Cord Blood Transplantation In Adults Research Articles

Higher relapse and worse overall survival in recipients with CTLA-4 AA genotype of rs231775 following single-unit cord blood transplantation in adults

We retrospectively investigated the impact of CTLA-4 polymorphism on outcomes for adult patients who received single-unit cord blood transplantation (CBT) at our institution. CTLA-4 genotyping was performed using real-time polymerase chain reaction with the TaqMan® SNP genotyping assay for rs231775. This study included 143 recipient–donor pairs. The multivariate analysis showed that recipient rs231775 AA was associated with worse overall survival (OS) (hazard ratio [HR], 2.92; p = 0.008) and a higher relapse rate (HR, 4.79; p = 0.002), but donor rs231775 was not. The rs231775 polymorphism in recipients and donors did not affect non-relapse mortality, hematopoietic recovery, or acute and chronic graft-versus-host disease. The beneficial effects of rs231775 GG+GA recipients on OS and relapse were notable in subgroups of patients with high-risk disease status and those with myeloid diseases. The polymorphism of CTLA-4 rs231775in recipients might be associated with the clinical outcomes of single-unit CBT.

Haploidentical transplantation with post-transplant cyclophosphamide versus single cord blood transplantation in adults with relapsed/refractory non-Hodgkin lymphoma.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for relapsed or refractory non-Hodgkin lymphoma (R/R NHL). Allo-HSCT using post-transplant cyclophosphamide (PTCY-haplo) and umbilical cord blood transplantation (uCBT) are important donor options in the absence of matched related siblings. However, the data comparing these two donor sources in R/R NHL are limited. Using the Japanese nationwide transplantation registry data, we identified 857 patients with R/R NHL, including 169 patients who received PTCY-haplo and 688 who received uCBT for their first allo-HSCT between January 2013 and December 2021; 514 patients (60%) had B-cell lymphoma. More PTCY-haplo recipients received allo-HSCT using a reduced-intensity conditioning regimen in recent years. The 3-year overall survival (OS), progression-free survival (PFS), and graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) rates in the PTCY-haplo and uCBT groups were 44% versus 39% (P = 0.326), 34% versus 33% (P = 0.660), and 19% versus 23% (P = 0.910), respectively; the adjusted hazard ratios for OS, PFS, and GRFS were 0.89 (95% confidence interval: 0.69-1.15, P = 0.373), 0.98 (0.78-1.22, P = 0.852), and 0.92 (0.83-1.21, P = 0.920), respectively. The PTCY-haplo group showed faster neutrophil and platelet engraftment and a lower incidence of grade III-IV acute GVHD. Thus, PTCY-haplo and uCBT could serve as alternative donor sources in patients with R/R NHL.

Levels of C-Reactive Protein and Body Temperature Elevation During Neutropenia Predict Engraftment and Non-Relapse Mortality for Unrelated Single-Unit Cord Blood Transplantation in Adults

