Cord Blood Transplant Recipients Research Articles

Successful Treatment of Epstein-Barr Virus Reactivation-associated Transverse Myelitis Following Herpes Zoster with Intravenous Rituximab in a Cord Blood Transplant Recipient.

The Epstein-Barr virus (EBV) is associated with many malignancies and autoimmune diseases, including multiple sclerosis. In addition, EBV rarely but occasionally causes central nervous system (CNS) complications. We herein report a case of transverse myelitis (TM) associated with systemic EBV reactivation after herpes zoster infection in a cord blood transplant recipient. Identification of EBV-infected peripheral blood cells revealed a predominance of B cells. Notably, intravenous rituximab ameliorated EBV reactivation and TM. Since the CNS infiltration rate of intravenous rituximab is markedly low, the clinical efficacy of rituximab against TM suggests that EBV reactivation may cause TM via immune-mediated mechanisms.

UM171 Expanded Cord Blood Transplantation Outcomes Compare Favorably to All Different Stem Cell Sources: An EBMT Registry Case-Control Analysis

Background: Cord blood (CB) transplantation (CBT) has several advantages compared with other graft sources, such as permissive human leucocyte antigen (HLA) mismatches, and low risk of chronic graft-versus-host disease (GVHD) and relapse. However, CBT has fallen into disfavor because of its high risk of non-relapse mortality (NRM) and prolonged hospitalization due to its low cell dose. Furthermore, the need for the rare large cord bloods (CBs) leads to selection of poorly HLA-matched CBs, known to further increase NRM. UM171 is a small molecule that expands hematopoietic stem cells. A phase I-II study of a single UM171-expanded, myeloablative and reduced intensity CBT for patients with high-risk hematologic malignancies who lacked a donor, demonstrated prompt neutrophil engraftment, the ability to use smaller, better HLA-matched CBs, and a low NRM of 5% (Cohen S et al. Lancet Haematol 2020). The aim of the current analysis was to compare outcomes after a UM171 CBT to real-world cohorts of 6 other stem cell sources identified in the European Society for Blood and Marrow Transplantation (EBMT) registry. Methods: This is a retrospective study comparing 22 adults who received a single UM171-expanded CBT in the phase I-II study between 2016-2018, to 6 cohorts of patients allografted from different stem cell sources and reported to the EBMT registry. Control patients were eligible if they had received a myeloablative or reduced intensity allogeneic transplant for a hematologic malignancy in Europe during 2010-2021, were between the ages of 18-65 years, and had a Karnofsky performance status (KPS) score ≥70. The different donor control cohorts were: 1) CB, single or double units, with a calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF) for GVHD prophylaxis, 2) 10/10 HLA-matched unrelated donor (MUD) peripheral blood stem cells (PBSC) with a CNI and MMF or methotrexate (MTX), 3) 10/10 MUD bone marrow (BM) with a CNI and MMF or MTX, 4) 9/10 HLA-MUD BM or PBSC (9/10 UD), 5) T cell replete haploidentical donor (haplo) BM or PBSC, and 6) matched sibling donor (MSD) BM or PBSC. Exclusion criteria included in vitro manipulated grafts and CBT recipients who received anti-thymocyte globulin or alemtuzumab. Patients were directly matched for disease and status at transplant and propensity score matching was used for prior allograft, age, KPS, and conditioning regimen. Endpoints included engraftment, GVHD, NRM, relapse, progression-free survival (PFS), overall survival (OS), and GVHD-free relapse-free survival (GRFS). The EBMT attempted to identify 3 controls for each patient. If no control was identified for a UM171 patient, the latter was excluded from the analysis. Results: Between 17 and 21 UM171 CB patients were compared to 36 to 62 controls depending on the donor group as 1-3 controls could not be identified for each patient (Table 1). Median follow-up for the UM171 group was 36 months and generally longer for the controls. Neutrophil engraftment with UM171 CB was similar to all donor groups except slower for CB and MUD BM. Platelet engraftment was consistently slower for UM171 CB except when compared to conventional CB. The incidence of severe acute GVHD was similar across all donor groups. As there was no severe chronic GVHD in the UM171 group, the latter was associated with less extensive/severe chronic GVHD compared to MUD (PBSC and BM) and MSD. There was a trend towards lower NRM for UM171 CB compared to haplo and 9/10 UD but it did not reach statistical significance. PFS, OS and GRFS were all better with UM171 CB compared to haplo. Finally, GRFS was improved with UM171 CB when compared to MUD PBSC (Figue 1), 9/10 UD, and MSD. Conclusions: This registry matched case-control analysis demonstrated real-word evidence suggesting UM171-expanded CBT recipients have improved outcomes compared to other donor types. More specifically and due to the absence of severe chronic GVHD with UM171 CB, GRFS was better with UM171 CB when compared to other graft sources except for CB and MUD BM. Also, OS and PFS were superior with UM171 CB compared to haplo donors. Limitations of this study included the small number of UM171 patients, the inability to identify controls for each case, and certain missing data for the controls. UM171 expansion of CB appeared to achieve the desired outcome of maintaining benefits of CB while removing its disadvantages. Thus, prospective randomized studies are warranted to confirm these results.

