade III-IV GVHD (33%, 95% CI 21-45%, versus 17%, 95% 7-26%, p=0.03) than PBPCT group respectively. Incidence of chronic GVHD at 2 years was similar in two groups. In univariate analysis, risk of relapse at 3-years was significantly lower in UCBT (19%, 95% CI 9-28%) than PBPCT group (35%, 95% CI 22-48%), p=0.05. There was no difference in overall survival at 3 years (72% vs 66%, respectively, p=0.34).
Conclusion: After myeloablative conditioning, UCBT group has significantly delayed neutrophil engraftment and reconstitution of all T cell subsets and NKT cells, compared to that of PBPCT group, which along with a higher incidence of acute GVHD explains higher infection density in the UCBT group. Conversely, rapid recovery of NK and B cells may partly explain lower risk of relapse in the UCBT group. Despite significantly lower numbers of Tregs in UCBT group, risk of chronic GVHD was similar to that of PBPCT group. Ongoing multivariate analysis of the impact of CMV serostatus and other cell subsets on clinical outcomes will provide further answers.

Disclosures
Miller: Oxis Biotech Scientific Advisory Board: Membership on an entity's Board of Directors or advisory committees.