Research AdvancesBy Karen Ballen, MD, Michael Horwitz, MD, Junya Kanda, MD, PhD, and Elisabetta Xue, MD RECENTLY PUBLISHED ARTICLESImproved Outcomes of UM171-Expanded Cord Blood Transplantation Compared with Other Graft Sources: Real-World Evidence Cohen S, et al. Blood Advances, 2023 Hôpital Maisonneuve Rosemont, Université de Montréal, Montreal, Quebec, Canada. A phase I-II trial of UM171-expanded CB transplants demonstrated safety and favorable preliminary efficacy. The aim of the current analysis was to retrospectively compare results of the phase I-II trial to those after unmanipulated CB and matched unrelated donor (MUD) transplants.
Methods: Data from recipients of CB and MUD transplants were obtained from the CIBMTR database. Patients were directly matched for the number of prior allogeneic hematopoietic stem cell transplants (alloHCT), disease and refined Disease Risk Index. Patients were further matched by propensity score for age, comorbidity index and performance status.
Findings: Overall, 137 CIBMTR (67 CB, 70 MUD) and 22 UM171-expanded CB patients were included. NRM at 1 and 2 years was lower, PFS and GRFS at 2 years and OS at 1 year were improved for UM171-expanded CBs compared to CB controls. Compared to MUD controls, UM171 patients had lower 1- and 2-year NRM, higher 2-year PFS, and higher 1- and 2-year GRFS. Furthermore, UM171-expanded CB recipients experienced less grades III-IV acute GVHD and chronic GVHD compared to MUD graft recipients.
Conclusions: Compared to real-world evidence with CB and MUD alloHCT, this study suggests that UM171-expanded CB recipients may benefit from lower NRM and higher GRFS.
Intrabone Transplantation of a Single Unwashed Umbilical Cord Blood Unit with Antithymocyte Globulin-Free and Sirolimus-Based Graft-versus-Host Disease Prophylaxis: Fast Immune Reconstitution and Long-Term Disease Control Patients with High-Risk Diseases. Giglio F, et al. Transplantation and Cellular Therapy, 2023 IRCCS San Raffaele Hospital, Milan, Italy. The aim of this retrospective analysis was to examine the safety and efficacy of intrabone transplantation of a single unwashed cord blood unit in an antithymocyte globulin-free, sirolimus-based graft-versus-host disease prophylaxis platform.
Methods: Authors collected data for all consecutive UCBTs infused intrabone (IB) and unwashed at San Raffaele Hospital in Milan between 2012 and 2021.
Findings: Thirty-one consecutive UCBTs were identified. At the time of cryopreservation, the median CD34+ cell count was 1 × 105/kg (range, 0.6 to 12.0 × 105/kg) and the median total nucleated cell (TNC) count was 2.8 × 107/kg (range, 1.48 to 5.6 × 107/kg). No adverse events were related to the IB infusion at bedside under short-conscious periprocedural sedation or to the no wash technique. After thawing, median CD34+ cell and TNC counts were 0.8 × 105/kg (range, 0.1 to 2.3 × 105/kg) and 1.42 × 107/kg (range, 0.69 to 3.2 × 107/kg). The median time to engraftment was 27 days for neutrophils and 53 days for platelets. One patient experienced graft rejection and was subsequently rescued with a salvage transplantation. The median time to a CD3+ cell count >100/μL was 30 days. The 2-year cumulative incidence of moderate-to-severe chronic GVHD (cGVHD) was 11.8%. At 2 years, overall survival was 52.7% (95% CI, 33% to 69%), relapse incidence was 30.7% (95% CI, 13.7% to 49.6%), and transplantation-related mortality was 29% (95% CI, 14.3% to 45.6%).
Conclusions: IB infusion of a single cord blood unit was feasible, with no adverse reactions related to the no wash/IB infusion, low rates of cGVHD and disease relapse, and rapid immune reconstitution.
Outcomes of graft failure after umbilical cord blood transplantation in acute leukemia: a study from Eurocord and the Acute Leukemia Working Party of the EBMT. Baron F, et al. Bone Marrow Transplantation, 2023 University and CHU of Liege, GIGA-I3, Liege, Belgium The outcomes of patients who experienced graft failure after CBT were analyzed.
Methods: Inclusion criteria were patients (age ≥ 18 years) experiencing graft failure after unrelated CBT (single or double) between 2005 and 2016, for acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL), no prior allogeneic or autologous transplantation, no other stem cell product.
