Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment

Abstract

Background: Delayed hematopoietic recovery is a major drawback of umbilical cord blood (UCB) transplantation. Transplantation of ex vivo-expanded UCB shortens time to hematopoietic recovery, but long-term, robust engraftment by the expanded unit has yet to be demonstrated. We tested the hypothesis that a UCB-derived cell product consisting of stem cells expanded for 21 days in the presence of nicotinamide and a noncultured T cell fraction (NiCord) can accelerate hematopoietic recovery and provide long-term engraftment.

Methods: In a phase I trial, 11 adults with hematologic malignancies received myeloablative bone marrow conditioning followed by transplantation with NiCord and a second unmanipulated UCB unit. Safety, hematopoietic recovery, and donor engraftment were assessed and compared with historical controls.

Results: No adverse events were attributable to the infusion of NiCord. Complete or partial neutrophil and T cell engraftment derived from NiCord was observed in 8 patients, and NiCord engraftment remained stable in all patients, with a median follow-up of 21 months. Two patients achieved long-term engraftment with the unmanipulated unit. Patients transplanted with NiCord achieved earlier median neutrophil recovery (13 vs. 25 days, P < 0.001) compared with that seen in historical controls. The 1-year overall and progression-free survival rates were 82% and 73%, respectively.

Conclusion: UCB-derived hematopoietic stem and progenitor cells expanded in the presence of nicotinamide and transplanted with a T cell-containing fraction contain both short-term and long-term repopulating cells. The results justify further study of NiCord transplantation as a single UCB graft. If long-term safety is confirmed, NiCord has the potential to broaden accessibility and reduce the toxicity of UCB transplantation.

Trial registration: Clinicaltrials.gov NCT01221857.

Funding: Gamida Cell Ltd.

Figure 1. CONSORT diagram for this phase I nonrandomized trial.

Figure 2. Myeloid (CD15⁺) and T cell (CD3⁺) chimerism measurements following transplantation.

Bars demonstrate the median percentage of cells derived from the NiCord unit, the unmanipulated unit, and the host at serial time points following transplantation. Patient 8 experienced primary graft failure and was excluded. Whole-blood chimerism analysis was performed on samples from patient 10, showing 100% NiCord engraftment. Patients were censored at the time of documented relapse or death. *Whole-blood chimerism analysis demonstrated 100% NiCord engraftment.

Figure 3. Hematopoietic recovery following transplantation.

(A) Early white blood cell recovery with associated neutrophil engraftment and (B) durability of white blood cell count at late time points in patients transplanted with NiCord and in a historical control cohort. Bars represent the interquartile range. (C) Early platelet recovery and (D) durability of platelet count at late time points in patients transplanted with NiCord and in a historical control cohort. The historical control patients were transplanted with 2 unmanipulated UCB units.

Figure 4. Overall and event-free survival.

Overall and event-free survival for all subjects who received NiCord-expanded UCB stem cells.