Effects of HLA Allele and Killer Immunoglobulin-Like Receptor Ligand Matching on Clinical Outcome in Leukemia Patients Undergoing Transplantation With T-cell–Replete Marrow From an Unrelated Donor

Abstract Lack of a matched sibling or unrelated donor can be a significant barrier to allogeneic hematopoietic cell transplantation (HCT). Haploidentical (haplo) donors are readily available for nearly all such patients. However, donor selection criteria to determine the optimal haplo donor are not readily available. In order to determine which donor characteristics are most important in predicting transplant success, we retrospectively analyzed 208 consecutive donor-recipient pairs receiving haplo HCT with post-transplant cyclophosphamide for hematologic malignancy. Donor characteristics were evaluated by multivariate Cox analysis and correlated with overall survival (OS), disease-free survival (DFS), relapse/progression, and non-relapse mortality (NRM), while controlling for significant patient and transplant-related factors. Donor variables analyzed included age, sex, relationship to recipient, CMV status, ABO compatibility, HLA disparity and several NK alloreactivity models (KIR receptor-ligand, ligand-ligand, haplotype, B content, activating KIR-based education systems, Sekine donor licensing model). Median (range) recipient and donor age was 52 (19-75) and 38 (15-73) years respectively, and 41% of donor-recipient pairs were non-Caucasian. Patients were transplanted for AML (34%), MDS/MPS/CML (20%), ALL (17%), NHL/HD/CLL (25%). PBSC was used as the stem cell source in 66% of patients, and conditioning intensity was myeloablative in 41%. The donor was a child, sibling, or parent in 47%, 38%, and 14% respectively. Median (range) follow-up for surviving patients was 33 (7-130) months. In multivariate Cox analysis, patient/transplant characteristics associated with improved OS and DFS included recipient age <55 years, black race, CMV seronegativity, low/intermediate disease risk index (DRI), and more recent transplant year. When adjusting for significant patient/transplant variables, donor characteristics independently associated with improved overall survival included presence of HLA-DR mismatch [GVH direction] (HR 0.35, p=0.010), the presence of HLA DP non-permissive mismatch [GVH direction] (HR 0.51, p=0.033), KIR receptor-ligand mismatch (HR 0.56, p=0.023), the presence of KIR B/x haplotype with KIR2DS2 (HR 0.38, p=0.005 vs. B/x without KIR2DS2; HR 0.47, p=0.013 vs. A/A), donor CMV positivity (HR 0.49, p=0.009) and donor relation (child vs. parent - HR 0.31, p=0.016; sibling vs. parent - HR 0.48, p=0.087). Donor characteristics independently associated with reduced risk of disease relapse/progression included the presence of KIR receptor-ligand mismatch (HR 0.39, p=0.001), KIR B/x haplotype with KIR2DS2 (HR 0.43, p=0.023 vs. B/x without KIR2DS2), the presence of ≥4 (out of 10) HLA allelic mismatches [GVH direction] (HR 0.29, p=0.001), the presence of a non-permissive HLA-DP mismatch (HR 0.25, p<0.001) and the use of a non-parental donor (child vs. parent - HR 0.26, p=0.010; sibling vs. parent - HR 0.37, p=0.039). Donor characteristics associated with increased NRM included higher HLA disparity (HR 7.86, p=0.016), HLA-DR match (HR 15.99, p<0.001), absence of KIR B/x haplotype with KIR2DS2 (A/A haplotype - HR 5.03, p=0.003; B/x without KIR2DS2 - HR 3.92, p=0.034), CMV seronegativity (HR 2.99, p=0.026), and female donor-male recipient (HR 2.35, p=0.071). Adjusted 3-yr OS was improved in patients with the presence of KIR R-L mm (66% vs 50%, p=0.013), KIR B/x with KIR2DS2 (69% vs. 55% [A/A] or 43% [B/x without KIR2DS2, p=0.052 and 0.007, respectively]), HLA-DR mm (64% vs. 45%, p=0.071), and HLA-DP non-permissive mm (72% vs. 56%, p=0.026), emphasizing the importance of donor HLA and KIR typing for optimal donor selection (see figure). This large, single institution analysis demonstrates the significance of HLA-DR/HLA-DP disparity, NK alloreactivity, and other clinical variables in the donor selection process for haplo HCT. These results suggest that HLA-DP and donor KIR typing should be performed routinely in T cell-replete haplo HCT to assist in donor selection and risk stratification. Disclosures Solh: ADC Therapeutics: Research Funding; Amgen: Speakers Bureau; Celgene: Speakers Bureau.

