Cord Blood Units Research Articles

Human leukocyte antigen allele and haplotype frequencies in Singapore bone marrow donors and cord blood units.

We describe the allele and haplotype frequencies seen in a volunteer unrelated bone marrow donor registry, a public cord blood bank, and donor/recipient samples processed by the Health Sciences Authority (HSA) in Singapore. Historical human leukocyte antigen (HLA) typing reports were anonymized and combined. They were checked for HLA typing nomenclature discrepancies or ambiguities using the HLA-net UNIFORMATE tool, and for analysis, the validated data were subsequently separated into Chinese, Malay, Indian, and "Others," according to the race classification system used in Singapore. Individual ethnic allele and haplotype frequencies were calculated with the HLA-net GENE[RATE] pipeline using basic statistics. The Basic Statistics Tool of HLA-net was used to estimate haplotype frequency using an expectation maximization algorithm, given a set of multi-allelic data pairs for a given HLA locus. The outputs downloaded from the site comprised plain text files with haplotype frequency estimates, results of a global linkage disequilibrium test, and standardized residuals (stdres) corresponding to deviations from expected frequencies. HLA typing results from 59,186 individuals met the inclusion criteria, yielding 118,372 analyzable alleles. In our study population, the haplotype A*33:03-B*58:01-C*03:02-DRB1*03:01～DQB1*02:01:01G with a frequency of 4.91% was the most common. This haplotype was also the most common among Singaporean Chinese donors. Consistent with the predominant Chinese population, haplotypes with a frequency greater than 1% were also the most frequently observed haplotypes in the Singaporean population. In the Malay donor population, the most common haplotype was A*33:03～B*44:03～C*07:01:01G～ DRB1*07:01-DQB1*02:01:01G, with a frequency of 3.41%, whereas within the Indian donor population, the most common haplotype was A*01:01-B*57:01-C*06:02～DRB1*07:01-DQB1*03:03, with a frequency of 3.42%. Haplotype diversity and composition statistics within donor pools provide HLA background data required for the targeted recruitment of donors to support the hematopoietic stem cell donor requirements of the country. These data may be used in the future to devise donor recruitment strategies for optimizing the donor pool through targeted publicity and accruals.

Preparation and growth factor characterization of cord blood-derived plasma, serum, growth factor-rich plasma and induced serum.

In recent years, there has been a significant decline in the demand for cord blood units (CBUs). This trend has led to cord blood banks (CBBs) exploring complementary uses of CBUs in order to exploit the full potential of this unique, valuable, and readily available product. The aim of this study was to establish standardized protocols for the preparation of four cord blood (CB) derivatives: plasma (CB-P), serum (CB-S), induced-serum (CB-IS) and growth factor-rich plasma (GFRP); to measure their respective growth-factor content and their potential as cell culture supplements, and finally, to identify the characteristics of each derivative beyond their growth-factor composition, in the context of optimizing CBBs resources. To this end, CB plasma and serum were prepared and their concentrations for ten growth factors (TGF-β1, TGF-β2, TGF-β3, EGF, HGF, PDGF-BB, VEGF-A, VEGF-D, IGF-I, IGF-II) were determined using a multiplex bead array, and compared to adult plasma and serum. Protocols for the preparation of CB-IS and GFRP with reverse anticoagulation using CaCl2·2H2O were also established, and all four derivatives were compared for their EGF and TGF-β1 content by enzyme-linked immunosorbent assay (ELISA), and also for their cell culture supplement capacity. CB plasma was shown to be richer than adult plasma for TGF-β2 and TGF-β3, with a lower concentration of IGF-I and IGF-II. CB serum was shown to be richer than adult serum for TGF-β2, TGF-β3, EGF, HGF, PDGF-BB, and VEGF-A and D, and poorer in IGF-I and II. The measure of EGF and TGF-β1 concentrations has shown that CB serum is the most concentrated (1874pg/ml and 41 094pg/ml) of the CB derivatives, followed by induced-serum (405pg/ml and 16 735pg/ml), growth factor-rich plasma (131 and 7947pg/ml) and plasma (8 and 2845pg/ml). All four CB derivatives were shown to be superior to FBS in sustaining cell growth at low doses. Our study shows that four CB derivatives can be easily prepared and pooled to provide significant volume of products that vary in their growth factor composition. A cord blood bank interested in introducing such manufacturing will need to evaluate the financial and processing characteristics of each derivative. The use of standardized manufacturing protocols such as the ones we suggest could help research initiatives exploring the potential therapeutic uses of such rich and high-quality starting material.

