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  • American Society of Hematology  (14)
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  • American Society of Hematology  (14)
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  • 1
    In: Blood Advances, American Society of Hematology, Vol. 4, No. 22 ( 2020-11-24), p. 5846-5857
    Abstract: Infection is one of the primary causes of death from immune thrombocytopenia (ITP), and the lungs are the most common site of infection. We identified the factors associated with hospitalization for community-acquired pneumonia (CAP) in nonsplenectomized adults with ITP and established the ACPA prediction model to predict the incidence of hospitalization for CAP. This was a retrospective study of nonsplenectomized adult patients with ITP from 10 large medical centers in China. The derivation cohort included 145 ITP inpatients with CAP and 1360 inpatients without CAP from 5 medical centers, and the validation cohort included the remaining 63 ITP inpatients with CAP and 526 inpatients without CAP from the other 5 centers. The 4-item ACPA model, which included age, Charlson Comorbidity Index score, initial platelet count, and initial absolute lymphocyte count, was established by multivariable analysis of the derivation cohort. Internal and external validation were conducted to assess the performance of the model. The ACPA model had an area under the curve of 0.853 (95% confidence interval [CI], 0.818-0.889) in the derivation cohort and 0.862 (95% CI, 0.807-0.916) in the validation cohort, which indicated the good discrimination power of the model. Calibration plots showed high agreement between the estimated and observed probabilities. Decision curve analysis indicated that ITP patients could benefit from the clinical application of the ACPA model. To summarize, the ACPA model was developed and validated to predict the occurrence of hospitalization for CAP, which might help identify ITP patients with a high risk of hospitalization for CAP.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 2
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1013-1013
    Abstract: Introduction Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), with mortality over 80%. Effective management of TA-TMA is hampered by obscure pathogenesis and delayed diagnosis. There are no well-acknowledged therapeutic strategies for TA-TMA. TA-TMA-directed therapy includes therapeutic plasma exchange (TPE), eculizumab, rituximab, and defibrotide. The efficacy and outcome of TPE for the treatment of TA-TMA remain controversial. To our knowledge, this is the largest cohort to date of patients treated with TPE for TA-TMA after allo-HSCT. We aimed to identify predictors of response and mortality in patients with TA-TMA who received TPE, and to recognize patients who will benefit from TPE management. Methods A total of 6241 subjects who underwent allo-HSCT were performed at Peking University People's Hospital from January 2010 to December 2019, of whom 538 patients were diagnosed with TA-TMA, with a cumulative incidence of 8.6%. Among them, 82 consecutive critically ill TA-TMA patients received TPE. TA-TMA was diagnosed using the criteria proposed by Cho et al. TPE was not performed in a protocol-defined manner. Patients were classified as achieving complete response (CR) if they showed disappearance of schistocytes, resolution of any changes in mental status, normalization of lactic dehydrogenase, and were not receiving red blood cells and platelet transfusions. Patients were considered to have achieved no response (NR) when they showed no improvement of laboratory features, remained dependent on red blood cell and/or platelet transfusions, or died with active TA-TMA. Subjects were considered to have a partial response (PR) when they did not meet the criteria for either CR or NR (BMT 2010; Blood 2020). Results TA-TMA was diagnosed at a median time of 64.5 [IQR 38.8-158] days post-HSCT. The 42 men (51.2%) and 40 women (48.8%) had an average age of 35.3 years. Renal involvement (59.8%), central nervous system dysfunction (70.7%), gastrointestinal (GI) bleeding (73.2%), and concomitant acute graft-versus-host disease (aGVHD, 78%) were common in our cohort of TA-TMA patients. All 82 patients in our analysis received TPE, and adjunctive TA-TMA-targeted therapy included the use of rituximab (11 patients), rituximab plus eculizumab (1 patient), and defibrotide (1 patient). However, the additional therapy showed no significant difference between the response and nonresponse groups. The median time from TA-TMA to TPE initiation was 8 days [IQR 2.0-16.5], and the cumulative volume of TPE was 6 L [IQR 3.6-8.5] . Our data revealed that the overall response was 52.4% (43/82), comprising 