Effect of Differences in Immunological Reconstitution By Donor Age and Recipient Age on the Incidence of Chronic Graft-Versus-Host Disease

Background: Development of chronic graft-versus-host disease (cGVHD) has been reported to be associated with donor age and recipient age. We hypothesized that differences in post-transplantation immunological reconstitution depending on donor age and recipient age might be responsible for the incidence of cGVHD. Redevelopment of regulatory T (Treg) cell expansion and cytokine production was investigated over time according to donor age and recipient age at the time of transplantation after allogeneic hematopoietic cell transplantation (HCT). Methods: The subjects were 39 consecutive patients who underwent HCT for different hematologic diseases at our hospital between December 2008 and December 2021 and survived for more than 3 years after HCT without cGVHD. The patients were classified into younger (age ≤59, n=23) and older (age ≥60, n=16) groups. The donor source was divided into subgroups based on use of cord blood or an adult donor: cord blood (younger, n=5; older, n=8) and adult donor (younger, n=18; older, n=8). Peripheral blood was drawn from all patients on day 200 and at 24 and 36 months after HCT. Analysis of Treg, T, B, and NK cells was performed using flow cytometry. T cells were isolated using EasySep kits and cultured at 37℃ in 5% CO 2 in air for 4 days with 10% heat-inactivated fetal calf serum as controls, interleukin-2 (IL-2) and transforming growth factor-β1 (TGFβ1) as samples, or concanavalin A (ConA) (10 µg/ml) at a density of 1×10 6 cells/ml. Treg cells were analyzed by flow cytometry and ConA-stimulated culture supernatants were tested for concentrations of IL-4, IL-5, IL-6, IL-10, IL-13, TGFβ1, tumor necrosis factor α (TNFα) and interferon-γ (IFNγ). Results: The results for patients who underwent HCT at our institution during the same observation period as this study suggested that donor source and patient age may be involved in development of cGVHD (p=0.032, p=0.015, respectively). In younger patients, CD4/8 in peripheral blood showed a tendency to increase over time after transplantation: 0.91±1.0 at 200 days, 0.54±0.29 at 2 years, and 1.32±0.57 at 3 years (R=0.308, p=0.072); and young patients after cord blood transplantation showed a marked improvement: 0.30±0 at 200 days, 0.59±0.18 at 2 years, and 1.84±0.27 at 3 years (R=0.913, p=0.0016). Percentages of Treg cells in peripheral blood and stimulated cultures were positively correlated in younger (R=0.349, p=0.043) and older (R=0.381, p=0.029) patients. The percentage, absolute number, and amplification rate of Treg cells in stimulation culture of T cells from younger patients (6.37±4.02%, 3759.4±1963.3 /mL, 12.4±11.5 times) at 200 days after transplantation were significantly higher than those for older patients (3.04±1.48%, 1783.9±1152.0 /mL, 5.4±3.7 times) (p=0.027, p=0.003, p=0.023). Post-transplant Treg cell expansion rates in younger cord blood transplant recipients significantly increased by 2.4±0 times at 200 days, 2.8±0.6 times at 2 years, and 5.8±2.1 times at 3 years (R=0.711, p=0.046). Regarding cytokine production, IL-5 in stimulation culture from younger patients showed a tendency to increase over time: 4.75±8.89 pg/mL at 200 days, 20.04±27.20 pg/mL at 2 years, and 59.51±104.93 pg/mL at 3 years (R=0.294, p=0.087). Conclusions: T cell reconstitution and cytokine production tended to increase over time after transplantation in younger patients. The ability to reconstitute Treg cells was higher in younger patients early after transplantation and increased over time in young cord blood transplant recipients. These factors may account for the high incidence of cGVHD in older transplant recipients from adult donors, although the number of cases in the study is limited and the data are preliminary.

Infusion of UM171-Expanded Cord Blood Led to Excellent Survival in Patients with High-Risk Leukemias: Results from Two Independent Phase II Studies