Association between haploidentical hematopoietic stem cell transplantation combined with an umbilical cord blood unit and graft-versus-host disease in pediatric patients with acquired severe aplastic anemia.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) based on granulocyte colony-stimulating factor plus anti-thymocyte regimens ('Beijing Protocol') provides a salvage treatment for patients of acquired severe aplastic anemia (SAA) in China. However, graft-versus-host disease (GVHD) is a major impediment of haplo-HSCT due to human leukocyte antigen disparity. Recently, haplo-HSCT combined with umbilical cord blood (UCB) (haplo-cord HSCT) is performed in clinical trials to potentially reduce the risk of severe GVHD. Nevertheless, studies comparing GVHD in pediatric patients receiving haplo and haplo-cord HSCT for SAA are limited. The objective of this study was to investigate the impact of UCB co-infusion on GVHD in pediatric patients receiving haplo-HSCT for SAA. We conducted a retrospective study of 91 consecutive SAA children undergoing haploidentical transplantation based on the 'Beijing Protocol' with or without co-infusion of UCB in our center. All patients received uniform non-myeloablative conditioning and GVHD prophylaxis. We compared baseline characteristics and transplant outcomes between the haplo (n = 35) and haplo-cord (n = 56) recipients. All 91 patients achieved hematopoietic recovery from haploidentical donors, with a higher incidence of peri-engraftment syndrome observed with the haplo-cord group as compared with the haplo group (75.0% versus 48.6%, p = 0.029). Notably, the haplo-cord group showed a lower incidence of II-IV acute GVHD (aGVHD) than the haplo group (16.1% versus 42.9%, p = 0.002). Observed incidences of chronic GVHD (cGVHD) and moderate to severe cGVHD in the haplo-cord group were also lower than that in the haplo group (25.6% versus 51.3%, p = 0.019; 16.2% versus 41.3%, p = 0.016, respectively). Haplo-cord HSCT was identified as the only factor associated with a lower incidence of II-IV aGVHD and cGVHD in multivariate analysis. However, no differences were observed between the two groups for infections and survival outcomes. Our data indicated that co-infusion of UCB in 'Beijing Protocol'-based haplo-HSCT may be effective for reducing the risk of severe GVHD in SAA children.

Clinical Outcomes of B Cell Acute Lymphoblastic Leukemia Patients Treated with Haploidentical Stem Cells Combined with Umbilical Cord Blood Transplantation

