Update on umbilical cord blood transplantation.
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ABSTRACT:
SUBMITTER: Ballen K
PROVIDER: S-EPMC5580430 | biostudies-literature | 2017
REPOSITORIES: biostudies-literature
Publications
Allogeneic hematopoietic cell transplant is a curative procedure for many patients with leukemia, lymphoma, myelodysplasia, myeloproliferative neoplasms, and genetic disorders. Umbilical cord blood transplantation is a graft source for patients who do not have a matched donor in their family or in the unrelated registry. It is particularly difficult for Black, Hispanic, and White patients of non-Western European background to find fully matched adult volunteer donors. An estimated 700,000 umbili ...[more]
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Project description:Umbilical cord blood transplantation (UCBT) has been performed in the clinic for over 30 years. The biological and immunological characteristics of umbilical cord blood (UCB) have been re-recognized in recent years. UCB, previously considered medical waste, is rich in hematopoietic stem cells (HSCs), which are naïve and more energetic and more easily expanded than other stem cells. UCB has been identified as a reliable source of HSCs for allogeneic hematopoietic stem cell transplantation (allo-HSCT). UCBT has several advantages over other methods, including no harm to mothers and donors, an off-the-shelf product for urgent use, less stringent HLA match, lower incidence and severity of chronic graft-vs-host disease (GVHD), and probably a stronger graft-vs-leukemia effect, especially for minimal residual disease-positive patients before transplant. Recent studies have shown that the outcome of UCBT has been improved and is comparable to other types of allo-HSCT. Currently, UCBT is widely used in malignant, nonmalignant, hematological, congenital and metabolic diseases. The number of UCB banks and transplantation procedures increased exponentially before 2013. However, the number of UCBTs increased steadily in Asia and China but decreased in the United States and Europe year-on-year from 2013 to 2019. In this review, we focus on the development of UCBT over the past 30 years, the challenges it faces and the strategies for future improvement, including increasing UCB numbers, cord blood unit selection, conditioning regimens and GVHD prophylaxis for UCBT, and management of complications of UCBT.
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Project description:Since the first successful allogeneic transplants performed in Seattle 50 years ago, the field of transplantation has evolved considerably, with improvements in human leukocyte antigen typing, patient selection, reduced intensity regimens, and graft-versus-host disease prophylaxis. A major breakthrough has been the availability of more donor options, first via the National Marrow Donor Program-Be the Match [Biol Blood Marrow Transplant 2008;14:2-7]. Then, in the 1990s, unrelated umbilical cord blood transplantation became available, first for children and then for adults [New Engl J Med 1996;35:157-166]. More recently mismatched unrelated transplants and haploidentical donor options became available [Blood 2011;118:282-288]. In 2017, there is a donor for almost every patient who needs a transplant. In this review, we will discuss the state of the science (and art) of cord blood transplant, focusing on successes, challenges, and future directions. Stem Cells Translational Medicine 2017;6:1312-1315.
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Project description:At present there is no effective treatment of pathologies associated with the death of neurons and glial cells which take place as a result of physical trauma or ischemic lesions of the nervous system. Thus, researchers have high hopes for a treatment based on the use of stem cells (SC), which are potentially able to replace dead cells and synthesize neurotrophic factors and other molecules that stimulate neuroregeneration. We are often faced with ethical issues when selecting a source of SC. In addition to precluding these, human umbilical cord blood (hUCB) presents a number of advantages when compared with other sources of SC. In this review, we consider the key characteristics of hUCB, the results of various studies focused on the treatment of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), ischemic (stroke) and traumatic injuries of the nervous system and the molecular mechanisms of hUCB-derived mononuclear and stem cells.
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Project description:Umbilical cord blood (UCB) is a valuable source of hematopoietic stem cells (HSCs) for use in allogeneic transplantation. Key advantages of UCB are rapid availability and less stringent requirements for HLA matching. However, UCB contains an inherently limited HSC count, which is associated with delayed time to engraftment, high graft failure rates, and early mortality. 16,16-Dimethyl prostaglandin E2 (dmPGE2) was previously identified to be a critical regulator of HSC homeostasis, and we hypothesized that brief ex vivo modulation with dmPGE2 could improve patient outcomes by increasing the "effective dose" of HSCs. Molecular profiling approaches were used to determine the optimal ex vivo modulation conditions (temperature, time, concentration, and media) for use in the clinical setting. A phase 1 trial was performed to evaluate the safety and therapeutic potential of ex vivo modulation of a single UCB unit using dmPGE2 before reduced-intensity, double UCB transplantation. Results from this study demonstrated clear safety with durable, multilineage engraftment of dmPGE2-treated UCB units. We observed encouraging trends in efficacy, with accelerated neutrophil recovery (17.5 vs 21 days, P = .045), coupled with preferential, long-term engraftment of the dmPGE2-treated UCB unit in 10 of 12 treated participants.
