bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparable Outcomes Among Adult Patients Allotransplanted for Myelodysplastic Syndrome Using Haploidentical, Matched Unrelated or Matched Sibling Donors: A Single-Center Study
Authors: Garnier Alice , Jullien Maxime , Guillaume Thierry , Peterlin Pierre , Le Bourgeois Amandine , Mahé Béatrice , Dubruille Viviane , Blin Nicolas , Touzeau Cyrille , Gastinne Thomas , Lok Anne , Tessoulin Benoit , Vantyghem Sophie , Bene Marie C , Moreau Philippe , Le Gouill Steven , Chevallier Patrice 
Published: November 2021

Abstract

Introduction: Allogeneic stem cell transplantation (allo-SCT) remains the only curative option for patients with myelodysplastic syndrome (MDS). If recent data have shown encouraging results with haploidentical (haplo) donors in this context, no comparison with allo-SCT using other source of graft (matched sibling [MSD] or unrelated [MUD] donors) has been reported so far.
Methods: We retrospectively considered 102 consecutive adults transplanted for MDS between March 2010 and August 2020 in our Department, comparing outcomes between those receiving a graft from a MSD, a MUD or a haplo-donor.
Results : Thirty-three, 48 and 21 patients respectively received a graft from a MSD, MUD or haplo donor. Peripheral blood stem cells (PBSC) were the source of graft for all patients. The median age of the whole cohort was 63 years old (range: 20-74) and the median follow-up was 23 months (range: 0-125). The three groups shared similar characteristics (gender, type of MDS, disease status, disease risk index, CMV status, ABO compatibility, peripheral blood stem cells graft count, conditioning regimen) except median recipient age which was younger in matched patients ( 61 vs 65 MUD vs 65 Haplo, p=0,04) and median donor age which was older in matched transplant ( 61 vs 34 MUD vs 42 Haplo, p&lt; 0,001) (Table 1). With a median follow-up of 46,4 months, the 4-year OS (Figure 1) was comparable between the three groups (haplo: 60.1 % ± 11,0 % , MSD: 59,0 % ±9,4 % and MUD: 61.2 % ± 7,2 %, p = 0.88) as well as the 4-year DFS (Figure 2) (55.9 % ± 11,1 % vs 51,2 % ±9,2 % vs 59.6 % ± 7,2 %, p = 0.78) and the cumulative incidence (CI) of NRM (34.6 % ±12,4 % , 15,4% ± 6,4% and 23.8 % ± 6,4 %, p = 0.21). Also, the 4-year CI of acute grade 3-4 GVHD (14,3% vs 15,2% vs 20,8%, p=0.79) and of moderate/severe chronic GVHD (14,3% vs 24.2% vs 27,1%, p=0.56) were not significantly different. The 4-year GRFS seemed better with haplo (Figure 3) but this was not statistically significant (56,1 % ± 11,0% vs 28,1% ±9,2 % vs 32,8 % ± 7,4%,p=0 .41).
Conclusions: These data suggest that haplo-identical donors represent a valid alternative in MDS patients lacking a MSD or a MUD for allo-SCT.
Figure 1 Figure 1.

Disclosures
Moreau: Oncopeptides: Honoraria; Amgen: Honoraria; Celgene BMS: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria.
The Non-Erythropoietic EPO Analogue (Cibinetide) Preserves Bone Mass in Mice
Authors: Awida Zamzam , Bachar Almog , Saed Hussam , Gorodov Anton , Ben-Califa Nathalie , Ibrahim Maria , Kolomansky Albert , Iden Jennifer Ana , Graniewitz Visacovsky Liad , Liron Tamar , Hiram-Bab Sahar , Brines Michael , Gabet Yankel , Neumann Drorit 
Published: November 2021

