Research Advances

By Karen Ballen, MD, Michael Horwitz, MD, Junya Kanda, MD, PhD, and Elisabetta Xue, MD
Updated:  July 2021


High Progression-Free Survival after Intermediate Intensity Double Unit Cord Blood Transplantation in Adults

Barker J et al, Blood Advances, 2020
Memorial Sloan Kettering Cancer Center, New York, NY, USA

Cord blood transplantation (CBT) after high intensity or nonmyeloablative conditioning has limitations.
Methods: The study investigated cyclosporine-A/mycophenolate mofetil-based intermediate intensity (cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 10 mg/kg, total body irradiation 400 cGy) unmanipulated double-unit CBT (dCBT) with prioritization of unit quality and CD34+ cell dose in graft selection.
Findings: The cumulative incidences of sustained CB engraftment, day 180 grade III-IV acute, and 3-year chronic graft-versus-host disease were 99%, 24%, and 7%, respectively. Three-year transplant-related mortality and relapse incidences were 15% and 9%, respectively. Three-year overall survival is 82%, and progression-free survival (PFS) is 76%. In 52 remission acute leukemia patients, there was no association between minimal residual disease (MRD) and 3-year PFS: MRD negative of 88% vs MRD positive of 77% (P = 0.375).
Conclusions: Intermediate intensity dCBT is associated with high PFS. Use of highly HLA mismatched and unmanipulated grafts permits wide application of this therapy, and the low relapse rates support robust graft-versus-leukemia effects even in patients with MRD.

Optimizing Selection of Double Cord Blood Units for Transplantation of Adult Patients with Malignant Diseases

Fatobene G et al, Blood Advances, 2020
Eurocord, Paris, France

Current guidelines on unrelated cord blood (UCB) unit selection are mainly based on single-unit UCB data.
Methods: A total of 1375 adult recipients of DUCBT for hematologic malignancies were retrospectively analyzed to determine optimal criteria for graft selection for double-unit unrelated cord blood transplantation (DUCBT).
Findings: Cryopreserved CD34+ cell dose ≥0.7 × 105/kg in the winning UCB was associated with improved overall survival. Low total nucleated cell (TNC) (≤3.5 × 107/kg) and CD34+ (≤1.4 × 105/kg) cell doses were related to decreased neutrophil recovery. DUCBT recipients with ≥2 HLA mismatches had a higher incidence of grade II-IV and III-IV acute graft-versus-host disease.
Conclusions: The data support selecting adequately HLA-matched UCB units with a double-unit cryopreserved TNC dose >3.5 × 107/kg and CD34+ cell dose of ≥0.7 × 105/kg per unit in DUCBT candidates.

Impact of T-cell Repertoire Diversity on Mortality following Cord Blood Transplantation

Milano F et al, Frontiers in Oncology, 2020
Fred Hutchinson Cancer Research Center, USA

There are no data on the association of T-cell receptor (TCR) and clinical outcomes after cord blood transplantation (CBT).
Methods: Peripheral blood (PB) samples of 34 CBT patients was collected for retrospective analysis of immune recovery utilizing high-throughput sequencing of TCRβ rearrangements from genomic DNA extracted from PB mononuclear cells.
Results: Rapid turnover of T-cell clones was observed at each time point, with TCR repertoires stabilizing by 1-year posttransplant. TCR diversity values at day 100 for patients who died between 100 and 365 days posttransplant were significantly lower than those of the surviving patients (p = 0.01).
Conclusions: Using a fast high-throughput TCR sequencing assay, the study demonstrated that high TCR diversity is associated with better patient outcomes following CBT. Importantly, this assay is easily performed on posttransplant PB samples, even as early as day 28 posttransplant, making it an excellent candidate for early identification of patients at high risk of death.