Clinical outcomes of hematopoietic stem cell transplantation (HSCT) using a haploidentical stem cell graft and an unrelated umbilical cord blood unit (haplo-cord HSCT) for the treatment of B cell acute lymphoblastic leukemia (B-ALL) remain unclear. This study was conducted to explore the clinical outcomes of haplo-cord HSCT in patients with B-ALL. A total of 112 B-ALL patients who underwent haplo-cord HSCT and 64 B-ALL patients who underwent haploidentical HSCT (haplo-HSCT) at our center between 2010 and 2020 were retrospectively included in this study, and clinical outcomes and prognostic factors were further analyzed. Of the 112 haplo-cord HSCT recipients, 106 (94.6%) achieved complete haploidentical chimerism and 6 (5.4%) had mixed cord blood chimerism. No differences in neutrophil and platelet recovery or in the incidences of graft-versus-host disease, cytomegalovirus/Epstein-Barr virus viremia, bloodstream infection, or hemorrhagic cystitis were observed between the haplo-cord HSCT and haplo-HSCT groups. Compared with the haplo-HSCT group, the haplo-cord HSCT group had a higher absolute number of CD3+ cells (P=.029) and a lower ratio of CD3+CD4+ /CD3+CD8+ cells (P=.049) at 1 month post-transplantation. Moreover, the haplo-cord HSCT group had lower minimal residual disease (MRD) levels at 1 month (P=.020) and 100 days (P=.038) post-transplantation and a better 3-year prognosis (overall survival, P=.016; disease-free survival, P=.041; cumulative incidence of relapse [CIR], P=.016). The CIRs in patients with adverse genomic features (P=.040) or flow cytometry-based MRD (FCM-MRD) ≥1×10-4 (P=.033) were improved by haplo-cord HSCT. Multivariate analysis revealed that haplo-cord HSCT could independently improve the 3-year OS, DFS, and CIR of B-ALL patients (OS, P=.029; DFS, P=.024; CIR, P=.024). In addition, allo-HSCT at first complete remission was an independent parameter associated with 3-year OS for B-ALL patients (P=.014). An FCM-MRD ≥1×10-4 pre-HSCT could independently predict unfavorable 3-year DFS and CIR (DFS, P=.020; CIR, P=.036) in B-ALL patients. Our data suggest that the use of haplo-cord HSCT can independently improve survival in patients with B-ALL.

Effects of cryopreservation on gram-positive bacteria contaminants in umbilical cord blood.

To evaluate the effects of cryopreservation in post-thaw umbilical cord blood units for the survivability of Gram-positive bacteria strains. Microbial screening is required for all cord blood units (CBUs). Four gram-positive contaminants were documented to survive cryopreservation poorly and isolation of other contaminants were reported. Forty-eight contaminated CBUs detected with either Staphylococcus epidermidis, Corynebacterium species, Peptostreptococcus or Streptococcus species before cryopreservation were used in this study. CBUs were processed, DMSO-infused and microbial screened before cryopreservation. Post-thaw microbial screening was achieved using 1 and 10ml inoculants in BACTEC culture bottles. Positive bottles were subjected for microbial identification and results were compared with those from pre-freeze. A higher rate of microbial contamination was found using the 10ml inoculant. Screening of 11 CBUs did not detect any contaminants while 30 CBUs screened detected more than one unknown contaminants and majority of contaminants were identified to be gram-negative species. A higher inoculation volume used at post-thaw for microbial screening improves contamination detection but leads to the loss of precious cord blood. Some contaminants did not survive cryopreservation or were not identified due to their low microbial levels. Contrasting contaminants found at post-thaw suggest the improvements made in detection and identification of contaminants over the years.

Umbilical Cord Blood or HLA-Haploidentical Transplantation: Real-World Outcomes versus Randomized Trial Outcomes

