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1.
HLA peptide-binding pocket diversity modulates immunological complications after cord blood transplant in acute leukaemia
Boukouaci, W., Rivera-Franco, M. M., Volt, F., Lajnef, M., Wu, C. L., Rafii, H., Cappelli, B., Scigliuolo, G. M., Kenzey, C., Ruggeri, A., et al
British journal of haematology. 2024
Abstract
Pocket motifs and their amino acid positions of HLA molecules are known to govern antigen presentation to effector cells. Our objective was to analyse their influence on the risk of graft-versus-host disease (GVHD) and relapse after umbilical cord blood transplant (UCBT). The transplant characteristics of 849 patients with acute leukaemia were obtained from the Eurocord/EBMT database. Higher acute (a) GVHD was associated with homozygosity of UCB HLA-C amino acid positions 77 and 80 (NN/KK) (p = 0.008). Severe aGVHD was associated with HLA-A pocket B YSAVMENVHY motif (p = 0.002) and NN and RR genotypes of the HLA-C amino acid positions 77 and 156 (p = 0.006 and p = 0.002). Such risk was also increased in case of recipient and UCB mismatches in P4 (p < 0.0001) and P9 (p = 0.003) pockets of HLA-DQB1 alleles. For chronic GVHD, the pocket B YYAVMEISNY motif of the HLA-B*15:01 allele and the absence of mismatch between recipient and UCB in the P6 pocket of HLA-DRB1 were associated with a lower risk (p = 0.0007 and p = 0.0004). In relapse, both UCB pocket B YFAVMENVHY belonging to HLA-A*32:01 and recipient pocket B YDSVGENYQY motif of the HLA-C*07:01 allele were associated with higher risk (p = 0.0026 and p = 0.015). We provide clues on HLA-mediated cellular interactions and their role in the development of GVHD and relapse.
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2.
Upfront umbilical cord blood transplantation versus immunosuppressive therapy for pediatric patients with idiopathic severe aplastic anemia
Zhao, X., Lv, W., Song, K., Yao, W., Li, C., Tang, B., Wan, X., Geng, L., Sun, G., Qiang, P., et al
Transplantation and cellular therapy. 2024
Abstract
BACKGROUND Umbilical cord blood transplantation (UCBT) has been rarely reported as a first-line treatment for idiopathic severe aplastic anemia (SAA) patients lacking HLA-matched sibling donors (MSD). OBJECTIVE Our study aimed to compare the clinical outcomes of pediatric SAA patients who received UCBT and immunosuppressive therapy (IST) upfront. STUDY DESIGN A retrospective analysis was performed on 43 consecutive patients who received frontline IST (n = 17) or UCBT (n = 26) between July 2017 and April 2022. RESULTS The 3-year overall survival (OS) was comparable between the UCBT and IST groups (96.2% vs. 100%, P = 0.419), while the 3-year event-free survival (EFS) was significantly better in the former than in the latter (88.5% vs. 58.8%, P = 0.048). In the UCBT group, 24 patients achieved successful engraftment, 2 patients developed severe acute graft-versus-host disease (aGVHD), no extensive chronic GVHD (cGVHD), and a high GVHD-free, failure-free survival (GFFS) of 84.6% at 3 years. After one year of treatment, 12 patients in the IST group responded, while 5 patients did not achieve remission and 2 patients had disease relapse. At both 3 and 6 months after treatment, the proportion of transfusion-independent patients was higher in the UCBT group than in the IST group. Faster immune recovery and earlier transfusion independence further reduced the risk of infection and bleeding, thereby improving health-related quality of life in the UCBT-treated group. CONCLUSION Our results suggested that UCBT as upfront therapy may be an effective and safe option for pediatric SAA patients, with favorable outcomes in experienced centers.
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3.
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
Takano, K., Monna-Oiwa, M., Isobe, M., Kato, S., Takahashi, S., Nannya, Y., Konuma, T.
Scientific reports. 2024;14(1):1413
Abstract
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.
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4.
Validation of a Parvovirus B19 NAT Assay for Screening of Umbilical Cord Blood for Allogenic Hematopoietic Stem Cell Donation
Steininger, P., Korn, K., Hackstein, H., Strasser, E. F.
Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie. 2024;51(1):48-51
Abstract
INTRODUCTION Parvovirus B19 transmitted by umbilical cord blood (UCB) products may cause severe disease in allogenic hematopoietic stem cell transplant recipients. Thus, commercially available nucleic acid test (NAT) assays for highly sensitive detection of parvovirus B19 DNA validated for the specimen cord blood plasma (CBP) are required to avoid parvovirus B19 transmission by umbilical hematopoietic stem cell preparations. METHODS The multiplex cobas DPX NAT assay was validated for detection of parvovirus B19 DNA in CBP derived from citrate anticoagulated UCB units which have been processed by the Rubinstein method. In total, 363 retained CBP samples pretested negative for parvovirus B19 DNA were prepared for analyzing sensitivity, specificity, and interference of that NAT assay. The 3rd WHO International Standard for parvovirus B19 DNA was used for determining the 95% limit of detection (LOD95) by probit analysis. RESULTS The validation of the parvovirus B19 NAT assay for CBP demonstrated high sensitivity, specificity, intra- and inter-assay precision. Dilution series and replicate analyses showed a high linearity of the assay with a coefficient of determination above 0.99 and revealed a LOD95 of 17 International Units (IU)/mL (95% confidence interval, 14-44 IU/mL) for parvovirus B19 DNA in CBP samples. CONCLUSION The validation of a commercially available parvovirus B19 NAT assay for the specimen CBP demonstrated a high assay performance fulfilling German guidelines and international regulations.
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5.
Comparison of fludarabine-based conditioning regimens in adult cord blood transplantation for myeloid malignancy: A retrospective, registry-based study
Kurita, N., Imahashi, N., Chiba, S., Tanaka, M., Kobayashi, H., Uchida, N., Kuriyama, T., Anzai, N., Nawa, Y., Nakano, N., et al
American journal of hematology. 2024
Abstract
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/m(2) ) and low-dose total body irradiation (TBI; FM140T); melphalan (80-99 mg/m(2) ) 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.
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6.
Prognostic impact of HLA supertype mismatch in single-unit cord blood transplantation
Sugio, T., Uchida, N., Miyawaki, K., Ohno, Y., Eto, T., Mori, Y., Yoshimoto, G., Kikushige, Y., Kunisaki, Y., Mizuno, S., et al
Bone marrow transplantation. 2024
Abstract
The "human leukocyte antigen (HLA) supertype" is a functional classification of HLA alleles, which was defined by structural features and peptide specificities, and has been reportedly associated with the clinical outcomes of viral infections and autoimmune diseases. Although the disparity in each HLA locus was reported to have no clinical significance in single-unit cord blood transplantation (sCBT), the clinical significance of the HLA supertype in sCBT remains unknown. Therefore, we retrospectively analyzed clinical data of 1603 patients who received sCBT in eight institutes in Japan between 2000 and 2017. Each HLA allele was categorized into 19 supertypes, and the prognostic effect of disparities was then assessed. An HLA-B supertype mismatch was identified as a poor prognostic factor (PFS: hazard ratio [HR] = 1.23, p = 0.00044) and was associated with a higher cumulative incidence (CI) of relapse (HR = 1.24, p = 0.013). However, an HLA-B supertype mismatch was not associated with the CI of acute and chronic graft-versus-host-disease. The multivariate analysis for relapse and PFS showed the significance of an HLA-B supertype mismatch independent of allelic mismatches, and other previously reported prognostic factors. HLA-B supertype-matched grafts should be selected in sCBT.
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7.
Updated comparable efficacy of cord blood transplantation for chronic myelomonocytic leukaemia: a nationwide study
Kurosawa, S., Shimomura, Y., Ishiyama, K., Fuse, K., Shimazu, Y., Doki, N., Uchida, N., Tanaka, M., Takahashi, S., Sakurai, M., et al
Bone marrow transplantation. 2024
Abstract
Chronic myelomonocytic leukaemia (CMML) is a haematological malignancy with a poor prognosis. Allogeneic haematopoietic stem cell transplantation remains the only curative approach. Without human leucocyte antigen-matched related sibling donors, the optimal alternative donor has yet to be established. Although unrelated bone marrow transplantation (UBMT) has been extensively studied, cord blood transplantation (CBT) for CMML remains largely unexplored. This nationwide retrospective study compared the outcomes of UBMT and single-unit umbilical CBT in patients with CMML. This study included 118 patients who underwent their first allo-HSCT during 2013-2021. Of these, 50 received BMT (UBMT group), while 68 underwent CBT (CBT group). The primary endpoint was the 3-year overall survival (OS). There were comparable 3-year OS rates between the UBMT (51.0%, 95% confidence interval [CI]: 34.1-65.5%) and CBT (46.2%, 95% CI: 33.2-58.1%; P = 0.60) groups. In the inverse probability of treatment weighting analysis, CBT did not show significantly improved outcomes compared with UBMT regarding the 3-year OS rate (hazard ratio 0.97 [95% CI: 0.57-1.66], P = 0.91). Thus, CBT may serve as an alternative to UBMT for patients with CMML. Further research is necessary to optimise transplantation strategies and enhance outcomes in patients with CMML undergoing CBT.