Background: Cord blood transplant (CBT) recipients experience delayed hematopoietic recovery and an increased risk of non-relapse mortality (NRM). UM171 is a small molecule that expands hematopoietic stem and progenitor cells (HSPC). An initial phase I-II clinical trial of a single UM171-expanded CBT was associated with low NRM and excellent long-term outcomes. (S Cohen et al. Lancet Haematology 2020). With the primary goal of generating increased numbers of HSPC to supplement a conventional single cord blood (CB) graft, we tested the same approach exclusively in high and very high-risk patients with acute leukemias/myelodysplastic syndromes (MDS). Methods: Between 2019 and 2022, two single independent prospective phase II studies were conducted in Montreal, at the Maisonneuve Rosemont Hospital and in Seattle, at the Fred Hutchinson Cancer Center. Primary objectives were safety/NRM and progression free survival at 2-years post-transplant. Only patients with high and very-high risk acute myeloid leukemia (AML), acute lymphoid leukemia (ALL) and MDS were eligible. Patients were required to have adequate organ function and comorbidity index as defined by the transplant center. Patients received a single UM171 7-day expanded and cryopreserved CB after either a myeloablative or mid-intensity conditioning regimen. All patients received tacrolimus and mycophenolate mofetil for GVHD prophylaxis. Results: A total of 52 patients were enrolled (31 in Montreal and 21 in Seattle) with 2 patients not receiving the UM171 expanded product and therefore removed from the final analysis. Patient's characteristics are shown in Table 1. The median age was 44 years (range 19-66) and weight 78 kg (range, 44-145). Twenty-eight patients (54%) were either in a no complete response (CR) status or in ≥CR2, ten (19%) were p53+ and 17 (33%) were second or third transplants. Forty patients (77%) received a 5/8 HLA-matched CB unit and the median of CD34+ cells infused was 4.7 10 6/Kg (0.9-7.5). All patients engrafted (ANC >500 10^ 9/L for 2 consecutive days) at a median of 17 days (range, 9-39 days). The median time to platelet recovery (>20 x 10^ 9/L) was 37 days (range 24-116). With a median follow-up of 24 months (range 0.7 - 39), the probability of 2-year overall survival (OS) and progression-free survival (PFS) was 67% (95% CI, 54-82) and 63% (95% CI, 50-79). OS for second/third transplants and p53+ patients was 64% (95% CI, 43-96) and 40 (95% CI, 19-86), PFS was 51 % (95% CI, 29-87) and 40 (95% CI, 19-86), respectively. At 2 years, the cumulative incidence of NRM was 19% (95% CI, 8-31) while the incidence of relapse was 18% (95% CI, 6-29). The incidence of grade II-IV and III-IV acute GVHD was 69% (95% CI, 56−82%) and 16% (95% CI, 6−27%). The rate of moderate/severe chronic GVHD was 7% (95% CI,1−15%) and translated in an incidence of a chronic-relapse-free-survival of 55% (95% CI, 42−72%). Of note, Kaplan-Meier analysis of all clinical outcomes showed no difference for patients treated in Montreal and Seattle, and results were similar for both centers (Figure 1). Conclusions: The results of 2 independent Phase II clinical studies demonstrated that infusion of a UM171 single CBT led to excellent clinical outcomes in patients with high and very-high risk malignancies including patients with p53+ mutation. We also observed encouraging results for patients undergoing second/third transplants (33% of the entire cohort). Clinical outcomes were similar between the two Transplant Centers. Based on these positive results, a multicenter randomized clinical trial is currently in the planning stage.

The Area Under Tacrolimus Concentrations on Day 14-28 Is the Independent Predictor of the Development of Chronic Gvhd in Patients without Severe Acute Gvhd after Unrelated Allogeneic HSCT

Introduction: In unrelated allogeneic hematopoietic stem cell transplantation (UR-SCT), chronic graft-versus-host disease (GVHD) is a critical complication that affects not only patients' quality of life but also post-transplant outcome. Acute GVHD is a major risk factor for the subsequent development of chronic GVHD. The combination of tacrolimus and short-term methotrexate (TAC+sMTX) has been widely used as a GVHD prophylaxis for UR-SCT in Japan. Previous reports have shown that tacrolimus blood concentrations early after transplantation are associated with the development of acute GVHD, but not with that of chronic GVHD. On the other hand, among UR-SCT recipients who did not develop severe acute GVHD, the relationship between tacrolimus blood concentrations and the development of chronic GVHD remains unclear. Methods: To examine the association between tacrolimus blood concentrations and post-transplant outcomes, the area under the tacrolimus concentration on day 0-14 (AUTC 0-14) and day 14-28 (AUTC 14-28) was calculated simply as the sum of the area of the trapezoid for the corresponding period ( Figure). Tacrolimus was initiated by continuous intravenous administration from day -1 in all patients, and no patients were switched to oral administration prior to day 28. Short-term methotrexate was administered at 10 mg/m 2 on day 1 and 7 mg/m 2 on day 3, day 6, and day 11. Among all 151 adult patients with hematopoietic malignancies who underwent first UR-SCT with GVHD prophylaxis of TAC+sMTX between 2010 and 2022 at the Jikei University Hospital, the following were excluded from the analysis: developing grade III-to-IV acute GVHD, using prednisolone or methyl-prednisolone ≥0.5 mg/kg within day 100, engraftment failure, death before day 100, and relapse before day 100. Results: A total of 68 patients were included in the analysis. Median age was 50.5 (range, 16-68) years. Twenty-seven (40%) patients had acute myeloid leukemia, and 18 (27%) had acute lymphoblastic leukemia. Fifty-five (81%) were in complete remission/chronic phase/early stage. The donor source consisted of 42 (62%) bone marrow transplantation (BMT), 20 (29%) cord blood transplantation (CBT), and 6 (9%) peripheral blood stem cell transplantation (PBSCT). BMT recipients transplanted from 22 (52%) HLA 8/8 matched donor, 19 (45%) HLA 7/8 matched donor, and one (3%) HLA 6/8 matched donor. CBT recipients transplanted from 15 (75%) HLA 4/6 matched donor and 5 (25%) HLA 5/6 matched donor. PBSCT recipients transplanted from 5 (83%) HLA 8/8 matched donor and one (17%) HLA 7/8 matched donor. Fifteen (22%) patients were administered additional low-dose anti-thymocyte globulin (ATG) as GVHD prophylaxis. Fifteen male patients transplanted from female donors (22%). Thirty-nine (57%) patients received myeloablative conditioning regimen. The median time from UR-SCT to neutrophil engraftment was 19 days (range, 11-34). Regarding acute GVHD, 46 patients (68%) developed none, 13 patients (19%) developed grade I, and 9 patients (13%) developed grade II. The median observation period for all 68 patients was 48.2 months (4.0 years). The 4-year cumulative incidence (CI) of chronic GVHD was 51%, of which 24% were moderate-to-severe. The CI of moderate-to-severe chronic GVHD was not associated with age, disease status, donor source, HLA incompatibility, ATG use, female to male, intensity of conditioning regimen, and grade I-to-II acute GVHD development. AUTC 14-28 <200 was the only risk factor (AUTC 14-28<200: 32% vs AUTC 14-28≥200: 11%; p=0.047). Multivariate analysis also showed that AUTC 14-28 <200 was the independent factor for development of moderate-to-severe chronic GVHD ( p=0.04). In all 68 patients, 4-year CI of relapse was 20%, 4-year CI of non-relapse mortality was 10%, 4-year GVHD-free, relapse-free, survival (GRFS) was 50%, and 4-year Overall survival was 80%, all of which did not differ between AUTC 14-28 <200 and AUTC 14-28 ≥200 groups. Conclusion: In UR-SCT, our data showed that AUTC 14-28 <200 may be an independent risk factor for developing moderate-to-severe chronic GVHD, even in patients who did not develop severe acute GVHD.