Abstract
Background and aims: Erythropoietin (EPO) is a pleiotropic cytokine, which besides its classical role in driving erythropoiesis, displays tissue protective and immunomodulatory activities. EPO also induces bone loss. While hematopoiesis is mediated via the homodimeric EPO receptor (EPOR), tissue protection is conferred via a heteromer composed of EPOR and CD131. Cibinetide (CIB), a non-erythropoietic analogue of EPO, specifically binds to the heteromeric receptor and confers tissue protection. Our published findings that EPO stimulates osteoclast precursors and entrains a decrease in bone density, raise questions regarding the underlying molecular mechanisms. Here, we evaluated the role of the heteromeric complex in bone metabolism using CIB alone and in combination with EPO in vivo and in vitro.
Results: CIB injections to 12-week-old female mice (120 µg/kg thrice weekly for 4 weeks) resulted in a significant increase in tissue mineral density in cortical bone by 5.8% (1416.4±39.27 vs 1338.74±16.56 mgHA/cm 3) and in trabecular bone by 5.2% (1056.52±30.94 vs 1004.13±16.91 mg HA/cm 3) (n=10 in each group, p&lt; 0.05 versus saline-injected controls), as measured by microCT (Figure 1A).
To evaluate the capacity of CIB to attenuate EPO mediated bone loss, we administered CIB (300 µg/kg) for 5 consecutive days, to 13-week-old female mice that also received 2 injections of 120U EPO on days 1 and 4. Flow cytometry analysis revealed a 1.8-fold reduction in the number of osteoclast progenitors, defined as Lin -CD11b −CD115 +Ly6C hi, in the EPO + CIB injected mice, compared to the mice injected with EPO alone (n=7 in each group, p&lt; 0.05). Hemoglobin levels and TER119 + bone marrow (BM) erythroid progenitors were similar in both groups.
In vitro, EPO administration to BM-derived macrophages (BMDM) enhanced osteoclastogenesis, whereas CIB had an opposite, dose-dependent effect. Combining CIB with EPO inhibited osteoclastogenesis in BMDM, suggesting that CIB overrides the pro-osteoclastogenic effect of EPO (Figure 1B).
Conclusions: Our findings highlight the increasing complexity of EPOR signaling in bone and pave the way for clinical translation through potential combination therapy of EPO and CIB in anemic and in cancer patients. Adjunctive administration of CIB may prevent or attenuate bone loss while preserving the erythropoietic actions of EPO.
This study was supported by a grant from the Dotan Hemato-oncology Fund, the Cancer Biology Research Center, Tel Aviv University to DN and YG.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Vaccine-Induced Thrombotic Thrombocytopenia: Novelty Testing in the Diagnostic Work-up?
Authors: Cacciola Rossella Rosari , Vecchio Veronica , Gentilini Cacciola Elio , Cacciola Emma 
Published: November 2021

Abstract
COVID-19 vaccination campagnies with several vaccines types are currently undeway. Recently, the ASTRA ZENECA vaccine has raised public alarm with concerns regarding the development of thrombotic events known as vaccine-induced thrombotic thrombocytopenia (VITT). Early and limited studies have implicated an antibody-mediated platelet activation as the mechanism of the clotting events. Aim of this study was to investigate the platelet and coagulation activation using specialized tests. In this study we enrolled 60 patients (40 men, 20 women; mean age 55±10 years) without cardiovascular risk factors or a history of thrombosis who reported having poplitea deep vein thrombosis (35/60) and pulmonary embolism (25/60) revealed with lower-limb ultrasonography and computed tomography (CT) angiography, respectively, 7 days after vaccination with ASTRA ZENECA. All patients were evaluated for initial testing such as platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib) and D-dimer (DD). Platelets were measured by automated analyzer, PT and APTT by coagulometric test, Fib using Clauss method, and DD using ELISA. Complete blood hemostasis was studied by platelet function assay (PFA-100) on Collagen/ADP (CT-ADP) and Collagen/Epinephrine (CT-EPI) cartridges and Thromboelastometry method on Clotting Time (CT), Clotting Formation Time (CFT), Maximum Clot Firmness (MCF), and clot lysis at 30 minutes (LY-30). All patients had thrombocytopenia (60±5x109/L), longer PT (28±10 s) and PTT (50±10 s), lower Fib (80±20 mg/dl), higher DD ((550±100 mg/l). All patients had shorter C/ADP and C/EPI (C/ADP, n.v. 68-121 s (42±10 s) and C/EPI n.v. 84-160 s (38±5 s) and shorter CT (CT, unit: s. n.v. 100-240 s) (INTEM 30±20 s, EXTEM 18±10 s), shorter CFT (CFT, unit: s, n.v. 30-160 s (INTEM 11±10 s, EXTEM 19±10 s), longer MCF (MCF, unit: mm, n.v. 50-72 mm (INTEM 128±10 mm, EXTEM 110±10 mm), and lower LY-30 (LY-30, %: v.n. 15% (INTEM 0.8%, EXTEM 0.7%). These interesting findings may be the novelty in the diagnostic work-up of the VITT. If these tests may aid in the diagnosis of VITT deserve to be confirmed and need reproducing in other studies.