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8.
Machine Learning Prediction Model for Neutrophil Recovery after Unrelated Cord Blood Transplantation
Kuwatsuka, Y., Kasajima, R., Yamaguchi, R., Uchida, N., Konuma, T., Tanaka, M., Shingai, N., Miyakoshi, S., Kozai, Y., Uehara, Y., et al
Transplantation and cellular therapy. 2024
Abstract
BACKGROUND Delayed neutrophil recovery is an important limitation to the administration of cord blood transplantation (CBT) and leaves the recipient vulnerable to life-threatening infection and increases the risk of other complications. OBJECTIVES A predictive model for neutrophil recovery after single-unit CBT was developed by using a machine learning method, which can handle large and complex datasets, allowing for the analysis of massive amounts of information to uncover patterns and make accurate predictions. STUDY DESIGN Japanese registry data, the largest real-world dataset of CBT, was selected as the data source. Ninety-eight variables with observed values for more than 80% of the subjects known at the time of CBT were selected. Model building was performed with a competing risk regression model with lasso penalty. Prediction accuracy of the models was evaluated by calculating area under curve (AUC) using a test dataset. The primary outcome was neutrophil recovery at day 28 (D28), and D14 and D42 were analyzed as secondary outcomes. RESULT The final cord blood engraftment prediction (CBEP) models included 2,991 single-unit CBT recipients with acute leukemia. Median AUC of a D28-CBEP lasso regression model run 100 times was 0.74, and those of D14 and D42 were 0.88 and 0.68, respectively. The D28-CBEP model predictivity was higher than four different legacy models that were separately constructed. CONCLUSIONS A highly predictive model for neutrophil recovery by 28 days after CBT was constructed using machine learning techniques. However, identification of significant risk factors was insufficient for outcome prediction for an individual patient, which is necessary for improving therapeutic outcomes. Notably, the prediction accuracy for days 14, 28, and 42 post-transplant decreased, and the model became more complex with more associated factors with increased time after transplantation.
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9.
Donor NKG2D rs1049174 polymorphism predicts hematopoietic recovery and event-free survival after single-unit cord blood transplantation in adults
Konuma, T., Hamatani-Asakura, M., Monna-Oiwa, M., Kato, S., Isobe, M., Yokoyama, K., Nannya, Y., Takahashi, S.
Bone marrow transplantation. 2024
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10.
Cord Blood Transplantation for Very Early-Onset Inflammatory Bowel Disease Caused by Interleukin-10 Receptor Deficiency
Wang, P., Qian, X., Jiang, W., Wang, H., Wang, Y., Zhou, Y., Zhang, Y., Huang, Y., Zhai, X.
Journal of clinical immunology. 2024;44(3):67
Abstract
PURPOSE Interleukin-10 receptor (IL-10R) deficiency can result in life-threatening very early-onset inflammatory bowel disease (VEO-IBD). Umbilical cord blood transplantation (UCBT) is a curative therapy for patients with IL-10R deficiency. This study aimed to investigate the efficacy of UCBT in treating IL-10R deficiency and develop a predictive model based on pre-transplant factors. METHODS Eighty patients with IL-10R deficiency who underwent UCBT between July 2015 and April 2023 were retrospectively analyzed. Cox proportional hazards regression and random survival forest were used to develop a predictive model. RESULTS Median age at transplant was 13.0 months (interquartile range [IQR], 8.8-25.3 months). With a median follow-up time of 29.4 months (IQR, 3.2-57.1 months), the overall survival (OS) rate was 65.0% (95% confidence interval [CI], 55.3%-76.3%). The engraftment rate was 85% (95% CI, 77%-93%). The cumulative incidences of acute and chronic graft-versus-host disease were 48.2% (95% CI, 37.1%-59.4%) and 12.2% (95% CI, 4.7%-19.8%), respectively. VEO-IBD-associated clinical symptoms were resolved in all survivors. The multivariate analysis showed that IL-6 and stool occult blood were independent prognostic risk factors. The multivariate Cox proportional hazards regression model with stool occult blood, length- or height-for-age Z-score, medical history of sepsis, and cord blood total nucleated cells showed good discrimination ability, with a bootstrap concordance index of 0.767-0.775 in predicting OS. CONCLUSION Better inflammation control before transplantation and higher cord blood total nucleated cell levels can improve patient prognosis. The nomogram can successfully predict OS in patients with IL-10R deficiency undergoing UCBT.