Clinical implications of augmented renal clearance after unrelated single cord blood transplantation in adults

Augmented renal clearance (ARC) is a phenomenon characterized by increased renal functionality, which can impact the pharmacokinetics and pharmacodynamics of antimicrobial drugs eliminated by the kidneys. It is a potential concern for infection treatment. Cord blood transplantation (CBT) is primarily impeded by delayed neutrophil recovery and immune reconstitution, thereby increasing susceptibility to infection. However, the clinical implications of ARC following CBT remain unexplored. We retrospectively assessed the influence of ARC on post-transplant outcomes at various time points in 194 adult recipients of single-unit unrelated CBT between 2007 and 2022 at our institution. ARC was observed in 52.9% of patients at 1 day, 39.8% at 15 days, and 26.5% at 29 days post-CBT. ARC was not significantly associated with bloodstream infection, acute graft-versus-host disease, or veno-occlusive disease/sinusoidal obstruction syndrome at any time point. ARC at 1 day, 15 days, and 29 days post-CBT was not significantly associated with overall survival, non-relapse mortality, or relapse rates. These findings suggest that ARC is common in adults during the early stages of CBT, but does not discernibly influence clinical outcomes or post-CBT complications.

Single-unit unrelated cord blood transplantation versus HLA-matched sibling transplantation in adults with advanced myelodysplastic syndrome: A registry-based study from the adult MDS working group of the Japanese society for transplantation and cellular therapy.

Allogeneic hematopoietic stem cell transplantation (HCT) remains the only potential curative therapeutic modality for advanced myelodysplastic syndrome (MDS). Within HCT, the advancement of cord blood transplantation (CBT) procedures has resulted in a drastic expansion of CBT as a donor source for MDS. However, data comparing matched sibling donors (MSDs) HCT with CBT for advanced MDS, which was defined as refractory anemia with an excess of blasts (RAEB)-1 and RAEB-2 according to the World Health Organization classification at the time of HCT, have not been explored. We retrospectively compared survival and other posttransplant outcomes in 999 adult patients with advanced MDS after receiving allogeneic HCT in Japan between 2011 and 2020, using either MSD (n=331) or single-unit unrelated cord blood (UCB) (n=668). In the multivariate analysis, there were no significant differences in overall survival (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.90-1.34; P=0.347), disease-free survival (HR, 1.01; 95% CI, 0.84-1.23; P=0.845), relapse (HR, 0.88; 95% CI, 0.68-1.15; P=0.370), or non-relapse mortality (HR, 1.15; 95% CI, 0.87-1.50; P=0.310) between MSD recipients and UCB recipients. UCB was significantly associated with lower neutrophil (HR, 0.28; 95% CI, 0.24-0.33; P<0.001) and lower platelet (HR, 0.29; 95% CI, 0.23-0.36; P<0.001) recovery compared to MSD. UCB was significantly associated with a lower incidence of chronic graft-versus-host disease (GVHD) (HR, 0.57; 95% CI, 0.44-0.75; P<0.001) and extensive chronic GVHD (HR, 0.46; 95% CI, 0.32-0.67; P<0.001) compared to MSD. Similar results were observed after adjusting for differences between MSD and UCB recipients by propensity score matching analysis. Our study demonstrated that single CBT and MSD HCT had similar survival outcomes for adult patients with advanced MDS despite the lower hematopoietic recovery in CBT recipients and higher chronic GVHD in MSD recipients.