Randomized clinical trials offer the highest-quality data for modifying clinical practice. Results of a phase III randomized trial of nonmyeloablative transplantation for adults with high-risk hematologic malignancies with 2 umbilical cord blood (UCB) units (n=183) or HLA-haploidentical relative bone marrow (Haplo-BM; n=154) revealed a 2-year progression-free survival (PFS) of 41% after Haplo-BM transplantation and 35% after 2-unit UCB transplantation (P=.41), with overall survival (OS) of 57% and 46%, respectively (P=.04). We sought to examine the generalizability of BMT CTN 1101 to a contemporaneous cohort beyond the trial's prespecified 2-year outcomes. All transplantations were performed between June 2012 and June 2018 in the United States. We hypothesized that the results of a rigorous phase III randomized trial would be generalizable. Changes in graft selection for HLA-haploidentical relative transplantation during the trial period allowed comparison of outcomes after transplantation with Haplo-BM with those after haploidentical peripheral blood (Haplo-PB). The trial's broad eligibility criteria were applied to the data source of the Center for International Blood and Marrow Transplant Research to select nontrial subjects. Extended follow-up of trial subjects was obtained from this data source. Three separate analyses were performed: (1) trial subjects beyond the trial's 2-year endpoint; (2) comparison of trial subjects with a contemporaneous cohort of nontrial subjects (195 2-unit UCB, 358 Haplo-BM, and 403 Haplo-PB); and (3) comparison of nontrial subjects by donor and graft type. Multivariate analyses were performed using Cox proportional hazards models for comparison of outcomes by treatment groups. With longer follow-up of the trial cohorts, 5-year PFS (37% versus 29%; P=.08) and OS (42% versus 36%; P=.06) were not significantly different between the treatment groups. We then compared the trial results with outcomes of comparable real-world transplantations. Five-year OS did not differ between trial and nontrial 2-unit UCB transplantations (36% versus 41%; P=.48) or between trial and nontrial Haplo-BM transplantations (42% versus 47%; P=.80), confirming generalizability. The randomized trial did not accrue as planned and therefore lacked the statistical power to detect a 15% difference in PFS. With substantially larger numbers of nontrial Haplo-BM transplantations, 5-year survival was higher after nontrial Haplo-BM compared with trial 2-unit UCB (47% versus 36%; P=.012). Nontrial patients who underwent Haplo-PB transplantation had higher 5-year survival (54%) compared with trial Haplo-BM (hazard ratio [HR], 0.76; P=.044) and nontrial Haplo-BM (HR, 0.78; P=.026). Similarly, survival was better after Haplo-PB compared with trial UCB (HR, 0.57; P < .0001) and nontrial UCB (HR, 0.63; P=.0002). When considering alternative donor low-intensity conditioning regimen transplantation, a haploidentical relative is preferred, and PB is the preferred graft source.

Impact of COVID-19 Pandemic on Global Unrelated Stem Cell Donations in 2020 - Report from World Marrow Donor Association

Introduction: World Marrow Donor Association (WMDA) promotes global collaboration for the benefit of stem cell donors and transplant patients. WMDA activities include recording the number of unrelated hematopoietic stem cell (HSC) donations globally.Because the COVID-19 pandemic also has an impact on the treatment of patients with other diseases, we hypothesise that it also impacted the practice of unrelated hematopoietic stem cell transplantation (HSCT).We used the 2020 WMDA data to examine the trends in unrelated HSC donations during the COVID-19 pandemic globally, per continent and per country/region.Methods: Donor registries (DRs) and cord blood banks (CBBs) from 61 countries participated in the 2020 survey, compared to 59 countries in the 2019. Slight differences in participation between the data sets of 2019 and 2020 do not explain the trends we observe in HSC donations. Country/region-specific COVID-19 data on cases and deaths were obtained from the data repository operated by the Johns Hopkins University Center for Systems Science and Engineering(https://github.com/CSSEGISandData/COVID-19, accessed July 12, 2021); and population data were retrieved from the Worldometer website(https://www.worldometers.info/, accessed July 12, 2021).Results: HSC donations from unrelated donors (peripheral blood stem cells (PBSC) and bone marrow (BM)) decreased from 20,330 in 2019 to 19,623 in 2020 (-3.5%), compared to an average annual growth rate of 3.9% from 2015 to 2019 (figure 1). The 3.5% decrease is composed of a 29.0% decrease for BM and a 2.6% increase for PBSC, resulting in a drop in the BM share of unrelated HSC donations from 19.3% in 2019 to 14.2% in 2020. The number of cord blood unit (CBU) shipments globally decreased with 3.5% from 2,851 to 2,750. The percentage of national use of HSC products (PBSC and BM) increased from 51.2% to 53.5%.When considering the continent on which the patient is transplanted (table 1), the change rate of use of HSC donated products in 2020 vs. 2019 ranged from -28.0% in South America to +18.2% in Africa. In absolute numbers, the largest decrease of HSC donations occurred for patients in Asia (n=-485) followed by Europe (n=-205), and the largest increase occurred in North America (n=+88) followed by Oceania (n=+25). The share of HSC donations requiring intercontinental transport decreased from 24.6% in 2019 to 21.9% in 2020.In terms of the country/region of transplant (table 2), the largest percentage decrease occurred in Colombia (-90,5%) followed by Russia (-55,5%). In absolute numbers, the largest decrease occurred in Turkey (-147), with Japan following (-128, although Japan saw an increase of CBU use of +106). The highest growth rate was observed in Iran (+28,7%), followed by South Africa (+28,2%). In absolute figures, the greatest increase occurred in Italy (+67). The two countries receiving the largest HSC donation numbers showed no major changes versus the previous year: USA: +0.6% (although a decrease for CBU of -21,0% was observed) and Germany: -2.4%.We did not find any significant correlation between the numbers of COVID-19 cases or COVID-19-related deaths per 1 million inhabitants with the HSC donation numbers (Spearman's r=0.05 for cases and =0.08 for deaths).Discussion: The decline in the number of unrelated HSC donations in 2020 suggests an impact of the COVID-19 pandemic on HSC donation and unrelated HSCT.The significant decrease in BM collections and intercontinental/cross-border shipments can be explained by logistically complex processes, as well the increased risk to the donor of being exposed to an operative procedure. CBU as a stem cell source potentially circumvents these logistical complications. However, on a global scale our data does not show increased use of CBU suggesting that decisions to use CBU as a stem cell source did not change in the pandemic .We were unable to demonstrate a correlation between country/region-specific severity of the pandemic and HSC donation numbers. We suspect this is due to the data quality of reported number of COVID-19 cases and COVID-19-related deaths. Also, we did not gather monthly data and therefore could not specify pandemic waves.In conclusion, we would like to point out the fact that global exchanges of HSC products continued and only decreased slightly is an extraordinary achievement of DRs, CBBs and their donors and is a testament to the importance of international collaborations in the WMDA. [Display omitted] DisclosuresDevine: Orca Bio: Consultancy, Research Funding; Johnsonand Johnson: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Magenta Therapeutics: Current Employment, Research Funding; Tmunity: Current Employment, Research Funding; Vor Bio: Research Funding; Kiadis: Consultancy, Research Funding; Be the Match: Current Employment. Shaw: Orca bio: Consultancy; mallinkrodt: Other: payments. Forman: Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy.

