Research Advances

By Karen Ballen, MD, Michael Horwitz, MD, Junya Kanda, MD, PhD, and Elisabetta Xue, MD
Updated:  December 2022

RECENTLY PUBLISHED ARTICLES

Cord Blood Transplantation for Nonmalignant Disorders: Early Functional Immunity and High Survival

Martinez C et al, Blood Advances, 2022
Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA

There is no consensus about the best donor for children with non-malignant disorders and immune deficiencies in the absence of a matched related donor (MRD).
Methods: Authors evaluate the 2-year overall survival after unrelated cord blood transplant (UCBT) in patients with non-malignant disorders from 2009-2020 enrolled on a prospective clinical trial using either 5/6 or 6/6 umbilical cord blood as cell source. Patients receive a fully ablative busulfan, cyclophosphamide and fludarabine without serotherapy. 55 children were enrolled, median age 5 months (range, 1-111 months).
Findings: The overall survival (OS) at 2 years was 91% (95% CI:79-96%) with a median follow up of 4.3 years. The median time to neutrophil and platelet recovery were 17 days (range 5-39 days) and 37 days (range 20-92 days), respectively. All but one evaluable patient achieved full donor chimerism. The cumulative incidence of aGvHD grade II-IV by day 100 was 16% (n=9). All patients with viral infections at the time of transplant cleared the infection at a median time of 54 days (range 44-91 days). All evaluable patients have had correction of their immune or metabolic defect.
Conclusions: In the absence of a MRD, UCBT following myeloablative conditioning without serotherapy is an excellent curative option in young children with non-malignant disorders.

Outcomes of Subsequent Neoplasms after Umbilical Cord Blood Transplantation in Europe

Rafii H et al, Blood Advances, 2022
Monacord, Centre Scientifique de Monaco, Monaco.

Subsequent neoplasms (SNs) compromise long-term survivors after hematopoietic cell transplantation.
Methods: Authors performed a retrospective analysis of SNs in a cohort of 10,358 recipients of unrelated cord blood transplants (UCBT) reported to Eurocord/EBMT registries from 1988 to 2018.
Findings: A total of 233 patients developed SNs. Median age at UCBT was 31 years (y) (0.3-69), and 84 were pediatric patients. Three groups of SNs were observed. Post-transplant lymphoproliferative disorders (PTLD) were reported in 145 patients in a median of 4 months after UCBT. Of these, 9/145 patients died from relapse, 83/145 from PTLD, and 24/145 from transplant-related causes. At last follow-up, 29/145 were alive; 5y-overall survival (OS) after PTLD diagnosis was 21±3%. Acute leukemia/myelodysplasia (AL/MDS) was diagnosed in 23 patients in a median of 28 months after UCBT and included 3 donor-cell AL. Four of 23 patients died from relapse of primary disease, 8/23 from progression of SNs, and 4/23 from TRM. Seven patients were alive at last follow-up; 5y-OS after AL/MDS diagnosis was 36±10%. Solid tumors (ST) were reported in 65 patients in a median of 54 months after UCBT. Most common tumor sites were lung, thyroid, bone and soft tissue. A total of 33/65 patients died (26 due to ST, 6 to relapse of primary disease, 1 cause missing). At last follow-up, 32/65 patients were alive; 5y-OS after the diagnosis of ST was 51±6%.
Conclusions: Despite their poor outcomes, SNs that occur after UCBT are extremely rare. Identification of associated risk factors and early detection may help to improve OS.

Comparable Survival Outcomes with Haploidentical Stem Cell Transplantation and Cord Blood Transplantation

Sugita J et al. Bone Marrow Transplantation, 2022
Hokkaido University Hospital, Sapporo, Japan

HLA-haploidentical stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) and unrelated cord blood transplant are alternative to HLA-matched stem cell transplantation.
Methods: Authors conducted a matched-pair analysis of PTCy-haplo and UCBT using the Japanese registry data. They identified 136 patients aged between 16 and 69 years who received PTCy-haplo as their first transplantation for acute leukemia or myelodysplastic syndromes. Control group included 408 UCBT recipients selected to match the PTCy-haplo group.
Findings: Overall and relapse-free survival probabilities at 2 years were comparable between the PTCy-haplo and UCBT groups: 55% vs. 53% for overall survival (p = 0.46), and 47% vs. 48% for relapse-free survival (p = 0.79), respectively. The cumulative incidence of relapse was significantly higher (43% vs. 29%, respectively, p = 0.006), while the cumulative incidence of non-relapse mortality (NRM) was significantly lower (9% vs. 23%, respectively, p < 0.001) in the PTCy-haplo group. The cumulative incidence of grade II-IV acute GvHD was lower in the PTCy-haplo group compared to the UCBT group, while those of grade III-IV acute GvHD and chronic GvHD were not statistically different between the two groups.
Conclusions: Both PTCy-haplo and UCBT are viable alternatives to HLA-matched stem cell transplantation.

