Influence of interruption of oral mycophenolate mofetil for graft-versus-host disease prophylaxis on outcomes after single cord blood transplantation.

Mycophenolate mofetil (MMF), in combination with a calcineurin inhibitor, is used as the prophylaxis for graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Compared to intravenous methotrexate (MTX), MMF is associated with a lower incidence of mucositis and shorter time for hematopoietic engraftment but comparable incidence of acute GVHD, resulting in the preferred use of MMF for GVHD prophylaxis in elderly patients or those undergoing cord blood transplantation (CBT). Although several studies have evaluated the clinical impact of MTX omission due to toxicity after allogeneic HCT, the impact of oral MMF interruption for GVHD prophylaxis on transplant outcomes remains unclear. Therefore, in this study, we retrospectively analyzed the consecutive data of adult patients who underwent single-unit unrelated CBT and received oral MMF in combination with cyclosporine for GVHD prophylaxis at our hospital. Among the 53 patients, the planned dose of MMF was interrupted in 14 with a median of 19.5 d (range, 3-27 d) of CBT. In multivariate analysis, MMF interruption, which was treated as a time-dependent covariate, was significantly associated with poorer overall survival (hazard ratio [HR], 5.41; 95% confidence interval [CI], 2.03-14.43; P < 0.001) and higher non-relapse mortality (HR, 7.56; 95% CI, 1.99-28.79; P = 0.002). Further studies with larger cohorts are necessary to confirm the clinical significance of oral MMF interruption in GVHD prophylaxis.

Cellular and humoral immunogenicity against SARS-CoV-2 vaccination or infection is associated with the memory phenotype of T- and B-lymphocytes in adult allogeneic hematopoietic cell transplant recipients.

We conducted a cross-sectional study to evaluate cellular and humoral immunogenicity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination or infection and examine how lymphocyte subpopulations in peripheral blood correlate with cellular and humoral immunogenicity in adult allogeneic hematopoietic cell transplantation (HCT) recipients. The median period from SARS-CoV-2 vaccination or infection to sample collection was 110.5 days (range, 6-345 days). The median SARS-CoV-2 spike-specific antibody level was 1761 binding antibody units (BAU)/ml (range, 0 to > 11,360 BAU/ml). Enzyme-linked immunosorbent spot (ELISpot) assay of T cells stimulated with SARS-CoV-2 spike antigens showed that interferon-gamma (IFN-γ)-, interleukin-2 (IL-2)-, and IFN-γ + IL-2-producing T cells were present in 68.9%, 62.0%, and 56.8% of patients, respectively. The antibody level was significantly correlated with frequency of IL-2-producing T cells (P = 0.001) and IFN-γ + IL-2-producing T cells (P = 0.006) but not IFN-γ-producing T cells (P = 0.970). Absolute counts of CD8+ and CD4+ central memory T cells were higher in both IL-2- and IFN-γ + IL-2-producing cellular responders compared with non-responders. These data suggest that cellular and humoral immunogenicity against SARS-CoV-2 vaccination or infection is associated with the memory phenotype of T cells and B cells in adult allogeneic HCT recipients.

Feasibility and safety of the discontinuation of systemic immunosuppressive treatment after single-unit cord blood transplantation in adults.

We retrospectively evaluated the incidence, factors, and clinical outcomes of the discontinuation of immunosuppressive treatment (IST) after single-unit unrelated cord blood transplantation (CBT) in adults receiving cyclosporine-based graft-versus-host disease (GVHD) prophylaxis at our institute. Among the 309 patients who achieved engraftment, 247 were able to discontinue IST with a median follow-up of 121 months for survivors. The cumulative incidence of the discontinuation of IST was 46.2% at 180 days, 72.8% at 2 years, and 79.3% at 5 years post-CBT. In the multivariate analysis, discontinuation of IST after CBT was significantly associated with the requirement for steroid therapy (hazard ratio [HR]: 0.46; P < 0.001) and the recent calendar year of CBT (HR: 1.79; P < 0.001). In the conditional landmark analysis at 180 days, discontinuation of IST was not associated with the development of extensive chronic GVHD (HR: 1.00; P = 0.989), non-relapse mortality (HR: 0.49; P = 0.122), relapse (HR: 1.46; P = 0.388), or overall survival (HR: 1.91; P = 0.065). Our data showed that successful discontinuation of IST is common after single-unit CBT in adults. Discontinuation of IST did not affect subsequent outcomes, suggesting that discontinuation of IST is both feasible and safe in adults undergoing single-unit CBT.