Cord blood transplantation (CBT) presents unique challenges related to inflammation during neutropenia, such as mucosal damage, infections, and the potential development of pre-engraftment syndrome or pre-engraftment immune reaction. These factors can contribute to significant inflammation and infection shortly after CBT. However, the effect of severe inflammation during neutropenia, specifically elevated C-reactive protein (CRP) level and body temperature, on post-transplant outcomes after CBT remains unclear. This retrospective study aimed to investigate the association between maximum CRP level, maximum body temperature during neutropenia, and post-transplantation outcomes in adult patients undergoing single-unit CBT. We retrospectively evaluated the impact of maximum CRP level and maximum body temperature during neutropenia on post-transplantation outcomes in adults who underwent single-unit unrelated CBT between 1998 and 2023 at our institution. A total of 336 adult patients were included in this study. The median maximum CRP level before neutrophil recovery was 7.75 mg/dL (interquartile range [IQR], 4.70 to 12.05 mg/dL) at a median of 14 d (IQR, 8 to 16 d). The median maximum body temperature before neutrophil recovery was 39.5°C (IQR, 39.0 to 40.0°C) at a median of 15 d (IQR, 12 to 17 d). In the multivariate analysis, a maximum CRP level≥20 mg/dL was significantly associated with lower neutrophil recovery (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.23 to 0.59; P < .001), lower platelet recovery (HR, 0.28; 95% CI, 0.16 to 0.48; P < .001), and a higher incidence of veno-occlusive disease/sinusoidal obstruction syndrome (HR, 16.42; 95% CI, 4.11 to 65.54; P < .001), which resulted in higher non-relapse mortality (NRM) (HR, 5.16; 95% CI, 2.62 to 10.15; P < .001) and worse overall survival (HR, 2.81; 95% CI, 1.66 to 4.78; P < .001). Similarly, a maximum body temperature≥40.5°C was significantly associated with lower neutrophil recovery (HR, 0.51; 95% CI, 0.33 to 0.79; P = .002), lower platelet recovery (HR, 0.55; 95% CI, 0.38 to 0.79; P = .001), higher incidence of grades III to IV acute GVHD (HR, 2.93; 95% CI, 1.24 to 6.88; P = .013), and extensive chronic GVHD (HR, 2.47; 95% CI, 1.22 to 4.97; P = .011), which resulted in higher NRM (HR, 3.43; 95% CI, 1.53 to 7.67; P = .002). Maximum CRP level and maximum body temperature during neutropenia were significantly associated with lower hematopoietic recovery and higher NRM following single-unit CBT in adults. Further studies are warranted to explore early intervention strategies aimed at preventing severe inflammation and improving post-transplant outcomes in single-unit CBT.

Prognostic Value of the Pretransplant Fibrosis-4 Index on Non-Relapse and Overall Mortality following Unrelated Single-Unit Cord Blood Transplantation in Adults

Introduction: The fibrosis-4 (FIB-4) index is a noninvasive marker of liver fibrosis. The FIB-4 index predicts poor outcomes in patients with hepatic and non-hepatic diseases. However, the association of the FIB-4 index with mortality and liver-related clinical outcomes following cord blood transplantation (CBT) is unclear. Methods: We retrospectively evaluated the impact of the pretransplant FIB-4 index on outcomes in 336 adults following single-unit unrelated CBT at our institution. Results: In multivariate analyses, when the FIB-4 index <1.3 group was used as the reference, non-relapse mortality was significantly higher in the FIB-4 index 1.3–2.67 (hazard ratio [HR], 2.51; 95% confidence interval [CI], 1.19–5.30) and FIB-4 index >2.67 (HR, 2.34; 95% CI, 1.12–4.90) groups. Overall mortality was significantly higher in the FIB-4 index >2.67 group (HR, 1.66; 95% CI, 1.00–2.73), but with only marginal significance in the FIB-4 index 1.3–2.67 group (HR, 1.59; 95% CI, 0.96–2.64). Hematopoietic recovery, acute and chronic graft-versus-host disease of the liver, and veno-occlusive disease/sinusoidal obstruction syndrome were not associated with the pretransplant FIB-4 index. Conclusion: The pretransplant FIB-4 index is accurate and useful in predicting mortality in adult patients undergoing single-unit unrelated CBT.

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.

Comparison of fludarabine-based conditioning regimens in adult cord blood transplantation for myeloid malignancy: A retrospective, registry-based study.

Fludarabine/busulfan and fludarabine/melphalan are viable options as conditioning regimens. However, the optimal fludarabine-based conditioning in cord blood transplantation (CBT) remains unclear. Therefore, this retrospective, registry-based study aimed to analyze the impact of five fludarabine-containing conditioning regimens on 1395 adult patients (median age, 61 years) with acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia who underwent their first CBT. Treatment outcomes of fludarabine combined with melphalan (100-140 mg/m2 ) and low-dose total body irradiation (TBI; FM140T); melphalan (80-99 mg/m2 ) and TBI (FM80T); busulfan (12.8 mg/kg) and melphalan (FB4M); busulfan (12.8 mg/kg) and TBI (FB4T); and busulfan (6.4 mg/kg) and TBI (FB2T) were compared. The 3-year survival rate was 67%, 53%, 44%, 36%, and 39%, respectively (p < .0001). The FM140T survival rate was the most favorable after adjusting for confounders, and the hazard ratios (vs. FM140T) for overall mortality were as follows: FM80T, 1.6 (95% confidence interval [CI], 1.2-2.2); FB4M, 2.1 (95% CI, 1.6-2.8); FB4T, 2.7 (95% CI, 2.0-3.7); and FB2T, 2.2 (95% CI, 1.6-3.1). The better survival observed with FM140T, regardless of the disease, disease risk, age, or transplant year, was attributed to the lower relapse rate and lower non-relapse mortality (NRM) associated with fewer infectious deaths. Conversely, FB4T was associated with a higher relapse rate and higher NRM. The findings indicate that the outcomes of CBT in myeloid malignancies were highly dependent on both the alkylating agent and its dose in combination with fludarabine. Therefore, compared with fludarabine/busulfan-based conditioning, FM140T may be the preferred regimen.