Single Cord Blood Transplantation Versus HLA-Haploidentical-related Donor Transplantation Using Posttransplant Cyclophosphamide in Patients With Hematological Malignancies

Wada F et al, Transplantation, 2022
Kyoto University, Kyoto, Japan

Unrelated cord blood (UCB) and haploidentical related donor transplantation using post-transplant cyclophosphamide (PTCy-haplo) have become alternative options to treat patients with hematological malignancies without an HLA-matched donor.
Methods: Authors conducted a retrospective study using registry data from the Kyoto Stem Cell Transplantation Group for patients who received allogeneic transplantation using a single UCB unit (n = 460) or PTCy-haplo (N = 57) between 2013 and 2019.      
Findings: Overall survival in the UCB group was comparable to that in the PTCy-haplo group (hazard ratio, 1.00; 95% confidence interval, 0.66-1.52), although neutrophil and platelet engraftment were significantly delayed. Non-relapse mortality risk and the incidence of graft-versus-host disease in the UCB group were also comparable to those in the PTCy-haplo group. Although the relapse risk was similar between the UCB group and the PTCy-haplo group regardless of the disease risk, acute myeloid leukemia patients benefit from UCB transplant with a significantly lower relapse rate (hazard ratio, 0.38; 95% confidence interval, 0.18-0.76).
Conclusions: UCB transplant gives outcomes comparable to PTCy-haplo transplant, and both UCB and PTCy-haplo units are suitable as alternative donor sources.

The Safety and Efficacy of Umbilical Cord Blood Mononuclear Cells in Individuals with Spastic Cerebral Palsy: a Randomized Double-Blind Sham-Controlled Clinical Trial 

Zarrabi M et al, BMC Neurology, 2022
Royan Institute for Stem Cell Biology and Technology, Tehran, Iran

In this multi-center, randomized, double blind, placebo-controlled study, the authors assessed the safety and efficacy cord blood-derived mononuclear cell in pediatric patients with cerebral palsy.
Methods: Patients with cerebral palsy between 4 and 14 years of age were included. Patients in the study arm were tested for HLA and received a single 5 × 10⁶ /kg dose of HLA-matched CB-mononuclear cells intrathecally. Primary endpoint was change in gross motor function measure (GMFM)-66 from baseline to one year after treatment. Adverse events were safety endpoint. Other scores were also evaluated, including modified Ashworth scale (MAS), pediatric evaluation of disability inventory (PEDI), and quality of life.
Results: Seventy-two patients were treated, 36 in each group. Other than headaches right after intrathecal administration, no side effects were observed during follow-up. Authors observed more prominent improvement in GMFM-66 score in the study group (+9.62) than in the control arm (β:7.10); mean MAS was reduced in individuals in the study group (-0.87) and control group (β: -0.58). Mean PEDI and quality of life scores were higher in the study group than in the placebo group. Also, imaging data suggested improvements in white matter structure only in the study group.
Conclusions: This trial showed that intrathecal injection of cord blood-derived mononuclear cells was safe and potentially effective in children with cerebral palsy.

Systemic Administration of Allogeneic Cord Blood Mononuclear Cells in Adults with Severe Acute Contusion Spinal Cord Injury: Phase 1/2a Pilot Clinical Study-Safety and Primary Efficacy Evaluation

Smirnov V et al, World Neurosurgery, 2022
Sklifosovsky Research Institute of Emergency Care, Moscow, Russian Federation

In this Phase I trial, the authors evaluated the safety and efficacy of systemic administration of cord blood mononuclear cells in patients with acute severe spinal cord contusion.
Methods: Safety was the primary endpoint, whereas restoration of motor and sensory function in lower limbs within a 1-year period was secondary. Ten patients with acute contusion spinal cord injury were enrolled between 2015 and 2017 and received a total of four weekly infusions of AB0 group and rhesus-matched, non-HLA matched, cord blood-derived mononuclear cells. Infusion was given after primary surgery, starting within 3 days after injury, at the dose of 1.48 × 10⁷/kg. All patients were followed up for 12 months after infusion.
Results: Despite an overall 419 adverse events, only 2 were estimated as possibly related to the cellular therapy administration, which were transitory hyperthermia, both categorized as mild, whereas the remaining 417 were related to spinal cord injury or other concomitant diseases. No patients developed GVHD or immunization against the cellular product. Neurological deficit level improvement was seen in all but one patient, whereas significant functional restoration of lower limb motor function was seen in six cases. Two patients showed complete restoration of spinal cord function.
Conclusions: The authors concluded that intravenous administration of mononuclear cells from umbilical cord blood is safe and might potentially improve neurological deficit in patients with contusion spinal cord injury.

 
Human Umbilical Cord Mesenchymal Stem Cells for Psoriasis: a Phase 1/2a, Single-Arm Study

Cheng L et al, Signal Transduction Targeted Therapy, 2022
Institute of Reproductive and Stem Cell Engineering, Changsha, China

The authors investigated the immunomodulatory and clinical effect of cord blood-derived mesenchymal stem cells (MSCs) in patients with psoriasis, a chronic immune-mediated systemic disease that has no definitive treatment.
Methods: In this Phase 1/2a clinical trial, 17 patients with psoriasis were enrolled and received cord blood-derived MSC systemic infusions. Adverse events and laboratory parameters were evaluated. Scores, including psoriasis area severity index (PASI), and physician global assessment (PGA) were analyzed for efficacy evaluation.
Results: Patients were followed for 6 months after infusion. No major adverse events occurred. Eight patients had at least 40% improvement in the PASI score, 6 at least 75% and 3 had more than 90% improvements, with a better trend in response in female patients. Three had no sign of disease at the physician global assessment. After administration, frequencies of regulatory T cells and CD4+ memory T cells were significantly increased, especially in responder patients, whereas the number of T helper 17, CD4+ naive T cells and serum level of interleukin 17, known to play a major role in psoriasis pathogenesis, were significantly decreased. These observations were in line with the hypothesis that MSCs would promote a more “immune tolerant” T cell phenotypes.
Conclusion: The authors concluded that allogeneic cord blood MSCs is safe and partially effective in psoriasis patients, and level of Tregs may be used as a biomarker to predict the clinical response.