Viral Encephalitis after Hematopoietic Cell Transplantation: A Systematic Review

Viral encephalitis is a rare but serious complication after hematopoietic cell transplantation (HCT). The nonspecific early signs and symptoms and rapid progression can make it difficult to diagnose and treat in a timely fashion. To better inform clinical decision making in post-HCT viral encephalitis, a systematic review of prior studies of viral encephalitis was performed, with the goal of characterizing the frequency of various infectious etiologies and their clinical course, including treatments and outcomes. A systematic review of studies of viral encephalitis was performed. Studies were included if they described a cohort of HCT recipients who were tested for at least 1 pathogen. Of 1613 unique articles initially identified, 68 met the inclusion criteria, with a total of 72,423 patients studied. A total of 778 cases of encephalitis were reported (1.1%). Human herpesvirus 6 (HHV-6) (n=596), Epstein-Barr virus (n=76), and cytomegalovirus (n=33) were the most commonly reported causes of encephalitis, and HHV-6 encephalitis tended to occur the earliest, accounting for most cases prior to day +100 post-transplantation. Of 29,671 patients with available transplantation data, encephalitis was diagnosed in 282 of 4707 (6.0%) cord blood transplantation (CBT) recipients, in 372 of 24,664 (1.5%) non-CBT allogeneic HCT recipients, and in 5 of 300 (1.7%) autologous HCT recipients. Of the 282 CBT encephalitis cases, 270 (95.7%) were caused by HHV-6. Overall, 288 (37.0%) of the 778 patients with encephalitis died, and 75 deaths were attributable to encephalitis, with the time between diagnosis and death ranging from 3 to 192 days. Viral encephalitis occurs in approximately 1% of HCT recipients, and HHV-6 is the most common cause. Mortality following encephalitis in HCT recipients is high, indicating an urgent need for advancement in preventive and therapeutic strategies.

Granulocyte transfusion during cord blood transplant for relapsed, refractory AML is associated with massive CD8+ T-cell expansion, significant cytokine release syndrome and induction of disease remission.

In high-risk myeloid malignancy, relapse is reduced using cord blood transplant (CBT) but remains the principal cause of treatment failure. We previously described T-cell expansion in CBT recipients receiving granulocyte transfusions. We now report the safety and tolerability of such transfusions, T-cell expansion data, immunophenotype, cytokine profiles and clinical response in children with post-transplant relapsed acute leukaemia who received T-replete, HLA-mismatched CBT and pooled granulocytes within a phase I/II trial (ClinicalTrials.Gov NCT05425043). All patients received the transfusion schedule without significant clinical toxicity. Nine of ten patients treated had detectable measurable residual disease (MRD) pre-transplant. Nine patients achieved haematological remission, and eight became MRD negative. There were five deaths: transplant complications (n = 2), disease (n = 3), including two late relapses. Five patients are alive and in remission with 12.7 months median follow up. Significant T-cell expansion occurred in nine patients with a greater median lymphocyte count than a historical cohort between days 7-13 (median 1.73 × 109 /L vs. 0.1 × 109 /L; p < 0.0001). Expanded T-cells were predominantly CD8+ and effector memory or TEMRA phenotype. They exhibited markers of activation and cytotoxicity with interferon-gamma production. All patients developed grade 1-3 cytokine release syndrome (CRS) with elevated serum IL-6 and interferon-gamma.

Acute kidney injury and chronic kidney disease in umbilical cord blood transplant recipients.

Acute kidney injury (AKI) is a frequent early complication post hematopoietic stem cell transplant (HSCT), associated with high morbidity and mortality. Cord blood transplant (CBT) recipients are potentially exposed to more nephrotoxic insults, compared to patients undergoing HSCT from other donor sources. We aimed to identify risk factors for AKI in patients undergoing CBT. We also aimed to identify the impact of AKI on chronic kidney disease (CKD) and survival outcomes by one-year post-CBT. Adults and children who underwent a first CBT at our Institution were retrospectively evaluated. AKI was staged according to Kidney Disease Improving Global Outcomes (KDIGO) definitions. Cox regression models were used to estimate the association of demographic factors and post-CBT parameters with the cause-specific hazard of AKI. We identified 276 patients. Median age was 32 years, 28% (77/276) were children (<18 years) and 129 (47%) were white. A myeloablative conditioning regimen was administered to 243 patients (88%) and 248 (90%) received cyclosporine for GVHD prophylaxis. One-hundred and eighty-six patients (67%) developed AKI by day 60 post-transplant, with 72 (26%) developing severe AKI (stage 2 and 3). In a multivariable analysis, each increase in bilirubin level of 1 mg/dL was associated with a 23% increase in the risk of severe AKI (adjusted HR 1.23, 95% CI 1.13 - 1.34, p<.0001). Conversely, systemic steroid administration appeared to be protective of severe AKI (unadjusted HR 0.36, 95% CI 0.18 - 0.72, p=.004) in a univariate model . Two-hundred-forty-seven patients were evaluable at the one-year time point. Among those, 100 patients (40%) developed CKD one-year post-CBT. Severe AKI was associated with a higher hazard of non-relapse mortality (adjusted HR=3.26, 95% CI 1.65-6.45, p=.001) and overall mortality (adjusted HR=2.28, 95% CI 1.22-4.27, p=.01). AKI is a frequent complication after CBT and is associated with worse outcomes. Questions remain as to the mechanism of the protective role of steroids on kidney function in the setting of CBT.

Outcomes of subsequent neoplasms after umbilical cord blood transplantation in Europe.