Updated Comparison of 7/8 HLA Allele-Matched Unrelated Bone Marrow Transplantation and Single-Unit Umbilical Cord Blood Transplantation as Alternative Donors in Adults with Acute Lukemia

Miyao K et al, Biology of Blood and Marrow Transplantation, 2020
Anjo Kosei Hospital, Japan

The outcomes of 7/8 allele-matched unrelated bone marrow transplantation (7/8 UBMT) and umbilical cord blood transplantation (UCBT) have been improving.
Methods: Adults with acute leukemia who underwent their first 7/8 UBMT or UCBT in Japan were analyzed.
Results: Overall survival at 3 years was 54% for 7/8 the UBMT group and 46% for the UCBT group, a nonsignificant difference in multivariate analysis. The 7/8 UBMT and UCBT groups showed a similar non-relapse mortality rate and relapse rate. However, the UCBT group had a lower risk of grade II-IV acute GVHD (HR, 0.76; 95% CI, 0.65 to 0.88; P < .001) and chronic GVHD (HR, 0.77; 95% CI, 0.66- 0.91; P = 0.002) compared with the 7/8 UBMT group.
Conclusions: Both 7/8 UBMT and UCBT are appropriate alternative donor procedures.

Double Unrelated Umbilical Cord Blood versus HLA-Haploidentical Bone Marrow Transplantation (BMT CTN 1101)

Fuchs E et al, Blood, 2020
Sidney Kimmel Cancer Center at Johns Hopkins University, USA

Two parallel Phase II trials of transplantation of unrelated umbilical cord blood and bone marrow from HLA-haploidentical relatives provided equipoise for direct comparison of the donor sources.
Methods: Between June 2012 and June 2018, 368 patients aged 18-70 years with chemotherapy-sensitive lymphoma or acute leukemia in remission were randomly assigned to undergo cord blood (n=186) or haploidentical (n=182) transplant.
Results: Two-year progression-free survival was 35% compared to 41% after cord blood and haploidentical transplants, respectively (p=0.41). Pre-specified analysis of secondary endpoints recorded higher 2-year non-relapse mortality after cord blood, 18% compared to haploidentical transplantation, 11%, p=0.04. This led to lower 2-year overall survival after cord blood compared to haploidentical transplantation, 46% and 57%, respectively (p=0.04).
Conclusion: The trial did not demonstrate a statistically significant difference in the primary endpoint, 2-year progression-free survival, between the donor sources. While both donor sources extend access to reduced intensity transplantation, analyses of secondary endpoints, including overall survival, favor haploidentical bone marrow donors.

Umbilical Cord Blood-Derived ILC1-like Cells Constitute a Novel Precursor for Mature KIR+NKG2A- NK Cells

SB Bennstein et al, eLife, 2020  
Heinrich-Heine University Düsseldorf, Germany

The study aimed at dissecting the developmental relationship between human ILC1 and NK cells in umbilical cord blood (CB).
Methods: CB ILC1 and both NK cell subsets (CD56dim and CD56bright NK cells) were sorted for transcriptomic comparison via RNA sequencing. The developmental potential of CB ILC1 was explored by single cell cloning and in vitro differentiation assays.
Findings:  The study demonstrates that neonatal ILC1-like cells are very different from NK cells on the transcriptional, epigenetic, and functional level but instead constitute a potent NK cell precursor (NKP). The ILC1-like NKP is distinguished from previously defined NKPs and ILCPs by the absence of CD117, the presence of T cell-specific molecules such as CD5 and CD6, and the property to generate diversified NK cell repertoires characterized by KIR expression as well as the downregulation of NKG2A.
Conclusion: Based on this data, a branched model of NK cell development is proposed, where where CB ILC1-like cells as well as CD56bright NK cells both harbor NKP potential and contribute to the diverse phenotypes seen in CD56dim NK cell in vivo.

