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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.
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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3.
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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4.
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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5.
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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6.
Development of an umbilical cord blood transplantation-specific non-relapse mortality risk assessment score
Okada, Y., Usui, Y., Hayashi, H., Nishikubo, M., Toubai, T., Uchida, N., Tanaka, M., Onizuka, M., Takahashi, S., Doki, N., et al
Blood advances. 2024
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Abstract
Higher rate of non-relapse mortality (NRM) remains yet to be resolved in umbilical cord blood transplantation (UCBT). Considering that UCBT has some unique features compared with allogeneic hematopoietic cell transplantation from other graft sources, a UCBT-specific NRM risk assessment system is required. Thus, in this study, we sought to develop a UCBT-specific NRM Risk Assessment (CoBRA) score. Using a nationwide registry database, we retrospectively analyzed 4437 recipients who had received their first single-unit UCBT. Using the backward elimination method, we constructed the CoBRA score in a training cohort (n = 2687), which consisted of recipients age ≥ 55 (score 2), hematopoietic cell transplantation-specific comorbidity index (HCT-CI) ≥ 3 (score 2), male recipient, graft-versus-host disease (GVHD) prophylaxis other than tacrolimus in combination with methotrexate, performance status (PS) 2-4, HLA allele mismatch ≥ 2, refined disease risk index (DRI) high-risk, myeloablative conditioning (MAC), and CD34+ cell doses < 0.82 x 105/kg (score 1 in each). The recipients were categorized into three groups: Low (0-4 points), Intermediate (5-7 points), and High (8-11 points) groups according to the CoBRA score. In the validation cohort (n = 1750), the cumulative incidence of NRM at 2 years was 14.9%, 25.5%, and 47.1% (P < 0.001), and 2-year overall survival (OS) was 74.2%, 52.7%, and 26.3% (P < 0.001) in the Low, Intermediate, and High groups, respectively. In summary, the CoBRA score could predict the NRM risk as well as OS after UCBT. Further external validation will be needed to confirm the significance of the CoBRA score.
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7.
Adverse effect of donor-specific anti-human leukocyte antigen (HLA) antibodies directed at HLA-DP/-DQ on engraftment in cord blood transplantation
Jo, T., Arai, Y., Hatanaka, K., Ishii, H., Ono, A., Matsuyama, N., Mori, J., Koh, Y., Azuma, F., Kimura, T.
Cytotherapy. 2023;25(4):407-414
Abstract
BACKGROUND AIMS While 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. METHODS We retrospectively analyzed 567 single-unit CBT recipients to evaluate impact of DSAs against HLA-DP and -DQ on CBT outcomes. RESULTS Among 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. CONCLUSIONS Our results suggest the importance of evaluating DSAs against HLA-DP and -DQ in recipients before selecting CB units.
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8.
Reconstitution of double-negative T cells after cord blood transplantation and its predictive value for acute graft-versus-host disease
Pan, T., Ding, P., Huang, A., Tang, B., Song, K., Sun, G., Wu, Y., Yang, S., Chen, X., Wang, D., et al
Chinese medical journal. 2023
Abstract
BACKGROUND With an increasing number of patients with hematological malignancies being treated with umbilical cord blood transplantation (UCBT), the correlation between immune reconstitution (IR) after UCBT and graft-versus-host disease (GVHD) has been reported successively, but reports on double-negative T (DNT) cell reconstitution and its association with acute GVHD (aGVHD) after UCBT are lacking. METHODS A population-based observational study was conducted among 131 patients with hematological malignancies who underwent single-unit UCBT as their first transplant at the Department of Hematology, the First Affiliated Hospital of USTC, between August 2018 and June 2021. IR differences were compared between the patients with and without aGVHD. RESULTS The absolute number of DNT cells in the healthy Chinese population was 109 (70-157)/μL, accounting for 5.82 (3.98-8.19)% of lymphocytes. DNT cells showed delayed recovery and could not reach their normal levels even one year after transplantation. Importantly, the absolute number and percentage of DNT cells were significantly higher in UCBT patients without aGVHD than in those with aGVHD within one year (F = 4.684, P = 0.039 and F = 5.583, P = 0.026, respectively). In addition, the number of DNT cells in the first month after transplantation decreased significantly with the degree of aGVHD increased, and faster DNT cell reconstitution in the first month after UCBT was an independent protective factor for aGVHD (HR = 0.46, 95% confidence interval [CI]: 0.23-0.93; P = 0.031). CONCLUSIONS Compared to the number of DNT cells in Chinese healthy people, the reconstitution of DNT cells in adults with hematological malignancies after UCBT was slow. In addition, the faster reconstitution of DNT cells in the early stage after transplantation was associated with a lower incidence of aGVHD.