Subsequent neoplasms (SNs) compromise long-term survivors after hematopoietic cell transplantation. We performed a retrospective analysis of SNs in 10 358 recipients ofumbilical cord blood transplantation (UCBT) from 1988 to 2018. SNs developed in 233patients and 84 were of pediatric age. Indications for UCBT were malignant hematological diseases in 199 patients (85%). Three groups of SNs were observed. Posttransplant lymphoproliferative disorders (PTLD) were reported in 145 patients in a median of 4 months after UCBT. Of these, 9 patients died from relapse, 83 from PTLD, and 24 from transplant-related causes. At last follow-up, 29 were alive; 5-year overall survival (OS) after PTLD diagnosis was 21%. 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 from progression of SNs, and 4 from TRM. Seven patients remain alive; the 5-year OS after AL/MDS diagnosis was 36%. 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 patients died (26 owing to ST, 6 to relapse of primary disease, and 1 cause missing). At last follow-up, 32 of 65 patients were alive; the 5-year OS after the diagnosis of ST was 51%. In conclusion, despite their poor outcomes, SNs that occur after UCBT are extremely rare. Identification of risk factors and early detection may help to improve OS.

Fulminant Metastatic Cellulitis Caused by Stenotrophomonas Maltophilia Infection and Subsequent Candida Parapsilosis Fungemia After Cord Blood Transplantation

Stenotrophomonas maltophilia is known to be an opportunistic pathogen with intrinsic and acquired resistance mechanisms to multiple antibiotics. Bloodstream infection caused by S. maltophilia is a potentially fatal complication, especially in recipients of umbilical cord blood transplantation (CBT). Infrequent reports of S. maltophilia skin and soft tissue infections (SSTIs), including metastatic cellulitis and ecthyma gangrenosum, have been reported as wound infections. Metastatic cellulitis lesions due to S. maltophilia are typically reported to be tender, erythematous, and to show warm subcutaneous infiltration. There are only a few available reports about the clinical course of metastatic cellulitis due to S. maltophilia. We experienced a case involving the development of metastatic cellulitis with fulminant and extensive exfoliation in a patient who underwent CBT. Despite controlling the bloodstream infection caused by S. maltophilia, the patient succumbed to secondary fungal infection due to the devastation of the skin barrier. Our case highlights that SSTIs due to S.maltophilia can cause the unexpected development of fulminant metastatic cellulitis with systemic epidermal peeling in severely immunocompromised hosts, including CBT recipients undergoing steroid therapy.

Effect of Graft-versus-Host Disease on Post-Transplantation Outcomes following Single Cord Blood Transplantation Compared with Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for Adult Acute Myeloid Leukemia

The possibility that HLA mismatches could reduce relapse after alternative HLA-mismatched allogeneic hematopoietic cell transplantation (HCT) is an attractive concept for treating acute myeloid leukemia (AML). However, it remains unclear whether the prognostic effect of graft-versus-host disease (GVHD) on survival differs between recipients of single-unit cord blood transplantation (CBT) and recipients of haploidentical HCT using post-transplantation cyclophosphamide (PTCy-haplo-HCT) for AML. The objective of this retrospective study was to compare the effect of acute GVHD and chronic GVHD on post-transplantation outcomes between recipients of CBT and recipients of PTCy-haplo-HCT. We retrospectively evaluated the effect of acute and chronic GVHD on post-transplantation outcomes following CBT and PTCy-haplo-HCT in adults with AML (n=1981) between 2014 and 2020 using a Japanese registry database. In univariate analysis, the probability of overall survival was significantly greater in patients who developed grade I-II acute GVHD (P < .001, log-rank test) and limited chronic GVHD (P < .001, log-rank test) among CBT recipients, but these effects were not significant among PTCy-haplo-HCT recipients. In multivariate analysis, in which the development of GVHD was treated as a time-dependent covariate, the effect of grade I-II acute GVHD on reducing overall mortality differed significantly between CBT and PTCy-haplo-HCT (adjusted hazard ratio [HR] for CBT, .73, 95% confidence interval [CI], .60 to .87; adjusted HR for PTCy-haplo-HCT, 1.07; 95% CI, .70 to 1.64; P for interaction=.038). Our data demonstrate that grade I-II acute GVHD was associated with a significant improvement in overall mortality in adults with AML receiving CBT but not in recipients of PTCy-haplo-HCT.

Improved Outcomes of UM171-Expanded Cord Blood Transplantation Compared with Other Graft Sources: Real World Evidence