Findings: The study included 87 patients. At 1-year, cumulative incidence of relapse and non-relapse mortality (NRM) was 35% and 37%, respectively. One-year overall survival (OS) and progression-free survival (PFS) was 40% and 29%, respectively. Forty-six patients underwent a salvage second transplantation with 1-year and 2-year OS and PFS from second transplantation 41% and 34% for OS, and 37% and 34% for PFS, respectively. In multivariate analysis, complete remission (CR) at CBT and reduced-intensity conditioning were associated with better OS.
Conclusions: In this retrospective study, approximately one-quarter of patients experiencing graft failure after CBT remained alive without relapse 2 years later.
Dynamic comparison of early immune reactions and immune cell reconstitution after umbilical cord blood transplantation and peripheral blood stem cell transplantation. Zhao X, et al. Frontiers in Immunology, 2023 University of Science and Technology of China, Hefei, Anhui, China The differences in the immune cell reconstitution and the immune reactions during initial stages post-transplantation are not well established between UCBT and PBSCT.
Methods: Authors analyzed the differences in the immune reactions during the early stages such as pre-engraftment syndrome (PES), engraftment syndrome (ES), and acute graft-versus-host disease (aGVHD) and the immune cell reconstitution between the UCBT and the PBSCT group of patients. They enrolled a cohort of patients that underwent UCBT or PBSCT and healthy controls (n=25 each).
Findings: The incidences of early immune reactions such as PES, ES, and aGVHD were significantly higher in the UCBT group compared to the PBSCT group. Furthermore, in comparison with the PBSCT group, the UCBT group showed higher proportion and numbers of naïve CD4+ T cells, lower proportion and numbers of Tregs, higher proportion of CD8+ T cells with increased activity, and higher proportion of mature CD56dim CD16+ NK cells during the early stages post-transplantation. Moreover, the plasma levels of GM-CSF were significantly higher in the UCBT group compared to the PBSCT group in the third week after transplantation. Overall, our findings demonstrated significant differences in the post-transplantation immune cell reconstitution between the UCBT and the PBSCT group of patients.
Conclusions: These characteristics were associated with significant differences between the UCBT and the PBSCT groups regarding the incidences of immune reactions during the early stages post transplantation.
Epitope Mismatch at HLA-DRB1 Associates with Reduced Relapse Risk in Cord Blood Transplantation for Standard-Risk Hematologic Malignancy. Morita-Fujita M, et al. Transplantation and Cellular Therapy, 2023 Kyoto University, Kyoto, Japan Given that HLA molecules contain epitopes comprising polymorphic amino acids that determine their immunogenicity, authors investigated associations between epitope-level HLA mismatches and relapse following single-unit CBT.
Methods: A total of 492 patients with hematologic malignancies who underwent single-unit, T cell-replete CBT were included in this multicenter retrospective study. HLA epitope mismatches (EMs) were quantified using HLA matchmaker software from donor and recipient HLA-A, -B, -C, and -DRB1 allele data.
Findings: Patients were dichotomized by median EM value and divided into 2 groups: patients who underwent transplantation in complete/partial remission and others. The median number of EMs in the graft-versus-host direction (GVH-EM) was 3 (range, 0 to 16) at HLA class I and 1 (range, 0 to 7) at HLA-DRB1. Higher HLA class I GVH-EM was associated with increased nonrelapse mortality (NRM) in the advanced stage group, with no significant advantage for relapse in either stage. In contrast, higher HLA-DRB1 GVH-EM was associated with better disease-free survival in the standard stage group, which was attributed to lower relapse risk.
Conclusions: High HLA-DRB1 GVH-EM may lead to potent GVT effects and a favorable prognosis following CBT, especially in patients who underwent transplantation at the standard stage. This approach may facilitate appropriate unit selection and improve the overall prognosis of patients with hematologic malignancies who undergo CBT.
Effect of Graft-versus-Host Disease on Post-Transplantation Outcomes following Single Cord Blood Transplantation Compared with Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for Adult Acute Myeloid Leukemia. Konuma T, et al. Transplantation and Cellular Therapy, 2023 The Institute of Medical Science, The University of Tokyo, Tokyo, Japan The objective of this retrospective study was to compare the effect of acute GVHD and chronic GVHD on post-transplantation outcomes between recipients of CBT and recipients of PTCy-haplo-HCT.
Methods: Authors retrospectively evaluated the effect of acute and chronic GVHD on post-transplantation outcomes following CBT and PTCy-haplo-HCT in adults with AML (n = 1981) between 2014 and 2020 using a Japanese registry database.