Disclosures
No relevant conflicts of interest to declare.
Efficacy and Safety of Apixaban for Primary Prevention of Thromboembolism in Cancer Patients with a Newly Inserted Central Venous Catheter: A Post-Hoc Analysis of the Avert Trial
Authors: Brandt Willem , Brown Cameron , Zahrai Amin , Mallick Ranjeeta , Wells Philip S. , Carrier Marc 
Published: November 2021

Abstract
Background
Venous thromboembolism (VTE) is a common complication in ambulatory patients with cancer initiating systemic chemotherapy. Central venous catheters (CVCs) used for chemotherapy administration are associated with a heightened risk of VTE in this patient population. Primary thromboprophylaxis using a direct oral anticoagulant decreases the risk of VTE without significantly increasing the risk of major bleeding complications in ambulatory cancer patients at intermediate-to-high risk of VTE with a Khorana risk score of ≥ 2. We sought to determine the efficacy and safety of apixaban in intermediate-to-high risk patients with cancer and a CVC.
Methods
This post-hoc analysis was done using the AVERT trial data, which was a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban for primary thromboprophylaxis in intermediate-to-high risk patients with cancer initiating chemotherapy. The primary efficacy outcome was major VTE within 180 days of randomization and the primary safety outcome was major bleeding. The hazard ratios (HRs) for the primary efficacy and safety outcomes in patients with and without CVC were calculated using a Cox regression model controlling for age, gender, and study center.
Results
A total of 217 patients were included in the subgroup analyses with 126 and 91 patients receiving apixaban or placebo, respectively. The baseline characteristics are depicted in Table 1. Major VTE occurred in 6 (4.8%) patients in the apixaban group and 17 (18.7%) patients in the placebo group (HR 0.26; 95% CI, 0.14-0.47; p&lt;0.0001). Major bleeding occurred in 2 (1.6%) patients in the apixaban group and 2 (2.2%) patients in the placebo group (HR 0.69; 95% CI, 0.20-2.35; p=0.556).
Conclusions
Primary thromboprophylaxis with apixaban in patients with cancer and a CVC seems to reduce the risk of VTE without increasing the risk of major bleeding. Future studies are needed to confirm these findings.
Figure 1 Figure 1.