Background: Cord blood (CB) transplantation (CBT) has several advantages compared with other graft sources. CBT has low rates of chronic graft-versus-host disease (GVHD) and allows for several human leukocyte antigen (HLA) mismatches, thus expanding donor availability. However, CBT has fallen into disfavor because of its low cell dose and associated prolonged cytopenias, which result in prolonged hospitalization and higher risk of non-relapse mortality (NRM). Furthermore, the need for large CBs leads to selection of poorly HLA matched CBs, further increasing NRM. UM171 is a small molecule that expands hematopoietic stem cells. From 2016 to 2018, 22 patients with high-risk malignancies who lacked a donor were transplanted on a phase I-II clinical trial with a single UM171-expanded CB (Cohen S et al. Lancet Haematol 2019) after a myeloablative conditioning. The goal was to accelerate engraftment while selecting smaller, better HLA matched CBs to decrease NRM while preserving the benefits of CBT. Results demonstrated that indeed UM171-expanded CB has the potential to overcome slow neutrophil engraftment and diminish NRM. The aim of the current analysis was to examine outcomes after conventional single/double ≥ 4/6 HLA-matched CB and 8/8-matched unrelated donor (MUD) peripheral blood stem cell (PBSC) transplantation with UM171-expanded CBT. Methods: Data on UM171-expanded adult CBT recipients were drawn from the phase I-II trial. Data for adult recipients of myeloablative CB and PBSC transplants for hematologic malignancies (acute myeloid and lymphoblastic leukemia, chronic myeloid leukemia, non-Hodgkin and Hodgkin lymphoma) in the United States and Canada during 2014-2019 with a Karnofsky performance status (KPS) score ≥70 were obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. CB recipients who received anti-thymocyte globulin or alemtuzumab in the conditioning were excluded from the CIBMTR population. Patients were directly matched for the number of prior allogeneic transplants (alloHCT), refined disease risk index (for 1st alloHCT), disease status (for 2nd alloHCT), and acute myeloid leukemia cytogenetic risk. Patients were matched by propensity score for age, comorbidity index and KPS. CIBMTR attempted to identify 4 controls per UM171 patient. Clinical outcomes included engraftment, NRM, progression-free survival (PFS), overall survival (OS), relapse, GVHD-free, relapse-free survival (GRFS), acute GVHD grade III-IV, and chronic GVHD. PFS, OS, and GRFS were estimated by Kaplan-Meir method; other outcomes were calculated using cumulative incidence estimates; marginal Cox regression models were used for analyzing NRM and GRFS. Results: Overall, 137 CIBMTR (67 CB, 70 PBSC) and 22 UM171-expanded CBT patients participated. Univariate analysis and marginal Cox regression analysis results are shown in Tables 1 and 2, respectively. Median time to neutrophil engraftment was 18 days (range 10-30) for UM171-expanded CB recipients compared to 21 days (range 8-53) for CIBMTR CB recipients (p<0.01) (data not shown). Univariate analysis revealed less 1- and 2-year NRM, improved 2-year PFS, improved 1-year OS, and 1- and 2-year GRFS for UM171-expanded CBT compared to CIBMTR CB controls. The UM171 cases had less 1- and 2-year NRM, improved 2-year PFS, and improved 1- and 2-year GRFS compared to CIBMTR PBSC controls. Furthermore, UM171-expanded CB patients experienced less acute GVHD III-IV and chronic GVHD compared to PBSC recipients. In marginal Cox regression analysis, UM171-expanded CBT recipients were 87% and 63% less likely than CIBMTR CB controls to experience NRM and GRFS events, respectively, and 73% less likely to experience GRFS events than CIBMTR PBSC recipients. Conclusions: This real-word evidence suggests that UM171-expanded CB recipients have select improved outcomes compared to conventional CB and MUD PBSC recipients. While this study was limited by the small number of UM171 CB trial participants and inability to identify the planned number of controls for each case, UM171 expansion of CB appeared to achieve the desired outcome of maintaining CB's benefits while removing its disadvantages. Thus, prospective randomized studies of UM171-expanded CBT compared to MUD PBSC alloHCT are warranted to confirm these results. Study Support: This study was funded by ExCellThera. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Adverse effect of donor-specific anti-human leukocyte antigen (HLA) antibodies directed at HLA-DP/-DQ on engraftment in cord blood transplantation

Background aimsWhile donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) in the recipient before transplantation are associated with graft failure in cord-blood transplantation (CBT), effects of DSAs other than against HLA-A, -B or -DRB1 on transplantation outcomes remained poorly understood. MethodsWe retrospectively analyzed 567 single-unit CBT recipients to evaluate impact of DSAs against HLA-DP and -DQ on CBT outcomes. ResultsAmong 143 recipients (25.2%) who had anti-HLA antibodies, nine harbored DSAs against HLA-DP or -DQ. DSAs against HLA-DP or -DQ were associated with a significantly lower neutrophil engraftment rate (55.6% versus 91.8%, P = 0.032) and with a marginally lower platelet engraftment rate (46.7% versus 75.3%, P = 0.128) at day 100 after transplantation, compared with patients without anti-HLA antibodies. Time to neutrophil and platelet engraftment in patients with DSAs for HLA-DP or -DQ was significantly longer than that in patients without anti-HLA antibodies (median, 25 versus 21 days, P = 0.002 in neutrophil; median 61 versus 46 days, P = 0.014 in platelet). Cumulative incidence of bacterial infection at day 100 was significantly greater (88.9% versus 57.1%, P = 0.024), and re-transplant-free survival was marginally lower (55.6% versus 76.8%, P = 0.132) in patients with DSAs against HLA-DP or -DQ, compared with those without anti-HLA antibodies. These findings suggest that DSAs against HLA-DP or -DQ lead to unfavorable engraftment, which may increase risk of bacterial infection, and reduce survival soon after CBT. ConclusionsOur results suggest the importance of evaluating DSAs against HLA-DP and -DQ in recipients before selecting CB units.

Comparison of transplant outcomes between haploidentical transplantation and single cord blood transplantation in non-remission acute myeloid leukaemia: A nationwide retrospective study.