Combination of Haploidentical Hematopoietic with Low-Dose TBI and Cord Blood Transplantation for Hematologic Malignancies

Objective: To evaluate the efficacy and safety of the combination of haploidentical hematopoietic with low-doseTotal body irradiation（TBI）and cord blood transplantation for hematologic malignancies.Methods: This study was conducted as a retrospective review of medical records of 5 patients with hematologic malignancies who received a combination of haploidentical hematopoietic with low-dose TBI and cord blood transplantation at Affiliated HangZhou first people's hospital of Zhejiang University school of medicine, from March to June 2021.Results: 5 patients were included for the analysis. There were 1 acute myeloid leukemia (AML),2 acute lymphoblastic leukemia (ALL) and 2 Non-Hodgkin's Lymphoma(NHL). The minimal residual disease (MRD) of the two patients with ALL was positive before allo-HCT.Median age of patients at the time of allo-HCT was 30 years (range 21-63 years). All patients received low-dose TBI(4-6GY) +antithymocyte globulin（ATG）based conditioning.Cord blood units were selected based on the results of HLA typing and cell doses evaluated before freezing. Units with at least 4/6 matched HLA loci became the candidates. The median values of absolute total nucleated cell counts were 139.0 (80.8-240.0) × 10 7 / kg in The haploidentical grafts and 2.25 (1.32-3.10)× 10 7 / kg in the cord blood units,respectively. The median doses of CD34+ cells infused were 28.6 (22.0-51.1) × 10 5 / kg in the haploidentical grafts and 1.5 (1.0-3.5)×10 5/kg in the cord blood units, respectively.All patients attained complete engraftment,of which 3 were haploidentical engraftment and 2 were mixed hematopoietic chimerism that included haploidentical and cord blood engraftment.The median time to neutrophil engraftment was 12 (10-22) days and 13 (11-22) days for platelets. All patients were in complete remission with MRD-negetive during a median follow-up of 83 (34-136) days.No patients developed grade II-IV acute graft versus host desease.Conclusion:The results suggested that the combination of haploidentical hematopoietic with low-dose TBI and cord blood transplantation may potentially improve the outcome of HSCT. It offers a transplant alternative for patients with hematologic malignancies who lack matching donors. DisclosuresNo relevant conflicts of interest to declare.