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Duvelisib as bridge to allotransplantation in refractory peripheral T-cell lymphoma with T-follicular helper phenotype: case report

Tumori Journal ◽

10.1177/03008916211027219 ◽

2021 ◽

pp. 030089162110272

Author(s):

Ginevra Lolli ◽

Beatrice Casadei ◽

Cinzia Pellegrini ◽

Lisa Argnani ◽

Federica Cocito ◽

...

Keyword(s):

Case Report ◽

T Cell ◽

Human Leukocyte ◽

Complete Response ◽

Unrelated Donor ◽

Phosphatidylinositol 3 Kinase ◽

Leukocyte Antigen ◽

Follicular Helper ◽

T Cell Lymphomas ◽

T Cell Malignancies

Objective: Peripheral T-cell lymphomas (PTCLs) are a group of heterogeneous T-cell malignancies representing 5%–10% of aggressive lymphomas. The prognosis is poor for patients with relapsed/refractory (R/R) disease, with a median overall survival of less than 6 months and no standardized treatments. We discuss the role of the phosphatidylinositol 3-kinase (PI3K) γδ inhibitor duvelisib as bridge to allotransplantation in a patient with R/R PTCL. Methods: Case report. Results: A 55-year-old woman diagnosed with relapsed nodal PTCL with T-follicular helper phenotype received PI3K γδ inhibitor duvelisib in the context of the phase II PRIMO clinical trial. After two cycles at a dose of 75 mg twice daily, the patient achieved complete response (CR), which was subsequently consolidated with human leukocyte antigen fully matched unrelated donor allotransplantation. No major toxicities were recorded during the duvelisib treatment period or during hospitalization for allotransplantation. At the latest follow-up, the patient was alive and still in CR 10 months posttransplant. Conclusions: Duvelisib should be further explored as a bridge to allotransplantation in patients with R/R PTCL, given the success and low toxicity in our patient.

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Low T-cell Receptor Diversity, High Somatic Mutation Burden, and High Neoantigen Load as Predictors of Clinical Outcome in Muscle-invasive Bladder Cancer

European Urology Focus ◽

10.1016/j.euf.2015.09.007 ◽

2016 ◽

Vol 2 (4) ◽

pp. 445-452 ◽

Cited By ~ 39

Author(s):

Noura J. Choudhury ◽

Kazuma Kiyotani ◽

Kai Lee Yap ◽

Alexa Campanile ◽

Tatjana Antic ◽

...

Keyword(s):

Bladder Cancer ◽

T Cell ◽

Clinical Outcome ◽

T Cell Receptor ◽

Somatic Mutation ◽

Cell Receptor ◽

Invasive Bladder Cancer ◽

Muscle Invasive Bladder Cancer ◽

Mutation Burden ◽

Muscle Invasive

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The Impact of Opportunistic Infections on Clinical Outcome and Healthcare Resource Uses for Adult T Cell Leukaemia

PLoS ONE ◽

10.1371/journal.pone.0135042 ◽

2015 ◽

Vol 10 (8) ◽

pp. e0135042 ◽

Cited By ~ 5

Author(s):

Toshiki Maeda ◽

Akira Babazono ◽

Takumi Nishi ◽

Midori Yasui ◽

Shinya Matsuda ◽

...

