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

Abstract

PurposeIncreasing 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.MethodsThirty-six patients with hematologic malignancies underwent transplantation at 11 sites.ResultsThe 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.ConclusionUCB 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.

Successful engraftment of haploidentical bone marrow with post‐transplantation cyclophosphamide in patients with aplastic anemia

“…Additionally, ongoing improvements in graft manipulation of alternative donor sources may provide further options in the future. Recent technology applied to the expansion of umbilical cord blood products may result in improved engraftment rates that would make them acceptable in the treatment of SAA . Alpha‐beta T‐cell depletion may become a viable alternative to previous methods of T‐cell depletion that would often leave patients more vulnerable to infectious complications.…”

Expansion of Haematopoietic Stem and Progenitor Cells: Paving the Way for Next- Generation Haematopoietic Stem Cell Transplantation

“…High-throughput screening of over 100,000 heterocycles compounds identified a purine derivative, StemRegenin-1(SR-1) , that could increase the absolute 69 . The CD133 -⊘CD34fraction of Omidubicel, MGTA-456, and ECT-001 were cryopreserved for infusion into the patients along with the manipulated CD34 ＋ fraction thus enabling the infusion of minimally manipulated T, B, and other immune cells that potentially supports engraftment after transplantation [66][67][68][69] . Production failure rates of approximately 10% and 22% was reported for Omidubicel and MGTA-456, respectively [66][67][68] .…”

“…The CD133 -⊘CD34fraction of Omidubicel, MGTA-456, and ECT-001 were cryopreserved for infusion into the patients along with the manipulated CD34 ＋ fraction thus enabling the infusion of minimally manipulated T, B, and other immune cells that potentially supports engraftment after transplantation [66][67][68][69] . Production failure rates of approximately 10% and 22% was reported for Omidubicel and MGTA-456, respectively [66][67][68] . Majority of the patients(71%)in these trials received a second unmanipulated UCB graft along with expanded UCB product as a measure of clinical safety.…”

“…All the stated clinical trials reported significant expansion of CD34 cells (as outlined in Table 2) which resulted in patients receiving significantly higher cell dose(TNC and CD34)that resulted in faster hematopoietic recovery [66][67][68][69] for graft-derived neutrophils and platelets( Table 2) . Post-transplant acute GvHD(aGvHD)for Omidubi-cel recipients manifested primarily as grade Ⅱ to Ⅳ whereas MGTA-456 and ECT-001 exhibited very low risk of aGvHD [66][67][68][69] . Immune cell reconstitution of patients receiving these investigational cell therapy products did not exhibit any abnormalities compared to conventional UCBT [66][67][68][69] .…”

“…Post-transplant acute GvHD(aGvHD)for Omidubi-cel recipients manifested primarily as grade Ⅱ to Ⅳ whereas MGTA-456 and ECT-001 exhibited very low risk of aGvHD [66][67][68][69] . Immune cell reconstitution of patients receiving these investigational cell therapy products did not exhibit any abnormalities compared to conventional UCBT [66][67][68][69] . Transplantation of Omidubicel, MGTA-456, and ECT-001 did not cause any acute infusional toxicities (＜24 hours)or adverse events(up to 30 days posttransplant) , and no patient experienced graft failure [66][67][68][69] .…”