GMP-Grade CD34
+Selection from HLA-Homozygous Licensed Cord Blood Units and Short-Term Expansion under European ATMP Regulations

Liedtke S et al, Vox Sang, 2020
University Clinic, Düsseldorf

Based on a synergistic consortium, the Düsseldorf cord blood bank Düsseldorf was responsible for the selection of HLA-homozygous donors (HLA-h), re-consenting the mothers, GMP-grade CD34+ enrichment, followed by short term expansion of CD34+ cells and qualification as advanced therapy medicinal product.
Methods: Among 20,639 licensed cord blood units (CBUs), 139 potential donors were identified with the most frequent 10 German haplotypes and, for 47.5%, consent was obtained. Thawing/washing of CBUs was performed in the presence of Volulyte/HSA with Sepax, CD34+ selection by automated GMP-grade CliniMACS-system, expansion with qualified GMP-grade cytokines in the GMP-facility.
Findings: The investigators confirmed that n=10 CB units with a maximal storage time of 16 years with >80% CD34+ purity and > 70%viability after CD34+ selection could be expanded until day 3/4 to a mean purity of 86.0 +10.38% and a viability of 96.07+4.72% and provided for reprogramming.
Conclusions: Approval by the local government was obtained for this product as a starting material under European ATMP regulations as a requirement for clinical translation and implementation of a qualified manufacturing process. This approach considers the main obstacle of rejection of transplanted cells by preselection of HLA-homozygous transplants.

Effect of Graft-versus-Host Disease on Outcomes after Pediatric Single Cord Blood Transplantation

Kanda J et al, Bone Marrow Transplantation, 2020
Kyoto University, Japan

The effect of GVHD on transplant outcomes after unrelated cord blood transplantation (UCBT) is not yet fully understood.
Methods: Pediatric patients aged 0-15 years with acute leukemia or myelodysplastic syndrome who underwent their first UCBT (n = 740) were selected from the Japanese registry.
Findings: The occurrence of grade III-IV acute GVHD was associated with a higher risk of non-relapse mortality compared with no acute GVHD. Grade I-II acute GVHD was not associated with non-relapse mortality. The occurrence of grade I-II or grade III-IV acute GVHD was not associated with a relapse risk. The occurrence of limited chronic GVHD was associated with a low risk of overall mortality.
Conclusions: Severe acute GVHD should be prevented because of its association with high overall mortality and non-relapse mortality in pediatric single UCBT. Mild acute GVHD provides no overall benefit. Mild chronic GVHD may be beneficial for survival.


Adult Cord Blood Transplant Results in Comparable Overall Survival and Improved GRFS vs Matched Related Transplant

Sharma P et al, Blood Advances, 2020
University of Colorado, USA

Methods: Outcomes among adult matched related donor (MRD) patients undergoing peripheral blood stem cell transplantation and adult patients undergoing double unit CBT were compared.
Findings: A total of 190 CBT patients were compared with 123 MRD patients. Comparing all CBT with all MRD patients, overall survival (OS) was comparable and GVHD relapse-free survival (GRFS) was significantly improved among CBT patients. Among patients undergoing most commonly used MRD and CB myeloablative regimens, OS was comparable and GRFS was significantly improved among CBT patients. Cumulative incidence of relapse trended toward decreased in the CBT group, whereas transplant-related mortality was comparable.
Conclusions: Among patients able to tolerate more intensive conditioning regimens at high risk for relapse, CB may be the preferred donor source.

Splenomegaly Negatively Impacts Neutrophil Engraftment in Cord Blood Transplantation

Yuasa M et al, Biology of Blood and Marrow Transplantation, 2020
Toranomon Hospital, Japan

Splenomegaly exerts negative effects on neutrophil engraftment, but the appropriate cell dose for the patients with splenomegaly has not yet been determined, especially in CBT.
Methods: We retrospectively investigated the effect of splenomegaly and number of CD34+ cells infused on neutrophil engraftment through the analysis of outcomes of 502 consecutive patients who underwent single CBT for the first time at Toranomon Hospital between 2011 and 2018.
Findings: Splenomegaly and low dose of infused CD34+ cells had significant negative impact on neutrophil engraftment, whereas neither CFU-GM dose nor TNC dose had any impact on neutrophil engraftment in multivariate analysis. Without splenomegaly, even patients infused with <0.8 × 105/kg CD34+ cells achieved up to 94.3% neutrophil engraftment, with the median value observed at 21 days post-CBT.
Conclusions: This study shows that aplenomegaly has a significant negative impact on neutrophil engraftment after CBT. Cord blood units with <0.8× 105/kg CD34+ cells may still be a suitable choice for patients without splenomegaly.

