Research Advances

By Karen Ballen, MD, Michael Horwitz, MD, and Michael Verneris, MD
Updated:  November 2019


Phase I/II Study of Stem-Cell Transplantation Using a Single Cord Blood Unit Expanded Ex Vivo with Nicotinamide

Horwitz ME et al, Journal Clinical Oncology, 2018
Duke University, USA

Delayed count recovery can increase the risk of infection after cord blood transplantation. Ex vivo expansion (expansion of cord blood cells in the lab) is a way to improve count recovery.
Methods:  36 patients with blood cancers underwent single umbilical cord blood transplantation at 11 different hospitals. Patients received a myeloablative conditioning regimen. The cord blood units was cultured for 21 days in nicotinamide.
Findings: The median time to neutrophil recovery was 12 days, compared to 21 days for historical controls without expansion. The 2-year overall survival was 51%, and 2-year disease-free survival was 43%.
Conclusion:  Unrelated cord blood expanded ex vivo with nicotinamide shortens neutrophil recovery and is a safe and effective transplant. A randomized study is planned to compare expanded and unexpanded cord blood transplantation.

Outcomes of Advanced Hodgkin Lymphoma after Umbilical Cord Blood Transplantation: A Eurocord and EBMT Lymphoma and Cellular Therapy and Immunobiology Working Party Study

Paviglianiti A et al, Biology of Blood and Marrow, 2018
Eurocord, Hôpital St Louis, Paris, France

131 adults, Hodgkins disease, relapsed after prior autologous stem cell transplant.
Unrelated umbilical cord blood transplant.
Findings: Four year overall survival 46%.
Patients with refractory disease had a higher rate of relapse.
Four-year overall survival 62% for patients in complete remission at time of transplant.
Patients who received the reduced intensity conditioning of cyclophosphamide, fludarabine and total body radiation had improved survival.
Conclusion: Unrelated umbilical cord blood transplant is a good option for patients with Hodgkins disease that has relapsed after autologous stem cell transplant. Patients who are in remission have improved overall survival.


Promising Outcome of Umbilical Cord Blood Transplantation in Patients with Multiple Comorbidities

Adachi Y et al, Biology of Blood and Marrow Transplantation, 2018
Konan Kosei Hospital, Konan, Japan

53 adult patients with hematologic malignancies who received single unrelated umbilical cord blood transplantation (UCBT) were compared with 90 adult recipients of other transplants.
A comorbidity score which awards points for other medical conditions such as heart disease, obesity, etc. (HCT-CI) was used to stratify patients into good and poor risk groups.
Findings:  UCBT: 2 years overall survival (OS) for HCT-CI < 3 was 66%. 2 years OS for HCT-CI> 3 was 69%.
Non-UCBT group: 2 years OS for HCT-CI < 3 was 67%. 2 years OS for HCT-CI > was 26%.
UCBT showed excellent OS even in complex patients with high HCT-CI scores.
UCBT should be considered as a graft source even in patients with co-morbidities.

Autologous Cord Blood Infusions Are Safe and Feasible in Young Children with Autism Spectrum Disorder: Results of a Single-Center Phase 1 Open-Label Trial

Dawson G et al, Stem Cells Translational Medicine, April 2017
Duke University Medical Center, USA

25 children, median age 4.6 years
Autism spectrum disorder
Single intravenous infusion of autologous umbilical cord blood
Findings: Treatment safe and well tolerated
Significant improvement in parent-reported outcomes, vocabulary and eye-tracking measures.
Behavioral improvements noted for the first 6 months
Conclusion: Autologous umbilical cord blood infusions are safe in children with autism, and further study is warranted to determine effectiveness.

Transplantation of Ex Vivo Expanded Umbilical Cord Blood (NiCord) Decreases Early Infection and Hospitalization

Anand S et al, Biology of Blood and Marrow Transplantation, April 2017
Duke University Medical Center, USA

18 adult patients with hematologic malignancies who received unrelated umbilical cord blood transplantation (UCBT) using 1 ex vivo expanded graft with nicotinamide (NiCord), and (11 patients) 1 unmanipulated UCB unit
Compared to 80 adults with hematologic malignancies who received unmanipulated single or double unrelated UCBT
All received myeloablative TBI- based regimen
Findings: Median time to neutrophil engraftment shorter in the Nicord recipients (13 vs 26 days, 0<0.001)
Risk of total infection reduced in Nicord recipients (p=0.01).
Nicord recipients more days out of hospital in the first 100 days (70 vs. 50 days, p=.005).
Conclusion:  UCBT with NiCord expanded graft associated with improved time to engraftment and fewer infections.