Effect of IL-2 polymorphism rs2069762 on single-unit cord blood transplant outcomes.

BACKGROUND: Interleukin-2 (IL-2) is one of the most important cytokines that regulate the activation and proliferation of T cells and natural killer cells. The production of IL-2 may be affected by polymorphisms in the promoter region of the IL-2 gene (rs2069762). In allogeneic hematopoietic cell transplantation (HCT) from adult donors, rs2069762 has been associated with the incidence of acute and chronic graft-versus-host disease (GVHD). However, the impacts of IL-2 polymorphism on cord blood transplantation (CBT) outcomes remain unclear. OBJECTIVE: The objective of this study was to assess the impact of IL-2 polymorphism rs2069762 on transplant outcomes, such as hematopoietic recovery, GVHD, overall survival, relapse, and non-relapse mortality (NRM) after CBT. STUDY DESIGN: We conducted a retrospective analysis of data from adult patients who underwent single-unit CBT at our institution from November 2005 to March 2023 for whom DNA samples from recipients and donors were available. IL-2 genotyping was performed using real-time polymerase chain reaction with the TaqMan® SNP genotyping assay for rs2069762. RESULTS: A total of 143 recipient and donor pairs were included in this study. The proportion of recipient IL-2 polymorphism rs2069762 was 48 % (n = 69) for AA, 42 % (n = 60) for CA, and 10 % (n = 14) for CC. The proportion of donor IL-2 polymorphism rs2069762 was 43 % (n = 61) for AA, 48 % (n = 69) for CA, and 9 % (n = 13) for CC. In the multivariate analysis, the use of an rs2069762 CA + CC donor was associated with lower neutrophil recovery compared to an rs2069762 AA donor (hazard ratio [HR], 0.66; 95 % confidence interval [CI], 0.50-0.88; P = 0.004). Furthermore, recipients of rs2069762 CA + CC were associated with higher NRM compared to recipients of rs2069762 AA (HR, 2.32; 95 % CI, 1.01-5.34; P = 0.047). Serum IL-2 levels at 8 weeks were significantly higher in rs2069762 CA + CC recipients compared to those with rs2069762 AA recipients (P = 0.014). CONCLUSION: Our data showed that donor IL-2 polymorphism affects neutrophil recovery and recipient IL-2 polymorphism affects NRM in adults undergoing single-unit CBT. The polymorphism of IL-2 rs2069762 in recipients and donors might be associated with the clinical outcomes of single-unit CBT.

Low urinary sodium-to-potassium ratio in the early phase following single-unit cord blood transplantation is a predictive factor for poor non-relapse mortality in adults.

Although daily higher urinary sodium (Na) and potassium (K) excretion ratio is associated with the risk of cardiovascular disease in the general population, a low Na/K ratio is associated with renal dysfunction in critically ill patients. Thus, we retrospectively analyzed the impact of daily urinary Na and K excretion and their ratio on non-relapse mortality (NRM) and overall mortality in 172 adult single-unit cord blood transplantation (CBT) patients treated at our institution between 2007 and 2020. Multivariate analysis showed that a low urinary Na/K ratio at both 14 days (hazard ratio [HR], 4.82; 95% confidence interval [CI], 1.81-12.83; P = 0.001) and 28 days (HR, 4.47; 95% CI 1.32-15.12; P = 0.015) was significantly associated with higher NRM. Furthermore, a low urinary Na/K ratio at 28 days was significantly associated with higher overall mortality (HR, 2.38; 95% CI 1.15-4.91; P = 0.018). Patients with a low urinary Na/K ratio had decreased urine volume, more weight gain, experienced more grade III-IV acute graft-versus-host disease, and required corticosteroids by 28 days after CBT. These findings indicate that a low urinary Na/K ratio early after single-unit CBT is associated with poor NRM and survival in adults.

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.

Pretransplantation EASIX Score Predicts Nonrelapse and Overall Mortality of Adult Patients Undergoing Single-Unit Unrelated Cord Blood Transplantation.