Optimal Donor for African Americans with Hematologic Malignancy: HLA-Haploidentical Relative or Umbilical Cord Blood Transplant

Solomon SR et al, Biology of Blood and Marrow Transplantation, 2020
Northside Hospital, USA

As only about 20% of African Americans will have an HLA-matched unrelated donor, many of these patients undergo HLA-haploidentical relative or umbilical cord blood transplantation.
Methods: The current analyses studied transplant-outcomes after HLA-haploidentical relative (n=249) and umbilical cord blood (n=118) transplants for African Americans with hematologic malignancy between 2008 and 2016.
Findings: Grade II-IV and III-IV acute GVHD was higher after umbilical cord blood (56% and 29%, respectively) compared to HLA-haploidentical relative transplantation (33% and 11%). The 2-year incidence of transplant-related mortality adjusted for age and conditioning regimen intensity was higher after umbilical cord blood compared to HLA-haploidentical relative transplantation (31% versus 18%, p=0.008). However, there were no differences in the 2-year adjusted incidence of relapse (30% versus 34%, p=0.51), overall survival (54% versus 57%, p=0.66), or disease-free survival (43% versus 47%, p=0.46).
Conclusions: HLA-haploidentical and umbilical cord blood extend access to transplantation with comparable leukemia-free and overall survival for African Americans with hematologic malignancy.

Prognostic Factors for Adult Single Cord Blood Transplantation among European and Japanese Populations: the Eurocord/ALWP-EBMT and JSHCT/JDCHCT Collaborative Study

Kanda J et al, Leukemia, 2020
Kyoto University, Japan

Large differences in patient and transplant backgrounds make it difficult to identify consistent prognostic factors of unrelated cord blood transplantation (UCBT) among different populations.
Methods: Adults with acute leukemia who underwent a single UCBT were eligible. In total, 3764 and 1027 patients of the JSHCT/JDCHCT and Eurocord/ALWP-EBMT registries, respectively, were included.
Findings: The median total nucleated cell (TNC) counts were 2.58 and 3.51 × 10*7/kg in the Japanese and European cohorts, respectively. Anti-thymocyte globulin was used in only 2% of the Japanese cohort compared with 65% of the European cohort. In the multivariate analysis, TNC dose and HLA matching had no significant effect on overall survival in either cohort, whereas transplant year, age, and disease risk affected overall survival in both cohorts.
Conclusion: Despite considerable differences in characteristics between the Japanese and European cohorts, similar prognostic factors affecting UCBT outcomes were identified.

Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors

Liu E et al, New England Journal of Medicine, 2020
M.D. Anderson Cancer Center, USA

In this phase 1 - 2 trial, 11 patients with relapsed/refractory CD19+ malignancies received HLA-mismatched anti-CD19 CAR-NK cells derived from umbilical cord blood units.
Methods: NK cells were isolated and transduced with a retroviral vector expressing genes that encode anti-CD19 CAR. Furthermore, they were also transduced with interleukin-15 to improve survival and long-term persistence, and inducible caspase 9 as a safety switch. The cells were expanded ex vivo and administered in a single infusion at one of three doses (1×105, 1×106, or 1×107 CAR-NK cells per kilogram of body weight) after lymphodepleting chemotherapy.
Findings: No cytokine release syndrome, neurotoxicity and graft versus host disease were documented. The maximum tolerated dose was not reached. 73% (8/11) had a clinical response. Responses were rapid and seen within 30 days after infusion at all dose levels. The infused CAR-NK cells expanded and persisted at low levels for at least 12 months.
Conclusion: Among 11 patients with relapsed or refractory CD19-positive cancers, a majority had a response to treatment with CAR-NK cells without the development of major toxic effects.