| S-EPMC3811179 | biostudies-literature
Project description:For patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplantation, umbilical cord blood transplantation (UCBT) has become an acceptable alternative donor source in the absence of a matched sibling or unrelated donor. To date, however, there have been few published series dedicated solely to describing the outcomes of adult patients with myelodysplastic syndrome (MDS) who have undergone UCBT. Between 2004 and 2013, 176 adults with MDS underwent UCBT as reported to the Center for International Blood and Marrow Transplant Research. Median age at the time of transplantation was 56 years (range, 18-73 years). The study group included 10% with very low, 23% with low, 19% with intermediate, 19% with high, and 13% with very high-risk Revised International Prognostic Scoring System (IPSS-R) scores. The 100-day probability of grade II-IV acute graft-versus-host disease (GVHD) was 38%, and the 3-year probability of chronic GVHD was 28%. The probabilities of relapse and transplantation-related mortality (TRM) at 3 years were 32% and 40%, respectively, leading to a 3-year disease-free survival (DFS) of 28% and an overall survival (OS) of 31%. In multivariate analysis, increasing IPSS-R score at the time of HCT was associated with inferior TRM (P = .0056), DFS (P = .018), and OS (P = .0082), but not with GVHD or relapse. The presence of pretransplantation comorbidities was associated with TRM (P = .001), DFS (P = .02), and OS (P = .001). Reduced-intensity conditioning was associated with increased risk of relapse (relative risk, 3.95; 95% confidence interval, 1.78-8.75; P < .001), and although a higher proportion of myeloablative UCBTs were performed in patients with high-risk disease, the effect of conditioning regimen intensity was the same regardless of IPSS-R score. For some individuals who lack a matched sibling or unrelated donor, UCBT can result in long-term DFS; however, the success of UCBT in this population is hampered by a high rate of TRM.
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Project description:Umbilical cord blood (UCB) is an important source of hematopoietic stem cells (HSC) for allogeneic transplantation when HLA-matched sibling and unrelated donors (MUD) are unavailable. Although the overall survival results for UCB transplantation are comparable to the results with MUD, UCB transplants are associated with slow engraftment, delayed immune reconstitution, and increased opportunistic infections. While this may be a consequence of the lower cell dose in UCB grafts, it also reflects the relative immaturity of cord blood. Furthermore, limited cell numbers and the non-availability of donor lymphocyte infusions currently prevent the use of post-transplant cellular immunotherapy to boost donor-derived immunity to treat infections, mixed chimerism, and disease relapse. To further develop UCB transplantation, many strategies to enhance engraftment and immune reconstitution are currently under investigation. This review summarizes our current understanding of engraftment and immune recovery following UCB transplantation and why this differs from allogeneic transplants using other sources of HSC. It also provides a comprehensive overview of promising techniques being used to improve myeloid and lymphoid recovery, including expansion, homing, and delivery of UCB HSC; combined use of UCB with third-party donors; isolation and expansion of natural killer cells, pathogen-specific T cells, and regulatory T cells; methods to protect and/or improve thymopoiesis. As many of these strategies are now in clinical trials, it is anticipated that UCB transplantation will continue to advance, further expanding our understanding of UCB biology and HSC transplantation.
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Project description:Umbilical cord blood (UCB) transplantation has a high early mortality rate primarily related to transplanted stem cell dose. To decrease early mortality and enhance engraftment, a portion of selected cord blood units (20% to 50%) was expanded with cytokines and the copper chelator tetraethylenepentamine (carlecortemcel-L) and transplanted with the unmanipulated fraction after myeloablative conditioning. The primary endpoint was 100-day survival, which was compared with a contemporaneous double-unit cord blood transplantation (DUCBT) group. We enrolled 101 patients at 25 sites; the DUCBT comparison (n?=?295) was selected from international registries using study eligibility criteria. Baseline carlecortemcel-L study group unit nucleated cell (NC) and CD34+ were 3.06?×?107 cell dose/kg and 1.64?×?105 cell dose/kg. Median NC and CD34+ fold expansion were 400 and 77, with a mean total CD34 infused of 9.7?×?105/kg. The 100-day survival was 84.2% for the carlecortemcel-L study group versus 74.6% for the DUCBT group (odds ratio, .50; 95% CI, .26 to .95; P?=?.035). Survival at day 180 was similar for the 2 groups; the major cause of death after day 100 was opportunistic infections. Faster median neutrophil (21 days versus 28 days; P?<?.0001), and platelet (54 days versus 105 days; P?=?.008) engraftment was seen in the carlecortemcel-L study group; acute and chronic graft-versus-host disease rates were similar. In this multinational comparative study, transplanting expanded CD34+ stem cells from a portion of a single UCB unit, with the remaining unmanipulated fraction improved 100-day survival compared with DUCBT control patients while facilitating myeloid and platelet engraftment. This trial was registered at www.clinicaltrials.gov as #NCT00469729.
