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Background Aims: Despite widespread use of umbilical cord blood (UCB) transplantation and distinct practice preferences displayed by individual UCB banks and transplant centers, little information exists on how processing variations affect patient outcomes., Methods: We reviewed 133 adult double UCB transplants performed at a single center: 98 after reduced-intensity and 35 after myeloablative conditioning. Processing associated with contributing UCB banks and units was surveyed to identify differences in practice. We analyzed effect of selected variables on clinical outcomes of engraftment, dominance, transplant-related mortality, and survival., Results: Eighty-eight percent of banks queried currently practice red blood cell (RBC) depletion before cryopreservation. This reflects a shift in practice because previously 65% of banks employed RBC-replete processing methods (i.e., cryopreservation or plasma/volume reduction). Neither neutrophil nor platelet engraftment was affected by processing conditions analyzed. RBC depletion was not associated with clinical outcomes, except in 17 recipients of 2 RBC-replete units, where survival was better than that observed in 116 recipients of ≥1 RBC-depleted units (hazard ratio 3.26, P = 0.004). When analyzed by attributes of the dominant unit, RBC depletion, time in storage, bank years in existence, and inventory size did not affect clinical outcomes. Postthaw viability and CD34 dose were factors impacting engraftment. Notably, all RBC-replete units in this cohort were washed in dextran-human serum albumin before infusion., Discussion: These findings support continued utilization of the entire existing pool of cord blood units, despite recent trends in processing, and have important implications for banking resources and UCB selection practices., (Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Umbilical cord blood (UCB) is a graft source for patients with malignant or genetic diseases who can be cured by allogeneic hematopoietic cell transplantation (HCT), but who do not have an appropriately HLA-matched family or volunteer unrelated adult donor. Starting in the 1990s, unrelated UCB banks were established, accepting donations from term deliveries and storing UCB units for public use. An estimated 730 000 UCB units have been donated and stored to date and ~35 000 UCB transplants have been performed worldwide. Over the past 20 years, private and family banks have grown rapidly, storing ~4 million UCB units for a particular patient or family, usually charging an up-front and yearly storage fee; therefore, these banks are able to be financially sustainable without releasing UCB units. Private banks are not obligated to fulfill the same regulatory requirements of the public banks. The public banks have released ~30 times more UCB units for therapy. Some countries have transitioned to an integrated banking model, a hybrid of public and family banking. Today, pregnant women, their families, obstetrical providers and pediatricians are faced with multiple choices about the disposition of their newborn's cord blood. In this commentary, we review the progress of UCB banking technology; we also analyze the current data on pediatric and adult unrelated UCB, including the recent expansion of interest in transplantation for hemoglobinopathies, and discuss emerging studies on the use of autologous UCB for neurologic diseases and regenerative medicine. We will review worldwide approaches to UCB banking, ethical considerations, criteria for public and family banking, integrated banking ideas and future strategies for UCB banking.

Recovery of thymopoiesis is critical for immune reconstitution after HSCT. IL-7 and SCF are two major thymotropic cytokines. We investigated whether the kinetics of circulating levels of these cytokines might provide insight into the prolonged immunodeficiency after double umbilical cord blood transplantation (dUCBT) in adults. We examined plasma levels of IL-7 and SCF, T-cell receptor rearrangement excision circle (TREC) levels and T cell subsets in 60 adult patients undergoing dUCBT. Median levels of IL-7 increased by more than 3-fold at 4 weeks and remained elevated through 100 days after dUCBT. SCF showed a less than 2-fold increase and more protracted elevation than IL-7. IL-7 levels inversely correlated with the reconstitution of various T cell subsets but not with TRECs. SCF levels inversely correlated with reconstitution of CD4+T cells, especially the naïve CD4+CD45RA+ subset, and with TRECs suggesting that SCF but not IL-7 had an effect on thymic regeneration. In Cox models, elevated levels of IL-7 and SCF were associated with higher non-relapse mortality (p = 0.03 and p = 0.01) and worse overall survival (p = 0.002 and p = 0.001). Elevated IL-7 but not SCF was also associated with development of GvHD (p = 0.03). Thus, IL-7 and SCF are elevated for a prolonged period after dUCBT and persistently high levels of these cytokines may correlate with worse clinical outcomes.

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.

