Research Advances

By Karen Ballen, MD, Michael Horwitz, MD, and Elisabetta Xue, MD
Updated:  August 2020

RECENTLY PUBLISHED ARTICLES

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.


Unlicensed Umbilical Cord Blood Units Provide a Safe and Effective Graft Source for a Diverse Population: A Study of 2456 Umbilical Cord Blood Recipients

Ballen K et al, Biology of Blood and Marrow Transplantation, 2019
University of Virginia Health System

In 2011, the U.S. Food and Drug Administration (FDA) required that unrelated umbilical cord blood transplantation (UCBT) use either licensed umbilical cord blood (UCB) or unlicensed UCB via an Investigational New Drug (IND). To allow for widespread use of the unlicensed units, the National Marrow Donor Program (NMDP) managed an IND to study outcomes of UCBT using unlicensed units.
Methods: 2456 patients (1499 adults and 957 children; among the children 564 malignant disease and 393 non-malignant disease) received single or double UCBT between October 2011 and December 2016.Median age was 31 years (<1 to 81); 50% of children and 36% of adults were non-Caucasian.
Findings: Median days to neutrophil engraftment (absolute neutrophil count ≥ 500/mm3) were 22, 20 and 19 days for adults, children with cancer, and children with non-malignant diseases, respectively. One year overall survival (OS) was 57%, 71%, and 79% for adults, children with cancer, and children with non-malignant diseases. In multivariate analysis, younger age, early stage, chemotherapy sensitive disease, and higher performance score predicted improved OS for adults. In a subset analysis of children with malignancies receiving single UCBT, use of either licensed (n=48) or unlicensed UCB (n=382) was associated with similar engraftment and survival.
Conclusion: Use of unlicensed UCB units is safe, effective and provides an important graft source for a diverse population. Further studies will look at the effect of licensure on UCBT outcomes.


No Engraftment Advantage after Single or Double Umbilical Cord Blood Transplant (CBT) with the Addition of a Non-HLA Matched Off-the-Shelf Expanded Cord Blood Unit Compared to Conventional CBT: Results of a Randomized Trial

Milano F et al, Blood, 2019
Fred Hutchinson Cancer Research Center, USA

In this multi-center randomized controlled phase II trial, the authors investigated the effect of the infusion of an off-the-shelf non-HLA matched expanded cord blood unit along with an unmanipulated unit on transplant outcome.
Methods: 160 patients with hematologic malignancies were enrolled to receive a cord blood transplant (CBT) with or without the expanded graft.
Findings: The authors found no significant difference in primary endpoint (neutrophil engraftment). In particular, they documented a time to neutrophil recovery in the control group 7 days faster than historically reported. No significant differences were documented also in secondary endpoints (platelet engraftment, overall survival, disease free-survival, acute/chronic graft-versus-host disease, non-relapse mortality, and relapse).
Conclusion: The improvement in CB donor selection criteria, as well as the higher quality of the CB inventory, might explain these results.

Safety and Feasibility of Virus-Specific T Cells Derived from Umbilical Cord Blood in Cord Blood Transplant Recipients

Abraham A et al,  Immunobiology and Immunotherapy, 2019
George Washington University, USA

In this study, the authors investigated the use of ex vivo expanded virus-specific T (VST) cells in single UCB transplant pediatric recipients.
Methods: A small fraction (20%) of the main CB unit was separated and CB-derived T cells were expanded ex vivo and subsequently manufactured to generate multi-virus specific T cells, targeting EBV, CMV and adenovirus. The remaining 80% of the unit was used for the primary CBT. 14 patients received VST cell infusion. Among the 7 patients who received VST cells as part of antiviral prophylaxis, only 1 had viral reactivation requiring treatments; no one developed end-organ viral disease. Among the 7 patients who received VST cells as part of antiviral treatment, only one case developed end-organ viral disease, which occurred in an immune privileged site (CMV retinitis), whereas the others showed complete infection resolution.
Findings: No delayed engraftment and no increase of GvHD after VST cells infusion were observed. The VST cells were demonstrated to persist long term after infusion.
Conclusion: These data suggest that CB-VSTs are a feasible tool for antiviral pharmacotherapy.