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.

Impact of Allele-Level HLA-Matching on Outcomes after Double Cord Blood Transplantation in Adults with Malignancies.

In single unrelated cord blood transplantation (UCBT), an increasing number of HLA allele mismatches (MM) has been associated with inferior overall survival (OS) attributed to higher transplant-related mortali-ty (TRM). Previous studies on the role of allele-level HLA matching following double UCBT (dUCBT) showed conflicting results. Herein we report the impact of allele-level HLA matching on outcomes of a large dUCBT cohort . We included 963 adults with hematologic malignancies, with available allele-level HLA matching at HLA-A, -B, -C and -DRB1, receiving dUCBT between 2006-2019. Assignment of donor-recipient HLA match was performed considering the unit with the highest disparity with the recipient. 392 patients received dUCBT with 0-3 and 571 with ≥4 allele MM. Day-100 and 4-year TRM were 10% and 23%, for recipients of dUCBT with 0-3 MM compared to 16% and 36% for those with ≥4 MM (HR 1.58, p=.002; and HR 1.54, p=.002), respectively. Higher degree of allele MM was also associated with worse neutrophil recovery and lower incidence of relapse; no significant effect on graft-versus-host disease was observed. Patients receiving units with 0-3 MM had a 4-year OS of 54% versus 43% for those with ≥4 MM (HR 1.40, p=.005). The inferior OS associated with higher HLA disparity was only partially mitigated by increased total nucleated cell doses. Our results confirm that allele-level HLA typing is a significant factor for OS following dUCBT and units with ≥4 MM (≤4/8 HLA-matched) should be avoided if possible.

Impact of Allele-Level HLA-Matching on Outcomes after Double Unrelated Cord Blood Transplantation in Adults with Malignant Diseases