The main limitations to umbilical cord blood (UCB) transplantation (UCBT) in adults are delayed engraftment, poor immunological reconstitution and high rates of non-relapse mortality (NRM). Double UCBT (DUCBT) has been used to circumvent the issue of low cell dose, but acute GVHD remains a significant problem. We describe our experience in 32 subjects, who underwent DUCBT after reduced-intensity conditioning with fludarabine/melphalan/antithymocyte globulin and who received sirolimus and tacrolimus to prevent acute GVHD. Engraftment of neutrophils occurred in all patients at a median of 21 days, and platelet engraftment occurred at a median of 42 days. Three subjects had grade II-IV acute GVHD (9.4%) and chronic GVHD occurred in four subjects (cumulative incidence 12.5%). No deaths were caused by GVHD and NRM at 100 days was 12.5%. At 2 years, NRM, PFS and OS were 34.4, 31.2 and 53.1%, respectively. As expected, immunologic reconstitution was slow, but PFS and OS were associated with reconstitution of CD4(+) and CD8(+) lymphocyte subsets, suggesting that recovery of adaptive immunity is required for the prevention of infection and relapse after transplantation. In summary, sirolimus and tacrolimus provide excellent GVHD prophylaxis in DUCBT, and this regimen is associated with low NRM after DUCBT.

Umbilical cord blood grafts are increasingly used as sources of hematopoietic stem cells in adults. Data regarding the outcome of this approach in adults are consistent with delayed and insufficient immune reconstitution resulting in high infection-related morbidity and mortality. Using cytomegalovirus (CMV)-specific immunity as a paradigm, we evaluated the status, mechanism, and clinical implications of immune reconstitution in adults with hematologic malignancies undergoing unrelated double unit cord blood transplantation. Our data indicate that CD8(+) T cells capable of secreting interferon-gamma (IFN-gamma) in a CMV-specific enzyme-linked immunosorbent spot (ELISpot) assay are detectable at 8 weeks after transplantation, before reconstitution of thymopoiesis, but fail to clear CMV viremia. Clearance of CMV viremia occurs later and depends on the recovery of CD4(+)CD45RA(+) T cells, reconstitution of thymopoiesis, and attainment of T-cell receptor rearrangement excision circle (TREC) levels of 2000 or more copies/mug DNA. In addition, overall survival was significantly higher in patients who displayed thymic regeneration and attainment of TREC levels of 2000 or more copies/mug DNA (P = .005). These results indicate that reconstitution of thymopoiesis is critical for long-term clinical outcome in adult recipients of umbilical cord blood transplant. The trial was prospectively registered at http://www.clinicaltrials.gov (NCT00133367).

Twenty years has passed since the first report of a successful cord blood transplant was reported in 1989 in a child with Fanconi's anemia. During these 20 years, the cord blood field has had dramatic growth, with over 400,000 cord blood units donated and stored worldwide for unrelated use. Approximately, 14,000 unrelated cord blood transplants have been performed to date for patients with hematologic malignancies and bone marrow disorders, and who do not have matched family or unrelated donors. In contrast, about 900,000 cord blood units have been stored privately for personal use, with about 100 autologous transplants performed. Twenty years ago, due to the low cell dose, cord blood transplants were only performed in children. Today, with the use of better banking techniques, reduced intensity transplants, and double cord blood transplantation, the majority of cord blood transplants are being performed in adults. In this chapter, we review the scientific basis for cord blood transplantation, and outcome data in both pediatric and adult transplantation. We will then focus on the recent concerns regarding private and public cord blood banking. Finally, we discuss the future of cord blood transplantation, and the exciting work beginning outside of oncology.

Intrauterine and perinatal factors have been linked to risk of childhood leukemia, testicular cancer, and breast cancer in the offspring. The pool of stem cells in target tissue has been suggested as a critical factor linking early life exposures to cancer. We examined the relation between intrauterine hormone levels and measurements of stem cell potential in umbilical cord blood. Cord blood donors were 40 women, ages >/=18 years, who delivered, from August 2002 to June 2003, a singleton birth after a gestation of at least 37 weeks. We assayed plasma concentrations of estradiol, unconjugated estriol, testosterone, progesterone, prolactin, sex hormone binding globulin, insulin-like growth factor-I (IGF-I), and IGF binding protein-3. For stem cell potential, we measured concentrations of CD34(+) and CD34(+)CD38(-) cells and granulocyte-macrophage colony-forming unit (CFU-GM). We applied linear regression analysis and controlled for maternal and neonatal characteristics. We found strong positive associations between IGF-I and stem cell measures, 1 SD increase in IGF-I being associated with a 41% increase in CD34(+) (P = 0.008), a 109% increase in CD34(+)CD38(-) (P = 0.005), and a 94% increase in CFU-GM (P = 0.01). Similar associations were observed for IGF binding protein-3. Among steroid hormones, estriol and testosterone were significantly positively associated with CD34(+) and CFU-GM. These findings indicate that levels of growth factors and hormones are strongly associated with stem cell potential in human umbilical cord blood and point to a potential mechanism that may mediate the relationship between in utero exposure to hormones and cancer risk in the offspring.