Keyword(s):

T Cell ◽

Clinical Outcome ◽

Healthcare Resource ◽

Opportunistic Infections ◽

Cell Leukaemia ◽

The Impact

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Association between preconditioning absolute lymphocyte count and transplant outcomes in patients undergoing matched unrelated donor allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning and anti-thymocyte globulin

Therapeutic Advances in Hematology ◽

10.1177/20406207211063783 ◽

2021 ◽

Vol 12 ◽

pp. 204062072110637

Author(s):

Jeongmin Seo ◽

Dong-Yeop Shin ◽

Youngil Koh ◽

Inho Kim ◽

Sung-Soo Yoon ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Cell Depletion ◽

Unrelated Donor ◽

Reduced Intensity Conditioning ◽

Matched Unrelated Donor ◽

T Cell Depletion ◽

Reduced Intensity

Background: Allogeneic stem cell transplantation (alloSCT) offers cure chance for various hematologic malignancies, but graft- versus-host disease (GVHD) remains a major impediment. Anti-thymocyte globulin (ATG) is used for prophylactic T-cell depletion and GVHD prevention, but there are no clear guidelines for the optimal dosing of ATG. It is suspected that for patients with low absolute lymphocyte counts (ALCs), current weight-based dosing of ATG can be excessive, which can result in profound T-cell depletion and poor transplant outcome. Methods: The objective of the study is to evaluate the association of low preconditioning ALC with outcomes in patients undergoing matched unrelated donor (MUD) alloSCT with reduced-intensity conditioning (RIC) and ATG. We conducted a single-center retrospective longitudinal cohort study of acute leukemia and myelodysplastic syndrome patients over 18 years old undergoing alloSCT. In total, 64 patients were included and dichotomized into lower ALC and higher ALC groups with the cutoff of 500/μl on D-7. Results: Patients with preconditioning ALC <500/μl were associated with shorter overall survival (OS) and higher infectious mortality. The incidence of acute GVHD and moderate-severe chronic GVHD as well as relapse rates did not differ according to preconditioning ALC. In multivariate analyses, low preconditioning ALC was recognized as an independent adverse prognostic factor for OS. Conclusion: Patients with lower ALC are exposed to excessive dose of ATG, leading to profound T-cell depletion that results in higher infectious mortality and shorter OS. Our results call for the implementation of more creative dosing regimens for patients with low preconditioning ALC.

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Fludarabine Exposure Predicts Outcome after CD19 CAR T Cell Therapy in Children and Young Adults with Acute Leukemia; An Exploratory, Observational Study

Blood ◽

10.1182/blood-2021-146450 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3871-3871

Author(s):

Linde Dekker ◽

Friso Calkoen ◽

Yilin Jiang ◽

Hilly Blok ◽

Maike Spoon ◽

...

Keyword(s):