The Endothelial Activation and Stress Index (EASIX) is a laboratory-based score used to estimate endothelial damage occurring after hematopoietic cell transplantation (HCT). The EASIX score exhibits dynamic changes during the course of transplantation and has been identified as a predictor of nonrelapse mortality (NRM) and worse overall survival (OS) in studies focused mainly on patients who received matched related or unrelated donor allogeneic HCT. However, the role of EASIX score in the setting of cord blood transplantation (CBT) is unclear. This study examined the association between pretransplant EASIX score and post-transplantation outcomes in adult patients undergoing single-unit CBT. We retrospectively evaluated the impact of EASIX score at different time points on post-transplantation outcomes in adults following single-unit unrelated CBT between 1998 and 2022 at our institution. EASIX scores were calculated at the start of conditioning (EASIX-PRE), at day 30 post-CBT (EASIX-d30), at day 100 post-CBT (EASIX-d100), and at the onset of grade II-IV acute graft-versus-host disease (GVHD) (EASIX-GVHD II-IV). A total of 317 patients were included in this study. In the multivariate analysis, log2-EASIX-PRE (continuous variable) was significantly associated with lower risks of neutrophil engraftment (hazard ratio [HR], .87; 95% confidence interval [CI], .80 to .94; P < .001) and platelet engraftment (HR, .91; 95% CI, .83 to .99; P = .047), lower risk of grade II-IV acute GVHD (HR, .85; 95% CI, .76 to .94; P = .003), and higher risk of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) (HR, 1.44; 95% CI, 1.03 to 2.02; P = .032). Log2-EASIX-PRE also was significantly associated with higher NRM (HR, 1.42; 95% CI, 1.08 to 1.86; P = .011) and worse OS (HR, 1.26; 95% CI, 1.08 to 1.46; P = .003), but not with relapse (HR, 1.02; 95% CI, .88 to 1.18; P = .780). Similarly, log2-EASIX-d30 (HR, 1.60; 95% CI, 1.26 to 2.05; P < .001), and log2-EASIX-d100 (HR, 2.01; 95% CI, 1.63 to 2.48; P < .001) were also significantly associated with higher NRM, but log2-EASIX-GVHD II-IV was not (HR, 1.15; 95% CI, .85 to 1.55; P = .360). Pretransplantation EASIX score is a powerful predictor of engraftment, VOS/SOS, NRM, and OS in adult patients undergoing single-unit unrelated CBT who mainly received intensified conditioning regimens. EASIX is an easily evaluable and dynamic prognostic score for accurately predicting post-transplantation outcomes in patients at any time during the course of allogeneic HCT, particularly for CBT.

Higher Cryopreserved CD34+ Cell Dose Is Associated with Decreased Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Single-Unit Cord Blood Transplantation in Adults Given Prophylactic Ursodeoxycholic Acid and Intravenous Heparin.

Hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is one of the most serious complications to occur early after allogeneic hematopoietic cell transplantation (HCT). However, detailed data on VOD/SOS after cord blood transplantation (CBT) are not available. The objective of this retrospective study was to evaluate the incidence, risk factors, and clinical impact of VOD/SOS after single-unit unrelated CBT for adult patients at our institution. We retrospectively evaluated the incidence, risk factors, and outcomes of VOD/SOS after 390 single-unit unrelated CBTs performed in 332 adults under a prophylactic strategy of ursodeoxycholic acid (UDCA) and i.v. heparin at our institution between 1998 and 2021. VOD/SOS was observed in 24 of the 390 CBTs. The cumulative incidence of VOD/SOS was 5.9% at 30 days and 6.2% at 100 days after CBT. Multivariate analysis showed that cryopreserved CD34+ cell dose ≥1.0 × 105/kg was significantly associated with a decreased risk of VOD/SOS after CBT (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.12 to 0.91; P = .032). In multivariate analysis, the development of VOD/SOS was significantly associated with higher overall mortality (HR, 6.19; 95% CI, 3.61 to 10.65; P < .001), treatment failure (HR, 4.79; 95% CI, 2.95 to 7.76; P < .001), and nonrelapse mortality (HR, 12.60; 95% CI, 6.90 to 23.00; P < .001). Our study shows that the incidence of hepatic VOD/SOS was relatively low after unrelated single-unit CBT under a prophylactic strategy of UDCA and i.v. heparin. A higher cryopreserved cord blood CD34+ cell dose was associated with a reduction in VOD/SOS, suggesting that selection of a higher cord blood unit CD34+ cell dose could be efficient in preventing hepatic VOD/SOS in adults undergoing single-unit CBT.