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 American Society of Hematology Annual Meeting

Incidence of HLA Loss in a Global Multicentric Cohort of Post-Transplantation Relapses:  Results from the HLA Loss Collaborative Study 

Vago L et al, San Raffaele Scientific Institute (Italy)

Introduction:  In a previous study, loss of one of the 2 chromosomes expressing HLA antigens has been found as one of the mechanisms by which relapses occur in patients with leukemia undergoing an allogeneic transplant.
Methods:  in a multicenter study including 3 different continents, Vago et al. collected  a total of 619 cases of hematologic relapse from adult patients with acute myeloid leukemia (78.5%), acute lymphoblastic leukemia (13.9%), myelodysplastic syndromes (4%) or myeloproliferative neoplasms (1.1%) after allogeneic HSCT from HLA-haploidentical relatives (31.7%), HLA-mismatched unrelated donors (MMUD, 21.3%), 10/10-matched unrelated donors (MUD, 37.2%), or unrelated cord blood units (UCB, 9.8%).
Findings:  Out of the 476 relapses analyzed, 396 (83.2%) were informative for the study of HLA loss. In total, they detected 51 HLA loss post-transplantation relapses out of the 396 cases analyzed (12.8%). Of these, 35 occurred after haploidentical HSCT (22.6% of relapses in this setting), 12 after MMUD HSCT (11.9%), 4 after 10/10 MUD HSCT (4.3%) and, notably, none after UCB transplant.
Conclusion:  This study confirms shows HLA loss as one of the mechanisms responsible of relapse post-transplant in all type of transplants but the ones from UCB. This phenomenon might be responsible to the lower incidence of relapse reported for UCB compared to other stem cell sources.

Outcome after Unrelated Cord Blood Transplantation in Patients with Chronic Myeloid Leukemia:  A Retrospective Study from the EBMT Chronic Malignancies Working Party

De Lavallade et al, European Blood and Marrow Transplant Registry

Introduction:  150 recipients of umbilical cord blood transplantation for chronic myeloid leukemia were identified in the EBMT registry database.
Findings:  Overall survival at 3 years was 41.2%.  24-month non-relapse mortality was 38.9%, and relapse was 25.3%. There was no difference in overall and disease-free survival for those receiving reduced intensity or myeloablative conditioning.
Conclusion:  Cord blood transplantation is most effective when performed in first chronic phase. Outcomes remain respectable for those in > first chronic phase. 

Single UM171 Expanded Cord Blood Permits Transplantation of Better HLA Matched Cords with Excellent GvHD Relapse Free Survival

Cohen S et al, University of Montreal and Maisonneuve-Rosemont Hospital, Canada

Introduction:  21 adult patients with hematologic malignancies were transplanted with a 7-day ex-vivo expanded single cord blood graft after myeloablative conditioning. The active agent in the expansion culture system was UM171.
Findings:  Median time to ANC >100 cells/µl was 10 days and ANC>500 was 18 days.  Full donor chimerism was achieved in all cell subsets.  Overall and progression-free survival at 12 months was 95% and 77%, respectively.
Conclusion:    A 7-day expansion of umbilical cord blood stem cells using UM171 can be safely delivered as a single umbilical cord blood graft, resulting in prompt hematopoietic and immunologic recovery.

Reduction of Graft Rejection by Fludarabine Combined with Busulfan, Cyclophosphamide and Anti-thymocyte Globulin Conditioning in Cord Blood Transplantation for Children with Wiskott-Aldrich Syndrome

Xiao P et al, Children’s Hospital of Soochow University, China

Introduction:  17 children with Wiskott-Aldrich Syndrome underwent umbilical cord blood transplantation between 2013 and 2018.  The conditioning consisted of fludarabine 160 mg/m2, busulfan 12.8 mg/kg, cyclophosphamide 120 mg/kg, and ATG 7.5 mg/kg.
Findings:  All children achieved stable engraftment.  Acute GVHD grade II-IV was observed in 35%, and chronic GVHD observed in 24% of patients.
Conclusion:  Myeloablative conditioning with the combination of fludarabine, busulfan, cyclophosphamide and ATG results facilitates reliable engraftment of umbilical cord blood stem cells in children with Wiskott-Aldrich syndrome.

Intrabone Delivery of CD34+ Cells Using an Optimized Delivery System Does Not Enhance Engraftment in a Rhesus Macaque Model of Hematopoietic Stem Cell Transplantation

Stringaris K et al,  NIH National Heart Lung and Blood Institute, USA

Introduction:  Intrabone infusion of umbilical cord blood stem cells has been proposed as a technique to reduce the risk of graft failure following umbilical cord blood stem cell transplantation. Autologous primate CD34+ cells were transduced with either a green or yellow reporter gene. The marked cells were infused either intrabone or into the peripheral blood following myeloablative conditioning.
Findings:  Intrabone injected CD34+ cells did not engraft more quickly,than those infused into peripheral blood.  Engraftment of intrabone cells was lower than those transplanted by peripheral blood.
Conclusion:  Transplantation of stem cells intrabone does not provide clinical benefit.


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.