Introduction: In single unrelated cord blood transplantation (sCBT), an increasing number of HLA-mismatches (MM) has been associated with inferior overall survival (OS) attributed to higher transplant-related mortality (TRM). These findings have prompted current guidelines to endorse high resolution HLA typing in the selection of CB (cord blood) units, including double CBT (dCBT). However, a comprehensive appraisal of the effect of allele-level HLA matching following dCBT was likely hindered by the relatively small sample sizes in previous studies. Herein we aimed to analyze the impact of allele-level HLA-matching on outcomes of a large cohort of dCBT recipients to improve CB unit selection and further explore the unique dCBT biology. Methods: We included patients ≥18 years-old receiving a dCBT between 2006-2019 with the availability of HLA typing minimally at HLA-A, -B, -C at the antigen-level and HLA-DRB1 at the allele-level for the recipient and both CB units. A validated high-resolution imputation tool, HaploStats, was used to adjudicate allele-level match status for a subset of cord and recipient pairs (n = 173) having only antigen-level typing at HLA-A, -B or -C. A sensitivity analysis for OS was performed excluding imputed cases, and results were unchanged. HLA matching was classified according to the CB unit with the greatest degree of HLA mismatch with the patient, meaning that only the most mismatched unit was considered and that the interunit matching was not considered. Continuous covariates were dichotomized to find an optimal cutoff value by using the Contal-O'Quigley method, except for cryopreserved CD34 and total nucleated cell (TNC) count, whose cutoffs were based on previous findings reported by our group. Pairwise comparisons of the numbers of allele MM showed that receiving units with ≥4 MM had the highest negative impact on OS. Cox and Fine-Gray regression models were built for the different outcomes using the backward elimination method (p<.05 to stay). Results: 963 patients met the eligibility criteria, of which 392 received at least one CB unit with 0-3 allele MM while 571 with ≥4 allele MM. Of those receiving at least one unit with ≥4 allele MM, 18% had a maximum HLA disparity of 5/6 at lower HLA-typing resolution, 69% of 4/6 and 13% of ≤3/6. Median age at dCBT was 49 years old. Acute leukemia and myelodysplastic syndrome (MDS) accounted for 70% of the cases. There was a larger proportion of patients receiving CB units with fewer allele MM after 2012. Other patient-, disease- and CB unit-related characteristics are summarized in Table 1. The day-42 cumulative incidence of neutrophil recovery was 83% (95%CI 81-85). The number of allele MM had no significant impact on neutrophil recovery (≥ 4 MM vs 0-3 MM, multivariate HR 0.94 [0.80-1.11], P=.46). The cumulative incidence of TRM at 4 years was 36% (95% CI 32-40) for patients receiving CB units with ≥4 MM vs. 23% (95% CI 19-28) for those with 0-3 MM (multivariate HR 1.58 [95%CI 1.18-2.11], P=.002] - Fig. 1A). Infectious complications were the most frequent cause of TRM in the group receiving dCBT with ≥ 4 allele MM (40%). Relapse, grade II-IV/III-IV acute and chronic GVHD were not significantly different between the two groups. Patients receiving CB units with 0-3 allele MM had a 4-year survival of 54% (95%CI 49-59) compared to 43% (95%CI 39-47) for those receiving units with ≥4 allele MM (multivariate HR 1.40 [1.11-1.78], P=.005 - Fig. 1B). The inferior OS associated with higher allele HLA disparity was only partially mitigated by increasing the TNC count in multivariate analysis (0-3 MM + TNC ≤ 3.9x10ˆ7/kg vs.0-3 MM + TNC > 3.9x10ˆ7/kg, HR 1.50 [0.97-2.32], P=.07; ≥4 MM + TNC > 4.9x10ˆ7/kg vs. 0-3 MM + TNC > 3.9x10ˆ7/kg, HR 1.42 [1.06-1.89], P=.02; ≥4 MM + TNC ≤ 4.9x10ˆ7/kg vs. 0-3 MM + TNC > 3.9x10ˆ7/kg, HR 1.66 [1.24-2.22], P=<.001 - Fig. 1C). Discussion: Our results confirm that allele-level HLA typing is a significant factor for OS following dCBT. The inferior OS associated with the increasing number of allele-level MM was driven by higher TRM. Selection of CB units with 0-3 allele-level MM is recommended. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

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.

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

Durable outcomes of double cord blood transplantation in adults with acute lymphoblastic leukemia: high-risk features for early and long-term mortality.

Background:Cord blood transplantation (CBT) has been reported as an acceptable option with comparable outcomes to conventional donors in adults with acute lymphoblastic leukemia (ALL). We aimed to analyze the long-term CBT outcomes and risk factors for early and long-term mortalities.Methods:Between 2006 and 2020, 112 patients (median age: 35 years; 62 Ph-negative ALL and 50 Ph-positive ALL) were treated with double CBT. Conditioning regimen consisted of total body irradiation (12 Gy) plus cytarabine (9.0 g/m2) plus fludarabine (150 mg/ m2), and graft-versus-host disease (GVHD) prophylaxis was attempted by administering tacrolimus plus mycophenolate mofetil.Results:The median time for neutrophil and platelet recovery was 25 days (range: 5–59 days) and 34 days (range: 7–185 days), respectively. The cumulative incidence of acute GVHD at 1 year was 43.8%, and the incidence of acute GVHD with grades III–IV was 8.9%. The overall cumulative incidence of chronic GVHD was 22.0%, and the incidence of moderate to severe chronic GVHD was 8.5%. After a median follow-up of 60.1 months (range: 5.7–181.3 months), the 5-year cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) were 15.9% and 28.5% (9.7% and 27.2% for CR1), respectively, and the 5-year overall survival (OS) was 57.9% (66.5% for CR1). In multivariate analysis of 88 patients receiving double CBT in CR1, delayed CR1 was related to high CIR, and age older than 40 years was associated with high NRM and early mortality. Unexpectedly, Ph-positive ALL with MRD had a higher NRM and early mortality than Ph-negative ALL and Ph-positive ALL without MRD subgroups, possibly due to delayed neutrophil and platelet recovery.Conclusion:Our data suggest that double CBT for adult ALL in CR1 has a greater benefit in younger patients and in patients with Ph-positive ALL without MRD or Ph-negative ALL.