T Cell ◽

Clinical Outcome ◽

Cell Therapy ◽

B Cell ◽

T Cell Therapy ◽

Free Survival ◽

Cell Numbers ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Abstract The addition of fludarabine to cyclophosphamide as lymphodepleting regimen prior to adoptive transfer of CD19 chimeric antigen receptor (CAR) T cells significantly improves CAR T cell expansion and correlates with longer B cell aplasia and a decreased probability of developing a CD19+ relapse (Gardner, 2017). Dosing of fludarabine is currently based on body surface area. We previously showed that this leads to a highly variable plasma exposure that correlates with clinical outcome after allogeneic hematopoietic cell transplantation (Langenhorst, 2019). We therefore hypothesized that optimal exposure of fludarabine might be of clinical importance in the CD19 CAR T setting. An observational cohort analysis was conducted with data from 26 consecutive patients receiving tisagenlecleucel as treatment for refractory/relapsed B cell acute lymphoblastic leukemia (B-ALL; table 1). Prior to CAR T cell infusion, patients received fludarabine on 4 consecutive days at a daily dosage of 30 mg/m 2 and cyclophosphamide on 2 consecutive days at a daily dosage of 500 mg/m 2. Fludarabine concentrations were measured longitudinally after fludarabine infusion using a liquid chromatography mass spectrometry method. The total exposure (Area Under the Curve (AUC 0−∞)) was subsequently determined using a fludarabine population pharmacokinetic model (Langenhorst, 2019). The study was performed in accordance with the Declaration of Helsinki. The primary outcome parameter was leukemia free survival, defined as the time between CAR19 T cell infusion and the moment of measurable leukemic blasts (>5% or >0.01% by two subsequent measurements). The effect of fludarabine on leukemia free survival and the secondary outcome measures CD19+ relapse and B cell aplasia were explored using martingale residuals and further identified by fitting univariable Cox Proportional Hazards models. In addition, Kaplan Meier and cumulative incidence curves were plotted and compared with log-rank tests. To compare CAR T cell numbers over time in peripheral blood, the AUCs were computed and compared between exposure groups with the Mann-Whitney test. Analyses were performed using R4.03 with packages pknca, survival and survminer. The fludarabine AUC 0−∞ was highly variable, resulting in a large range of 8.7-21.8 mg*h/L. Exposure of fludarabine was shown to be a predictor for leukemia free survival, B cell aplasia, and CD19+ relapse following CAR T cell infusion. Minimal event probability was observed at a cumulative fludarabine exposure ≥14 mg*h/L and underexposure was therefore defined as an AUC 0−∞ <14 mg*h/L. In the underexposed group, leukemia free survival was lower (p<0.001; Figure 1A) and the occurrence of CD19+ relapse was higher (p<0.0001; figure 1B) compared to the group with an AUC 0−∞ ≥14 mg*h/L. Furthermore, the duration of B cell aplasia was shorter (p=0.009) and the AUCs of CAR T cell numbers lower (p=0.03) in the underexposed group. No significant differences in baseline characteristics were present between the two exposure groups. To our knowledge, this is the first study describing the effect of fludarabine exposure on outcome in a cohort of paediatric and young adults receiving CD19 CAR T cell therapy as treatment for B-ALL. These preliminary results suggest that optimizing fludarabine exposure may have a relevant impact on leukemia free survival following CAR T cell therapy. However, it should be noted that multivariate regression models are needed to show consistency of the relationship between fludarabine exposure and outcome. The limited number of patients did not allow for inclusion of potential covariates that may influence clinical outcome into the analysis. Therefore, our results need to be confirmed in a larger cohort. In conclusion, clinical outcome in patients receiving CAR19 T cell therapy might be improved by the optimization of fludarabine exposure in the lymphodepleting regimen. LD and FC contributed equally to this study. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Checkpoint-blocker induced autoimmunity is associated with pretreatment T cell expression profiles and favourable outcome in melanoma

10.1101/2020.06.23.20138594 ◽

2020 ◽

Author(s):