4 CRs and 39 PRs. Early TPE initiation trended towards a better response, but this difference was not statistically significant. The multivariate analysis showed that patients with GI bleeding (OR, 6.26; 95% CI, 1.30-30.12), grade III-IV aGVHD (OR, 5.00; 95% CI, 1.50-16.68), lower cumulative volume of TPE (OR, 8.51; 95% CI, 1.91-38.05), and severe anemia (OR, 7.48; 95% CI, 2.20-25.49) were less likely to respond to TPE. Regarding treatment outcome, 57% (47/82) of cases survived 100 days post HSCT, and 20% (16/82) survived 100 days after the diagnosis of TA-TMA. With a median follow-up of 467 days [IQR 248-1002], the OS at 1 year after TA-TMA was 15%. The leading causes of death were infection, active TA-TMA, and multiple organ dysfunction syndrome (MODS). The Kaplan-Meier analysis showed that GI bleeding, grade III-IV aGVHD, and no response to TPE were associated with poor survival at 1-year post TA-TMA (Figure 1). By multivariate analysis, TA-TMA patients treated with TPE had dismal survival with GI bleeding, lower loading volume of TPE, and elevated total bilirubin. Conclusions The results of this large cohort of real-world practice indicate that TPE may be effective for TA-TMA depending on given clinical circumstances. Our data underscore that GI bleeding is independently associated with poor response to TPE and mortality, while grade III-IV aGVHD is again confirmed as predicting a dismal response to TPE. We hypothesize that higher volume of TPE is warranted to achieve resolution and favorable outcome of TA-TMA. Multicenter prospective studies are required to further verify whether these patients could benefit from TPE and seek a paradigm for TPE in the management of TA-TMA. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
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  • 3
    In: Blood, American Society of Hematology, Vol. 142, No. 10 ( 2023-09-07), p. 903-917
    Abstract: The bone marrow microenvironment (BMM) can regulate leukemia stem cells (LSCs) via secreted factors. Increasing evidence suggests that dissecting the mechanisms by which the BMM maintains LSCs may lead to the development of effective therapies for the eradication of leukemia. Inhibitor of DNA binding 1 (ID1), a key transcriptional regulator in LSCs, previously identified by us, controls cytokine production in the BMM, but the role of ID1 in acute myeloid leukemia (AML) BMM remains obscure. Here, we report that ID1 is highly expressed in the BMM of patients with AML, especially in BM mesenchymal stem cells, and that the high expression of ID1 in the AML BMM is induced by BMP6, secreted from AML cells. Knocking out ID1 in mesenchymal cells significantly suppresses the proliferation of cocultured AML cells. Loss of Id1 in the BMM results in impaired AML progression in AML mouse models. Mechanistically, we found that Id1 deficiency significantly reduces SP1 protein levels in mesenchymal cells cocultured with AML cells. Using ID1-interactome analysis, we found that ID1 interacts with RNF4, an E3 ubiquitin ligase, and causes a decrease in SP1 ubiquitination. Disrupting the ID1-RNF4 interaction via truncation in mesenchymal cells significantly reduces SP1 protein levels and delays AML cell proliferation. We identify that the target of Sp1, Angptl7, is the primary differentially expression protein factor in Id1-deficient BM supernatant fluid to regulate AML progression in mice. Our study highlights the critical role of ID1 in the AML BMM and aids the development of therapeutic strategies for AML.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2023
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  • 4
    In: Blood Advances, American Society of Hematology, Vol. 5, No. 24 ( 2021-12-28), p. 5479-5489
    Abstract: Transplant-associated thrombotic microangiopathy (TA-TMA) is a potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Information on markers for early prognostication remains limited, and no predictive tools for TA-TMA are available. We attempted to develop and validate a prognostic model for TA-TMA. A total of 507 patients who developed TA-TMA following allo-HSCT were retrospectively identified and separated into a derivation cohort and a validation cohort, according to the time of transplantation, to perform external temporal validation. Patient age (odds ratio [OR], 2.371; 95% confidence interval [CI] , 1.264-4.445), anemia (OR, 2.836; 95% CI, 1.566-5.138), severe thrombocytopenia (OR, 3.871; 95% CI, 2.156-6.950), elevated total bilirubin (OR, 2.716; 95% CI, 1.489-4.955), and proteinuria (OR, 2.289; 95% CI, 1.257-4.168) were identified as independent prognostic factors for the 6-month outcome of TA-TMA. A risk score model termed BATAP (Bilirubin, Age, Thrombocytopenia, Anemia, Proteinuria) was constructed according to the regression coefficients. The validated c-statistic was 0.816 (95%, CI, 0.766-0.867) and 0.756 (95% CI, 0.696-0.817) for the internal and external validation, respectively. Calibration plots indicated that the model-predicted probabilities correlated well with the actual observed frequencies. This predictive model may facilitate the prognostication of TA-TMA and contribute to the early identification of high-risk patients.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 5