Disclosures
Wells: BMS/Pfizer: Research Funding; Bayer: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Servier: Honoraria. Carrier: Bristol Myers Squibb: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aspen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Honoraria; Servier: Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; LEO Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees.
Transcriptomic Profiling of Circulating Extrafollicular Helper T-like Cells in Patients with Active Chronic Graft-Versus-Host Disease Reveals Distinct Apoptosis Resistance
Authors: Liu Jiapei , Yang Kaibo , Jin Hua , Liu Qifa 
Published: November 2021

Abstract
In our previous studies, we identiﬁed circulating extrafollicular helper T-like cells (CD44 hiCD62L loPSGL-1 loCD4 +, c-extrafollicular Th-like) in human peripheral blood. C-extrafollicular Th-like cells are associated with the development of cGVHD. However, the exact molecular mechanism of these cells in patient with active cGVHD is still unclear. We performed the whole transcriptome analysis of c-extrafollicular Th-like cells from patients with active cGVHD and without cGVHD to explore the molecular mechanism. We identified 4661 differentially expressed genes between two groups by RNA-sequencing. Upregulated expression of Ca2 + influx and protein kinase C signaling pathway induced genes that establish T cell receptor hyper-activation signature were observed in active cGVHD patients. Expression of several inflammation cytokines and receptors were also increased, including IL23, IL27, IL2RA, IL32, IL24 and IL7R. Furthermore, tumor necrosis factor receptor associated factor 1 (TRAF1) and Bcl-2 genes that linked to resist apoptosis were found upregulated. Consistently, we confirmed that the BCL-2 expression of c-extrafollicular helper Th-like cells was significant higher in active cGVHD patients than no cGVHD patients(P=0.02) by quantitative polymerase chain reaction (qPCR). Our study sheds new light on molecular mechanism of the c-extrafollicular Th-like in patient with active cGVHD. Targeting these signaling pathways might blunt the development of cGVHD.

Disclosures
No relevant conflicts of interest to declare.
Essential Roles of Transcription Factor MEF2D in the Maintenance of MLL-Rearranged Acute Myeloid Leukemia
Authors: Zhang Pengcheng , Zhao Lianzhong , Qiu Shaowei , Bhatia Ravi , Lu Rui 
Published: November 2021

Abstract
Acute myeloid leukemia (AML) is an aggressive disease with uncontrolled proliferation of myeloid progenitor cells and a failure of proper cell differentiation. Chromosomal translocations of the KMT2A (MLL) gene are found in about 10% AMLs affecting both children and adults. Patients harboring MLL rearrangement (MLL-r) have a high relapse rate and poor overall survival, emphasizing an unmet need to understand MLL-r AML pathogenesis and develop new therapeutic means. Through a comparative analysis of super-enhancers in AML cell lines and primary samples, we discovered that MLL-r leukemia cells preferentially gain super-enhancer signals at the MEF2D gene. MEF2D is aberrantly activated in MLL-r AML patient samples and predicts poor disease outcomes, implying a potential oncogenic role of MEF2D. Indeed, depletion of MEF2D inhibits human MLL-r leukemia growth and induces profound differentiation. Mechanistically, MEF2D directly represses CEBPE, a master regulator of myeloid differentiation. CEBPE depletion could rescue the growth defect and cell differentiation induced by MEF2D loss. We also demonstrated that MEF2D is positively regulated by HOXA9, and downregulation of MEF2D is an important mechanism for DOT1L inhibitor-induced anti-leukemia effects. Interestingly, MEF2C, a target of MLL fusion oncoproteins, is by far the most studied MEF2 family member with essential roles in MLL-r AML. Our genetic, biochemical, and integrative genomic data shows that MEF2D and MEF2C, both upregulated in MLL-r AML, interact with each other, colocalize genome-widely, and co-regulate target gene expression. We are currently investigating the molecular mechanisms underlying the interdependent function between MEF2 paralogs in MLL-r AML. Collectively, our findings suggest that MEF2D is a novel transcriptional dependency in MLL-r AML and uncover the MEF2-CEBPE axis as a crucial transcriptional mechanism regulating leukemia cell self-renewal and differentiation block.

