Phase I/II Study of Stem-Cell Transplantation Using a Single Cord Blood Unit Expanded Ex Vivo With Nicotinamide

Abstract

Purpose: Increasing the number of hematopoietic stem and progenitor cells within an umbilical cord blood (UCB) graft shortens the time to hematopoietic recovery after UCB transplantation. In this study, we assessed the safety and efficacy of a UCB graft that was expanded ex vivo in the presence of nicotinamide and transplanted after myeloablative conditioning as a stand-alone hematopoietic stem-cell graft.

Methods: Thirty-six patients with hematologic malignancies underwent transplantation at 11 sites.

Results: The cumulative incidence of neutrophil engraftment at day 42 was 94%. Two patients experienced secondary graft failure attributable to viral infections. Hematopoietic recovery was compared with that observed in recipients of standard UCB transplantation as reported to the Center for International Blood and Marrow Transplant Research (n = 146). The median time to neutrophil recovery was 11.5 days (95% CI, 9 to 14 days) for recipients of nicotinamide-expanded UCB and 21 days (95% CI, 20 to 23 days) for the comparator ( P < .001). The median time to platelet recovery was 34 days (95% CI, 32 to 42 days) and 46 days (95% CI, 42 to 50 days) for the expanded and the comparator cohorts, respectively ( P < .001). The cumulative incidence of grade 2 to 4 acute graft-versus-host disease (GVHD) at day 100 was 44%, and grade 3 and 4 acute GVHD at day 100 was 11%. The cumulative incidence at 2 years of all chronic GVHD was 40%, and moderate/severe chronic GVHD was 10%. The 2-year cumulative incidences of nonrelapse mortality and relapse were 24% and 33%, respectively. The 2-year probabilities of overall and disease-free survival were 51% and 43%, respectively.

Conclusion: UCB expanded ex vivo with nicotinamide shortens median neutrophil recovery by 9.5 days (95% CI, 7 to 12 days) and median platelet recovery by 12 days (95% CI, 3 to 16.5 days). This trial establishes feasibility, safety, and efficacy of an ex vivo expanded UCB unit as a stand-alone graft.

Trial registration: ClinicalTrials.gov NCT01816230.

FIG 1.

NiCord graft characteristics. Median (range) total nucleated cell (TNC) content, median (range) CD34+ cell content, and median (range) CD34+ cell dose are shown before and after ex vivo expansion of the umbilical cord blood unit. (*) Pre-expansion values represent cell content as reported by the cord blood bank before cryopreservation of the umbilical cord blood unit.

FIG 2.

Hematopoietic recovery. (A) Weighted cumulative incidence of neutrophils by day 42, and (B) platelet recovery by day 100 among recipients of NiCord and a comparable retrospective cohort from the Center for International Blood and Marrow Transplant Research.

FIG 3.

Kaplan-Meier estimate and log-rank test of (A) disease-free survival and (B) overall survival after transplantation with NiCord and a comparable retrospective cohort from the Center for International Blood and Marrow Transplant Research (CIBMTR).

FIG 4.

Immune reconstitution. Median and interquartile range for quantitative recovery of (A) CD3, (B) CD4, (C) CD8, (D) CD19, and (E) natural killer cells measured at target day 70, day 100, 6 months, and 1 year after transplantation with NiCord.

FIG A1.

CONSORT diagram.