Adoptive Therapy with Allogeneic Cord Blood T Regulatory Cells Improves Transfusion Requirement in Bone Marrow Failure Syndromes

Adoptive Therapy with Allogeneic Cord Blood T Regulatory Cells Improves Transfusion Requirement in Bone Marrow Failure Syndromes

Review of Unrelated Donor Cord Blood Transplantation in Children over the Past 3 Decades

Review of Unrelated Donor Cord Blood Transplantation in Children over the Past 3 Decades

Modulation of Purinergic Signaling Prior to Transplantation Both in Hematopoietic Stem Progenitor Cells (HSPCs) or Recipient Bone Marrow (BM) Microenvironment - As Novel Strategies to Accelerate and Facilitate HSPCs Homing and Engraftment

Background. The success rate of hematopoietic stem cell transplantation strongly depends on the number of transplanted hematopoietic stem/progenitor cells (HSPCs) and their speed of engraftment after infusion to the myeloablated transplant recipient. Therefore, clinical outcomes will benefit from accelerating the speed of homing and engraftment rate of transplanted HSPCs. This is important when the number of available HSPCs is low, as seen after poor harvest from BM, poor mobilization efficiency of the donor, and a low number of HSPCs present in the available umbilical cord blood (UCB) unit for an adult recipient. Our recent research demonstrated that purinergic signaling involving extracellular adenosine triphosphate (eATP) and its extracellular metabolite adenosine (eAdo) play a significant opposite role in homing/engraftment of HSPCs - reviewed in Curr Opin Hematol 2021, 28:251-261. To explain this eATP released from the cells of conditioned for transplantation by myeloablation recipient's BM facilitates homing of HSPCs, and subsequently becomes metabolized by cell surface ectonucleotidases CD39 and CD73 to eAdo, that inhibits this process. Therefore, eATP and eAdo upregulated in PB and BM modulate homing/engraftment in i) infused to the recipient donor-derived HSPCs and ii) in recipient BM microenvironment - in an opposite way. We also reported that the beneficial effect of eATP on homing/engraftment of HSPCs depends on the promotion of membrane lipid raft formation on the surface of HSPCs that incorporate homing receptors for their optimal interaction with BM released homing chemoattractants. This process is promoted by eATP activated Nlrp3 inflammasome. On the other hand, Nlrp3 inflammasome and membrane lipid raft formation are inhibited by eAdo in heme oxygenase-1 (HO-1)-dependent manner (Leukemia 2020; 34:1512-1523). Hypothesis. We hypothesized that proper modulation of eATP - eAdo signaling both at the level of transplanted HSPCs and recipient BM microenvironment will speed up the seeding efficiency of transplanted cells to BM niches. Material and Methods. We exposed HSPCs before transplantation ex vivo to i) exogenous eATP or ii) small molecular CD39 and CD73 inhibitors. We also inhibited CD39 and CD73 in transplant recipients BM at the time of myeloablative conditioning. In addition, we also activated ex vivo Nlrp3 inflammasome in HSPCs to be transplanted by specific activator nigericin. In control experiments, eATP stimulated Nlrp3 inflammasome activity was inhibited by the HO-1 activator that is CoPP. Homing of HSPCs was evaluated by measuring a number of donor-derived fluorochrome-labeled cells and clonogenic progenitors in BM of myeloablated hosts at 24 hours after transplantation. Early engraftment was assessed by counting the number of CFU-S and clonogeneic progenitors 12 days after transplantation and by evaluating kinetics of recovery of PB hematopoietic cell counts. Finally, while activation of Nlrp3 inflammasome was assessed by immunofluorescence assay, membrane lipid raft formation was evaluated by confocal microscopy. Results. We noticed that homing and engraftment of HSPCs was significantly accelerated after i) short exposure before transplantation to eATP, ii) inhibition of eAdo formation by CD39, and CD73 inhibitors, and iii) activation of Nlrp3 inflammasome by nigericin. Similarly, inhibition of eAdo formation in recipient BM microenvironment of transplanted mice by CD39 and CD73 inhibitors also improved homing and engraftment efficiency. This correlated with activation in the eATP-dependent manner of Nlrp3 inflammasome in HSPCs followed by membrane lipid raft formation. In the BM microenvironment, upregulation of eATP and inhibition of eAdo also enhanced expression of homing chemoattractants. Conclusions. Since all purinergic signaling modifiers employed in our studies are non-toxic against HSPCs, our data obtained in the animal model indicates that modulation of purinergic signaling before transplantation in HSPCs as well as in BM of the myeloablated recipient would significantly accelerate hematopoietic recovery after hematopoietic transplantation. DisclosuresNo relevant conflicts of interest to declare.