W. Ye ◽

A Olsson-Brown ◽

R. A. Watson ◽

V. T. F. Cheung ◽

R. D. Morgan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Clinical Outcome ◽

Adverse Events ◽

Metastatic Melanoma ◽

T Cell Receptor ◽

Immune Checkpoint ◽

Single Agent ◽

Cell Receptor ◽

Pre Treatment

1Abstract1.1BackgroundImmune checkpoint blockers (ICBs) activate CD8+ T cells to elicit anti-cancer activity but frequently lead to immune-related adverse events (irAEs). The relationship of irAE with baseline parameters and clinical outcome is unclear. We investigated associations between irAE development, CD8+ T cell receptor diversity and expression and clinical outcome in a non-trial setting.1.2MethodsPatients ≥18 years old with metastatic melanoma (MM) receiving combination ICB (ipilimumab plus nivolumab – cICB, n=60) or single-agent ICB (nivolumab/pembrolizumab – sICB, n=78) were prospectively recruited. We retrospectively evaluated the impact of irAEs on survival. This analysis was repeated in an independent cohort of MM patients treated at a separate institution (n=210, cICB:74, sICB:136). We performed RNA sequencing of CD8+ T cells isolated from patients prior to treatment, analysing T cell receptor clonality differential transcript expression according to irAE development.1.3Results48.6% of patients experienced treatment-related irAEs within the first 5 cycles of treatment. Development of irAE prior to the 5th cycle of ICB was associated with longer progression-free and overall survival (PFS, OS) in the primary cohort (log-rank test, PFS: P=0.00034; OS: P<0.0001), replicated in the secondary cohort (OS: P=0.00064). Across cohorts median survival for those patients not experiencing irAE was 14.4 (95% CI:9.6-19.5) months vs not-reached (95% CI:28.9 - Inf), P=3.0×10−7. Pre-treatment performance status and neutrophil count, but not BMI, were additional predictors of clinical outcome. Analysis of CD8+ T cells from 128 patients demonstrated irAE development was associated with increased T cell receptor diversity post-treatment (P=4.3×10−5). Development of irAE in sICB recipients was additionally associated with baseline differential expression of 224 transcripts (FDR<0.1), enriched in pro-inflammatory pathway genes including CYP4F3 and PTGS2.1.4ConclusionsEarly irAE development post-ICB is strongly associated with favourable survival in MM and increased diversity of peripheral CD8+ T cell receptors after treatment. irAE post-sICB is associated with pre-treatment upregulation of inflammatory pathways, indicating irAE development may reflect baseline immune activation states.Key messageImmune-related adverse events (irAEs) commonly occur in patients with metastatic melanoma treated with immune checkpoint blockade (ICB) therapy. In real world setting we find development of early irAEs post-ICB treatment is associated with survival benefit, indicative of a shared mechanism with anti-tumour efficacy. CD8+ T cells from patients who develop irAE show increased receptor diversity, and pre-treatment samples from patients who develop irAE post single-agent anti-PD1 show over-expression of inflammatory pathways, indicating baseline immune state can determine irAE development.

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Impact of Different T Cell Depletion Protocols on Immune Reconstitution Following Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽

10.1182/blood-2020-139208 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 43-44

Author(s):

Amandine Pradier ◽

Adrien Petitpas ◽

Anne-Claire Mamez ◽

Federica Giannotti ◽

Sarah Morin ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Reconstitution ◽