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9.
Epitope Mismatch at HLA-DRB1 Associates with Reduced Relapse Risk in Cord Blood Transplantation for Standard-Risk Hematologic Malignancy
Morita-Fujita, M., Shindo, T., Iemura, T., Arai, Y., Kanda, J., Okada, K., Ueda, Y., Yoshiyuki, O., Anzai, N., Mori, T., et al
Transplantation and cellular therapy. 2023;29(6):347.e1-347.e11
Abstract
Cord blood transplantation (CBT) is an attractive therapeutic option for patients with hematologic malignancies. CBT tolerates HLA mismatches between donors and recipients, but the HLA mismatches that generate graft-versus-tumor (GVT) effects remain unknown. Given that HLA molecules contain epitopes comprising polymorphic amino acids that determine their immunogenicity, we investigated associations between epitope-level HLA mismatches and relapse following single-unit CBT. A total of 492 patients with hematologic malignancies who underwent single-unit, T cell-replete CBT were included in this multicenter retrospective study. HLA epitope mismatches (EMs) were quantified using HLA matchmaker software from donor and recipient HLA-A, -B, -C, and -DRB1 allele data. Patients were dichotomized by median EM value and divided into 2 groups: patients who underwent transplantation in complete/partial remission (standard stage: 62.4%) and others (advanced stage: 37.6%). The median number of EMs in the graft-versus-host direction (GVH-EM) was 3 (range, 0 to 16) at HLA class I and 1 (range, 0 to 7) at HLA-DRB1. Higher HLA class I GVH-EM was associated with increased nonrelapse mortality (NRM) in the advanced stage group (adjusted hazard ratio [HR], 2.12; P = .021), with no significant advantage for relapse in either stage. In contrast, higher HLA-DRB1 GVH-EM was associated with better disease-free survival in the standard stage group (adjusted HR, .63; P = .020), which was attributed to lower relapse risk (adjusted HR, .46; P = .014). These associations also were observed even within HLA-DRB1 allele-mismatched transplantations in the standard stage group, indicating that EM might have an impact on relapse risk independent of allele mismatch. High HLA-DRB1 GVH-EM did not increase NRM in either stage. High HLA-DRB1 GVH-EM may lead to potent GVT effects and a favorable prognosis following CBT, especially in patients who underwent transplantation at the standard stage. This approach may facilitate appropriate unit selection and improve the overall prognosis of patients with hematologic malignancies who undergo CBT.
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10.
Impact of MRD on clinical outcomes of unrelated hematopoietic stem cell transplantation in patients with Ph(+) ALL: A retrospective nationwide study
Hirabayashi, S., Kondo, T., Nishiwaki, S., Mizuta, S., Doki, N., Fukuda, T., Uchida, N., Ozawa, Y., Kanda, Y., Imanaka, R., et al
American journal of hematology. 2023
Abstract
Measurable residual disease (MRD) status before transplantation has been shown to be a strong prognostic factor in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL). However, the outcomes of unrelated hematopoietic stem cell transplantation based on the MRD status have not been fully investigated. In this retrospective study, we compared the outcomes of 715 consecutive adults with Ph(+) ALL in complete remission who underwent unrelated cord blood transplantation (UCBT) (single-unit UCBT, n = 232 [4/6, 5/6, and 6/6 HLA match]), HLA-matched unrelated bone marrow transplantation (UBMT; n = 292 [8/8 HLA match]), or HLA-mismatched UBMT (n = 191 [7/8 HLA match]). In the MRD(+) cohort, adjusted 3-year leukemia-free survival rates were 59.8%, 38.3%, and 55.5% after UCBT, HLA-matched UBMT, and HLA-mismatched UBMT, respectively. In the MRD(-) cohort, the corresponding rates were 65.3%, 70.4%, and 69.7%, respectively. The MRD(+) HLA-matched UBMT group had a significantly higher risk of relapse than the MRD(+) HLA-mismatched UBMT group (hazard ratio [HR] in the MRD(+) HLA-mismatched UBMT group, 0.33; 95% confidence interval [CI] 0.15-0.74) and the MRD(+) UCBT group (HR in the MRD(+) UCBT group, 0.38; 95% CI 0.18-0.83). Furthermore, HLA-matched UBMT had a significant effect of MRD on death (HR 1.87; 95% CI 1.19-2.94), relapse or death (HR 2.24; 95% CI 1.50-3.34), and relapse (HR 3.12; 95% CI 1.75-5.57), while UCBT and HLA-mismatched UBMT did not. In conclusion, our data indicate Ph(+) ALL patients with positive MRD may benefit from undergoing UCBT or HLA-mismatched UBMT instead of HLA-matched UBMT to reduce leukemic relapse.