Successful Umbilical Cord Blood Transplantation in Children with Leukocyte Adhesion Deficiency Type I

Qian X et al, Translational Pediatrics, 2020
Children’s Hospital of Fudan University, Shanghai

This study aims to investigate the efficacy and safety of cord blood transplantation (CBT) without serotherapy for treating children with leukocyte adhesion deficiency type I (LAD-I).
Methods: Five patients with LAD-I received CBT with myeloablative, busulfan-based conditioning, at a median age of 9 months.
Findings: Neutrophil and platelet engraftment were achieved after 20 (r 13-28) and 36 days (r 32-56) respectively, all 5 achieved full donor chimerism. Two patients developed grade III-IV GvHD. After a median follow up of 19 months, 4 out of 5 patients were alive and well.
Conclusion: Umbilical cord blood transplantation is an effective treatment method for LAD-I patients. Also, severe LAD-I patients should undergo stem cell transplantation as early as possible.

Locally Delivered Umbilical Cord Mesenchymal Stromal Cells Reduce Chronic Inflammation in Long-Term Nonhealing Wounds: A Randomized Study

Suzdaltseva Y et al, Stem Cells International, 2020
Vavilov Institute of General Genetics, Russia

In this randomized, placebo-controlled study, the authors investigated the ability of umbilical cord derived mesenchymal stromal cells (MSCs) to regulate chronic inflammation in patients with nonhealing wounds.
Methods: 108 patients with chronic wounds of different etiologies were enrolled: study group (n=59) received a single local subcutaneous infusion of UC-derived MSCs around the wound, whereas control group (n=49) received placebo.
Findings: The study group showed marked growth of granulation tissue, improved blood microcirculation, and reduction in wound size compared to the placebo group; complete wound resolution was achieved in 22% in the study group and 8.2% in the placebo group.
Conclusion: Locally delivered allogeneic umbilical cord MSCs can contribute to chronic wound repair and provide an additional support toward new therapeutic strategies.

Allogeneic Umbilical Cord-Derived Mesenchymal Stem Cell Transplantation for Treating Chronic Obstructive Pulmonary Disease: a Pilot Clinical Study

Bich P et al, Stem Cell Research and Therapy, 2020
Van Hanh General Hospital, Viet Nam

This study investigated the safety and efficacy of umbilical cord-derived (UC)- mesenchymal stem cells (MSCs) for treating chronic obstructive pulmonary disease (COPD).
Methods: Twenty patients were included, 9 at stage C and 11 at stage D per the Global Initiative for Obstructive Lung Disease (GOLD) classification. Patients received 10cells/kg of expanded allogeneic UC-MSCs.
Findings: No infusion-related toxicities or severe adverse events were documented. At a 6-month evaluation, patients showed significant improvement of several outcomes of COPD and reduced the number of exacerbations, likely due to downregulated inflammation.
Conclusion: Systemic UC-derived MSCs administration were safe in patients with moderate-to-severe COPD, can significantly improve their quality of life, and provides a basis for subsequent cell therapy investigations.

Therapeutic Evidence of Umbilical Cord-Derived Mesenchymal Stem Cell Transplantation for Cerebral Palsy: a Randomized, Controlled Trial

Gu J et al, Stem Cell Research and Therapy, 2020
First Affiliated Hospital of Xi’an Jiaotong University, People’s Republic of China

This randomized, placebo-controlled study aimed to evaluate the safety and efficacy of UC-derived MSC transplantation concomitant with rehabilitation in patients with cerebral palsy.
Methods: In addition to rehabilitation, patients in the study group (n=20) received four transfusions of UC-derived MSCs intravenously, while the control group (n=20) received placebo.
Findings: The study showed that hUC-MSC transplantation was safe and feasible and was not related to higher incidence of adverse events. Furthermore, the study group showed a significant improvement in activities of daily living, comprehensive function assessment and gross motor function measure. Five patients from the study group and 8 from the control group received PET/CT scan as optional assessment to explore cerebral glucose metabolism; 0/8 cases from the control group and 3/5 cases from the study group showed an increase in the SUV at 1 year evaluation.
Conclusion: Recovery of cerebral metabolic activity might play an essential role in brain function improvement in patients with cerebral palsy.