Cell Depletion ◽

Unrelated Donor ◽

T Cell Depletion ◽

Hematopoietic Stem ◽

Post Transplant ◽

The Impact

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapeutic modality for a variety of hematological malignancies and congenital disorders. One of the major complications of the procedure is graft-versus-host-disease (GVHD) initiated by T cells co-administered with the graft. Removal of donor T cells from the graft is a widely employed and effective strategy to prevent GVHD, although its impact on post-transplant immune reconstitution might significantly affect anti-tumor and anti-infectious responses. Several approaches of T cell depletion (TCD) exist, including in vivo depletion using anti-thymocyte globulin (ATG) and/or post-transplant cyclophosphamide (PTCy) as well as in vitro manipulation of the graft. In this work, we analyzed the impact of different T cell depletion strategies on immune reconstitution after allogeneic HSCT. Methods We retrospectively analysed data from 168 patients transplanted between 2015 and 2019 at Geneva University Hospitals. In our center, several methods for TCD are being used, alone or in combination: 1) In vivo T cell depletion using ATG (ATG-Thymoglobulin 7.5 mg/kg or ATG-Fresenius 25 mg/kg); 2) in vitro partial T cell depletion (pTCD) of the graft obtained through in vitro incubation with alemtuzumab (Campath [Genzyme Corporation, Cambridge, MA]), washed before infusion and administered at day 0, followed on day +1 by an add-back of unmanipulated grafts containing about 100 × 106/kg donor T cells. The procedure is followed by donor lymphocyte infusions at incremental doses starting with 1 × 106 CD3/kg at 3 months to all patients who had received pTCD grafts with RIC in the absence of GVHD; 3) post-transplant cyclophosphamide (PTCy; 50 mg/kg) on days 3 and 4 post-HSCT. Absolute counts of CD3, CD4, CD8, CD19 and NK cells measured by flow cytometry during the first year after allogeneic HSCT were analyzed. Measures obtained from patients with mixed donor chimerism or after therapeutic DLI were excluded from the analysis. Cell numbers during time were compared using mixed-effects linear models depending on the TCD. Multivariable analysis was performed taking into account the impact of clinical factors differing between patients groups (patient's age, donor type and conditioning). Results ATG was administered to 77 (46%) patients, 15 (9%) patients received a pTCD graft and 26 (15%) patients received a combination of both ATG and pTCD graft. 24 (14%) patients were treated with PTCy and 26 (15%) patients received a T replete graft. 60% of patients had a reduced intensity conditioning (RIC). 48 (29%) patients received grafts from a sibling identical donor, 94 (56%) from a matched unrelated donor, 13 (8%) from mismatched unrelated donor and 13 (8%) received haploidentical grafts. TCD protocols had no significant impact on CD3 or CD8 T cell reconstitution during the first year post-HSCT (Figure 1). Conversely, CD4 T cells recovery was affected by the ATG/pTCD combination (coefficient ± SE: -67±28, p=0.019) when compared to the T cell replete group (Figure 1). Analysis of data censored for acute or chronic GVHD requiring treatment or relapse revealed a delay of CD4 T cell reconstitution in the ATG and/or pTCD treated groups on (ATG:-79±27, p=0.004; pTCD:-100±43, p=0.022; ATG/pTCD:-110±33, p<0.001). Interestingly, pTCD alone or in combination with ATG resulted in a better reconstitution of NK cells compared to T replete group (pTCD: 152±45, p<0.001; ATG/pTCD: 94±36, p=0.009; Figure 1). A similar effect of pTCD was also observed for B cells (pTCD: 170±48, p<.001; ATG/pTCD: 127±38, p<.001). The effect of pTCD on NK was confirmed when data were censored for GVHD and relapse (pTCD: 132±60, p=0.028; ATG/pTCD: 106±47, p=0.023) while only ATG/pTCD retained a significant impact on B cells (102±49, p=0.037). The use of PTCy did not affect T, NK or B cell reconstitution when compared to the T cell replete group. Conclusion Our results indicate that all TCD protocols with the only exception of PTCy are associated with a delayed recovery of CD4 T cells whereas pTCD of the graft, alone or in combination with ATG, significantly improves NK and B cell reconstitution. Figure 1 Disclosures No relevant conflicts of interest to declare.

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Haploidentical Hematopoietic Stem-Cell Transplantation in Adults

Bone Marrow Research ◽

10.1155/2011/303487 ◽

2011 ◽

Vol 2011 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

Salem Alshemmari ◽

Reem Ameen ◽

Javid Gaziev

Keyword(s):

Stem Cell ◽

T Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Cell Depletion ◽

Unrelated Donor ◽

T Cell Depletion ◽

Hematopoietic Stem

Haploidentical hematopoietic stem-cell transplantation is an alternative transplant strategy for patients without an HLA-matched donor. Still, only half of patients who might benefit from transplantation are able to find an HLA-matched related or unrelated donor. Haploidentical donor is readily available for many patients in need of immediate stem-cell transplantation. Historical experience with haploidentical stem-cell transplantation has been characterised by a high rejection rate, graft-versus-host disease, and transplant-related mortality. Important advances have been made in this field during the last 20 years. Many drawbacks of haploidentical transplants such as graft failure and significant GVHD have been overcome due to the development of new extensive T cell depletion methods with mega dose stem-cell administration. However, prolonged immune deficiency and an increased relapse rate remain unresolved problems of T cell depletion. New approaches such as partial ex vivo or in vivo alloreactive T cell depletion and posttransplant cell therapy will allow to improve immune reconstitution in haploidentical transplants. Results of unmanipulated stem-cell transplantation with using ATG and combined immunosuppression in mismatched/haploidentical transplant setting are promising. This paper focuses on recent advances in haploidentical hematopoietic stem-cell transplantation for hematologic malignancies.

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