Allogeneic Stem Cell Transplantation with Omidubicel: Long-Term Follow-up from a Single Center

Allogeneic Stem Cell Transplantation with Omidubicel: Long-Term Follow-up from a Single Center

Haploidentical Versus Cord Blood Stem Cell Transplantation As the Second Transplant for Relapsed Acute Myeloid Leukemia Patients after the First Stem Cell Transplantation

Haploidentical Versus Cord Blood Stem Cell Transplantation As the Second Transplant for Relapsed Acute Myeloid Leukemia Patients after the First Stem Cell Transplantation

Umbilical cord blood transplantation: Still growing and improving.

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.

Primary graft failure, but not relapse, may be identified by early chimerism following double cord blood unit transplantation

AbstractUmbilical cord blood transplantation (UCBT) has increased access to potentially curative therapy for patients with life-threatening disorders of the bone marrow and immune system. The introduction of reduced intensity conditioning (RIC) regimens and double umbilical cord unit infusions (DUCBT) has broadened the applicability of UCBT to more frail or larger recipients. The kinetics of chimerism after RIC DUCBT and their clinical utility are poorly understood. The RIC CBT trial reported here sought to prospectively evaluate the role of lineage-specific chimerism after DUCBT in adult patients with hematologic malignancies in the United Kingdom. Fifty-eight patients with a median age of 52 years were recruited, with overall and progression-free survivals of 59% (95% confidence interval [CI], 45%-71%) and 52% (95% CI, 39%-64%), respectively, at 2 years. Nonrelapse mortality was 4% (95% CI, 1%-13%) at day 100, and the relapse rate was 31% (95% CI, 21%-45%) at 1 year. Peripheral blood lineage-specific chimerism was feasible from day 7 after transplant onward. Five patterns of chimerism were observed including (1) complete single unit dominance (39 patients), (2) sustained donor-donor mixed chimerism (3 patients), (3) sustained donor-recipient mixed chimerism (5 patients), (4) dominance reversion (1 patient), and (5) primary graft failure (4 patients). The RIC CBT trial enabled adult patients with high-risk hematologic malignancies to safely access UCBT in the United Kingdom and provided novel insights into the kinetics of donor and recipient chimerism after RIC DUCBT that are clinically relevant. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/trial/2004-003845-41/GB as #NCT00959231 and EudraCT 2004-003845-41.

Dimethyl sulfoxide-free cryopreservation solutions for hematopoietic stem cell grafts