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Project description:Allogeneic hematopoietic stem cell transplantation is an important treatment option for fit patients with poor-risk hematological malignancies; nevertheless, the lack of available fully matched donors limits the extent of its use. Umbilical cord blood has emerged as an effective alternate source of hematopoietic stem cell support. Transplantation with cord blood allows for faster availability of frozen sample and avoids invasive procedures for donors. In addition, this procedure has demonstrated reduced relapse rates and similar overall survival when compared with unrelated allogeneic hematopoietic stem cell transplantation. The limited dose of CD34-positive stem cells available with single-unit cord transplantation has been addressed by the development of double-unit cord transplantation. In combination with improved conditioning regimens, double-unit cord transplantation has allowed for the treatment of larger children, as well as adult patients with hematological malignancies. Current excitement in the field revolves around the development of safer techniques to improve homing, engraftment, and immune reconstitution after cord blood transplantation. Here the authors review the past, present, and future of cord transplantation.
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Project description:Limited cell numbers in umbilical cord blood (UCB) grafts present a major impediment to favorable outcomes in adult transplantation, largely related to delayed or failed engraftment. The advent of UCB transplantation (UCBT) using two grafts successfully circumvents this obstacle, despite the engraftment of only one unit. Preclinical models suggested that the addition of UCB T cells at the time of transplant can enhance engraftment. We tested whether ex vivo activation by CD3/CD28 costimulation and expansion of T cells from a single UCB graft would be safe and feasible in adults with advanced hematologic malignancies, with an overall objective of optimizing engraftment in single unit UCBT. In this phase 1 study, recipients of single UCB units were eligible if the unit was stored in two adequate fractions. Dose limiting toxicity was defined as grade 3 or grade 4 GVHD within 90 days of UCBT. Four patients underwent UCBT; all were treated at the first dose level (10(5) cells/kg). At the 10(5) cells/kg dose level two subjects experienced grade 3 intestinal GVHD, thus meeting stopping criteria. For three subjects, neutrophil engraftment was early (12, 17, and 20 days), while one subject experienced primary graft failure. We observed early donor T cell trafficking and found that expanded T cells produced supraphysiologic levels of cytokines relevant to engraftment and to lymphoid differentiation and function. Taken together, these preliminary data suggest rapid engraftment in recipients of a single UCBT combined with relatively low doses of activated T cells, though potentially complicated by severe GVHD.
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Project description:Delayed platelet engraftment is a common complication after umbilical cord blood transplantation (UCBT) accompanied by increased transplant-related complications or death. This study was designed to determine the safety and efficacy of recombinant human thrombopoietin (rhTPO) in promoting platelet engraftment after UCBT. A total of 120 patients scheduled to receive UCBT were randomly assigned to the rhTPO group (300 U/kg once daily from days 14 to 28 after UCBT, n = 60) or the control group (n = 60). The primary outcome was the 60-day cumulative incidence of platelet engraftment after single-unit cord blood transplantation. The 60-day cumulative incidence of platelet engraftment (platelet count ≥20 × 109/L) and the 120-day cumulative incidence of platelet recovery (platelet count ≥50 × 109/L) were both significantly higher in the rhTPO group than in the control group (83.1% vs 66.7%, P = .020; and 81.4% vs 65.0%, P = .032, respectively). In addition, the number of required platelet infusions was significantly lower in the rhTPO group than in the control group (6 vs 8 units, respectively; P = .026). The cumulative incidence of neutrophil engraftment and the probability of 2-year overall survival, disease-free survival, and graft-versus-host disease-free relapse-free survival did not differ between the 2 groups. Other transplant-related outcomes and complications did not differ between the 2 groups, and no severe adverse effects were observed in patients receiving rhTPO. This study demonstrated that rhTPO is well tolerated in patients and could effectively promote platelet engraftment after UCBT. This study was registered on the Chinese Clinical Trial Registry (http://www.chictr.org.cn/index.aspx) as ChiCTR-IPR-16009357.
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