Topical and Intravenous Administration of Human Umbilical Cord Mesenchymal Stem Cells in Patients with Diabetic Foot Ulcer and Peripheral Arterial Sisease: a Phase I Pilot Study with a 3-Year Follow-Up

Zhang C et al, Stem Cell Research and Therapy, 2022
The First Affiliated Hospital of Xi’an Jiaotong University,  Shaanxi, China

The authors evaluated the safety and efficacy of cord blood-derived mesenchymal stem cells (MSCs) in patients with diabetic foot ulcer.
Methods: In this Phase I pilot study, 14 patients with peripheral artery disease and refractory diabetic foot ulcer were enrolled. Each patient received a single local injection and two systemic administrations of cord blood-derived MSCs. Adverse events were documented for safety assessments. The therapeutic efficacy was assessed by ulcer healing status and recurrence rate.
Results: No major adverse events were observed. Two patients developed transitory fever early after administration. Ulcers status was evaluated 1.5 month after treatment. The lesion severity decreased significantly in all patients, and complete closure was observed in 14 of the 15 lesions. Similarly, the symptoms of chronic limb ischemia were alleviated, despite that no improvement in obstruction was seen in computed tomography angiography imaging. Rehospitalization due to ulcer recurrence occurred in 1 patient within one year, and 5 within three years.
Conclusions: Authors concluded that MSC infusion was well tolerated and shortened ulcer healing time.

The Impact of GVHD on Outcomes after Adult Single Cord Blood Transplantation in European and Japanese Populations

Kanda J, et al, Bone Marrow Transplant, 2021
Kyoto University, Kyoto, Japan

The impact of GVHD and graft-versus-leukemia effect in unrelated cord blood transplantation (UCBT) is controversial.
Methods: In the Eurocord/ALWP EBMT and JSTCT/JDCHCT collaborative study, the impact of GVHD on UCBT outcomes in Japanese and European registries were evaluated. A total of 3,690 adult patients with acute leukemia who received their first single UCBT were included.
Findings: A multivariate analysis of overall survival (OS) revealed a positive impact of grade II acute GVHD compared with grade 0-I GVHD, in the Japanese cohort, and an adverse impact in the European cohort. A negative impact of grade III-IV acute GVHD on OS was observed regardless of registries. In the analysis of relapse, a positive impact of grade II acute GVHD compared with grade 0-I GVHD was observed only in the Japanese cohort, regardless of disease risk. The positive impact of limited chronic GVHD on OS was observed only in the Japanese cohort.
Conclusions: A positive impact of mild GVHD after a single UCBT was observed only in the Japanese cohort. This could explain the ethnic difference in UCBT outcomes and might contribute to the preference usage of UCBT in Japan.

Comparison of Haploidentical and Umbilical Cord Blood Transplantation after Myeloablative Conditioning

Wagner JE, et al, Blood Advances 2021
University of Minnesota, Minneapolis, Minnesota, USA

Most reports comparing haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with posttransplant cyclophosphamide (PTCy) and other donor sources have focused on outcomes in older adults treated with reduced intensity conditioning.
Methods: The current study evaluated outcomes in patients with hematological malignancy treated with myeloablative conditioning prior to haplo- (n = 375) or umbilical cord blood (UCB; n = 333) HSCT.
Findings: All haplo recipients received a 4 of 8 HLA-matched graft, whereas recipients of UCB were matched at 6-8/8 (n = 145) or ≤5/8 (n = 188) HLA antigens. UCB recipients were more likely to have acute lymphoblastic leukemia and transplanted in second complete remission (CR), whereas haplo-HSCT recipients were more likely to have acute myeloid leukemia in the first CR. Survival at 3 years was similar for the donor sources (66% haplo- and 61% after ≤5/8 and 58% after 6-8/8 UCB). Notably, relapse at 3 years was lower in recipients of ≤5/8 UCB (21%, P = .03) compared with haplo- (36%) and 6-8/8 UCB (30%). However, non-relapse mortality was higher in ≤5/8 UCB (21%) compared with other groups (P < .0001).
Conclusions: Haplo-HSCT with PTCy after myeloablative conditioning provides an overall survival outcome comparable to that after UCB regardless HLA match group.