Allogeneic Human Umbilical Cord Mesenchymal Stem Cells for the Treatment of Autism Spectrum Disorder in Children: Safety Profile and Effect on Cytokine Levels

Riordan N et al, Stem Cells Translational Medicine, 2019
MediStem Panama, Inc., Republic of Panama

Immune dysregulation and inflammation have been linked to children with autism spectrum disorder, the latter manifesting in serum levels of macrophage-derived chemokine (MDC) and thymus and activation-regulated chemokine (TARC). This study aimed to investigate the safety and efficacy of umbilical cord derived- mesenchymal stem cells, known for their immune-modulatory and anti-inflammatory properties, in treating children with ASD.
Methods: 20 patients received UC-derived MSCs infusion every 12 weeks, up to 4 four infusions. Efficacy was evaluated with the Autism Treatment Evaluation Checklist (ATEC) and the Childhood Autism Rating Scale (CARS), and with measurements of MDC and TARC serum levels.
Findings: The infusion was safe, with no major adverse events related to treatment. According to the CARS and ATEC scores, 8/20 patients had clinical improvement after treatment. MDC and TARC inflammatory cytokine levels also decreased for five of these eight subjects.
Conclusion:  The treatment was safe and links between immune regulation and ASD should be further investigated.

Hematopoietic Stem Cell Transplantation with Unrelated Cord Blood or Haploidentical Donor Grafts in Adult Patients with Secondary Acute Myeloid Leukemia, a Comparative Study from Eurocord and the ALWP EBMT

Ruggeri A et al, Bone Marrow Transplantation, 2019
IRCCS Bambino Gesù Children's Hospital, Italy

Survival of patients with secondary acute myeloid leukemia (sAML) is poor. Cord blood transplantation (UCBT) and non-T-cell-depleted stem cell transplantation from haploidentical donors (HAPLO) are both strategies that have shown encouraging results in patients who do not have an HLA-matched sibling or unrelated donor.
Methods: Outcomes of 409 adults with sAML receiving either UCBT (n = 163) or HAPLO (n = 246) in EBMT centers were retrospectively analyzed.
Findings: In multivariate analysis, UCBT was associated with higher risk of grade II-IV acute GVHD and lower GHVD-free-relapse-free-survival (GRFS) compared to HAPLO.
Conclusion: These results indicate that HAPLO is associated with better GRFS and lower aGVHD compared to UCBT in patients with sAML.

 

SELECTED ABSTRACTS:  2019 American Society of Hematology Annual Meeting

Outcomes of Chronic Graft-Versus-Host Disease following Matched Sibling Donor versus Umbilical Cord Blood Transplant

Okoev G et al, University of Minnesota, USA

Single center retrospective study of 104 patients receiving matched sibling donor (MSD) and 41 patients receiving umbilical cord blood transplantation (UCBT).
Findings:  Severe chronic graft-versus-host disease (cGVHD) was more common following MSD transplantation.  Liver GVHD was more common in MSD peripheral blood stem cell transplant (PBSCT), whereas GI involvement was significantly more frequent in UCBT.  There was no difference in treatment response to cGVHD between MSD and UCBT.
Conclusion:  The treatment response to cGVHD was the same for recipients of matched sibling donor and umbilical cord blood transplantation.

Romiplostim Improves Platelet Recovery after Umbilical Cord Blood Transplant

Christakopoulos C et al,  University of Minnesota, USA

Single center dose-escalation study of romiplostim for patients who failed to achieve platelet recovery by day +28 following umbilical cord blood transplantation (UCBT).  21 patients were enrolled.
Findings:  All patients treated with romiplostim achieved platelet engraftment (>20 x 109/L) by day +45.  The maximum tolerated dose was determined to be 10mcg/kg/d.
Conclusions:  Romiplostim appears safe and well tolerated for management of delayed platelet recovery following UCBT.  Larger, confirmatory studies are justified.