Findings: In univariate analysis, the probability of overall survival was significantly greater in patients who developed grade I-II acute GVHD and limited chronic GVHD among CBT recipients, but these effects were not significant among PTCy-haplo-HCT recipients. In multivariate analysis, in which the development of GVHD was treated as a time-dependent covariate, the effect of grade I-II acute GVHD on reducing overall mortality differed significantly between CBT and PTCy-haplo-HCT (adjusted hazard ratio [HR] for CBT, 0.73, 95% confidence interval [CI], 0.60 to 0.87; adjusted HR for PTCy-haplo-HCT, 1.07; 95% CI, 0.70 to 1.64; P for interaction = 0.038).
Conclusions: Grade I-II acute GVHD was associated with a significant improvement in overall mortality in adults with AML receiving CBT but not in recipients of PTCy-haplo-HCT.
Impact of allele-level HLA matching on outcomes after double cord blood transplantation in adults with malignancies. Fatobene G, et al. Blood Advances, 2023 Universidade de Sao Paulo, Sao Paulo, Brazil In this study, authors report the impact of allele-level HLA matching on the outcomes of a large double UCBT (dUCBT) cohort.
Methods: Authors included 963 adults with hematologic malignancies, with available allele-level HLA matching at HLA-A, -B, -C, and -DRB1, receiving dUCBT between 2006 to 2019. Assignment of donor-recipient HLA match was performed considering the unit with the highest disparity with the recipient. Three hundred ninety-two patients received dUCBT with 0 to 3 MM and 571 with ≥4 allele MM.
Findings: For recipients of dUCBT with 0 to 3 MM, day-100 and 4-year TRM were 10% and 23%, respectively, compared with 16% and 36% for those with ≥4 MM. A higher degree of allele MM was also associated with the worse neutrophil recovery and lower incidence of relapse; no significant effect on graft-versus-host disease was observed. Patients receiving units with 0 to 3 MM had a 4-year OS of 54% compared with 43% for those receiving units with ≥4 MM. The inferior OS associated with higher HLA disparity was only partially mitigated by increased total nucleated cell doses.
Conclusions: The results confirm that allele-level HLA typing is a significant factor for OS after dUCBT, and units with ≥4 MM (≤4/8 HLA-matched) should be avoided if possible.
A Portrait of Cord Blood Units Distributed for Transplantation from Canadian Blood Services' Cord Blood Bank: First Analysis. Parmar G, et al. Current Oncology, 2022 Canadian Blood Services, Ottawa, Canada The Canadian Blood Services Cord Blood Bank (CBS CBB) was created to improve access to stem cell products for transplantation for patients across ethnic groups. An analysis of distributed units is needed to assess the effectiveness of the bank to meet the needs of patients from different ethnic groups.
Methods: A descriptive analysis was performed on all cord blood units distributed from the CBS' CBB as of 30 June 2022.
Findings: Distribution of the first 60 units based on CBS' CBB inventory has been linear over time. A similar proportion of cord blood unit (CBU) recipients were pediatric or adult. More than half of the cord blood units (56.7%) were distributed to recipients outside of Canada, and CBUs were used to treat a broad range of hematologic and immune disorders. 43.3% of distributed CBUs were of non-Caucasian ethnicity and 18% were from donors self-reporting as multi-ethnic. The mean total nucleated cell counts and total CD34+ cell counts were 1.9 ± 0.1 × 109 cells and 5.3 ± 0.5 × 106 CD34+ cells, respectively. CD34+ cells per kg (recipient weight) varied significantly between pediatric (age 0-4), adolescent (age 5-17) and adult recipients (age 18 and older) (3.1 ± 0.5, 1.4 ± 0.5 and 0.9 ± 0.07 × 105 CD34+ cells/kg, respectively). HLA matching was 6/6 (15%), 5/6 (47%) or 4/6 (38%).
Conclusions: The CBS' CBB has facilitated the utilization of banked units for patients across a broad range of ages, geographic distribution, ethnicity, and diseases. Distributed units were well matched for HLA alleles and contained robust cell counts, reflecting a high-quality inventory with significant utility.
Clinical Outcomes of Umbilical Cord Blood Transplantation Using Ex Vivo Expansion: A Systematic Review and Meta-Analysis of Controlled Studies. Saiyin T, et al. Transplantation and Cellular Therapy, 2023 University of Ottawa, Ottawa, Ontario, Canada Ex vivo culture strategies have been increasingly evaluated in controlled studies, but their impact on transplantation-related outcomes remains uncertain owing to the small patient numbers in these studies, necessitating an updated systematic review and meta-analysis.