Engraftment of Double Cord Blood Transplantation after Nonmyeloablative Conditioning with Escalated Total Body Irradiation Dosing to Facilitate Engraftment in Immunocompetent Patients

Brunstein CG, et al. Transplantation and Cellular Therapy, 2021
University of Minnesota, Minneapolis, Minnesota, USA

It is unknown whether a higher dose of total body irradiation (TBI) could improve engraftment rate or other transplant outcomes for less heavily treated patients.
Methods: This was a secondary analysis of double unrelated cord blood (dUCB) recipients in BMT CTN 1101, 161 who received total body irradiation (TBI) 200 cGy and 18 who received TBI 300 cGy. In BMT CTN 1101, dUCB recipients who had not received cytotoxic chemotherapy within 3 months of enrollment or a previous autologous HCT within 24 months received TBI 300 cGy instead of 200 cGy
Findings: The probability of neutrophil engraftment was 100% for patients who received TBI 300 cGy versus 91% for those who received TBI 200 cGy (P = .64). There was no significant difference in the 1-year incidences of non-relapse mortality (NRM) and relapse or in 1-year survival. Patients who received TBI 300 cGy and 200 cGy had similar engraftment and early mortality.
Conclusions: Inclusion of a modified regimen for dUCB transplantation had no demonstrable influence on this large randomized trial.

Omidubicel vs Standard Myeloablative Umbilical Cord Blood Transplantation: Results of a Phase 3 Randomized Study

Horwitz ME, et al. Blood, 2021
Duke University Medical Center, Durham, North Carolina, USA

Omidubicel is an ex vivo expanded hematopoietic progenitor cell and nonexpanded myeloid and lymphoid cell product derived from a single umbilical cord blood unit.
Methods: The present study reports the result of a phase 3 trial to evaluate the efficacy of omidubicel compared with standard umbilical cord blood transplantation (UCBT). Between January 2017 and January 2020, 125 patients age 13 to 65 years with hematologic malignancies were randomly assigned to omidubicel vs standard UCBT. The primary end point was time to neutrophil engraftment.
Findings: Median time to neutrophil engraftment was 12 days for the omidubicel arm and 22 days for the control arm (P < .001). The cumulative incidence of neutrophil engraftment was 96% for patients receiving omidubicel and 89% for patients receiving control transplants. The omidubicel arm had faster platelet recovery, had a lower incidence of first grade 2 to 3 bacterial or invasive fungal infection, and spent more time out of hospital during the first 100 days after transplant than controls.
Conclusions: Transplantation with omidubicel results in faster hematopoietic recovery and reduces early transplant-related complications compared with standard UCBT. The results suggest that omidubicel may be considered as a new standard of care for adult patients eligible for UCBT.

Single Cord Blood Transplantation Versus Unmanipulated Haploidentical Transplantation for Adults with Acute Myeloid Leukemia in Complete Remission

Konuma T, et al. Transplantation and Cellular Therapy, 2021
The University of Tokyo, Tokyo, Japan

Comparative data for cord blood transplantation (CBT) and haploidentical related donor hematopoietic cell transplantation (haplo-HCT) are limited for adult patients with acute myeloid leukemia (AML) in complete remission (CR).
Methods: The allogeneic HCT in 1313 adult patients with intermediate- or poor-risk AML in CR who received either SCBT (n = 1102) or unmanipulated haplo-HCT (n = 211) between 2007 and 2018 in Japan were retrospectively analyzed.
Findings: Among the whole cohort, the cumulative incidences of neutrophil and platelet recovery were significantly lower in SCBT recipients compared with those in haplo-HCT recipients. SCBT was significantly associated with a higher incidence of grade II to IV acute GVHD and lower incidence of extensive chronic GVHD compared to haplo-HCT. Haplo-HCT recipients developed a higher incidence of CMV antigenemia compared to SCBT recipients (P = .004). In the multivariate analysis, there were no significant differences for grades III or IV acute GVHD, relapse incidence, non-relapse mortality, OS, LFS, GRFS, or CRFS between the two donor types.
Conclusions: SCBT and unmanipulated haplo-HCT had similar survival outcomes for adult patients with AML in CR despite the lower hematopoietic recovery and higher grade II to IV acute GVHD in SCBT recipients and the higher CMV antigenemia in haplo-HCT recipients.

A Multicenter Phase II Study of Intrabone Single-Unit Cord Blood Transplantation without Antithymocyte Globulin

Nishida T et al. Annals of Hematology, 2021
Nagoya University Graduate School of Medicine, Nagoya, Japan

Delayed engraftment is still an unmet issue in umbilical cord blood (UCB) transplants.
Methods:  In this phase 2 study, authors investigated the use of intra-bone infusion of a single UCB unit without anti-thymocyte globulin to overcome this issue.
Results:  62 patients were analysed; median UCB cellularity was 2.57 × 10⁷/kg of total nucleated cells. Median time to neutrophil ≥ 500/ µL was 21 days; at day60, cumulative incidence of neutrophil engraftment was 80.6% (95% CI 68.2%-88.6%). Median time to platelet ≥ 20.000/ µL was 38 days, at day100 cumulative incidence was 75.8% (62.6-84.9%). Day100 cumulative incidence of grade III-IV acute GvHD was 6.5%, without steroid-refractory cases, whereas 1-year cumulative incidence of chronic GVHD was 9.9%.
Conclusions: The authors concluded that intra-bone infusion of single UCB unit was safe and feasible.