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.

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.

Respiratory syncytial virus pneumonia in an adult cord blood transplant recipient during the SARS‐CoV‐2 outbreak

Respiratory syncytial virus pneumonia in an adult cord blood transplant recipient during the SARS‐CoV‐2 outbreak

Assessment of a Multi-Cytokine Profile By a Novel Biochip-Based Assay Reveals Unique Correlation Patterns with Immune Reconstitution after Cord Blood Transplantation in Adults

Umbilical cord blood transplantation (UCBT) is an alternative stem cell source for allogeneic hematopoietic stem cell transplantation. The frequency of acute graft-versus-host-disease (aGvHD) in UCBT recipients is less than expected in recipients of adult donor allografts but delayed aGvHD can develop. Moreover, UCBT results in delayed and insufficient immune reconstitution leading to infection-related morbidity and mortality. We reasoned that an approach that would allow risk assessment for development of GvHD and/or for impaired immune reconstitution would be highly beneficial in adult UCBT recipients because it would guide therapeutic decisions for the prevention of these complications. Because reconstitution of hematopoietic lineages is delayed in UCB recipients, we focused on cytokines that can be assessed in patients' plasma at any time point before or after UCBT. Increase of proinflammatory cytokines IL-1b and TNF-α after BMT has been associated previously with the pathogenesis of GvHD. We previously determined that levels of IL-7 were inversely correlated with reconstitution of T cell subsets but were also associated with non-relapse mortality, development of GvHD and worse overall survival. In the present study, we employed a novel approach, which allows simultaneous assessment of multiple cytokines in a very small volume of patient's serum or plasma, to assess the prognostic value of this multi-cytokine profile in adult UCBT recipients. 32 patients with a median age of 50 years with hematopoietic malignancies were treated with reduced intensity conditioning (Flu/Mel/rATG) followed by two sequential UCB graft transplantation (dUCBT) and GvHD prophylaxis with tacrolimus and sirolimus. Results are based on 27 evaluable patients. Assessments were done prior to transplantation and at 1, 2, 3, 6, 12 and 24 months after dUCBT. Quantification of cytokines IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IFN-γ, TNF-α and GM-CSF in serum samples was conducted using the LUNARISTM Human 11-Plex Cytokine Biochip384 from AYOXXA Biosystems. Briefly, after diluting as 1:2 using the respective assay diluent, 5µl of samples or assay standards were loaded in duplicates on the AYOXXA Biochip and the assay was performed according to the manufacturers' instructions. Readout was performed using the AYOXXA Reader AR01 (Cat. No. LRS-001, AYOXXA Biosystems) and data were analyzed using the LUNARISTM Analysis Suite Software (Cat. No. LAS-001, AYOXXA Biosystems). Based on their median levels, cytokines could be categorized in four patterns of kinetics in comparison to pre-transplant baseline values: 1) Without significant changes (IL-2); 2) decrease over time (IL-1b, IL-17); 3) increase at 1-month after dUCBT and subsequent decline (IL-4, IL-5, IL-6, IL-8, IL-10, TNF-α, GM-CSF); 4) increase at 2 months after UCBT and subsequent decline (IFN-γ). At baseline, most cytokines correlated with total lymphocytes, CD4+, CD8+ subsets, CD4+CD25+ Treg, CD56+CD16+ NK cells, CD20+ B cells and CD14+ monocytes. At 1-month after dUCBT, the correlations with immune cell types disappeared for most cytokines and only CD14+ monocytes correlated with IFN-γ. At 2-months after dUCBT, most cytokines were positively correlated with T cell subsets. IL-8 displayed a unique pattern of correlation with CD14+ monocytes and B cells, both of which have potent antigen presenting function. Specifically, at 2-months after dUCBT IL-8 inversely correlated with CD14+ cells (r=-0.71, p=0.0007) and this pattern persisted until day 100, when CD20+ cells also showed a significant inverse correlation with IL-8 (r=-0.56, p=0.006). These inverse correlations declined by 6 months after dUCBT. IL-8 levels after BMT were previously associated with infectious complications, which subsequently drive elevation of IL-6 and development of GvHD. Our findings pose the intriguing possibility that multicytokine profile analysis might serve as a biomarker to guide patient management such as work-up for infectious complications that might prevent GVHD development in dUCBT recipients. Analysis of correlations between multicytokine profile and such clinical outcomes is currently ongoing. Our results provide evidence for the feasibility of a novel method for multicytokine assessment in patients' plasma, which might guide patient management, to diminish complications after dUCBT. [Display omitted] DisclosuresAntin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Long-Term Follow-up of Adult Double Unit Cord Blood (CB) Transplantation (dCBT) Recipients Reveals High Rates of Progression-Free Survival after a Novel Cy/ Flu/ Thio/ TBI 400 Intermediate Intensity Conditioning Regimen