Methods: A systematic literature search was conducted using the MEDLINE, Embase, and Cochrane databases to March 18, 2022. Nine cohort-controlled phase I to III trials were identified, and data of 1146 patients undergoing umbilical cord blood transplantation (UCBT) were analyzed (308 ex vivo expanded and 838 unmanipulated controls). Expansion strategies involved cytokine cocktails plus the addition of small molecules (UM171, nicotinamide [NiCord], copper chelation, Notch ligand, or Stem regenin-1 [SR-1]) and coculture with mesenchymal stromal cells in a single-unit transplant strategy (5 studies) or a double-unit transplant strategy with 1 unmanipulated unit (4 studies).
Findings: The included trials reported a median ex vivo expansion of CD34+ cells from 28-fold to 330-fold. Eight of the 9 studies demonstrated a significantly faster time to initial neutrophil and platelet engraftment using expanded cells compared with controls. Studies using UM171 and NiCord in single-unit UCBT and SR-1 or NiCord double-unit UCBT demonstrated long-term donor chimerism of the expanded unit at 100 days to 36 months post-transplantation in all single-unit recipients and in 35% to 78% of double-unit recipients. Our meta-analysis revealed a lower risk of death at the study endpoint in patients who received ex vivo expanded grafts (odds ratio [OR], 0.66; 95% confidence interval [CI], 0.47 to 0.95; P = 0.02), while the risk of grade II-IV acute graft-versus-host disease was unchanged (OR, 0.79; 95% CI, 0.58 to 1.08; P = 0.14).
Conclusions: This review indicates that UCBT following ex vivo expansion can accelerate initial engraftment. Durable donor chimerism can be achieved after transplanting cord blood units expanded using NiCord, UM171, or SR-1; however, long term outcomes remain unclear.
Cord Blood Transplantation for Nonmalignant Disorders: Early Functional Immunity and High Survival Martinez C et al, Blood Advances, 2022 There is no consensus about the best donor for children with non-malignant disorders and immune deficiencies in the absence of a matched related donor (MRD).
Rafii H et al, Blood Advances, 2022 Subsequent neoplasms (SNs) compromise long-term survivors after hematopoietic cell transplantation.
Sugita J et al. Bone Marrow Transplantation, 2022 HLA-haploidentical stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) and unrelated cord blood transplant are alternative to HLA-matched stem cell transplantation.
Wada F et al, Transplantation, 2022 Unrelated cord blood (UCB) and haploidentical related donor transplantation using post-transplant cyclophosphamide (PTCy-haplo) have become alternative options to treat patients with hematological malignancies without an HLA-matched donor.
Zarrabi M et al, BMC Neurology, 2022 In this multi-center, randomized, double blind, placebo-controlled study, the authors assessed the safety and efficacy cord blood-derived mononuclear cell in pediatric patients with cerebral palsy. Systemic Administration of Allogeneic Cord Blood Mononuclear Cells in Adults with Severe Acute Contusion Spinal Cord Injury: Phase 1/2a Pilot Clinical Study-Safety and Primary Efficacy Evaluation Smirnov V et al, World Neurosurgery, 2022 In this Phase I trial, the authors evaluated the safety and efficacy of systemic administration of cord blood mononuclear cells in patients with acute severe spinal cord contusion. Cheng L et al, Signal Transduction Targeted Therapy, 2022 The authors investigated the immunomodulatory and clinical effect of cord blood-derived mesenchymal stem cells (MSCs) in patients with psoriasis, a chronic immune-mediated systemic disease that has no definitive treatment.
Zhang C et al, Stem Cell Research and Therapy, 2022 The authors evaluated the safety and efficacy of cord blood-derived mesenchymal stem cells (MSCs) in patients with diabetic foot ulcer.
Kanda J, et al, Bone Marrow Transplant, 2021 The impact of GVHD and graft-versus-leukemia effect in unrelated cord blood transplantation (UCBT) is controversial.
Wagner JE, et al, Blood Advances 2021 Most reports comparing haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with posttransplant cyclophosphamide (PTCy) and other donor sources have focused on outcomes in older adults treated with reduced intensity conditioning.
Brunstein CG, et al. Transplantation and Cellular Therapy, 2021 It is unknown whether a higher dose of total body irradiation (TBI) could improve engraftment rate or other transplant outcomes for less heavily treated patients.