 
Allogeneic Stem Cell Transplantation with Omidubicel in Sickle Cell Disease

Parikh S et al. Blood Advances, 2021
Duke University School of Medicine, Durham, North Carolina, USA

Historically, patients with sickle cell disease transplanted with umbilical cord blood (UCB) had unacceptable rate of graft failure.
Method:  In this phase 1/2 study the authors aimed to evaluate engraftment rate in 13 patients transplanted with omidubicel in combination with an unmanipulated UCB and in 3 patients transplanted with a single omidubicel graft.
Results:  Median neutrophil engraftment occurred at 7 days. Long-term engraftment was derived from the unmanipulated graft in 10/13 of the double graft recipients. Two of the three single omidubicel recipients also had sustained engraftment.
Conclusions:  Authors concluded that omidubicel transplant determined rapid engraftment in this population, who is known to have intrinsic resistance to engraftment, and that this approach deserves further investigations also in other non-malignant disorders, including bone marrow failures.

Umbilical Cord Mesenchymal Stem Cells for COVID-19 Acute Respiratory Distress Syndrome: A Double-Blind, Phase 1/2a Randomized Controlled Trial

Lanzoni G et al. Stem Cells Translational Medicine, 2021
University of Miami Miller School of Medicine, Miami, Florida, USA

Mesenchymal stem cells’ anti-inflammatory properties might be effective in acute respiratory distress syndrome in patients with COVID-19
Methods:  in this double blind, randomized phase 1-2 study, the authors evaluated safety and feasibility of intravenous infusion of 100 ± 20 × 10⁶ UCB-derived MSCs in COVID-19 patients stratified by acute respiratory distress syndrome severity.
Results:  MSCs infusion was well tolerated, it determined a rapid decrease in inflammatory cytokines, and was associated with improved survival (91% vs 42%, p 0.015).
Conclusion:  UC-MSC infusions are safe and could be beneficial in treating subjects with COVID-19-related acute respiratory distress syndrome.

Umbilical Cord Mesenchymal Stromal Cells as Critical COVID-19 Adjuvant Therapy: A Randomized Controlled Trial

Dilogo IH, Stem Cells Translational Medicine, 2021
Medicine Universitas Indonesia, Jakarta, Indonesia

Umbilical cord blood-derived mesenchymal stromal cells are known to favor a more anti-inflammatory microenvironment.
Methods:  The authors conducted a double-blind, multicentre study, where 40 patients were randomized to receive standard therapy with or without an endovenous administration (1 × 10⁶/kg) of UCB-derived MSCs; primary endpoint was overall survival and length of assisted ventilation need.
Results: Infusion was well tolerated. Patients who received MSC had a survival rate 2.5 times higher compared to the control group, although no difference were seen in need of assisted ventilation.
Conclusion: The authors concluded that UCB-derived MSCs might be effective as an anti-inflammatory agent in patients with severe COVID-19.

Clinical and Imaging Outcomes after Intrathecal Injection of Umbilical Cord Tissue Mesenchymal Stem Cells in Cerebral Palsy: a Randomized Double-Blind Sham-Controlled Clinical Trial

Amanat M et al. Stem Cell Research & Therapy, 2021
University of Medical Sciences, Tehran, Iran

In this study, authors assessed safety and efficacy of intrathecal injection of umbilical cord blood-derived MSC in patients with spastic cerebral palsy.
Methods:72 paediatric patients with cerebral palsy were randomized to receive either a single 2×10⁷ MSC dose or placebo. The study primary endpoint was changes in clinical scores that measure gross motor function.
Results: Compared to controls, patients in the study group had significant measurable improvements in gross motor function, as well as in quality of life.
Conclusions:Authors concluded that intrathecal injection of UCB-derived MSC was safe and effective in this population and deserves further investigation.

Repeated Subarachnoid Administrations of Allogeneic Human Umbilical Cord Mesenchymal Stem Cells for Spinal Cord Injury: a Phase 1/2 Pilot Study

Yang Y et al. Cytotherapy, 2021
Guangdong Provincial Center for Engineering and Technology Research of Minimally Invasive Spine Surgery, Guangzhou, China

Umbilical cord blood-derived mesenchymal stem cells are a potential treatment for severe spinal cord injury.
Methods: In this prospective trial, 102 patients with severe spinal cord injury were enrolled to receive up to four, monthly subarachnoid infusion of UCB-derived MSCs (1 × 10⁶ cells/kg). Clinical and radiological scores were used to evaluate efficacy.
Results: No severe adverse events were observed. Authors reported significant improvement in sensory motor skills as well as autonomic function, regardless the severity and level of spinal injury.
Conclusion: Authors concluded that intrathecal administration of UCB-derived MSCs was well tolerated and significantly improved neurological dysfunction.

SELECTED ABSTRACTS:  2023 EBMT Annual Meeting

Robert Wynn – optimizing AML outcomes using CB in UK experience.

