Ex vivo expansion of umbilical cord blood (UCB) grafts by means of a stem cell-associated protein led to significantly quicker hematopoietic recovery after transplantation with less graft versus host disease (GVHD), a preliminary clinical trial showed.
The median time to posttransplant neutrophil recovery decreased by almost 50%, and the median time to platelet recovery by >25% in patients who received UCB grafts expanded ex vivo with nicotinamide (NiCord). The day-42 engraftment rate was numerically higher as compared with historical patients who received conventional UCB transplants. The incidence of grade 2-4 and grade 3-4 graft versus host disease at 100 days was significantly lower with the nicotinamide-derived grafts, according to Mitchell Horwitz, MD, of Duke University Medical Center in Durham, North Carolina, and colleagues.
Use of NiCord grafts allowed transplantation without coinfusion of a second, unmanipulated UCB unit, they reported in the Journal of Clinical Oncology.
"UCB transplantation has a 30-year track record of providing a hematopoietic stem-cell transplant option for patients without an available matched adult donor," the authors stated. "Many adult recipients require two UCB units to ensure reliable engraftment. However, the addition of a second unit significantly increases the expense of the transplantation and is associated with delayed platelet recovery and a higher incidence of chronic GVHD."
"This study suggests that NiCord obviates the need for a second UCB graft. NiCord paves the way for use of smaller, better-matched units for adult patients that otherwise could not be used because of excessive risk of graft failure," they added.
An ongoing phase III trial comparing NiCord grafts with standard myeloablative UCB transplantation will provide more definitive information about the future of the investigational therapy, the authors said.
The authors of an accompanying editorial found the results encouraging, but tempered their enthusiasm with caveats regarding logistical challenges of the NiCord approach. A NiCord unit requires 3 weeks to produce, as compared with 7 to 15 days for other ex vivo expansion strategies. Expansion at a centralized facility limits production capability, and together with the longer culture period, contributed to withdrawal of five patients from the study before infusion. Seven other patients did not receive the final expanded product because of quality issues and infection of the product.
"The study ... is the first to our knowledge to show that an expanded CB unit can be infused as a stand-alone graft and is capable of providing robust and durable hematopoiesis," wrote Elizabeth J. Shpall, MD, Rhotesh S. Mehta, MD, and Katayoun Rezvani, MD, PhD, of the MD Anderson Cancer Center in Houston. "This represents an important advance in the field, demonstrating the safety and efficacy of single CB (cord blood) transplantation, which will influence future resource use and CB banking practices such that smaller units may now be clinically effective."
Despite advances in UCB transplantation for adults, slow hematopoietic recovery remains a major limitation of the treatment. Additionally, conventional UCB transplants confer a risk of infection, prolonged hospitalization, and increased resource use. Ex vivo expansion of a UCB graft hematopoietic stem and progenitor cells prior to transplantation offers the potential to speed up the recovery process.
Proof of Principle
NiCord is derived from the CD133-positive fraction of banked UCB. Culturing with nicotinamide and stimulatory hematopoietic cytokines inhibits differentiation and enhances the functionality of hematopoietic stem and progenitor cells. The CD133-negative fraction (T cell containing) is refrozen, and at the time of transplant, both fractions are infused into the recipient.
A first-in-human pilot trial demonstrated nicotinamide's ability to expand committed and long-term populating stem cells during follow-up for more than 7 years, Horwitz and colleagues said. In that trial, patients received a second, unmanipulated UCB unit to ensure safety.
The pilot study led to a phase I/II clinical trial of NiCord in patients, ages 12 to 65, with high-risk hematologic malignancies and no available matched sibling or unrelated adult donor. After myeloablative conditioning and GVHD prophylaxis, recipients received the NiCord product as a stand-alone stem-cell graft.
Of 58 patients enrolled in the trial, 43 entered the treatment protocol, and 36 subsequently received NiCord transplants. For comparison, investigators selected 146 patients with similar characteristics from the Center for International Blood and Marrow Transplant Research registry.
The 36 patients had a median age of 44, and almost half (17) had acute myeloid leukemia, followed by acute lymphoblastic leukemia (nine) and myelodysplastic syndromes (seven). The primary endpoints were cumulative incidence of neutrophil engraftment at 42 days with ≤10% host cells and the incidence of secondary graft failure.
By day 42, 94% (34) of patients attained complete neutrophil engraftment, 32 of whom (89%) achieved engraftment within 21 days of transplantation. Two patients had secondary graft failure associated with viral infections. That compared with an 85% engraftment rate at day 42 for the historical control group.
The median time to neutrophil recovery was 11.5 days for patients who received the nicotinamide-expanded UCB and 21 days for the control group (P<0.001). The median times to platelet recovery were 34 and 46 days for the study and control groups, respectively (P<0.001).
Most other outcomes favored the patients who received nicotinamide-expanded UCB:
- Day 100 grade 2-4 acute GVHD: 44% vs 56% for the comparator cohort (P=0.20)
- Day 100 grade 3-4 acute GVHD: 11% vs 27% (P=0.09)
- Total chronic GVHD at 2 years: 40% vs 30% (P=0.10)
- Moderate-severe GVHD at 2 years: 10% in both groups
- 2-year nonrelapse mortality: 24%, hazard ratio 0.41 (P=0.02)
- 2-year relapse rate: 33%, HR 1.97 (P=0.11)
- 2-year survival: 51% vs 48%, P=0.22
- 2-year disease-free survival: 43% vs 45%, P=0.24
The NiCord patients also spent significantly more days out of hospital during the first 100 days posttransplant at 73 versus 57 (P<0.001).
The study was supported by Gamida Cell.
Horwitz disclosed relevant relationships with MolMed, MacroGenics, and Gamida Cell.
Shpall disclosed relevant relationships with Magenta, Novartis, Velos, and Adaptimmune. Rezvani disclosed relationships with EMD Serono, Adicet, Onkimmune, Synthorx, Formula Pharmaceuticals, Affirmed Therapeutics, CytomX Therapeutics, and Pharmacyclics, as well as patent/royalty interests.
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