Immunological influence of serum-free manufactured umbilical cord-derived mesenchymal stromal cells for steroid-resistant acute graft-versus-host disease.

This study investigated the safety, efficacy, and immunological influence of allogeneic umbilical cord-derived mesenchymal stromal cells (IMSUT-CORD) processed in serum-free medium and cryoprotectant, for treating steroid-resistant acute graft-versus-host disease (aGVHD). In a phase I dose-escalation trial, IMSUT-CORD were infused intravenously twice weekly over two cycles with up to two additional cycles. Four patients received a dose of 1 × 106 cells/kg, while three received 2 × 106/kg. Of 76 total adverse events, fourteen associated or possibly associated adverse events included 2 cases of a hot flash, headache, and peripheral neuropathy, 1 each of upper abdominal pain, hypoxia, increased γ-GTP, somnolence, peripheral vascular pain at the injection site, thrombocytopenia, hypertension, and decreased fibrinogen. At 16 weeks after the initial IMSUT-CORD infusion, three patients showed complete response (CR), two partial response (PR), one mixed response, and one no response. The overall response rate was 71.4%, and the continuous CR/PR rate was 100% for over 28 days after CR/PR. NK cell count significantly increased and correlated with treatment response, whereas IL-12, IL-17, and IL-33 levels decreased, but did not correlate with treatment response. CCL2 and CCL11 levels increased during IMSUT-CORD therapy. IMSUT-CORD are usable in patients with steroid-resistant aGVHD (UMIN000032819: https://www.umin.ac.jp/ctr ).

Optimal time and threshold of absolute lymphocyte count recovery as a prognostic factor after single-unit cord blood transplantation in adults.

We retrospectively evaluated the optimal time and threshold of absolute lymphocyte count (ALC) recovery as a prognostic factor in 174 adult patients who received single-unit cord blood transplantation (CBT) at our institute. We analyzed the impact of ALC ≥300, ≥600, and ≥900/µl by 30 and 60 days on transplant outcomes. Multivariate analysis showed that only ALC ≥300/µl at 60 days was significantly associated with overall mortality (hazard ratio, 0.24; p = 0.001) following CBT. The optimal time point to use ALC recovery as a prognostic tool following CBT could be later than those following adult donor transplantation.

Long-Term Incidence of Varicella Zoster Virus Disease in Adults Receiving Single-Unit Cord Blood Transplantation.

Although varicella zoster virus (VZV) disease is a common complication after allogeneic hematopoietic cell transplantation (HCT), research into the long-term incidence of VZV disease in adults receiving cord blood transplantation (CBT) has been limited. The objective of this study was to evaluate the incidence, risk factors, and clinical impact of VZV disease after CBT with long-term follow-up in our institution. We retrospectively analyzed the data for 156 adult patients who received single-unit CBT at our institution between 2007 and 2020 and who achieved neutrophil engraftment and survived at least 100 days without recurrence of the underlying disease. VZV disease occurred in 61 patients at a median of 608 days (range, 36 to 4090 days) after CBT. The cumulative incidence of VZV disease was 14% (95% confidence interval [CI], 9% to 20%) at 1 year post-CBT and 40% (95% CI, 31% to 48%) at 5 years post-CBT. Multivariate analysis identified the cessation of antiviral prophylaxis as an independent risk factor for an elevated risk of VZV disease (hazard ratio, 15.65; 95% CI, 6.59 to 37.21; P < .001). The cumulative incidence of VZV disease was significantly lower in the long-term antiviral prophylaxis group (who received prophylaxis for approximately 1 year after CBT or to the end of immunosuppressive therapy) compared with the short-term antiviral prophylaxis group (who received prophylaxis for 35 days after CBT) (P = .005). Among the patients who developed VZV disease, the median time to onset of VZV disease was significantly delayed in the long-term antiviral prophylaxis group compared with the short-term antiviral prophylaxis group (694 days versus 130 days; P < .001), but the median onset of VZV disease after the cessation of antiviral prophylaxis was not significantly different between the 2 groups (166 days versus 95 days; P = .087). These data demonstrate that the long-term incidence of VZV disease is relatively high in adult patients undergoing CBT. Given that the incidence of VZV disease remained high after the cessation of antiviral prophylaxis, additional interventions, such as recombinant zoster vaccine administration, could be required to prevent VZV disease in long-term adult survivors after CBT.