Disclosures
No relevant conflicts of interest to declare.
The Importance of Bone Marrow Lymphocyte Subtypes As Predicting Factors for Molecular Recurrence in Patients with Chronic Myeloid Leukemia after Discontinuation of Imatinib
Authors: Braga Arthur Gomes Oliveira , Pagnano Katia B , Campioni Marina Dal'Bó Pelegrini , Lopez Ana Beatriz P , Metze Konradin , Duarte Gislaine B O , Lorand-Metze Irene 
Published: November 2021

Abstract
Introduction: in recent years the feasibility of the discontinuation of tyrosine kinase treatment in chronic myeloid leukemia (CML) has been proven, and several clinical factors influencing the duration of treatment-free remission (TFR) after discontinuation have been studied.
Aim: we analyzed the influence of bone marrow (BM) lymphocyte subsets on the molecular recurrence after discontinuation of Imatinib (IM) in CML.
Methods: in a recent discontinuation study performed at our Institution (EDI-PIO trial) we assessed BM lymphocyte subsets before and after introduction of pioglitazone which was given 3 months before discontinuation of IM. Criterias for discontinuation were: patient in chronic phase at diagnosis, a minimum of 3 years on TKI and sustained molecular remission MR4.5 for at least 2 years. Lymphocyte populations studied: B, TCD8, TCD4, T CD4+CD8+ and T CD4- CD8- besides T naïve and memory, TCRαβ, TCRγδ, NK-t and NK cells. The influence of Sokal score at diagnosis, the duration of imatinib treatment together with the BM lymphoid subsets on the time of treatment-free remission (TFR) were examined by uni- and multivariate Cox regressions.
Results: we studied 30 out of 32 patients diagnosed between 1998 and 2013 that reached criteria for discontinuation that were included in EDI-PIO trial: 13 male and 17 female. Median age at diagnosis: 41 years (22-65). Median time of IM treatment: 116.3 months (38.2-209.3); 11 patients (36%) had a molecular recurrence in a median of 5,17 months (2.4-29.4). For patients remaining in TFR the median time of follow-up was 46 months (26.3-55.9). Median overall time of IM treatment (IM-Tr) was 65 months for patients recurring and 124 months for those remaining in TFR. In the univariate Cox regression a significant value was found for IM-Tr, higher percentages of T CD4+CD8+ and lower ones of TCRγδ lymphocytes at discontinuation. In the multivariate model only the T CD4+CD8+ remained.
Conclusion: discontinuation of IM is feasible in patients remaining in continuous MR4.5 for more than 2 years. A longer time of IM treatment and higher values of BM T CD4+CD8+ predict a lower risk of relapse.
Key words: chronic myeloid leukemia, imatinib, discontinuation, lymphocytes, pioglitazone

Disclosures
Pagnano: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pintpharma: Other: Lecture; EMS: Other: Lecture; Jansenn: Other: Lecture.
Pharmacokinetics-Guided Perioperative Replacement Therapy in Hemophilia a Patients
Authors: Meng Lei , Lv Jiaxin , Chen Bin , Li Qiang , Liu Zhuqin , Jiang Guiyong , Xun Yufang , Liu Fei , Chen Keyu , Liu Qifa , Sun Jing 
Published: November 2021