Horwitz ME, et al. Blood, 2021 Omidubicel is an ex vivo expanded hematopoietic progenitor cell and nonexpanded myeloid and lymphoid cell product derived from a single umbilical cord blood unit.
Konuma T, et al. Transplantation and Cellular Therapy, 2021 Comparative data for cord blood transplantation (CBT) and haploidentical related donor hematopoietic cell transplantation (haplo-HCT) are limited for adult patients with acute myeloid leukemia (AML) in complete remission (CR).
Nishida T et al. Annals of Hematology, 2021 Delayed engraftment is still an unmet issue in umbilical cord blood (UCB) transplants. Parikh S et al. Blood Advances, 2021 Historically, patients with sickle cell disease transplanted with umbilical cord blood (UCB) had unacceptable rate of graft failure.
Lanzoni G et al. Stem Cells Translational Medicine, 2021 Mesenchymal stem cells’ anti-inflammatory properties might be effective in acute respiratory distress syndrome in patients with COVID-19
Dilogo IH, Stem Cells Translational Medicine, 2021 Umbilical cord blood-derived mesenchymal stromal cells are known to favor a more anti-inflammatory microenvironment.
Amanat M et al. Stem Cell Research & Therapy, 2021 In this study, authors assessed safety and efficacy of intrathecal injection of umbilical cord blood-derived MSC in patients with spastic cerebral palsy.
Yang Y et al. Cytotherapy, 2021 Umbilical cord blood-derived mesenchymal stem cells are a potential treatment for severe spinal cord injury. SELECTED ABSTRACTS: 2023 EBMT Annual MeetingRobert Wynn – optimizing AML outcomes using CB in UK experience. Dr Wynn compared the outcomes of 112 children with acute myeloid leukemia (AML) undergoing T cell replete CB transplant versus 255 AML children who received transplant from other stem cell source, including matched unrelated donors (n=136), sibling donor (n=63), mismatched unrelated donor (n=36), haploidentical (n=11) and T cell deplete CB (n=9). All patients were transplanted in the same time frame, between 2014 and 2021. When patients were stratified by the minimal residual disease (MRD) status at the time of the transplant, no significant difference was seen between the two groups in terms of event free survival (EFS) among patients transplanted with a negative MRD. However, patients transplanted with a detectable MRD had a higher probability of long-term remission if they had received a T cell replete CB transplant (Figure): 2-year EFS 50% vs 21%, p=0.017 and relapse rate 36.2% vs 66.2%, p=0.007, confirming the data reported by other groups (Milano et al, 2016). Overall survival did not differ significantly between CB and non-CB cohort due to higher transplant-related mortality in the CB cohort, again remarking the need to work toward improving management of transplant-related complication. Dr Wynn also presented a prospective trial that will open in late 2023 that will randomize paediatric patients with AML in CR1 or CR2 to receiving expanded CB versus non-CB graft sources (expansion will use UM171 platform, as previously described by Cohen, Lancet Hametol 2020). Dr Wynn reported preliminary data on trial NCT05425043, which adopt third party granulocyte transfusion early after CB transplant to accelerate immune recovery in patients with relapsed/refractory diseases who failed a previous BMT. Seven doses of granulocytes infusions are planned according to trial design, starting from day +1 after CBT. Ten patients have been treated so far; granulocyte infusions were overall well tolerated, with some degree of cytokine release syndrome and, importantly, transient robust donor derived CD8 T cell expansion, which could potentially implement leukemic cell eradication, as suggested by pre clinic data. Five patients from the trial are still in complete remission, four died of disease relapse and one due to transplant-related complication.
Vinod K Prasad – Newborn screening for Hurler syndrome leads to early treatment and excellent outcomes with unrelated umbilical cord blood transplant. Dr. Prasad presented the data of CB transplants in children diagnosed with Hurler syndrome, a rare autosomal recessive, lysosomal storage disorder that is associate with early, progressive developmental delay, skeletal abnormalities, cognitive impairment, cardiovascular and respiratory problems. Early transplant, possibly at 4-5 months of age, is recommended to maximize the survival outcomes. A total of 10 patients were treated with CB transplants; all but three were below six months of age at the time of the transplant. Enzyme level prior to CBT was undetectable in all but one patient. All patients received a busulfan based, ATG containing conditioning regimen. Patients were followed for a median of 2.4 years (range 0.2 – 6.1). Engraftment rate of favourable (Figure): neutrophils (>500/mmc) and platelet (>50,000/mmc) engraftment occurred in all patients after a median of 16 and 56 days, respectively. All patients achieved complete donor chimerism with normal enzyme level at last evaluation. None experienced graft failure. Complications included veno-occlusive disease (n=2), haemolytic anemia (n=3, one of which was fatal), and microangiopathy (n=1). None developed severe acute or chronic GvHD. The authors concluded that children with Hurler syndrome can be successfully treated with CBT with favourable outcomes.