Anti-spike protein antibody titer at the time of breakthrough infection of SARS-CoV-2 omicron.

By December 2021, about 80% of people over the age of 12 had been vaccinated in Japan, and almost all people were vaccinated with the mRNA vaccine. We investigated here the anti-spike protein antibody titer at the time of breakthrough infection of SARS-CoV-2 omicron. A total of 32 SARS-CoV2 omicron breakthrough infection was included in the study. The median antibody titer at breakthrough infection was 776 AU/mL overall, of which the median antibody titer of BNT162b2 vaccinated was 633 AU/mL and that of mRNA-1273 vaccinated was 9416 AU/mL. This result suggests that low levels of antibody titers 6 months after vaccination do not provide sufficient antibodies to prevent the omicron variant breakthrough infection, which may occur with a higher anti-spike antibody titer after vaccination with mRNA-1273. However, antibody titers in some patients were comparable to those immediately after the second vaccination with either mRNA vaccine.

Total body irradiation-based versus busulfan-based myeloablative conditioning for single-unit cord blood transplantation in adults.

Comparative studies between total body irradiation (TBI)-based and busulfan-based myeloablative conditioning (MAC) regimens for cord blood transplantation (CBT) have been limited. We retrospectively analyzed the results of single-unit CBT in 333 adult patients who received either TBI-based (n = 258) or busulfan-based (n = 75) MAC regimens at our institute. After adjusting for significant variables in the univariate analysis, there were no significant differences in neutrophil recovery (hazard ratio (HR), 0.88; p = .460), grade III-IV acute graft-versus-host disease (GVHD) (HR: 1.40, p = .410), extensive chronic GVHD (HR: 0.73, p = .380), relapse (HR: 0.61, p = .270), non-relapse mortality (HR: 1.38, p = .420), overall survival (HR: 1.18, p = .637), or event-free survival (HR: 1.08, p = .773), although platelet recovery was lower with marginal significance for the busulfan-based regimen (HR: 0.67, p = .068). In subgroup analysis, TBI-based regimens were superior to busulfan-based regimens in terms of survival for acute lymphoblastic leukemia, but not for myeloid malignancies. Further investigation is warranted even for CBT.

Long-term outcomes following the addition of granulocyte colony-stimulating factor-combined high-dose cytarabine to total body irradiation and cyclophosphamide conditioning in single-unit cord blood transplantation for myeloid malignancies.

An intensified myeloablative conditioning regimen, involving the addition of granulocyte colony-stimulating factor (G-CSF)-combined high-dose cytarabine (12 g/m2) to standard total body irradiation and cyclophosphamide, has been performed for adult patients with myeloid malignancies in single-unit cord blood transplantation (CBT) since 1998 in our institute. We update the results of CBT, as the first allogeneic hematopoietic cell transplantation after this conditioning regimen, in 169 patients with a median long-term follow-up of 10.4 years. The median age was 43 years (range, 16 to 59 years). Ninety-four patients (56%) were in non-remission at the time of CBT, and 124 patients (73%) were acute myeloid leukemia. The median cryopreserved cord blood total nucleated cell dose and CD34+ cell dose was 2.40 × 107/kg and 0.93 × 105/kg, respectively. The cumulative incidence of neutrophil recovery at 42 days was 94.4% (95% confidence interval [CI]: 88.6-97.3%). Among the whole cohort, 105 patients were still alive at the end of the study period. The cumulative incidences of relapse and non-relapse mortality at 10 years were 26.0% (95% CI: 19.5-33.0%) and 16.9% (95% CI: 11.4-23.4%), respectively. There was an overall survival probability of 62.5% (95% CI: 54.3-69.7%) at 10 years. Higher disease risk index alone significantly affected higher overall mortality (hazard ratio 2.21, P = 0.003) in multivariate analysis. These outcomes demonstrate that G-CSF-combined myeloablative conditioning could have favorable long-term remission rates for adult patients with myeloid malignancies undergoing single-unit CBT.