Background: CB transplantation (CBT) can be associated with the advantages of low rates of chronic GVHD & relapse. These benefits, however, can be offset by early post-transplant transplant-related mortality (TRM). Therefore, we have investigated CBT after a novel intermediate intensity, reduced toxicity myeloablative cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 5-10 mg/kg, 400 cGy TBI regimen in an effort to reduce early organ toxicity while also maximizing engraftment & disease control.Methods: We analyzed CBT outcomes, including patient (pt) & graft characteristics associated with TRM, relapse and progression-free survival (PFS), in adult CBT recipients transplanted with this approach. Eligible pts were first allograft recipients </= 65 yrs transplanted for acute leukemia/ MDS/ MPD (</= 10% blasts pre-CBT), B-cell NHL or Hodgkin lymphoma. Graft-versus-host disease (GVHD) prophylaxis was with cyclosporine-A/ mycophenolate mofetil (no ATG).Results: 139 consecutive pts [74 (53%) non-European, 84 (60%) CMV seropositive, median age 51 yrs (range 23-65), median weight 83 kg (range 49-136)] were transplanted 10/2007-12/2016. Diagnoses included 102 acute leukemia, 22 MDS/ MPD, 15 B-cell NHL/ HL. All received double unit grafts [median donor recipient 8-allele HLA-match 5/8 (range 2-8), median infused CD34+ dose 1.0 x 105/kg/unit (range 0.2-8.6)]. 54 (39%) CB grafts were supplemented with haplo-identical CD34+ cells as a myeloid bridge. The incidence of CB engraftment was 96% (95%CI: 91-99). Day 180 incidence of grades II-IV & III-IV aGVHD was 78% (95%CI: 70-84) & 21% (95%CI: 15-28), respectively. 1-yr cGVHD was 8% (95%CI: 4-14). Cumulative incidence of day 180 TRM was 12% (95%CI: 7-17) & 21% (95%CI: 14-29) at 3 yrs. 11% (95%CI: 6-18) of pts relapsed by 3 yrs post-CBT. With a median survivor follow-up of 2.7 yrs (range 6.5 months-9.5 yrs), the 3-yr overall survival is 71% (95%CI: 63-80) & PFS is 67% (95%CI: 59-76). 3-yr PFS in 75 acute leukemia CR1 pts is 66% versus 74% in 27 other disease status pts (p = 0.574). 3-yr PFS in 23 FLT-3 mutated AML pts is 83%. The 3-yr PFS is 62% in 22 MDS/ MPD pts & 67% in 15 NHL/ HD pts. The revised disease risk index (rDRI) was not associated with TRM, relapse or PFS (Figure, Table). By contrast, pts with an age adjusted hematopoietic cell transplant-comorbidity index (aaHCT-CI) 0-2 (n = 54) had very low day 180 TRM [4% (95%CI: 1-11)] & high PFS [81% (95%CI: 71-94)] whereas the 85 pts with high aaHCT-CI (median 4, range 3-9) had a day 180 TRM of 17% (95%CI: 10-25) & 3-yr PFS of 58% (95%CI: 48-71). In multivariate analysis of TRM, aaHCT-CI had a HR of 4 (95%CI: 1.4-11.6, p = 0.01) whereas age alone was not significant [HR 1.9 (95%CI: 0.8-4.5), p = 0.12]. In multivariate analysis of PFS, aaHCT-CI HR was 2.4 (95%CI: 1.2-4.7, p = 0.01) whereas for recent pts (CBT 2014-2016) HR was 0.6 (95%CI: 0.3-1.2) although this was not significant (p = 0.17)Conclusions: The 3-yr PFS in this older (median 51 yrs) intermediate intensity dCBT population is very promising. The incidences of cGVHD & relapse are low & DRI was not associated with TRM, relapse or PFS. Notably, addition of haplo-identical cells & better CB HLA-match was not associated with better PFS, & older age (51-65 yrs), CMV sero-positivity & non-European ancestry did not adversely affect PFS. Notably, day 180 TRM in recent pts is 9%. While high aaHCT-CI pts require additional strategies to reduce early post-CBT complications, given PFS is excellent in low aaHCT-CI CBT recipients (39% of pts in this analysis), survival comparisons of intermediate intensity dCBT in this population versus all other HSC sources is warranted. CB can also be attractive in pts with high risk disease given its rapid availability. [Display omitted] Disclosuresvan den Brink:Seres: Research Funding; Therakos Institute: Other: Speaking engagement; PureTech Health: Consultancy; Jazz Pharmaceuticals: Consultancy.