High Incidence of Acute Kidney Injury after Cord Blood Transplant

E Xue et al, Biology of Blood and Marrow Transplantation, 2020
Fred Hutchinson Cancer Research Center, USA

In this retrospective study, the authors aimed to identify incidence and risk factors of acute kidney injury (AKI) in 276 patients who received CBT for hematologic malignancies and to evaluate the impact of AKI on transplant outcome.
Methods: AKI was staged using the Kidney Disease Improving Global Outcomes (KDIGO) system (stages 1-3). Most (88%) patients received myeloablative conditioning regimen, including high dose total body irradiation. 41%, 16% and 11% patients developed a maximum of stage 1, stage 2 and stage 3 AKI, respectively.
Findings: As expected, stage 2-3 AKI was associated with higher 1-year NRM and decreased overall survival. In MV analysis, bilirubin level was significantly associated with AK.
Conclusion: The use of steroids was associated with lower risk of developing AKI. The protective effect exerted by steroids is of clinical interest and warrants further investigation.

Hematopoietic Stem Cell Transplantation Using Single UM171-Expanded Cord Blood: a Single-Arm, Phase 1-2 Safety and Feasibility Study

Cohen S et al, Lancet Haematology, 2020
Maisonneuve-Rosemont Hospital, Canada

Authors investigated the safety and feasibility of single UM171-expanded cord blood transplantation in patients with hematological malignancies who do not have a suitable HLA-matched donor.
Methods: Patients were infused with the 7-day UM171-expanded CD34-positive cells and the lymphocyte-containing CD34-negative fraction.
Findings: Among the 22 patients who received single UM171-expanded cord blood transplantation, median time to engraftment of 100 neutrophils per μL was 9·5 days (IQR 8-12), median time to engraftment of 500 neutrophils per μL was 18 days (12·5-20·0), and no graft failure occurred.
Conclusion: UM171 cord blood stem cell expansion is feasible, safe, and allows for the use of small single cords without compromising engraftment.


Results 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.

SELECTED ABSTRACT:  2021 Transplantation and Cellular Therapy Meetings

MGTA-456, A CD34 Expanded Cord Blood Product, Permits Selection of Better HLA Matched Units and Results in Rapid Hematopoietic Recovery, Uniform Engraftment and Reduced Graft-Versus-Host Disease in Adults with High-Risk Hematologic Malignancies

Stefanski et al, University of Minnesota, USA

Methods:  The primary objective of the study was to determine if MGTA-456, an ex-vivo expanded umbilical cord blood-derived stem cell graft, improved outcomes by allowing for use of smaller but better matched umbilical cord blood units. Eighteen adult and pediatric patients with hematologic malignancies received myeloablative conditioning followed by allogeneic stem cell transplantation with MGTA-456.
Results:  Twenty-two patients were enrolled in the study and 18 were transplanted. Neutrophil engraftment was achieved in all patients at a median of 17 days.  The lower cell dose threshold provided by use of MGTA-456 allowed for use of better matched units compared to historical controls. This translated into a lower incidence of acute GvHD.
Conclusion:  MGTA-456 allows for the use of smaller, better matched umbilical cord blood units to be selected for transplantation. This has the potential to improve outcomes by reducing the risk of GvHD.

SELECTED ABSTRACTS:  2020 American Society of Hematology Annual Meeting

Rapid Engraftment, Immune Recovery, and Resolution of Transfusion Dependence in Treatment-Refractory Severe Aplastic Anemia Following Transplantation with Ex Vivo Expanded Umbilical Cord Blood (Omidubicel)

Samour M et al, National Heart Lung and Blood Institute, USA

Methods:  Adult and pediatric patients with transfusion dependent severe aplastic anemia, failure or intolerance of immunosuppressive therapy and lack of an HLA-identical stem cell donor were eligible for the study.  Eight subjects received non-myeloablative conditioning followed by transplantation with either a haploidentical stem cell graft in combination with an ex-vivo expanded umbilical cord blood stem cell graft (omidubicel) OR an omidubicel-only stem cell graft.
Results:  Seven of 8 subjects achieved sustained cord blood engraftment.  One patient died of an adenovirus infection. 
Conclusion:  The study demonstrates the feasibility of transplantation with omidubicel in heavily pre-treated patients with aplastic anemia.