Allogeneic haematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for some patients with acute myeloid leukaemia (AML) who are refractory to chemotherapy. Cord blood transplantation (CBT) is a reasonable option in such cases because of its rapid availability. Recently, a growing number of human leucocyte antigen (HLA)-haploidentical related donor HSCTs (haplo-HSCTs) have been performed, although its effectiveness remains undetermined. Using the Japanese nationwide transplantation registry data, we identified 2438 patients aged ≥16 years who received CBT or haplo-HSCT as their first transplant for non-remission AML between January 2008 and December 2018. After 2:1 propensity score matching, 918 patients in the CBT group and 459 patients in the haplo-HSCT group were selected. In this matched cohort, no significant difference in overall survival (OS) was observed between the CBT and haplo-HSCT groups (hazard ratio [HR] of haplo-HSCT to CBT 1.02, 95% confidence interval [CI] 0.89-1.16). Similarly, no significant difference in the cumulative incidence of relapse (HR 1.09, 95% CI 0.93-1.28) or non-relapse mortality (HR 0.94, 95% CI 0.76-1.18). Subgroup analysis showed that CBT was significantly associated with preferable OS in patients receiving myeloablative conditioning. Our data showed comparable outcomes between haplo-HSCT and CBT recipients with non-remission AML.

Predictors of Covid-19 Vaccination Response After In-Vivo T-Cell–Depleted Stem Cell Transplantation

Covid-19 vaccination is recommended in allogeneic transplant recipients, but many questions remain regarding its efficacy. Here we studied serologic responses in 145 patients who had undergone allogeneic transplantation using in vivo T-cell depletion. Median age was 57 (range 21-79) at transplantation and 61 (range 24-80) at vaccination. Sixty-nine percent were Caucasian. One third each received transplants from HLA-identical related (MRD), adult unrelated (MUD), or haploidentical-cord blood donors. Graft-versus-host disease (GVHD) prophylaxis involved in-vivo T-cell depletion using alemtuzumab for MRD or MUD transplants and anti-thymocyte globulin for haplo-cord transplants. Patients were vaccinated between January 2021 and January 2022, an average of 31 months (range 3-111 months) after transplantation. Sixty-one percent received the BNT162b2 (bioNtech/Pfizer) vaccine, 34% received mRNA-1273 (Moderna), and 5% received JNJ-78436735 (Johnson & Johnson). After the initial vaccinations (2 doses for BNT162b2 and mRNA-1273, 1 dose for JNJ-7843673), 124 of the 145 (85%) patients had a detectable SARS-CoV-2 spike protein (S) antibody, and 21 (15%) did not respond. Ninety-nine (68%) had high-level responses (≥100 binding antibody units [BAU]/mL)m and 25 (17%) had a low-level response (<100 BAU/mL). In multivariable analysis, lymphocyte count less than 1 × 109/ mL, having chronic GVHD, and being vaccinated in the first year after transplantation emerged as independent predictors for poor response. Neither donor source nor prior exposure to rituximab was predictive of antibody response. SARS-CoV-2 vaccination induced generally high response rates in recipients of allogeneic transplants including recipients of umbilical cord blood transplants and after in-vivo T cell depletion. Responses are less robust in those vaccinated in the first year after transplantation, those with low lymphocyte counts, and those with chronic GVHD.

Catheter-related bloodstream Mycobacterium wolinskyi infection in an umbilical cord blood transplant recipient: a case report

BackgroundCatheter-related bloodstream infection (CRBSI), caused by rapidly growing mycobacteria (RGM), is a rare infectious complication in hematopoietic stem cell transplant (HSCT) recipients and can often be misdiagnosed as Gram-positive rod (GPR) bacteremia.Case presentationWe present a case of CRBSI caused by Mycobacterium wolinskyi, a rare RGM, in a 44-year-old female patient who received an umbilical cord blood transplant.ConclusionsRapidly growing mycobacteria can stain as GPRs and may grow in routine blood culture media after 3–4 days of incubation. These features are not widely known to clinicians, and acid-fast staining is therefore recommended when unidentifiable GPRs are detected in blood cultures, especially in immunocompromised patients, such as those with hematologic malignancies or intravascular devices.

Infusion of Non-HLA-Matched Off-the-Shelf Ex Vivo Expanded Cord Blood Progenitors in Patients Undergoing Cord Blood Transplantation: Result of a Phase II Clinical Trial.

Recipients of myeloablative cord blood transplants (CBT) are known to experience delayed hematopoietic recovery and an increased risk of transplant related mortality (TRM). We developed methods for ex vivo expansion and cryopreservation of CB stem and progenitor cells. 15 patients with hematologic malignancies were enrolled in this single center phase II trial between September 2010 and August 2012 to assess the safety of infusing a non-HLA-matched expanded CB product to bolster a conventional CBT. On the day of transplant, an infusion of the expanded CB product followed the primary graft (1 or 2 unmanipulated CB units). All patients engrafted. Median time to neutrophil and platelet recovery was 19 and 35 days, respectively. Early myelomonocytic recovery was almost entirely due to cells arising from the non-HLA-matched expansion product and were no longer detected at day 14 in all but 2 patients. The probability of 3-years disease free survival was 86%. No TRM was observed throughout the study period, and only 2 patients relapsed. All patients presented with grade II acute graft-versus-host disease (aGVHD) at a median time of 32 days, with no grade III-IV aGVHD observed. At 2 years only 2 patients remain on immunosuppressive therapy for mild chronic GVHD. This phase II safety study demonstrate that infusion of an off-the-shelf non-HLA-matched expanded CB product in addition to a conventional CB graft was safe and led to sustained myeloid recovery. Based on these encouraging results, a prospective multicenter randomized trial utilizing this product has been conducted and results will be soon released. ClinicalTrials.gov Identifier: NCT01175785.

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

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