Dr Wynn compared the outcomes of 112 children with acute myeloid leukemia (AML) undergoing T cell replete CB transplant versus 255 AML children who received transplant from other stem cell source, including matched unrelated donors (n=136), sibling donor (n=63), mismatched unrelated donor (n=36), haploidentical (n=11) and T cell deplete CB (n=9). All patients were transplanted in the same time frame, between 2014 and 2021. When patients were stratified by the minimal residual disease (MRD) status at the time of the transplant, no significant difference was seen between the two groups in terms of event free survival (EFS) among patients transplanted with a negative MRD. However, patients transplanted with a detectable MRD had a higher probability of long-term remission if they had received a T cell replete CB transplant (Figure): 2-year EFS 50% vs 21%, p=0.017 and relapse rate 36.2% vs 66.2%, p=0.007, confirming the data reported by other groups (Milano et al, 2016). Overall survival did not differ significantly between CB and non-CB cohort due to higher transplant-related mortality in the CB cohort, again remarking the need to work toward improving management of transplant-related complication. Dr Wynn also presented a prospective trial that will open in late 2023 that will randomize paediatric patients with AML in CR1 or CR2 to receiving expanded CB versus non-CB graft sources (expansion will use UM171 platform, as previously described by Cohen, Lancet Hametol 2020).

Dr Wynn reported preliminary data on trial NCT05425043, which adopt third party granulocyte transfusion early after CB transplant to accelerate immune recovery in patients with relapsed/refractory diseases who failed a previous BMT. Seven doses of granulocytes infusions are planned according to trial design, starting from day +1 after CBT. Ten patients have been treated so far; granulocyte infusions were overall well tolerated, with some degree of cytokine release syndrome and, importantly, transient robust donor derived CD8 T cell expansion, which could potentially implement leukemic cell eradication, as suggested by pre clinic data. Five patients from the trial are still in complete remission, four died of disease relapse and one due to transplant-related complication.

Vinod K Prasad – Newborn screening for Hurler syndrome leads to early treatment and excellent outcomes with unrelated umbilical cord blood transplant.

Dr. Prasad presented the data of CB transplants in children diagnosed with Hurler syndrome, a rare autosomal recessive, lysosomal storage disorder that is associate with early, progressive developmental delay, skeletal abnormalities, cognitive impairment, cardiovascular and respiratory problems.  Early transplant, possibly at 4-5 months of age, is recommended to maximize the survival outcomes. A total of 10 patients were treated with CB transplants; all but three were below six months of age at the time of the transplant. Enzyme level prior to CBT was undetectable in all but one patient. All patients received a busulfan based, ATG containing conditioning regimen. Patients were followed for a median of 2.4 years (range 0.2 – 6.1). Engraftment rate of favourable (Figure): neutrophils (>500/mmc) and platelet (>50,000/mmc) engraftment occurred in all patients after a median of 16 and 56 days, respectively. All patients achieved complete donor chimerism with normal enzyme level at last evaluation. None experienced graft failure. Complications included veno-occlusive disease (n=2), haemolytic anemia (n=3, one of which was fatal), and microangiopathy (n=1). None developed severe acute or chronic GvHD. The authors concluded that children with Hurler syndrome can be successfully treated with CBT with favourable outcomes.  

Elizabeth Hicks - Outcomes of UCB transplant in children with chronic granulomatous disease

In this poster presentation, Dr Hicks reported the outcomes of 19 children with CGD treated between 2005 and 2022. Median age at transplant was 2.4 years. All but one had prior history of bacterial and fungal infection, in most cases with recurrent episodes, including pneumonia, cellulitis, and enteritis.  In three cases, CB was from a related donor. HLA matching include 4/6 (n=5), 5/6 (n=12) and 6/6 (n=2). All received busulfan based, myeloablative conditioning regimen, with ATG. After a median follow up of 6 years, 16 patients are still alive and disease free; two died due to transplant-related cause, and one for Duchenne syndrome, undiagnosed at the time of the transplant. Three patients had graft failure which required a subsequent transplant. None developed CGD-related infection after transplant. Two patients had high grade acute GVHD, whereas two experienced extensive chronic GVHD. The authors concluded supporting the use of CB in paediatric patients with CGD lacking HLA identical donor.

Vanderson Rocha – is there a role of CB in pediatric setting in the future?

Dr Rocha reported registry data from Eurocord and Duke University, which collected data from a large cohort of 1995 children who underwent CB transplant between 1993 and 2019 for a non-malignant disorder. The aim of this retrospective study was to evaluate how did CB transplant outcomes change over the course of the time.

Decades 1990-2004, 2005-2009 and 2010-2019 were analysed separately, as well as primary disease (inborn errors, primary immunodeficiency and aplastic anaemia). In all three disease-category, survival outcomes significantly improved overtime (Table), mostly due to better knowledge of CB selection and post-transplant management. Regardless timeframe, a trend toward a better outcome was seen in ATG-free and myeloablative conditioning setting, as well as with younger patient age, better patient-CB HLA matching and negative patient CMV serostatus. 

Similar analysis was performed for 3205 paediatric patients with malignant disorders, divided per myeloid or lymphoid leukemia. Also in this setting, patients transplanted after 2010 had a significant survival improvement. Use of total body irradiation and myeloablative conditioning also had a favourable impact. 

The author concluded by remarking the favourable outcomes in terms of disease relapse and long-term complications (e.g. chronic GVHD) in selected patients category undergoing CB transplant.