    Online Resource
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    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 4907-4907
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 4907-4907
    Abstract: Abstract 4907 Introduction: Despite improved treatment outcome in acute lymphoblastic leukemia (ALL), drug resistance and disease recurrence remain major obstacles in specific subgroups. Thus, there is an urgent need to identify new targets for therapy. Several studies showed that Aurora kinases were therapeutic targets in cancer therapy, including solid tumors and hematological malignancies. Here we describe preclinical testing of Aurora kinase inhibitors in ALL and the molecular mechanism of different drug activity. Materials and methods: Quantitative RT-PCR and Western blot were used to assess the expressions of Aurora kinases and their activators in ALL. RT-PCR was used to detect the expression of MDR-1. To test activity against Aurora kinases, different ALL cell lines were treated with various concentrations of Aurora kinase inhibitors “VE-465 and VX-680”. The effects of Aurora kinase inhibitors on the cell cycle were evaluated by flow cytometry. Gene expression profiling was performed to identify the candidate targets which regulate the different drug sensitivity. Transient knockdown and overexpression of candidate genes in ALL cell lines were also employed in this study. Results: Nine ALL cell lines treated with Aurora kinase inhibitors (VE-465 and VX-680) exhibited different drug sensitivity. Five ALL cell lines were sensitive to drug treatment with IC50 around 10–40 nM, including MLL-AF4-positive and BCR-ABL-positive cell lines. However, RPMI-8402 was one of the three cell lines which were resistant to VE-465 and VX-680 with IC50 more than 10 μM. Among these sensitive ALL cell lines, treatment of Aurora kinase inhibitors resulted in an increased G2/M and sub-G1 populations. In contrast, drug-resistant ALL cell lines showed increased polyploidy status after exposure to Aurora kinase inhibitors. The different treatment efficacy was not related to the expression of Aurora kinases, their activators or MDR-1. In order to elucidate the molecular mechanism to regulate the different drug sensitivity, microarray study was performed. It showed that treatment of Aurora kinase inhibitors resulted in differential expressions of genes (75 up-regulated and 90 down-regulated genes) and CDKN1Awas one of the potential molecules which regulated the treatment diversity. RT-PCR and Western blot confirmed the cDNA microarray data: CDKN1A was up-regulated after treatment with Aurora kinase inhibitors in the drug-sensitive cell lines, but no change in the level of CDKN1A in the drug-resistance cell lines. Knockdown of CDKN1A in drug-sensitive cell lines impaired the treatment activity. Over-expression of CDKN1A in drug-resistant cell lines increased the anti-leukemia effect of Aurora kinase inhibitors. Conclusion: These data suggest that treatment with Aurora kinase inhibitors may be a novel and effective therapy in specific subgroups of ALL, including MLL-AF4-positive ALL. These data show that status of Aurora kinases, their activators or MDR-1 does not correlate with the drug susceptibility in ALL cell lines. The susceptibility to Aurora kinase inhibitors in ALL depends on the activation status of CDKN1A. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 6
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3769-3769
    Abstract: Introduction Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by abnormal immune response. Though many therapies have been used, corticosteroid-resistance remains to be a challenge clinically. Extensive research has improved our understanding of ITP, showing that environmental factors affect the disease profile, such as Helicobacter pylori being proven to be associated with thrombocytopenia. Though evidence that the gut microbiota contributes to the development of auto-immune disorders is accumulating, there is no information available on relationship between gut microbiome and ITP. Berberine(BBR), a traditional compound isolated from a Chinese herb, has been widely used as a nonprescription drug to treat diarrhea. Recently, BBR has been reported to modulate microbiota structures, which contributes to improving metabolic disorders. Here, we hypothesized that BBR might modulate gut microbiota to treat ITP. Methods In order to investigate the relationship between gut microbiome and ITP, we performed deep shotgun sequencing on 253 fecal samples totally from consecutive ITP patients and healthy controls. Metagenome-wide association study (MWAS) was conducted, and clinical characteristics of patients were collected to analyze the correlation with gut microbiome (Nan Qin, et al. Nature. 