Umbilical Cord Blood
Human umbilical cord blood (UCB) is a rich source of the stem and progenitor cells that are present in bone marrow. Cord blood from related donors and unrelated donors has been successfully transplanted into children and adults. Concern use in adults due to the relatively small number of cells infused per kilogram of body weight persists however studies suggest that UCB can be “expanded” in culture and used for adult transplants. In general, UCB is utilized when no suitable family member or unrelated donor is available. Parents can also have the cord blood cryopreserved at the time of delivery of a child. This has been useful when a prior child has a disease treatable by marrow or blood stem cell transplantation and there is no other donor available.
Umbilical cord blood is cryopreserved in “cord blood banks”. HLA typing is performed and available for computer matching in the same way that the NMDP performs unrelated donor searches. Approved transplant centers are provided with the frozen cells when needed.
Currently the majority of units of cord blood has been provided by the New York Blood Center, which is funded by the National Heart Lung and Blood Institute (NHLBI). Participating Centers in the NHLBI study include the Dana Farber Cancer Research Center; the Fred Hutchinson Cancer Research Center, Seattle, WA; the University of California (UCLA) in Los Angeles; Children’s Hospital of Orange Co. Orange, CA; Indiana University, Indianapolis, IND; Duke University Medical Center, Durham NC; and the University of Minnesota, Minneapolis.
Umbilical Cord Blood an Acceptable Alternative for Stem Cell Transplantation
According to results from published in The New England Journal of Medicine, hematopoietic stem cells from the umbilical cords of newborn infants provide an effective alternative to hematopoietic stem cells from the bone marrow of donors for an allogeneic stem cell transplant in patients with leukemia who cannot find a matched donor.
Stem cell transplantation is the only curative treatment option for some types of aggressive leukemias and other blood cancers. Stem cell transplantation includes the use of high doses of chemotherapy and/or radiation. The higher doses of treatment kill more cancer cells than moderate doses of treatment; however, the high-dose treatment regimens also tend to kill more healthy cells in the body, such as blood cells, leading to increased rates of severe side effects. Following the high doses of treatment, patients receive infusions of hematopoeitic stem cells, or immature blood cells that mature in the body, to replace the blood cells that are killed during treatment.
In an allogeneic stem cell transplant, patients receive a donor’s hematopoietic stem cells following treatment. The donor’s cells must be “matched” to the patients, meaning that sequences of 6 specific proteins (HLA) found on the outside of the cells must be similar to that of the patients. If all HLA match between the donor and patient, it is referred to as a perfect match. Unfortunately, many patients in need of an allogeneic stem cell transplant cannot find a matched donor and are therefore denied treatment. Donor hematopoietic stem cells provide an added anti-cancer attack in that they attack the patients’ cancer cells. However, they also may attack the patients’ healthy tissues, resulting in a condition referred to as chronic or acute graft-versus-host disease (GVHD), which can lead to debilitating consequences.
Hematopoietic stem cells can be found in the bone marrow (spongy material inside large bones), circulating blood and the umbilical cord of infants at birth. Unfortunately, the rich source of stem cells within the umbilical cord is discarded in thousands of births that occur daily. Researchers have been evaluating the use of umbilical cord stem cells for use in allogeneic stem cell transplants, in the hopes of utilizing them for patients who cannot find a donor match. Previous trials have indicated their effectiveness in transplants, as well as a reduction in GVHD with the use of mismatched hematopoietic stem cells. Trials are ongoing to determine the role of cord blood in allogeneic stem cell transplants.
Registry Data Suggests Feasibility of UCB Transplant
Two studies published in The New England Journal of Medicine included data obtained from the analyzed data from the International Bone Marrow Transplant Registry and the National Cord Blood Program.1 The researchers from both studies found that cord blood represents a feasible option for a hematopoietic stem cell source in patients with aggressive leukemia undergoing an allogeneic stem cell transplant who are not able to find a matched donor. Umbilical cord blood transplant outcomes were similar except for delayed blood cell recovery which was more common with UCB. Patients who might benefit from an allogeneic stem cell transplant, but cannot find a matched donor may wish to speak with their physician about the risks and benefits of a transplant with the use of cord blood, or the participation in a clinical trial further evaluating transplants with cord blood.1,2
Omidubicel Ex Vivo Expanded Umbilical Cord Blood Stem Cells
The major disadvantage of using umbilical cord blood is the low number of stem cells collected. The lack of adequate numbers of stem cells in umbilical cord blood units has limited the use of this source of stem cells in adult patients, especially large adults who require more stem cells. One strategy to improve UCB transplantation is the ex vivo expansion of UCB units to improve cell dose using nicotinamide-associated expansion.
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Omidubicel is a UCB-derived product that is the result of ex vivo expansion with nicotinamide.5 To produce omidubicel, a UCB unit is procured, thawed, and sorted based on CD133 expression. CD133- cells are recryopreserved, whereas CD133+ cells are cultured for 21 days in the presence of nicotinamide and hematopoietic cytokines, including thrombopoietin, interleukin-6, FLT-3 ligand, and stem cell factor. Nicotinamide is the critical component of the culture system and is thought to alter the metabolic pathways of HSCs to mimic what is observed in the endosteal region of the bone marrow, which then allows for expansion of HSCs and HPCs. Patients then receive their preparative regimen and are infused with both the nicotinamide-expanded cells and the non-culture cells.