Comparison of Outcomes between Hematopoietic Stem Cell Transplant Donor Sources for Pediatric Patients with Hematologic Malignancies

Longo L et al,  Fred Hutchinson Cancer Research Center, USA

Retrospective analysis of the outcomes of 232 pediatric hematopoietic stem cell transplant recipients with 56 matched sibling donors, 89 matched unrelated donors, and 87 umbilical cord blood donors.
Findings:  There was no difference in 5-year unadjusted overall survival or non-relapse mortality between the groups.  The risk of disease relapse was significantly lower for recipients of umbilical cord blood grafts.
Conclusion:  This study is consistent with a previously reported study of adult patients from the same research center, suggesting a potent graft-versus-tumor response from the umbilical cord blood graft.


High Incidence of Herpes Zoster after Cord Blood Hematopoietic Cell Transplant Despite Longer Duration of Antiviral Prophylaxis

Xue E et al, Fred Hutchinson Cancer Research Center, USA

Retrospective assessment of the incidence of herpes zoster after umbilical cord blood transplantation (UCBT).
Findings:  The cumulative incidence of herpes zoster following UCBT was 1.8% at 1 year,  and 26% at 5 years.  Disseminated herpes zoster occurred in 5 cases (11%), and post-herpetic neuralgia occurred in 14 cases (31.8%).
Conclusion:  Herpes zoster occurs commonly after UBCT, particularly once herpes zoster prophylaxis is discontinued.  Until an effective vaccine strategy emerges, UBCT recipients should remain on long-term zoster prophylactic medications.


Unrelated Cord Blood Transplantation and Post-Transplant Cyclophosphamide

Chiusolo P et al, Universitario Agostino Gemelli, Italy

Pilot study to test feasibility of post-transplantation cyclophosphamide (PT-CY) as a graft-versus-host disease (GVHD) prophylaxis for recipients of umbilical cord blood transplantation (UCBT).
Findings:  10 patients received myeloablative conditioning with thiotepa (10 mg/kg), busulfan (9.6 mg/kg) and fludarabine (150 mg/m) (TBF). GVHD prophylaxis was cyclosporin, myophenolate mofetil and PT-CY (30 mg/kg days +3 and +5).   Of the 8 patients evaluable for engraftment, one patient experienced graft failure.  Mild acute GVHD was observed in 1 patient.
Conclusion:  Post-transplant cyclophosphamide following UCBT appears feasible.  More experience is needed to assess the risk of graft failure and the delay in hematopoietic recovery.

 


SELECTED ABSTRACTS:  2019 Cord Blood Connect International Congress

Impact of Zika Virus (ZIKV) Risk on Public Cord Blood Banking

Andromachi S et al, New York Blood Center, USA

Introduction: Mothers at risk for ZIKV exposure are declared ineligible donors.
Methods: Cord blood units collected at 5 collection sites. Detailed travel and residency history reviewed.
Findings: Of 4,153 cord blood units banked from 2016 to 2018, 1,141 (27%) were from ineligible donors. 803 had only ZIKV risk, and 48 had ZIKV and other risks. ZIKV risk units were higher in Hispanic donors. No difference in total nucleated cell count and colony forming units between KIKV risk and other donors.
Conclusions: ZIKV risk has a major financial impact on cord blood banking. An FDA approved screening test is urgently needed. 


Expanded Access Protocol of Umbilical Cord Blood Infusion for Children with Neurological Conditions

McLaughlin C et al, Duke University, USA

Introduction: Intravenous infusion of banked autologous and sibling cord blood has been tested in Phase I/II studies. An expanded access program is offering access to treatment.
Methods: Children with autism and cerebral palsy eligible. Cord blood must meet quality and viability characteristics.
Findings: 276 children received 302 cord blood infusions. 4% had transient infusion reaction. 2% positive cultures post thaw. Variable response to cord blood infusion.
Conclusions: Cord blood infusions tolerated well. Efficacy still to be determined from Phase II/III studies.