Elizabeth Hicks - Outcomes of UCB transplant in children with chronic granulomatous disease In this poster presentation, Dr Hicks reported the outcomes of 19 children with CGD treated between 2005 and 2022. Median age at transplant was 2.4 years. All but one had prior history of bacterial and fungal infection, in most cases with recurrent episodes, including pneumonia, cellulitis, and enteritis. In three cases, CB was from a related donor. HLA matching include 4/6 (n=5), 5/6 (n=12) and 6/6 (n=2). All received busulfan based, myeloablative conditioning regimen, with ATG. After a median follow up of 6 years, 16 patients are still alive and disease free; two died due to transplant-related cause, and one for Duchenne syndrome, undiagnosed at the time of the transplant. Three patients had graft failure which required a subsequent transplant. None developed CGD-related infection after transplant. Two patients had high grade acute GVHD, whereas two experienced extensive chronic GVHD. The authors concluded supporting the use of CB in paediatric patients with CGD lacking HLA identical donor.
Vanderson Rocha – is there a role of CB in pediatric setting in the future? Dr Rocha reported registry data from Eurocord and Duke University, which collected data from a large cohort of 1995 children who underwent CB transplant between 1993 and 2019 for a non-malignant disorder. The aim of this retrospective study was to evaluate how did CB transplant outcomes change over the course of the time. Decades 1990-2004, 2005-2009 and 2010-2019 were analysed separately, as well as primary disease (inborn errors, primary immunodeficiency and aplastic anaemia). In all three disease-category, survival outcomes significantly improved overtime (Table), mostly due to better knowledge of CB selection and post-transplant management. Regardless timeframe, a trend toward a better outcome was seen in ATG-free and myeloablative conditioning setting, as well as with younger patient age, better patient-CB HLA matching and negative patient CMV serostatus. Similar analysis was performed for 3205 paediatric patients with malignant disorders, divided per myeloid or lymphoid leukemia. Also in this setting, patients transplanted after 2010 had a significant survival improvement. Use of total body irradiation and myeloablative conditioning also had a favourable impact. The author concluded by remarking the favourable outcomes in terms of disease relapse and long-term complications (e.g. chronic GVHD) in selected patients category undergoing CB transplant.
SELECTED ABSTRACTS: 2023 Cord Blood Connect International CongressUmbilical Cord Blood Treatment to Improve Gross Motor Function in Individuals with Cerebral Palsy: Results from an Individual Participant Data Meta-Analysis Megan Finch-Edmondson, et al Umbilical Cord Blood Transplantation (UCBT) is an emerging treatment for cerebral palsy. Methods: A meta analysis was conducted looking at 9 published and 2 unpublished studies, including 7 randomized clinical trials. Long-Term Stability of Cord Blood Units after > 29 years of cryopreservation: follow-up data from the Jose Carreras Cord Blood Bank Stefanie Liedtke, et al The Jose Carreras Cord Blood Bank has over 21,000 umbilical cord blood (UCB) units and has released 1476 UCB units for Umbilical Cord Blood Transplant (UCBT). The study analyzes the stability of units under long term storage. SELECTED ABSTRACTS: 2022 Cord Blood Connect International CongressSafety of DUOC-01, Intrathecal Cord Blood-Derived Cellular Therapy, as an Adjunct to Allogeneic Cord Blood Transplantation in Children with Inherited Metabolic Diseases Sun J et al. Duke University, Durham, North Carolina, USA Unrelated umbilical cord blood transplantation (UCBT) improves function and extends life in children with inherited metabolic disorders. Neurologic disease can progress after UCBT, prior to donor engraftment in the brain. DUOC-01 is a monocyte-derived cord blood cell product, designed to accelerate donor cell delivery to the brain. Methods: DUOC-01 was manufactured from cord blood units. Cells were given intrathecally. Forty children, ages 0-15, received umbilical cord blood transplant. Thirty patients received DUOC-01 cells intrathecally at a median of 31 days post-transplant.