Comparison of Haploidentical Donor Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide to Matched-Sibling, Matched-Unrelated, Mismatched-Unrelated, and Umbilical Cord Blood Donor Transplantation in Adults with Acute Lymphoblastic Leukemia: A CIBMTR Study

Wieduwilt M et al, University of California, San Diego

Methods:  Retrospective analysis using the CIBMTR database comparing outcomes of haploidentical donor hematopoietic cell transplantation using post-transplant cyclophosphamide to matched-sibling, matched-unrelated, mismatched-unrelated, and umbilical cord.
Results:  For the entire cohort of 4,201 patients, haploidentical transplantation using post-transplant cyclophosphamide for patients with acute lymphoblastic leukemia resulted in superior overall survival and leukemia-free survival compared to umbilical cord blood transplantation.
Conclusion:  For patients with ALL who do not have a matched adult donor, haploidentical HCT with post-transplant cyclophosphamide may be the preferred graft source.

Alternative Donor Hematopoietic Cell Transplantation for Pediatric, Adolescent and Young Adult (PAYA) with Hematological Diseases

Karras N et al., City of Hope National Medical Center

Methods:  Retrospective, single-center (City of Hope, Duarte Calif.) comparison of PAYA patients undergoing myeloablative allogeneic HCT with either a matched unrelated, haploidentical or umbilical cord blood stem cell donor.  319 patients aged 1-39 were included.
Results:  Umbilical cord blood transplantation was associated with a lower relapse rate compared to matched unrelated donor transplantation. However, survival was worse in recipients of umbilical cord blood due to a higher non-relapse mortality rate, possibly due to more infections in these patients.
Conclusion:   Techniques to reduce the risk of infections following umbilical cord blood transplant are needed to improve outcomes.


Effect of Single or Double Mismatches at Each HLA Locus on the Outcomes after Single Cord Blood Transplantation: The JSHCT HLA WG Study

Junya Kanda et al, Kyoto University, Japan

This analysis identifies the effect of HLA locus mismatches on CBT outcome.

Methods:  4074 adults who received a first CBT between 2003 and 2017 were included. The impact of HLA mismatches was analysed after adjusting for other variables.
Results:  There was no impact of specific HLA locus mismatches on overall survival. Both single and double -B and double -DRB1 mismatches were associated with higher non-relapse mortality, whereas, double -A and -DRB1 mismatches and single -B mismatch were associated with a lower relapse risk. Higher risk of II-IV and III-IV acute GVHD was seen with either single or double HLA-DRB1 mismatches; single mismatch at the -A and -B loci also were associated with III-IV acute GVHD.
Conclusion:  Given the association of double -DRB1 mismatch with higher II-IV and III-IV GVHD, higher NRM and lower relapse risk, the authors concluded that not only locus mismatch but also the number of mismatches at the DRB1 locus should be considered in CBU selection.

An “All in One” T-cell Product from Non-Transplantable Cord Blood Units for Virus- and Leukemia-Specific T-cell Immunotherapy

Kyriakos Koukoulias et al, George Papanicolaou Hospital, Greece

The authors aimed to generate an “all-in-one” T-cell product with both AML antigen- and virus antigen- specific T-cells (LEVIS) starting from non-transplantable umbilical cord blood units.

Methods:  Matured CD34+-derived dendritic cells from CBU were stimulated with both leukemic (WT1 and PRAME antigen) and viral (from EBV, CMV, AdV and BKV) peptide mixes and used to “educate” naïve T-cells.
Results:  The resultant LEVIS products contain both CD4+ and CD8+ polyclonal population, expressing effector memory markers, with low amount of naïve and regulatory T-cells. LEVIS demonstrated low expression levels of PD-1 and of CTLA-4. Also, LEVIS showed high specificity against all targeted antigens suggesting successful T cell “training” and lack of antigen competition.
Conclusion:  Non-transplantable CBUs might represent the future for third-party, “off-the-shelf” immunotherapy tool for improving the outcome of allogeneic transplants.