In phase 1/2 trials omidubicel significantly decreased median time to both neutrophil and platelet recovery, compared with historical recipients of standard UCB transplantation from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry.3 A randomized phase 3 trial was designed to compare omidubicel with standard, unmanipulated UCB transplantation.4 in patients with high-risk hematologic malignancies who lack of a readily available HLA-matched donor.
Patients with acute myeloid leukemia or acute lymphoblastic leukemia were randomized to transplantation with omidubicel expanded UCB or standard UCB and their outcomes directly compared.
After expansion, the median CD34+ cell dose for omidubicel was 8.0 × 106/kg, compared with 0.3 × 106/kg for recipients of standard, unmanipulated UCB. The median time to neutrophil and platelet engraftment was improved with omidubicel expanded cells and this resulted in a lower risk of infections, and no worsening of acute GVHD at day 100 pos ttransplant, and chronic GVHD at 1 year posttransplant. These data suggest that omidubicel is an effective alternative to standard UCB transplantation.5
Japanese Researchers Report UCB Comparable to "Standard" Transplant
Researchers from Japan recently conducted a clinical trial including patients with leukemia or lymphoma who underwent umbilical cord blood transplants or peripheral or bone marrow allogeneic stem cell transplants.
- At three years mortality related to treatment was 9% for those treated with umbilical cord transplants and 13% for those treated with bone marrow or peripheral blood transplants.
- At three years relapses occurred in 17% for those treated with umbilical cord transplants and 26% for those treated with bone marrow or peripheral blood transplants.
- At three years cancer-free survival was 70% for those treated with umbilical cord transplants and 60% for those treated with bone marrow or peripheral blood transplants.
- For patients who were at a standard risk of developing a recurrence, cancer-free survival at three years was 93% for those treated with umbilical cord transplants and 85% for those treated with bone marrow or peripheral blood transplants.
- For patients who were at a high risk of developing a recurrence, cancer-free survival at three years was 56% for those treated with umbilical cord transplants, compared with 45% for those treated with bone marrow or peripheral blood transplants.
- GVHD was less frequent after umbilical cord transplants compared with bone marrow or peripheral blood transplants.
The researchers concluded that umbilical cord transplants provide results that are comparable to, or better than those achieved with standard allogeneic stem cell transplants utilizing peripheral blood or bone marrow stem cells from a related donor. These results provide additional evidence that the use of umbilical cord stem cells may be an effective alternative to an allogeneic stem cell transplant from an unrelated donor.
Umbilical Cord Transplant May Be Effective Treatment Option for Some Patients with Myelodysplastic Syndromes
Umbilical cord transplant may be an effective treatment option for patients with myelodysplastic syndrome that are not able to find a suitable donor for an allogeneic stem cell transplant.
Researchers from Japan conducted a clinical trial to evaluate the effectiveness of umbilical cord transplants in 12 patients with advanced MDS. These patients were eligible for an allogeneic stem cell transplant, but an appropriate donor could not be found. Two years following therapy, 76% of patients were alive and cancer-free. Acute GVHD occurred in 75% of patients and chronic GVHD occurred in approximately 73% of patients.
The Researchers concluded that umbilical stem cell sources should be offered to patients with MDS who are eligible for an allogeneic stem cell transplant but are not able to find a suitable donor. Patients with MDS who are considering an allogeneic stem cell transplant but cannot find a donor may wish to speak with their physician about the risks and benefits of an umbilical cord transplant or the participation in a clinical trial evaluating this or other therapeutic options.6,7
- Laughlin M, Eapen M, Rubinstein P, et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. New England Journal of Medicine . 2004; 351:2265-2275.
- Rocha V, Labopin M, Sanz G, et al. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. New England Journal of Medicine . 2004; 351:2276-2285.
Horwitz ME, Chao NJ, Rizzieri DA, et al. Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment. J Clin Invest. 2014;124(7):3121-3128.
Horwitz ME, Stiff P, Rezvani AR, et al. Improved clinical outcomes with omidubicel versus standard myeloablative umbilical cord blood transplantation: results of a phase III randomized, multicenter study. Slides presented at: 2021 Transplantation and Cellular Therapy Meetings; February 8-12, 2021; Virtual.
Horwitz ME, Wease S, Blackwell B, et al. Phase I/II study of stem-cell transplantation using a single cord blood unit expanded ex vivo with nicotinamide. J Clin Oncol. 2019;37(5):367-374.
Ooi J, Iseki T, Takahashi S, et al. Unrelated cord blood transplantation for adult patients with advanced myelodysplastic syndrome. Blood. Prepublished online February 23, 2003. Available at: http://www.bloodjournal.org/cgi/reprint/2002-12-3917v1.pdf. Accessed March 3, 2003.