The Effects of Caffeine Intake and Passive Smoking on Umbilical Cord Blood Unit Quality Parameters

Alasmari A et al, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

Introduction: Cord blood banks are investigating novel strategies to increase nucleated cells in collected units.
Methods: Information on smoking and caffeine use collected from donor mothers.
Findings: Mothers with high caffeine use had lower nucleated cell count (-40%) and CD34+ content (-70%) than mothers who did not use caffeine. Mothers exposed to passive smoke had slightly lower total nucleated cell count viability (-1.7%).
Conclusions: Caffeine use can negatively affect cord blood collections. This information may be used by cord blood banks to increase efficiency of cord blood collection programs.

 


SELECTED ABSTRACTS:  2018 Cord Blood Connect International Congress

Excellent Outcomes after Umbilical Cord Blood Transplantation Using a Centralized Cord Blood Registry 

Ballen K et al, University of Virginia and National Marrow Donor Program (NMDP)/Center for International Blood and Marrow Transplant Research (CIBMTR), USA

Introduction:  In 2011, the FDA introduced licensure of umbilical cord blood (UCB) units.  Less than 10% of the available UCB units are licensed. What are the clinical results with unlicensed units?
Methods:  The analysis included 982 adults and 607 children receiving UCB transplants using unlicensed UCB units under an IND managed by the NMDP. Patients received transplants between 2011 and 2014 (preliminary updated data through 2016 presented orally). 47% of children and 34% of adults were non-Caucasian.
Findings:  The median days to neutrophil engraftment was, respectively, 22, 20, and 19 days for adults, children with malignant diseases, and children with non-malignant disease. One-year overall survival was, respectively, 55%, 67%, and 79% for adults, children with malignant disease, and children with non-malignant disease respectively. Overall survival was similar for Caucasian and Black/African American patients.
Conclusion:  Unlicensed UCB units are safe and effective, serve a diverse population, and should continue to be available.

 
Microbial Contamination in Umbilical Cord Blood: A Comparison Before and After Cryopreservation

Li M et al, Cord Life, Singapore

Introduction:  Accurate testing of microbial contamination is essential to safe cord blood banking. Umbilical cord blood (UCB) contamination is usually tested with a very small sample.
Methods:  Seventy-six contaminated umbilical cord blood (UCB) samples were tested. Samples were frozen in dimethyl sulfoxide (DMSO), thawed, and injected into a blood culture bottle.
Findings:  11 strains of microorganisms were detected prior to cryopreservation. 10 strains were detected post thaw. Some of the streptococcus species did not survive the freezing process. Growth was observed in 28% of the Bacteroides contaminated samples. 54% of the cultures were positive post thaw.  A 10 ml sample showed better sensitivity in microbial contamination than a 1 ml sample.
Conclusion:  Some bacteria strains do not survive the freezing process. These results could have implications for public and family banking.

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

Min H, Duke University, USA

Introduction:  Neuroinflammation is common in many demyelinating diseases, such multiple sclerosis and cerebral palsy. The aim of the study was to test if mesenchymal stromal cells (MSC) derived from human cord tissue promote remyelination in a mouse model.
Methods:  Multiple cell lines of MSC developed. These were injected into mice with a disease similar to multiple sclerosis, autoimmune encephalomyelitis.
Findings:  The human cord tissue-derived MSC promoted remyelination in the spinal cord in the mouse model, and also inhibited activation of the microglial cells. In addition, the MSC suppressed the activation of immune cells ex vivo.
Conclusion:  These preliminary experiments are encouraging and suggest that human cord tissue-derived MSC may regulate the immune cells of the central nervous system, and promote remyelination.

 


SELECTED ABSTRACTS:  2018 Blood and Marrow Transplant Tandem Meetings

Single Cord Blood Units (CBU) Expanded with an Aryl Hydrocarbon Receptor (AHR) Antagonist, Demonstrate Uniform Engraftment and Rapid Hematopoietic Recovery

Wagner J et al, University of Minnesota, USA

Methods:  Phase I/II single center study of myeloablative and non-myeloablative transplantation using a single umbilical cord blood graft expanded ex vivo with MGTA-456 (aryl hydrocarbon receptor antagonist) (Magenta Therapeutics).
Findings:  Ten patients received myeloablative (TBI-based) (MAC) conditioning and 10 patients received non-myeloablative conditioning (NMAC) followed by transplantation of the MGTA-456 expanded single umbilical cord blood unit.  MAC recipients engrafted at a median of 14 days post transplantation and NMAC patients engrafted at a median of 7 days.
Conclusion:  Time to engraftment can be shortened with the use of an umbilical cord blood graft that is expanded ex vivo with MGTA-456.