SELECTED ABSTRACTS:  2022 Cord Blood Connect International Congress

Safety of DUOC-01, Intrathecal Cord Blood-Derived Cellular Therapy, as an Adjunct to Allogeneic Cord Blood Transplantation in Children with Inherited Metabolic Diseases

Sun J et al. Duke University, Durham, North Carolina, USA

Unrelated umbilical cord blood transplantation (UCBT) improves function and extends life in children with inherited metabolic disorders. Neurologic disease can progress after UCBT, prior to donor engraftment in the brain. DUOC-01 is a monocyte-derived cord blood cell product, designed to accelerate donor cell delivery to the brain.

Methods: DUOC-01 was manufactured from cord blood units. Cells were given intrathecally. Forty children, ages 0-15, received umbilical cord blood transplant. Thirty patients received DUOC-01 cells intrathecally at a median of 31 days post-transplant.
Results: Two patients developed transient fever and hypotension post infusion. No other adverse events related to DUOC-1 were reported.
Conclusion: DUOC-1 is a cord blood-derived product intended to accelerate donor cell delivery to the brain of children with inherited metabolic diseases undergoing cord blood transplant. It is well tolerated. Further studies are underway to determine efficacy.

Development of CAR-NK Cell Therapy for Hematologic Malignancies

Stoltzman C et al. Deverra Therapeutics and Fred Hutchinson Cancer Center, Seattle, Washington, USA

Chimeric antigen receptor (CAR) expression by natural killer (NK) cells may improve the potency and specificity for the NK cells anti-tumor efficacy. NK CAR cells may be a safer and more cost-effective way to deliver CAR T cell therapy.

Methods: CD 56+ NK cells are generated from cord blood-derived NK cells. The cells are transduced with a viral vector that targets a protein specific for acute lymphoid leukemia (ALL). A mouse model was used to test the cell product.
Results: The CAR-NK cell product was safely given in up to 8 repeat doses to mice with ALL. The mice had inhibited tumor growth and improved survival compared with the control mice, who received a control NK product.
Conclusions: Cord blood-derived CAR-NK cells can be manufactured and have specific potency vs ALL in a mouse model. Further preclinical studies are planned in other blood cancers.  

A Randomized, Placebo-Controlled, Phase II Trial of Intravenous Allogeneic Umbilical Cord Blood Infusion for Adults with Ischemic Stroke

Laskowitz D et al. Duke University, Durham, North Carolina, USA

Stroke is the 5th leading cause of death in the United States, and current treatments are not effective in all patients. The purpose of this study was to determine if infusion of a non-HLA matched unrelated umbilical cord blood unit (UCB) unit can improve outcomes.

Methods: A Phase II, multicenter, randomized, placebo-controlled study was performed in several U.S. centers. Cord blood units were infused 3-10 days post stroke. The primary endpoint was a change in the Modified Rankin Scale, a scale of functional activity.
Results: 79 patients were enrolled at 6 centers. The trial was closed early due to slow accrual attributed to COVID. There were 17 mild infusion reactions. There was no difference in the Modified Rankin Scale between patients who received and who did not receive the cord blood units.
Discussion:  UCB can be given safely after stroke. There was no difference in the primary endpoint in this small study.  A larger study with more functional outcomes could be considered.

Should Cord Blood Unit Distribution Patterns Impact Collection Strategies

Frenet E et al. New York Blood Center, New York, New York, USA

The National Cord Blood Program has an inventory of more than 60,000 cord blood units for clinical transplant use. This study characterizes the current inventory and the distributed cord blood units. It recommends the collection strategy moving forward.

Methods: 1,046 shipments of unrelated cord blood (UCB) from 2015 to 2022 were studied. Race/ethnicity, HLA match and cell dose information was reviewed.
Results: Non-Hispanic White (White) units represented 46% of the inventory and 38% of the distributed units. Match levels were higher among White units (55% 5/8 or greater) than for units collected from other race/ethnicities (40% 5/8 or greater). The median total nucleated cell dose was 167 x 10 (7) for transplanted cord blood units and 102 x 10 (7) for stored cord blood units.
Conclusions: White cord blood units are distributed most frequently, and had a higher allele match to the recipient. The goal for new collections should be to obtain UCB units with higher total nucleated cell and CD 34 counts.

 

SELECTED ABSTRACTS:  2022 Transplantation and Cellular Therapy Tandem Meetings

Hematopoietic Stem Cell Transplantation (HSCT) with Omidubicel Is Associated with Enhanced Circulatory Plasmacytoid Dendritic Cells (pDC), NK Cells and CD4+ T Cells with Lower Rates of Severe Infections Compared to Standard Umbilical Cord Blood Transplantation

Szabolcs P et al.  University of Pittsburg, Pittsburg, Pennsylvania, USA

Methods:  This was a sub-study of a recently reported randomized Phase III study comparing myeloablative transplantation with omidubicel versus standard umbilical cord blood transplantation.  Samples and data were obtained from 17 subjects transplanted with omidubicel and 20 patients transplanted with standard umbilical cord blood grafts.
Results:  At D+7 and D+14 post-transplant, CD3+, CD4+ T cells, and Tregs were significantly higher in omidubicel patients than in controls.  B cells and NK cells, as well as monocytes, myeloid and plasmacytoid DC, were also higher in omidubicel patients.
Conclusion:  Omidubicel recipients experience more rapid recovery of multiple lymphoid subsets, which may contribute to a reduction in viral infections recipients of omidubicel, compared to standard umbilical cord blood transplantation.