Background: The relative nucleated cell count of umbilical cord blood (CB) correlates with improved engraftment and survival. This study compares two collection methods to assess CB content, including cell numbers., Study Design and Methods: The Massachusetts CB bank used trained obstetricians and midwives to collect CB in utero before the delivery of the placenta. The banks in California, Ohio, Oregon, and Minnesota used trained American Red Cross (ARC) personnel who collected CB ex utero after the delivery of the placenta. All banks processed CB by RBC sedimentation and volume reduction., Results: The volume and total nucleated cell count of collected CB before processing, as well as after processing CFU-GM and CD34+ cells, showed no advantage of either method. In utero collections resulted in more rejections of collected units (due to labeling problems, bacterial contamination, clotting, and delay between collection and processing) than ex utero collections. There were fewer medical exclusions after in utero collection., Conclusion: CB can be collected successfully using either the in utero or ex utero methods; both methods produce comparable nucleated cell, MNC, CD34+, and CFU-GM numbers. Bacterial contamination, low volume, clotting, and delay until processing are generally higher with in utero collection.

Umbilical cord blood is an alternative stem cell source for patients without matched family donors. In this study, we examined several parameters that have not been studied in detail -- radiation dose, cell dose, age of mice, and maternal and neonatal characteristics of the cord blood donor -- that affect engraftment of cord blood in non-obese diabetic-severe combined immunodeficient (NOD--scid) mice. Engraftment, measured using flow cytometry analyses of human CD45(+) cells, was highest in 400 cGy-treated mice. Successful engraftment was demonstrated up to 6 months, with a mean engraftment of 31% (range 0--67%) of human cells in recipient bone marrow. Engraftment was skewed to B lymphocytes. The radiation dose of 350 cGy resulted in superior survival of the murine recipients compared with 400 cGy (P = 0.03). The sex of the NOD--scid recipients had a significant effect on survival (female superior to male, P = 0.01), but not on engraftment. There were high levels of variability among different cord units and among animals injected with the same cord unit. This variability may limit the clinical usefulness of the NOD--scid mice as hosts for the quantification of human stem cells.

Cord blood (CB) transplantation has expanded the ability of the transplantation community to meet the growing needs of their patients. Clinical data over the last decade show promising results in CB transplantation using blood from related as well as unrelated donors. Basic science continues to look for ways to expand the quality and quantity of CB. CB banks are now established around the world, with major efforts to standardize banking to facilitate regulation, collection, processing, and distribution as a way of providing the highest-quality CB for patient use. This review article discusses the current status of CB transplantation and banking in the United States and Europe.

Umbilical cord blood (CB) is a useful stem cell source for patients without matched family donors. CB banking is expensive, however, because only a small percentage of the cord units stored are used for transplantation. In this study, we determined whether maternal factors, such as race, age, and smoking status have an effect on laboratory parameters of hematopoietic potential, such as viability, cell counts, CD34+ cell counts, and CFU-GM. We studied the effect of neonatal characteristics such as birth order, birth weight, gestational age, and sex of the baby on the same laboratory parameters. Race and maternal age had no effect on these laboratory parameters. In multivariate analysis, babies of longer gestational age had higher cell counts, but lower CD34+ cell counts and CFU-GM. Bigger babies had higher cell counts, more CD34+ cells, and more CFU-GM. Women with fewer previous live births also produced cord units with higher cell counts, CFU-GM, and CD34+ cell counts. Specifically, each 500 g increase in birth weight contributed to a 28% increase in CD34+ cell counts, each week of gestation contributed to a 9% decrease in CD34+cell counts, and each previous birth contributed to a 17% decrease in CD34+ cell counts (all P < 0.05). These data may be used to select the optimal cord blood donors and allow CB banks efficient resource allocation.

Umbilical cord blood transplantation is considered an alternative to traditional bone marrow transplantation for patients who do not have matched sibling donors. In this study, we examined the effects of ex vivo treatment of human cord blood cells with cytokine mixtures and assessed the ability of treated cells to engraft in NOD-scid mice. We incubated the cord blood with a four-factor cytokine mixture of interleukin (IL)-3, IL-6, IL-11 and stem cell factor, or with a two-factor cytokine mixture of thrombopoietin and flt-3. Incubation of cord blood for 48 h with either cytokine mixture did not affect progenitor cell number or proliferative potential as measured by the high proliferative potential (HPP) assay. Cytokine-treated cord blood injected into irradiated NOD-scid mice resulted in multilineage human engraftment. Overall, incubation with cytokines resulted in variable levels of engraftment with different cord blood samples. Incubation of cord blood with the four-factor cytokine mixture resulted in increased survival of irradiated NOD-scid recipients. These results demonstrate that short-term ex vivo treatment of human progenitor cells gives variable results on in vivo multipotential capabilities.