Abstract

Purpose: Pharmacokinetics(PK)-based prophylactic treatment has been proven to meet the pharmacoeconomics needs of patients with hemophilia to the greatest extent in recent years，but the way and significance of PK-guided perioperative replacement therapy remain unclear.
Methods :In this study, PK parameters (calculated by DAS software), including half-life and in vivo recovery(IVR), were used to guide individualized replacement therapy for surgical patients with hemophilia A. PK profiles were described by a two-compartment model. The collection of perioperative factor VIII(FVIII) plasma concentrations, factor consumption, and blood loss data was used to verify the efficacy of individualized programs.
Results :A total of 46 patients underwent 50 surgeries (median age: 32 years, median weight: 60.5 kg), all of which were major surgeries. The median half-life was 15.44h, and the median IVR was 2.29IU dl -1/IU kg -1. In total, 50 surgeries contributed with 528 plasma FVIII activity observations, of which 310 (58.71%) entered the target range. The median intraoperative blood loss of 43 surgeries was 446.9ml. No severe complications occurred during the perioperative period. Hematomas appeared after six surgeries, which have been resolved after treatment at discharge. Inhibitor developed in one patient and was transient. The median consumption of FⅧ concentrates during the perioperative period was 511.7U/kg, which reduced by 26.69% compared with the dosage based on weight (648.3U/kg, P＜0.001). During the perioperative period, the actual factor consumption was consistent with the PK-guided plan (P&gt;0.05). In addition, a negative correlation was found between intraoperative blood loss and immediate postoperative FVIII activity (r= -0.477, P=0.001).
Conclusion: PK-guided perioperative replacement therapy in hemophilia A patients can safely and effectively reduce the consumption of FⅧ concentrates.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
S1P/S1PR1 Signalis Required for Optimal T-Cell Pathogenicity to Induce Gvhd By RegulatingDrp1/mTOR Axis
Authors: Tian Linlu , Wu Yongxia , Choi Hee-Jin , Sui Xiaohui , Sofi Mohammed Hanief , Kassir Mohamed Faisal , Martin Paul J , Mehrotra Shikhar , Ogretmen Besim , Yu Xue-Zhong 
Published: November 2021

Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative option for the treatment of hematological malignancies, which is primarily mediated by donor immune cells. Acute graft-versus-host disease (aGVHD) mainly induced by transplanted donor T cells is a major and life-threating complication leading to severe "cytokines storm" and multiple organ damage, which contributes to high morbidity and mortality and thus limits the success of allo-HCT. Sphingosine-1-phosphate (S1P), a bioactive lysophospholipid, is synthesized from sphingosine by sphingosine kinase 1 (Sphk1) or Sphk2 and degraded by S1P lyase. S1P signal plays an important role in regulating biological functions and homeostasis of T lymphocytes, and thus has been considered as a therapeutic candidate against autoimmune disease. In current study, we demonstrated that Sphk1 but not Sphk2 is required for antigen-presenting cells (APC) to activate allogeneic T cells. Using murine allo-HCT models, we found that secretory S1P produced by Sphk1 in the recipients was required for the development of full-blown GVHD (Fig. 1 A-B). Consistently, S1PR1, a primary receptor for S1P, plays a critical role in the pathogenicity of donor T cells to induce GVHD (Fig. 1C). Using pharmacologic inhibitors, we demonstrated that specific inhibition of Sphk1 (PF543) or S1PR1 (W146) substantially attenuated GVHD while preserving graft-vs.-leukemia (GVL) effect (Fig. 1D). Mechanistically, S1P/S1PR1 signal facilitated T-cell activation and differentiation towards Th1/Th17 but away from Tregs (Fig. 1E) and also promoted T-cell migratory potential into GVHD target organs (Fig. 1F). S1P/S1PR1 signaling increased mitochondrial fission of pathogenic CD4 + T cells through PRKAA1 dependent Drp1 and phosphorylated S6 (pS6) activation (Fig. 1 G-H). Whereas CD8 + T cells were much less sensitive to S1P-S1PR1-PRKAA1-pS6/Drp1 axis, which likely contributed to the GVL maintenance when S1P/S1PR1 signaling is absent or inhibited (Fig. 1 D, G). Furthermore, clinical data demonstrated that patients with acute GVHD exhibited a comparable level of sphingosine but a significantly higher level of S1P, as compared to the patients without GVHD, suggesting a positive role of S1P in GVHD development in clinic (Fig. 1I). Finally, we validated the efficacy of inhibiting Sphk1/S1PR1 in GVHD prevention induced by human T cells in a xenograft model (Fig. 1J). Taken together, our results provide a rationale and novel mechanism of targeting Sphk1/S1PR1 in the prevention of GVHD and leukemia relapse after allo-HCT. This novel strategy may be translated in the clinic to benefit patients with hematologic malignancies.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.