Research Advances

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

RECENTLY PUBLISHED ARTICLES

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:  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.

Methods: In this multicenter trial, 125 subjects were randomized to receive either Omidubicel or standard UCB (single or double UCBs) between 2017 and 2020; both TBI-based and TBI-free myeloablative conditioning regimens were adopted, GvHD prophylaxis consisted of a calcineurin inhibitor and MMF. Primary endpoint of the study was time to neutrophil engraftment.
Results: Sixty-two patients received Omidubicel (study group) and 63 received standard UCB (single unit 33% or double unit 67%, control group). Median age was 41 years (range, 13–65); 81% of patients suffered from acute leukemia. Median CD34+ cell dose for Omidubicel recipients was 9 × 106/kg (124-fold CD34+ cell expansion) and 0.3 × 106/kg for controls (P < 0.0001). Patients were followed for a median of 10 months (range, 1–19 months). Median time to neutrophil engraftment was 12 days (95% CI, 10–15 days) in the study group and 22 days (95% CI,19–25 days) in the control group (P < 0.001). Furthermore, the authors reported a higher incidence of 42-day platelet engraftment in the study group, as well as a lower incidence of grade 2–3 bacterial/invasive fungal infection, a lower rate of viral infections, and a reduction in time spent in hospital during the first post-transplant 100 days (median 39 vs. 52 days); all these differences were statistically significant. No statistically significant differences were seen in acute and chronic GvHD rate between the two groups. There were no statistically significant differences also in survival outcomes, although there was an improving trend in the study group (1-y overall survival and 6-month non-relapse mortality were 73% and 11% in patients receiving Omidubicel, and 62% and 22% in the control group).
Conclusions: The authors concluded that, given the faster hematopoietic engraftment and the lower early transplant-related complications rate, as compared to standard UCB transplants, the use of Omidubicel should be considered in clinical routine.

 

Long-Term Outcomes after Intrabone Unrelated Umbilical Cord Blood Transplant in Patients with Hematological Malignancies: A Eurocord, CTIWPEBMT Analysis

Peccatori J et al, San Raffaele Scientific Institute, Italy

The direct intra-bone injection of umbilical cord blood (UCB) transplant has been previously reported by other authors (Frassoni et al, 2008, Bonifazi et al, 2018, etc), who demonstrated its safety and feasibility. The authors speculated that the direct infusion of the cellular product into the bone marrow would expose the UCB cells directly to the stem cell niche, improving cellular survival and potentially, indirectly, transplant outcomes.

Methods: In this study, Peccatori and colleagues reported the long-term outcomes of single UCB intra-bone transplants performed in patients with hematologic malignancies in fifteen transplant centers (Eurocord/ EBMT-centers).
Results: A total of 223 patients received an intra-bone UCB transplant between 2006 and 2019. In 30 cases, this was a second allogeneic transplant. More than 90% of patients were adults, for a median age at transplant of 41.4 years. Median follow-up was 9 years; acute leukemia was the most represented diagnosis (74%) and 61% were transplanted in disease remission. Myeloablative conditioning was adopted in 76% of cases; after 2010, most centers used ATG-free UCB transplant platforms. At cryopreservation, median total nucleated cells number was 3.3x107/Kg, and CD34+ was 1.43x105/Kg. UCB units were match at 5/6 and 4/6 HLA loci in 30% and 72%, respectively. At day 60, cumulative incidence of neutrophil engraftment was 79% (95%CI 74 – 85, median time 24 days), whereas at day 180 cumulative incidence for platelet engraftment was 63% (95%CI 57- 70, median time 37 days). Day 100 cumulative incidence of acute GVHD of any grade was 18%, (only 9 cases had grade 3-4 acute GvHD). At median follow up, cumulative incidence of chronic-GVHD was 37%, with only 17 cases of severe chronic GvHD; cumulative incidence of relapse was 34% (95%CI 27-42). At 5-years, overall survival was 33% and disease-free survival was 30%. Day 100 non relapse mortality was 22%, with infection being the most frequent cause of death. Female gender, disease type (MDS/MPN versus AML/ALL) and stage (remission versus not in remission) at transplant, and number of previous transplants (none versus one or more) were associated with improved survival.
Conclusion: The authors concluded that intra-bone infusion of UCB was overall safe and provided durable disease control, and suggested that this route of administration should be investigated also for ex-vivo expanded cellular products.



SELECTED ABSTRACT:  2021 Transplantation and Cellular Therapy Meetings

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

Stefanski et al, University of Minnesota, USA

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