A Phase I Study of Allogeneic Umbilical Cord Tissue Derived Mesenchymal Stromal Cells for Term and Near-Term Infants with Hypoxic-Ischemic Encephalopathy (HIE)

Cotton M et al. Duke University, Durham, North Carolina, USA

Methods:  This is a Phase I study of allogeneic umbilical cord tissue-derived mesenchymal stromal cells given to infants with hypoxic-ischemic encephalopathy.
Results:  6 infants were enrolled, 4 with moderate and 2 with severe hypoxic-ischemic encephalopathy.  No infusion reactions were observed.  While one product was culture positive for coag-negative staphylococci, no subjects contracted an infection.  5 infants were evaluable for neurocognitive studies at 12-16 months of age.   For the 5 evaluable subjects, cognitive, language and motor composite scores ranged from 90 – 100, 83 – 109, and 82 – 115, respectively.
Conclusion:  Allogeneic human cord tissue-derived mesenchymal stromal cells can be safely administered to infants with hypoxic-ischemic encephalopathy.

Bone Marrow and Umbilical Cord Blood Are Equivalent Stem Cell Sources for Hurler Syndrome

Lund P et al.  University of Minnesota, Minneapolis, Minnesota, USA

Methods:  The investigators compared leukocyte lysate and plasma iduronidase activity in patients with Hurler Syndrome who had received umbilical cord blood (n=20) and bone marrow transplantation (n=9).
Results:  There was no difference among the leukocyte or plasma IDUA levels between umbilical cord blood and bone marrow recipients (18.7 vs 16.4 nmol/hr/mg, p=0.58 and 4.5 vs 4.5 nmol/hr/mg, p=0.98, respectively)
Conclusion:   It has been proposed that umbilical cord blood should be the preferred source of stem cells in patients with Hurler Syndrome undergoing allogenic stem cell transplantation.  The results of this study suggest that bone marrow grafts could be equally effective in restoring iduronidase activity.

Extended Letermovir Prophylaxis Is Highly Effective Cytomegalovirus (CMV) Infection Prevention in Adult Cord Blood Transplantation (CBT) Recipients and Does Not Prevent Emergence of CMV-Specific Donor-Derived Immunity

Politikos I et al. Weill Cornell Medical College, New York, New York, USA

Methods:  The investigators report the efficacy and toxicity of a 6-month course (instead of the standard 3-month course) of letermovir as prophylactic treatment against cytomegalovirus in recipients of umbilical cord blood transplantation.
Results:  28 consecutive umbilical cord blood transplant recipients were enrolled, and 21 disease-free patients were evaluable after a 6-month course of letermovir prophylaxis.  None of these patients experienced a clinically significant CMV infection.    Following discontinuation of letermovir, 5 of 21 patients experienced a clinically significant CMV infection.
Conclusion:  A prolonged course of letermovir is safe and efficacious in preventing clinically significant CMV infections.  However, late infections after discontinuation are common, highlighting the need for prolonged CMV monitoring.

SELECTED ABSTRACTS:  2021 Cord Blood Connect International Congress

Umbilical Cord Blood and Umbilical Cord Tissue Mesenchymal Stromal Cells in Children with Cerebral Palsy: A Randomized Trial

Sun J et al. Duke University, Durham, North Carolina, USA

Small studies have demonstrated the safety of umbilical cord blood (CB) and mesenchymal stromal cells (MSC) in children with cerebral palsy (CP), but have been limited by small sample sizes and heterogeneous patient populations.  This study describes improvement in gross motor function in children with CP after treatment with allogeneic unrelated donor CB or allogeneic, third-party, human cord tissue-derived MSC.

Methods:  90 children ages 2-4 years with CP participated in a Phase 2 trial. Patients were randomized to allogeneic CB, allogenic MSC, or standard of care.
Results:  There were no serious adverse events.  At 6 months, there was no difference in the gross motor function scores.  In exploratory analyses, after adjustment for baseline severity, there was improvement in the gross motor function scores in the cord blood group compared to standard of care.
Conclusion: There was no statistical difference in gross motor function scores across the groups; however, exploratory analyses demonstrated greater motor gains with high-dose allogeneic CB treatment. The authors favor proceeding with a randomized study.

Identification and Successful Re-Consent of Existing Cord Blood Donors for the Creation of Induced Pluripotent Stem Cell Lines

Abberton K et al. BMDI Cord Blood Bank, Victoria, Australia

Induced pluripotent stem cell (iPSC) lines made from cord blood (CB) could help with a supply of stem cells for new cell-based therapies.  This study looks at the consent process for donors that had already donated cord blood.

Methods:  The team identified suitable cord blood units, confirmed HLA typing, and reviewed the medical/family history.  A Donor Information and Consent Form (DICF) and “permission to contact” form was mailed to selected donors, followed by a phone interview and signing of consent form.
Results:  18 cord blood units were selected; 44% donors granted contact for more information; 33% completed the full consent process.
Conclusion:  Cord blood donors can be contacted for consent for cell-based therapies.  Approximately a third of donors consented for additional uses of their stored cord blood.

SELECTED ABSTRACTS:  2021 EBMT Annual Meeting

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.

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.

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.