The Use of Post-Transplant Cyclophosphamide (PT-Cy) in Unrelated Umbilical Cord Blood Transplantation

Patrizia Chiusolo et al, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Italy

The use of anti-thymocyte globulin makes immune recovery slow in CBT setting. The authors aimed to substitute it with high-dose post-transplant cyclophosphamide (PT-CY) and analyze its effect on CBT outcome. 

Methods:  Ten adults diagnosed with acute leukaemia or myelodysplasia were enrolled. Conditioning regimen was TBF (Thiotepa, Busulfan, Fludarabine) and PT-CY 30 mg/kg on days+3&+5; patients received cyclosporine and mycophenolate mofetil. The median nucleated cell dose was 3.1x107/kg.
Results:   Median time to ANC > 0.5x109/l and PLT > 20x109/l was day 23 days (range 17-27) and 38 days (range 34-40), respectively. Two patients failed to engraft. The median CD4+ count on day +100 was 111/uL (range 100-136). CMV requiring treatment occurred in 3/6 evaluable patients. After a median follow up of 231 days, seven patients are alive and well; two patients died early of infections. None required treatment for acute/chronic GVHD, and none relapsed.
Conclusion:  The use of PT-CY in CBT feasible and leads to encouraging hematologic and immunologic recovery.

SELECTED ABSTRACTS:  2020 Cord Blood Connect International Congress

Targeting Neuroinflammation with Human Umbilical Cord Tissue-Derived Mesenchymal Stromal Cells

Min H et al, Duke University, USA

Mesenchymal stromal cells (MSCs) are a form of cellular therapy that reduces inflammation. Inflammation is common in many neurologic diseases, such as multiple sclerosis.  Umbilical cord tissue-derived MSCs were used in a mouse model of demyelinating neurologic disease.

Methods:  Umbilical cord tissue-derived MSCs lines were prepared from donated cord tissue from healthy, term, c-section deliveries, under GMP conditions. To monitor physical interactions between cells, the authors stained hCT-MSCs with cell tracking dyes and then assessed the response of monocytes and macrophages (immune system cells) by RNA sequencing and functional T cell suppression assays. Control and genetically manipulated umbilical cord tissue-derived  cells were studied in a mouse model of demyelination.
Results:  Macrophages engulfed cytoplasmic components of umbilical cord blood-derived MSCs and  suppressed T cells.  The cells enhanced remyelination in the spinal cord after induced demyelination.
Conclusion:  The authors determined that hCT-MSCs program macrophages to suppress T cells and enhance remyelination of the spinal cord.  These cells can alter the immune response and may be beneficial for the treatment of neurologic diseases.


Single UM171-Expanded Cord Blood Transplants Support Robust T-Cell Reconstitution with Low Rates of Severe Infections

Dumon-Lagace M et al, ExCellThera Inc., Hôpital Maisonneuve-Rosemont, Montréal, Quebec, Canada

Rapid T cell (immune system) recovery following stem cell transplantation is essential for protection against infections and has been associated with improved survival. Umbilical cord blood (UCB) transplants are associated with lower rates of chronic graft vs host disease and relapse, but the slower immune recovery leads to a higher risk of infections. Results of a smaller phase I/II trial revealed that a single expanded CB transplant allowed the use of smaller CB units without compromising engraftment.

Methods:  The authors performed a retrospective analysis of a cohort of 20 patients treated with UM171-expanded CB and compared it to a contemporary cohort of 12 patients treated in the same institution who received unmanipulated CB transplant with similar conditioning regimens.
Results:  The median T cell dose in the expanded graft was at least 2 to 3 times lower, but the phenotype of T cells at 3, 6, and 12 months post-transplant were similar between the two cohorts. T cell receptor sequencing analyses revealed that UM171 patients had greater T cell diversity at 12 months post-transplant. UM171 patients showed a significantly reduced incidence of severe infections, especially for bacterial and viral infections.
Conclusions:  These results suggest that patients receiving UM171 expanded cord blood units benefit from rapid T cell reconstitution, and have fewer infections.