Stoltzman C et al. Deverra Therapeutics and Fred Hutchinson Cancer Center, Seattle, Washington, USA Chimeric antigen receptor (CAR) expression by natural killer (NK) cells may improve the potency and specificity for the NK cells anti-tumor efficacy. NK CAR cells may be a safer and more cost-effective way to deliver CAR T cell therapy. Methods: CD 56+ NK cells are generated from cord blood-derived NK cells. The cells are transduced with a viral vector that targets a protein specific for acute lymphoid leukemia (ALL). A mouse model was used to test the cell product.
Laskowitz D et al. Duke University, Durham, North Carolina, USA Stroke is the 5th leading cause of death in the United States, and current treatments are not effective in all patients. The purpose of this study was to determine if infusion of a non-HLA matched unrelated umbilical cord blood unit (UCB) unit can improve outcomes. Methods: A Phase II, multicenter, randomized, placebo-controlled study was performed in several U.S. centers. Cord blood units were infused 3-10 days post stroke. The primary endpoint was a change in the Modified Rankin Scale, a scale of functional activity.
Frenet E et al. New York Blood Center, New York, New York, USA The National Cord Blood Program has an inventory of more than 60,000 cord blood units for clinical transplant use. This study characterizes the current inventory and the distributed cord blood units. It recommends the collection strategy moving forward. Methods: 1,046 shipments of unrelated cord blood (UCB) from 2015 to 2022 were studied. Race/ethnicity, HLA match and cell dose information was reviewed.
Hematopoietic Stem Cell Transplantation (HSCT) with Omidubicel Is Associated with Enhanced Circulatory Plasmacytoid Dendritic Cells (pDC), NK Cells and CD4+ T Cells with Lower Rates of Severe Infections Compared to Standard Umbilical Cord Blood Transplantation Szabolcs P et al. University of Pittsburg, Pittsburg, Pennsylvania, USA Methods: This was a sub-study of a recently reported randomized Phase III study comparing myeloablative transplantation with omidubicel versus standard umbilical cord blood transplantation. Samples and data were obtained from 17 subjects transplanted with omidubicel and 20 patients transplanted with standard umbilical cord blood grafts.
Cotton M et al. Duke University, Durham, North Carolina, USA Methods: This is a Phase I study of allogeneic umbilical cord tissue-derived mesenchymal stromal cells given to infants with hypoxic-ischemic encephalopathy.
Lund P et al. University of Minnesota, Minneapolis, Minnesota, USA Methods: The investigators compared leukocyte lysate and plasma iduronidase activity in patients with Hurler Syndrome who had received umbilical cord blood (n=20) and bone marrow transplantation (n=9).
Politikos I et al. Weill Cornell Medical College, New York, New York, USA Methods: The investigators report the efficacy and toxicity of a 6-month course (instead of the standard 3-month course) of letermovir as prophylactic treatment against cytomegalovirus in recipients of umbilical cord blood transplantation. SELECTED ABSTRACTS: 2021 Cord Blood Connect International Congress
Umbilical Cord Blood and Umbilical Cord Tissue Mesenchymal Stromal Cells in Children with Cerebral Palsy: A Randomized Trial Sun J et al. Duke University, Durham, North Carolina, USA Small studies have demonstrated the safety of umbilical cord blood (CB) and mesenchymal stromal cells (MSC) in children with cerebral palsy (CP), but have been limited by small sample sizes and heterogeneous patient populations. This study describes improvement in gross motor function in children with CP after treatment with allogeneic unrelated donor CB or allogeneic, third-party, human cord tissue-derived MSC. Methods: 90 children ages 2-4 years with CP participated in a Phase 2 trial. Patients were randomized to allogeneic CB, allogenic MSC, or standard of care. Identification and Successful Re-Consent of Existing Cord Blood Donors for the Creation of Induced Pluripotent Stem Cell Lines Abberton K et al. BMDI Cord Blood Bank, Victoria, Australia Induced pluripotent stem cell (iPSC) lines made from cord blood (CB) could help with a supply of stem cells for new cell-based therapies. This study looks at the consent process for donors that had already donated cord blood. Methods: The team identified suitable cord blood units, confirmed HLA typing, and reviewed the medical/family history. A Donor Information and Consent Form (DICF) and “permission to contact” form was mailed to selected donors, followed by a phone interview and signing of consent form. SELECTED ABSTRACTS: 2021 EBMT Annual MeetingResults of a Phase III Randomized, Multicenter Study Comparing Omidubicel with Standard Umbilical Cord Blood Transplantation (UCBT) in Patients with High-Risk Hematologic Malignancies following Myeloablation Guillermo F et al, University of Valencia, Spain In this phase III study, Guillermo and colleagues presented their experience with Omidubicel, a cryopreserved cellular product derived from a single UCB unit expanded ex vivo. The authors have previously demonstrated in a phase I-II trial the safety of Omidubicel and pointed at a rapid and robust hematopoietic reconstitution after its use. Methods: In this multicenter trial, 125 subjects were randomized to receive either Omidubicel or standard UCB (single or double UCBs) between 2017 and 2020; both TBI-based and TBI-free myeloablative conditioning regimens were adopted, GvHD prophylaxis consisted of a calcineurin inhibitor and MMF. Primary endpoint of the study was time to neutrophil engraftment.