2012). Certainly, a clinical cohort study was performed to assess the efficacy of BBR in corticosteroid-resistant ITP patients. To better characterize the role of gut microbiota in the development of ITP and to verify the modulating effect of BBR on gut microbiota structure, we performed colonization of mice with specific bacterium and established active murine models (immunized-splenocyte engraftment) of BBR treatment. Result We integrated the sequencing data into an existing gut microbial reference-gene catalog and identified 35275 genes that differ in abundance between ITP patients and healthy controls. We then clustered the genes into metagenomic species (MGS) and finally identified 15 MGS which were significantly different in both discovery cohort and validation cohort. Dysbiosis was detected in the gut microbiome of ITP patients, as both phylogenetic analysis and MGS annotation indicated that Lachnospiraceae bacterium, Clostridium asparagiforme were over-represented while Bacteroides spp was depleted in ITP patients comparing with healthy controls. Functionally, KEGG annotation showed that the most enriched orthologs in ITP patients were related to membrane transport. Moreover, the biosynthesis of microbe-associated molecular patterns (MAMPs) such as lipopolysaccharides (LPS), peptidoglycan biosynthesis and flagellin were highly abundant in patients. Gene biomarkers and cluster markers based on gut microbiome were established to identify ITP patients and were validated in an independent cohort. The alterations of gut microbiome in ITP patients are partly reversed after treatment. Furthermore, L. bacterium shows more abundant in corticosteroid-resistant ITP comparing with newly diagnosed ITP. Specifically, BBR treatment could improve the microbial dysbiosis of corticosteroid-resistant ITP patients, the complete response (CR), response(R), and overall response (OR) rates being 26.3%, 47.4% and 73.7%, respectively. Targeted QPCR assay determined that L. bacterium accumulated in corticosteroid-resistant ITP, consistent with the result of shotgun sequencing data. Gavage with L. bacterium results in significantly alterations of gut microbiota structure in mice comparing with mice without bacterial administration or those receiving Clostridium asparagiforme administration. Moreover, colonization of L. bacterium caused more severe thrombocytopenia and impaired the response to corticosteroid therapy in active ITP model. Intriguingly, BBR treatment, but not any other antibiotics, could reverse the effect of L. bacterium colonization on gut microbiota structure and enhance the response to corticosteroid therapy. Conclusion Our findings demonstrate that the gut microbiome alters in ITP and is partly normalized after treatment. Gut microbiota dysbiosis may contribute to the development of corticosteroid-resistant ITP. BBR may correct corticosteroid-resistance by modulating the gut microbiota structure, thus being a novel potential second-line candidate to treat ITP. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
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  • 7
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3261-3261
    Abstract: Introduction Late-onset hemorrhagic cystitis (LOHC) is a common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with an incidence ranging from 6.5% to 70% and leads to prolonged hospitalization and even death (Silva Lde P et al, Haematologica, 2010; LAM et al, Transpl Infect Dis, 2017). The pathogenesis of LOHC remains obscure, but in our previous study, viral infections and acute graft-versus-host disease (aGVHD) have frequently been shown to be associated with its development (Han et al., Am. J. Hematol, 2014). Therapeutic strategies for LOHC are still not standardized due to the complicated clinical background and given the paradoxical phenomenon that immunosuppressive agents, such as steroids, are necessary for aGVHD but cause an immunosuppressive state. We aimed to investigate the incidence, risk factors and outcomes of LOHC after allogeneic stem cell transplantation. Additionally, for the first time, we propose four therapeutic patterns and their impact on prognosis of LOHC to aid in clinical