Nicord Single Unit Expanded Umbilical Cord Blood Transplantation (UCBT): Final Results of a Multicenter Phase I/II Trial

Horwitz M et al, Duke University, USA

Methods:  Thirty-six patients at 11 centers received myeloablative conditioning followed by transplantation of a single umbilical cord blood graft that was expanded for 21 days ex vivo in the presence of nicotinamide (NiCord, Gamida Cell).
Findings:  The cumulative incidence of engraftment was 94%.  Neutrophil engraftment occurred at a median of 11 days compared to 21 days for a retrospective control cohort from the CIBMTR (p<0.001).  Time to platelet engraftment was also shorter, 34 days vs 46 days (P<0.001)
Conclusions:  Transplantation of NiCord can be performed safely as stand-alone graft, and results in faster neutrophil and platelet engraftment compared to a CIBMTR control cohort.


Long-Term Follow-up of Adult Double Unit Cord Blood (CB) Transplantation (dCBT) Recipients Reveals High Rates of Progression-Free Survival after a Novel Cy/Flu/Thio/TBI 400 Intermediate Intensity Conditioning Regimen

Politikos I et al, Memorial Sloan Kettering Cancer Center, USA

Methods:  Patient and graft characteristics associated with treatment-related mortality, relapse and progression-free survival (PFS) in adult dual cord blood transplant recipients conditioned with a myeloablative conditioning regimen consisting of cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 5-10 mg/kg, 400 cGy TBI.
Findings:  139 consecutive patients with a variety of high-risk hematologic malignancies  transplanted between 2007 and 2016 were included in the analysis.  Treatment-related mortality at day 180 was only 12%.  Relapse incidence at 3 years was 11%.  With a median survivor follow-up of 2.7 years (range 6.5 months-9.5 years), the 3-year overall survival is 71% (95%CI: 63-80), and progression-free survival is 67% (95%CI: 59-76).
Conclusion:  A myeloablative conditioning regimen consisting of cyclophosphamide, fludarabine, thiotepa and TBI 400cGy appears to be less toxic than the standard myeloablative umbilical cord blood transplant regimen of TBI 1350, Cytoxan and Fludarabine.


The Influence of Stem Cell Source on Chronic GvHD-Free, Leukemia-Free Transplant Survival in Pediatric Patients with Acute Myeloid Leukemia

Keating A et al, University of Colorado School of Medicine, USA

Methods:    Retrospective analysis of the outcomes of acute myeloid leukemia patients (age 0-21 years) in complete remission (CR) undergoing first allogeneic HSCT with myeloablative conditioning from 2005-2015.  Graft sources for comparison included umbilical cord blood, matched sibling and matched unrelated donor.
Findings:  316 consecutive patients from 8 centers were included; matched sibling (n=60), single umbilical cord blood (n=122) or double umbilical cord blood (n=66, with 71% having either 1-2 antigen mismatches) or matched unrelated donor (n=73, with 8.2% having 1 antigen mismatch).  Median age was 10 years.  The adjusted composite cGvHD-free leukemia-free survival measure, to extrapolate the quality of life of transplant survivors was similar between single umbilical cord blood, double umbilical cord blood, and matched sibling donors and significantly better than matched unrelated donor recipients (HR= 1.9, 95% CI 1.1-2.9; p=0.034).
Conclusion:  These data suggest that outcomes of umbilical cord blood transplantation are comparable to that of matched-sibling transplantation in pediatric patients with acute myeloid leukemia.  Outcomes may be superior to that of pediatric matched unrelated donor transplantation, however a prospective study will be required for confirmation.