Research Advances

By Karen Ballen, MD, Michael Horwitz, MD, and Michael Verneris, MD
Updated:  September 2018


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.

Cord Blood Transplantation in Patients with Minimal Residual Disease

Milano F et al, New England Journal of Medicine, Sept. 2016
Fred Hutchinson Cancer Research Center, USA.

582 patients ages 1-67 years with acute leukemia or myelodysplastic syndrome.
140 unrelated cord blood transplants (UCBT), 344 HLA matched unrelated donor (MUD), 98 HLA mismatched unrelated donor (MMUD).
At 4 years, survival 71% for UCBT, 63% MUD, 49% MMUD.
For patients with pre-transplant minimal residual disease, the risk of relapse was lower and survival higher for UCBT patients compared to MUD or MMUD.
Conclusion: Relapse rate is lower after UCBT in patients with minimal residual disease.

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.


SELECTED ABSTRACTS:  2016 American Society of Hematology Annual Meeting

Umbilical Cord Blood Transplantation in Children with Acute Leukemia: Impact of Conditioning Regimen on Transplant Outcomes

Eapen M et al, Medical College of Wisconsin, USA

Methods: 396 pediatric recipients of single umbilical cord blood (UCB) transplantation treated as per local standard of practice and reported to the Center for International Blood and Marrow Transplant Research, compared to 100 pediatric recipients of single or double UCB transplantation, treated on an NIH-sponsored clinical trial (BMT CTN 0501).
Findings: Patients who received conditioning with total body irradiation/cyclophosphamide/fludarabine (TCF) who were treated off study or on study had similar outcome.
Patients transplanted with TCF conditioning had better outcome then those conditioned with regimens not containing total body irradiation. This was primarily due to an increased risk of relapse.
Conclusion: The study supports the continued use of a conditioning regimen consisting of total body irradiation, cyclophosphamide and fludarabine for children undergoing umbilical cord blood transplantation.

Immune Reconstitution after Umbilical Cord Blood versus Peripheral Blood Progenitor Cell Transplantation in Adults Following Myeloablative Conditioning.

Mehta R et al, University of Minnesota, USA

Methods: Serial flow-cytometry based quantification of lymphocyte subsets following myeloablative umbilical cord blood and peripheral blood stem cell transplantation in adult recipients.
Findings: All lymphocyte subsets analyzed were lower in the 1-3 months following umbilical cord blood transplantation compared to peripheral blood stem cell transplantation.
All subsets except NK-T cells and naïve T-cells were comparable by 6 months following transplantation.
Umbilical cord blood recipient experienced more bacterial and viral infections during the first year compared to peripheral blood stem cell recipients.
Peripheral blood stem cell transplant recipients were more likely to experience relapse of the underlying malignancy.
Conclusion: Immune reconstitution following umbilical cord blood transplantation is delayed in the first 3 months compared to peripheral blood stem cell transplantation.

Allogeneic Umbilical Cord Blood Infusion of Adults with Ischemic Stroke (CoBIS): Clinical Outcomes from a Phase I Safety Study

Kurtzberg J et al, Duke University, USA

Methods: Ten adult patients who experienced a recent ischemic stroke were infused with an allogeneic umbilical cord blood unit.
Findings: No adverse events attributable to the umbilical cord blood infusion were reported.
Functional improvement was observed in all subjects within 3 months following infusion of the umbilical cord blood unit.
Conclusion: Infusion of allogeneic umbilical cord blood following stroke is feasible and safe. Further comparative studies are planned to confirm benefit.

Successful Engraftment of Donor Umbilical Cord Blood Cells after Co-Transplantation of NiCord (Ex Vivo Expanded UCB Progenitor Cells with Nicotinamide) and a Second Unmanipulated Cord Blood Unit after Myeloablative Chemotherapy in Pediatric Patients with Severe Sickle Cell Disease

Parikh S et al, Duke University, USA

Methods: Eight children with sickle cell disease underwent myeloablative dual umbilical cord blood transplantation. One unit was expanded ex vivo for 21 days prior to infusion (NiCord). The second unit was infused without manipulation.
Findings: Seven of 8 patients achieved long-term engraftment. One patient died of graft failure.
Long-term engraftment was provided by NiCord in 2 patients, the unmanipulated unit in 6 patients, and both units in 1 patient.
Conclusions: NiCord, an ex vivo expanded umbilical cord blood graft may improve the likelihood of donor engraftment following umbilical cord blood transplantation.

Pilot-Scale Production of Megakaryocytes/Platelets from Cord Blood CD34+ Cells in a Bottle Turning Device Culture System

Guan X et al, Peking Union Medical College of Tsinghua University, Suzhou, China.

Methods: Enriched cord blood CD34+ cells were cultured in a serum free cytokine cocktail consisting of stem cell factor, Flt-3 ligand, thrombopoietin and interleukin-3. The culture started in flasks for 6 days, and was later transitioned to turning bottles for another 7 days.
Findings: This culture system is capable of providing 4 x 1010 megakaryocytes/platelets, capable of treating 130 60kg patients with an infusion of 5 x 106 cells/kg.
Conclusion: Cord blood progenitor cells have the potential to address the clinical need for an alternative source of allogeneic platelets for therapeutic purposes.


SELECTED ABSTRACTS:  2016 European Bone Marrow Transplant Meeting

A New Approach of Dual SCT with Unmanipulated Haplo-Identical Graft and Unrelated Cord Blood in Patients with Hematologic Diseases

Chen J et al, Suzhou, China

219 patients, ages 15-60 years, 67% acute leukemia.
Myeloablative preparative regimen.
1 unrelated UCB unit and unmanipulated related haploidentical bone marrow, results compared to haplo alone
Progression-free survival 79% haplo/cord vs 59% haplo alone.
2-year relapse rate 15% haplo/cord vs 23% haplo alone.
Patients who received 5/6 or 6/6 HLA-matched cord units had better outcomes.
Conclusions: Results are promising with a combined unrelated cord blood and related haplo-identical graft.


Transplantation of Ex-vivo Expanded UCB (Nicord) Results in Decreased Infection Burden and Hospital Length of Stay in the First 100 Days

Anand S et al, Duke, USA

18 adult patients, 8 received single unrelated cord blood transplant (UCBT) expanded in the presence of nicotinamide (Nicord), and 10 patients one expanded and one unexpanded UCB.
Compared with 101 adults who received conventional, unexpanded CB units.
Median days to absolute neutrophil count >500 13 days Nicord vs 27 days unexpanded.
Bacterial infection rate 22% Nicord vs 54% unexpanded.
Patients who received Nicord transplant had a median additional 22 days alive and out of hospital in the first 100 days post-transplant compared to unexpanded.
Conclusions: These results suggest that the use of Nicord expanded CB product is associated with decreased incidence of bacterial infection and decreased length of stay in the hospital.