decision making. Methods This retrospective, nested, case-control study reviewed data from 2158 patients who received allo-HSCT from January 2014 to December 2018. In total, 364 (16.87%) patients were diagnosed with LOHC. Individual matching was performed by randomly selecting 3 controls from the same cohort for each identified LOHC patient according to the time of allo-HSCT. Standard basic measures included hyperhydration, forced diuresis, insertion of a vesical catheter for intermittent or continuous bladder irrigation and evacuation of clots. Patients with grade III-IV LOHC were divided into four groups according to immunosuppressant use (steroid, MMF and Basiliximab) 1 week before and after the onset of LOHC: an intensified-intensified (I-I) group, intensified-not intensified (I-N) group, not intensified-intensified (N-I) group and not intensified-not intensified (N-N) group. "Intensified" was defined as an increase in any immunosuppressant, and "not intensified" was defined as maintenance or tapering of all immunosuppressants. Data concerning the baseline characteristics, incidence, treatment patterns and outcomes were recorded. Results In total, 364 patients developed LOHC at a median of 29 days (range, 23-37.75 days), with a cumulative incidence of 16.87%. AML (HR =0.493 95% CI, 0.244-0.997; p=0.049), AA (HR =0.444, 95% CI,0.18-1.096; p=0.078), HLA match(HR =0.149, 95% CI, 0.036-0.616; p=0.009), days to platelet engraftment(HR =1.023, 95% CI, 0.998-1.049;p=0.069)and CMV viremia (HR =2.365, 95% CI, 1.179,4.733;p=0.015)were associated with LOHC. Only HLA match (HR =0.111, 95% CI, 0.014-0.878; p=0.037)remained significant in the multivariate analysis. 6.5%, 12.9%, 48.39% and 32.26% patients with III-IV LOHC were divided into I-I, I-N, N-I and N-N groups, respectively. There were no significant differences in overall survival (p=0.05) and the incidence of CMV viremia (p=0.187) among the four groups. The incidence of relapse (p=0.007) and the incidence of aGVHD (p=0.01) was highest in the I-I group, followed by the N-I, I-N and N-N groups. 50% of the patients in N-I group showed the improvement of LOHC, which is significantly highest among the four groups(p=0.000). However, no statistical significance was found regarding the CMV viremia turning shade or the improvement of aGVHD. Non-relapse mortality (NRM) was observed in 25% of patients without resolution of LOHC. NRM was 0% among patients without intensified immunosuppression but was 25%, 0% and 50% among those with intensified immunosuppression before LOHC, after LOHC and before and after LOHC, respectively. Conclusion The independent risk factors for LOHC after allo-HSCT were HLA mismatch. Avoiding intensified immunosuppression that damages endothelium or reactivates the related virus may improve transplant outcome. The N-N pattern could reduce the incidence of CMV viremia or aGVHD in the LOHC patients, and the N-I pattern might be more promising as a therapeutic strategy for LOHC. Disclosures No relevant conflicts of interest to declare. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
    In: Blood Advances, American Society of Hematology, Vol. 3, No. 9 ( 2019-05-14), p. 1416-1428
    Abstract: Impaired megakaryocyte (MK) maturation and reduced platelet production are important causes of immune thrombocytopenia (ITP). However, MK distribution and bone marrow (BM) niche alteration in ITP are unclear. To investigate the maturation and distribution of MKs in the BM niche and examine the components of BM niche regulation of MK migration, BM and peripheral blood were obtained from 30 ITP patients and 28 healthy donors. Nestin+ mesenchymal stem cells (MSCs) and CD41+ MKs were sorted by fluorescence-activated cell sorting. The components of the BM niche and related signaling were analyzed via immunofluorescence, flow cytometry, enzyme-linked immunosorbent assay, reverse transcription polymerase chain reaction, and western blot analysis. The number of MKs in the BM vascular niche was reduced in ITP. Moreover, the concentrations of CXCL12 and CXCR4+ MKs in the BM were decreased in ITP. Further investigation demonstrated that nestin+ MSCs and CXCL12 messenger RNA (mRNA) in nestin+ MSCs were both reduced whereas the apoptosis of nestin+ MSCs was significantly increased in ITP. Sympathetic nerves, Schwann cells, the proportion of β3-adrenoreceptor (β3-AR)+ nestin+ MSCs, and β3-AR mRNA in nestin+ MSCs were all markedly reduced in ITP. Moreover, matrix metalloproteinase 9, vascular endothelial growth factor (VEGF), and VEGF receptor 1 were significantly reduced in ITP. Our data show that impaired MK distribution mediated by an abnormal CXCL12/CXCR4 axis is partially involved in reduced platelet production in ITP. Moreover, sympathetic neuropathy and nestin+ MSC apoptosis may have an effect on the alterations of BM CXCL12 in ITP.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 9