Combined impact of HLA-allele matching and the CD34-positive cell dose on optimal unit selection for single-unit cord blood transplantation in adults

The combined effects of HLA-allele matching at six-loci (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1) and CD34+ cell dose on clinical outcomes were analyzed in 1,226 adult cases with single-unit unrelated cord blood transplantation. In the six-loci analysis, low HLA-allele matches did not significantly increase the overall mortality compared to higher matches, whereas in the five-loci analysis excluding HLA-DPB1, they caused a higher overall mortality (HR 1.42, p = .002), possibly due to the graft-versus-leukemia effect of HLA-DPB1 mismatches. A lower CD34+ cell dose (<.50 × 105/kg) resulted in higher mortality and lower engraftment; these inferior outcomes were offset by high HLA-allele matches (7-10/10 match), while the inferior outcomes of low HLA-allele matches were improved by increasing the CD34+ cell dose. Consideration of the combined effects of the CD34+ cell dose and HLA matching may expand the options for transplantable units when HLA matching or the CD34+ cell dose is inadequate.

Early-Phase Peripheral Blood Eosinophilia Predicts Lower Overall and Non-Relapse Mortality After Single-Unit Cord Blood Transplantation

Peripheral blood eosinophilia has been associated with the development of graft-versus-host disease (GVHD) and survival after allogeneic hematopoietic cell transplantation (HCT). However, the impacts of eosinophilia on cord blood transplantation (CBT) outcomes remain unclear. The objective of this study was to examine the associations between eosinophilia and overall survival, relapse incidence, non-relapse mortality, and acute and chronic GVHD after single-unit CBT for adults. We retrospectively analyzed the data for 225 adult patients who received single-unit CBT at our institute between March 2004 and March 2020. The cumulative incidence of eosinophilia, defined as an absolute eosinophil count of ≥500 × 106/L in peripheral blood, was 48.9% (95% confidence interval, 42.2% to 55.2%) at 60 days after CBT. Recipient cytomegalovirus seronegative status and higher cryopreserved cord blood CD34+ cell dose were significantly associated with a higher incidence of eosinophilia after CBT. Among patients who achieved neutrophil recovery, neutrophil recovery was significantly earlier in patient with eosinophilia compared to those without eosinophilia (P = .016). Serum levels of interleukin-5 at 4 weeks were significantly higher in patients with eosinophilia compared with those without eosinophilia (P = .041). Multivariate analysis, in which the development of eosinophilia was treated as a time-dependent covariate, showed that eosinophilia was significantly associated with lower overall mortality (hazard ratio [HR], .58; P = .034) and non-relapse mortality (HR, .41; P = .029), but not relapse incidence or development of acute or chronic GVHD. Our data suggested that early-phase eosinophilia is a predictor of favorable outcomes in adult patients undergoing single-unit CBT.