Background aimsThe use of effective methods for the cryopreservation of hematopoietic stem cells (HSCs) is vital to retain the maximum engraftment activity of cord blood units (CBUs). Current protocols entail the use of dimethyl sulfoxide (DMSO) as intracellular cryoprotective agent (CPA) and dextran and plasma proteins as extracellular CPAs, but DMSO is known to be cytotoxic, and its infusion in patients is associated with mild to moderate side effects. However, new, commercially available, DMSO-free cryopreservation solutions have been developed, but their capacity to protect HSCs remains poorly investigated. MethodsHerein the authors compared the capacity of four DMSO-free freezing media to cryopreserve cord blood (CB) HSCs: CryoProtectPureSTEM (CPP-STEM), CryoScarless (CSL), CryoNovo P24 (CN) and Pentaisomaltose (PIM). Clinical-grade DMSO/dextran solution was used as control. ResultsOf the four cryopreservation solutions tested, the best post-thaw cell viability, recovery of viable CD45+ and CD34+ cells and potency were achieved with CPP-STEM, which was equal or superior to that seen with the control DMSO. CSL provided the second best post-thaw results followed by PIM, whereas CN was associated with modest viability and potency. Further work with CPP-STEM revealed that CB CD34-enriched HSCs and progenitors cryopreserved with CPP-STEM maintained high viability and growth expansion activity. In line with this, a pilot transplantation assay confirmed that CPP-STEM-protected CB grafts supported normal short- and long-term engraftment kinetics. ConclusionsThe authors’ results suggest that new, valuable alternatives to DMSO are now available for the cryopreservation of HSCs and grafts, including CBUs.

A New Method to Predict the Quality of Umbilical Cord Blood Units based on Maternal and Neonatal Factors and Collection Techniques

The saving banks of “umbilical cord blood stem cells” are considered as strategic health-based institutions in most countries. Due to the limited capacity of cord blood sample storage tanks, the samples should be evaluated according to their quality. So these banks need a method to assess quality. In this paper, first, the effective factors on the quality index of the extracted cord blood from newborn infants are identified using the electronic records and database of Royan’s umbilical cord blood bank. Then by machine learning and various statistical methods such as multilayer perceptron neural networks, radial basis function neural networks, logistic regression, and C4.5 decision tree, the quality value of blood samples and their proper category (for discarding or freezing) are determined. Two different sets of data have been used to evaluate the proposed methods. The results show that the ensemble of radial basis function neural network with k-means clustering model has the best accuracy compared to other methods, which categorizes the samples with 91.5% accuracy for the first data set and 81.6% accuracy for the second one. The results also show that using this method can save about $1 million annually.

Enhanced self-renewal of human long-term hematopoietic stem cells by a sulfamoyl benzoate derivative targeting p18INK4C

AbstractThe use of umbilical cord blood transplant has been substantially limited by the finite number of hematopoietic stem and progenitor cells in a single umbilical cord blood unit. Small molecules that not only quantitatively but also qualitatively stimulate enhancement of hematopoietic stem cell (HSC) self-renewal ex vivo should facilitate the clinical use of HSC transplantation and gene therapy. Recent evidence has suggested that the cyclin-dependent kinase inhibitor, p18INK4C (p18), is a critical regulator of mice HSC self-renewal. The role of p18 in human HSCs and the effect of p18 inhibitor on human HSC expansion ex vivo need further studies. Here we report that knockdown of p18 allowed for an increase in long-term colony-forming cells in vitro. We then identified an optimized small molecule inhibitor of p18, 005A, to induce ex vivo expansion of HSCs that was capable of reconstituting human hematopoiesis for at least 4 months in immunocompromised mice, and hence, similarly reconstituted secondary recipients for at least 4 more months, indicating that cells exposed to 005A were still competent in secondary recipients. Mechanistic studies showed that 005A might delay cell division and activate both the Notch signaling pathway and expression of transcription factor HoxB4, leading to enhancement of the self-renewal of long-term engrafting HSCs and the pool of progenitor cells. Taken together, these observations support a role for p18 in human HSC maintenance and that the p18 inhibitor 005A can enhance the self-renewal of long-term HSCs.

The Effect of the Thermal Integrity of a Shipping Device on the Viability of Hematopoietic Stem Cells of Cord Blood Units.

The Effect of the Thermal Integrity of a Shipping Device on the Viability of Hematopoietic Stem Cells of Cord Blood Units.

Results of a Multicenter Evaluation of a Rapid Flow Cytometry Potency Assay for Cryopreserved Cord Blood Units: A BEST Collaborative Study

Results of a Multicenter Evaluation of a Rapid Flow Cytometry Potency Assay for Cryopreserved Cord Blood Units: A BEST Collaborative Study