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 13-13
    Abstract: Introduction Immune thrombocytopenia (ITP) is an acquired, organ-specific, autoimmune disease and one of the most common bleeding disorders seriously endangering human health. Glucocorticoids and intravenous immunoglobulin are first-line treatments recommended by guidelines for patients with ITP. However, approximately 50%-85% of patients relapse during the first year of treatment. In addition, long-term use of glucocorticoids increases the risk for dose- and time-dependent glucocorticoid-related complications and serious side effects. Therefore, in-depth studies investigating new solutions for the first-line treatment of ITP are urgently needed. Tacrolimus is a calcineurin inhibitor, which forms a complex by binding to FK506-binding protein. It is currently widely used in the prevention of graft-versus-host disease for organ transplantation as well as for the treatment of autoimmune diseases. In addition to recent retrospective studies and case reports demonstrating its effectiveness in ITP, tacrolimus has been shown to improve anti-platelet antibody-mediated thrombocytopenia in mice, suggesting it may be a potential treatment for ITP. The aim of this study was to compare two first-line treatment options for ITP-a standard glucocorticoid-only regimen versus tacrolimus in combination with a standard glucocorticoid regimen-to determine which could help patients achieve stable platelet counts faster and experience a longer duration of remission. Methods This open-label, randomized, phase 2 trial, enrolled adult ITP patients from seven different tertiary medical centers in China. Elderly patients had confirmed, newly diagnosed, treatment-naive ITP, platelet counts & lt;30×10 9/L, or & lt; 50×10 9/L and significant bleeding symptoms (World Health Organization bleeding scale ≥ 2). Eligible patients were randomly assigned 1:1 with an interactive web-based response system to receive either oral tacrolimus (initial 0.03 mg/kg/day and maintain blood concentration at 3-5 ng/mL for 12 weeks) plus high-dose dexamethasone (HD-DXM) or HD-DXM monotherapy for 12 weeks. DXM (40 mg) was administered orally daily for 4 consecutive days to both study arms. The 4-day course of DXM was repeated on days 11-14 in patients who lacked response by day 10. The primary endpoint was 6-month sustained response (SR), defined as platelet count maintained & gt;50×10 9/L without any additional ITP-modifying therapy at the 6-month follow-up. Key secondary endpoints included initial response by day 14 (OR, platelet count ≥30×10 9/L and at least 2-fold increase in baseline platelet count and absence of bleeding; and CR, platelet count ≥ 100×10 9/L), duration of response, bleeding scores, and adverse events (AEs). This trial was registered with ClinicalTrials.gov (NCT04747080). Results Total 140 patients newly diagnosed with ITP were randomly assigned to either the tacrolimus plus HD-DXM (n=72) or HD-DXM monotherapy (n=68) groups. At the 6-month follow-up, the proportion of patients exhibiting SR was significantly higher in the tacrolimus plus HD-DXM group than in the HD-DXM monotherapy group (65.3% vs 42.6%, p= 0.007). Of the 140 patients with ITP (males accounted for 48.6%), the mean age was 32.8 years, the mean platelet count was 16.7×10 9/L. The combination group exhibited a higher 14-day early remission rate than the monotherapy group (76.4% vs 55.9%, P=0.001). Significantly fewer treatment failures occurred in patients randomly assigned to the combination group(19.4% vs 38.2%, P=0.0014). During the follow-up period, fewer patients in the combination group experienced relapse than in the monotherapy group; the median time to relapse was 77 days (Tacrolimus+HD-DXM) vs 36 days (HD-DXM). The combination group exhibited a lower proportion of bleeding events and a lower bleeding score. The incidence of serious AEs, rescue therapy, and treatment side effects were similar between the two groups, and treatment was well tolerated by all patients, with no grade 4 AEs or treatment-related deaths reported. There was no statistically significant difference in the incidence of treatment-related AEs between the two groups. Conclusions Low-dose tacrolimus plus HD-DXM was an effective and safe treatment for ITP as first-line therapy and elicited a sustained prolonged response in adults. This therapy may be a new treatment option for adult patients with ITP. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: It includes information or discussion of off-label drug use of tacrilimus.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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    detail.hit.zdb_id: 80069-7