Results: Sixty-two patients received Omidubicel (study group) and 63 received standard UCB (single unit 33% or double unit 67%, control group). Median age was 41 years (range, 13–65); 81% of patients suffered from acute leukemia. Median CD34+ cell dose for Omidubicel recipients was 9 × 106/kg (124-fold CD34+ cell expansion) and 0.3 × 106/kg for controls (P < 0.0001). Patients were followed for a median of 10 months (range, 1–19 months). Median time to neutrophil engraftment was 12 days (95% CI, 10–15 days) in the study group and 22 days (95% CI,19–25 days) in the control group (P < 0.001). Furthermore, the authors reported a higher incidence of 42-day platelet engraftment in the study group, as well as a lower incidence of grade 2–3 bacterial/invasive fungal infection, a lower rate of viral infections, and a reduction in time spent in hospital during the first post-transplant 100 days (median 39 vs. 52 days); all these differences were statistically significant. No statistically significant differences were seen in acute and chronic GvHD rate between the two groups. There were no statistically significant differences also in survival outcomes, although there was an improving trend in the study group (1-y overall survival and 6-month non-relapse mortality were 73% and 11% in patients receiving Omidubicel, and 62% and 22% in the control group).
Conclusions: The authors concluded that, given the faster hematopoietic engraftment and the lower early transplant-related complications rate, as compared to standard UCB transplants, the use of Omidubicel should be considered in clinical routine.
Long-Term Outcomes after Intrabone Unrelated Umbilical Cord Blood Transplant in Patients with Hematological Malignancies: A Eurocord, CTIWPEBMT Analysis Peccatori J et al, San Raffaele Scientific Institute, Italy The direct intra-bone injection of umbilical cord blood (UCB) transplant has been previously reported by other authors (Frassoni et al, 2008, Bonifazi et al, 2018, etc), who demonstrated its safety and feasibility. The authors speculated that the direct infusion of the cellular product into the bone marrow would expose the UCB cells directly to the stem cell niche, improving cellular survival and potentially, indirectly, transplant outcomes. Methods: In this study, Peccatori and colleagues reported the long-term outcomes of single UCB intra-bone transplants performed in patients with hematologic malignancies in fifteen transplant centers (Eurocord/ EBMT-centers).
Results: A total of 223 patients received an intra-bone UCB transplant between 2006 and 2019. In 30 cases, this was a second allogeneic transplant. More than 90% of patients were adults, for a median age at transplant of 41.4 years. Median follow-up was 9 years; acute leukemia was the most represented diagnosis (74%) and 61% were transplanted in disease remission. Myeloablative conditioning was adopted in 76% of cases; after 2010, most centers used ATG-free UCB transplant platforms. At cryopreservation, median total nucleated cells number was 3.3x107/Kg, and CD34+ was 1.43x105/Kg. UCB units were match at 5/6 and 4/6 HLA loci in 30% and 72%, respectively. At day 60, cumulative incidence of neutrophil engraftment was 79% (95%CI 74 – 85, median time 24 days), whereas at day 180 cumulative incidence for platelet engraftment was 63% (95%CI 57- 70, median time 37 days). Day 100 cumulative incidence of acute GVHD of any grade was 18%, (only 9 cases had grade 3-4 acute GvHD). At median follow up, cumulative incidence of chronic-GVHD was 37%, with only 17 cases of severe chronic GvHD; cumulative incidence of relapse was 34% (95%CI 27-42). At 5-years, overall survival was 33% and disease-free survival was 30%. Day 100 non relapse mortality was 22%, with infection being the most frequent cause of death. Female gender, disease type (MDS/MPN versus AML/ALL) and stage (remission versus not in remission) at transplant, and number of previous transplants (none versus one or more) were associated with improved survival.
Conclusion: The authors concluded that intra-bone infusion of UCB was overall safe and provided durable disease control, and suggested that this route of administration should be investigated also for ex-vivo expanded cellular products.
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