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  • 10
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 5673-5673
    Abstract: Introduction: Graft-versus-host disease (GVHD) is a major complication of hematopoietic stem cell transplantation. Mesenchymal stem cells (MSCs) can modulate immune response and have been used as a treatment for aGVHD. The immune-modulating factors of MSCs are secreted and reside in supernatant fractions that are enriched for extracellular vesicles (EVs). MSC-derived EVs (MSC-EVs) also exhibit immunosuppressive activity, providing many advantages compared to MSCs and have been proven therapeutic in aGVHD. Arsenic trioxide (ATO) exhibits potent antitumor effects and increasing studies indicate its immunosuppressive effects. However, ATO at high concentrations can cause severe adverse effects. If encapsulated in some kind of drug vehicles, ATO can be made less toxic. Therefore, we believed that the combination of MSC-EVs with a low dose of ATO would be an effective therapy for aGVHD. Methods: We used a classical GVHD model (BALB/c→B6) and developed 4 groups: the control group (TCD-BM), the GVHD control group (TCD-BM + spleen T cells), the MSC-EVs treatment group and the MSC-ATO-EVs (MSC-derived ATO-encapsulating EVs) treatment group. OS, GVHD clinical and histological scores were evaluated. A20-luc lymphoma cells were injected to generate the GVL model. Using flow cytometry analysis, we analyzed Th cell subsets, cytokines and transcription factors (Th1*IFN-γ/TNF-α*T-bet, Th2*IL-4*GATA3, Th17*IL-17*RORγt, Treg*IL-10*Foxp3) and sorted CD8+ SLECs, and CD8+ MPECs in BM and spleen of recipients. Dll4 expression was analyzed on DCs. B6 cells were incubated with or without BALB/c spleen cells and complete medium alone, with 10 mM ATO alone. T cell apoptosis was determined with Yopro-1 staining. We used MLR assays to examine Th subsets, cytokines and notch targeted genes with or without ATO or neutralizing Ab specific to Dll4 (anti-Dll4). Results: BALB/c mice receiving B6 TCD-BM alone developed no sign of GVHD, whereas all BALB/c mice receiving B6 donor TCD-BM + spleen T cells died of GVHD. In contrast, injection of MSC-EVs and MSC-ATO-EVs inhibited GVHD in T cell recipients, with 20% and 29% of them surviving without severe GVHD, respectively. These survival rates were accompanied by significantly lower clinical and histological scores. GVL effects mediated by MSC-EVs and MSC-ATO-EVs were comparable to those obtained in the GVHD control group. Compared to the control group, CD4+T and CD8+T cells increased substantially in T cell recipients, resulting in severe GVHD. In contrast, treatment with MSC-ATO-EVs significantly reduced the number of CD4+T and CD8+T cells, while MSC-EVs recipients retained approximately the same number of T cells as the GVHD group. Compared to the GVHD control group, Th2 and Treg cells derived from the spleen increased, while Th1 and Th17 cells were reduced significantly in both the MSC-EVs and MSC-ATO-EVs groups. We also detected lower serum levels of TNF-α and IFNγ as well as lower expression of RORγt and T-bet in blood and BM CD4+ T cells in these two groups, while the expression of GATA3 and Foxp3 increased significantly. Treatment with MSC-ATO-EVs markedly raised the MPEC/SLEC ratio compared to the MSC-EVs and GVHD control groups. We also examined Dll4high DCs in different organs and different groups and found that only MSC-ATO-EVs significantly reduced the Dll4high DCs, especially in the spleen and intestine. Treatment of stimulated B6 CD4+ T and CD8+ T cells with ATO increased production of H2O2. Yopro-1 staining of activated B6 CD4+ T and CD8+ T cells indicated that ATO dramatically triggered apoptosis in those cells. DCs were isolated and cultured with B6 mouse-derived CD4+ T or CD8+ T cells, with or without addition of ATO or anti-Dll4. ATO and anti-Dll4 both led to significant reduction of IFN-γ and TNF-α, while IL-4 and IL-10 increased slightly. We next assessed the notch pathway targeted genes in T cells and found there were significantly increased GATA3 and reduced Dtx expression levels. Conclusion: Altogether, our findings demonstrate that MSC-ATO-EVs might be a highly promising therapy for aGVHD through reducing T cell amounts and modulating Th subsets and CD8+ T cell differentiation. These effects can be explained with the inhibition of the Dll4-notch pathway by ATO. Therefore, further exploitation of the potential application of ATO in aGVHD and the mechanisms of action of ATO may improve outcomes after allo-HSCT. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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