bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune-Mediated Hematologic Complications of Checkpoint Inhibitors: A Review of the Literature
Authors: Sallam Omar , Riaz Irbaz Bin , Go Ronald S. 
Published: October 2019

Abstract
Background:
The incidence and types of hematologic complications from immune check point inhibitors are not well known. We conducted this review to describe immune-mediated hematologic complications reported in clinical trials, case series, and case reports.
Methods:
A pre-defined comprehensive search strategy was used to identify case reports, case series, and clinical trials using PubMed. Any study that reported hematologic complications was included. Data were extracted for demographic characteristics and occurrence of immune-mediated hematologic complications. We pooled the data to calculate the frequency of immune-mediated hematologic adverse effects.
Results:
A total of 689 of studies were retrieved using the search criteria and 75 were included in the analysis (31 case reports and case series and 44 clinical trials). There were 44 patients reported having immune-mediated hematologic complications, 4 of them in clinical trials. The complications included aplastic anemia, autoimmune hemolytic anemia, cryoglobulinemia, graft versus host disease, hemophilia A (acquired), immune neutropenia, immune thrombocytopenia, macrophage activation syndrome, myelodysplastic syndrome, pure red cell aplasia, and thrombotic thrombocytopenic purpura. However, the overall rates were very low, ranging from 1-2.2% in clinical trials. Immune thrombocytopenia was the most common (29.5%), followed by autoimmune hemolytic anemia (15.9%), and immune neutropenia (13.6%). Immune-mediated hematologic complications were reported in all classes of checkpoint inhibitors including anti-programmed cell death protein 1 (nivolumab and pembrolizumab), anti-programmed death ligand 1 (avelumab and durvalumab), and anti-cytotoxic T-lymphocyte-associated protein 4 inhibitors (ipilimumab and tremelimumab). Among patients reported in case reports and case series, the median age was 57 years (range, 29-85) and most were males (52.9%). The majority of the complications occurred in patients treated with ipilimumab (38.8%), nivolumab (27.7%) and pembrolizumab (16.0%). The onset was usually within the first week of receiving the first dose but could occur up to 17 months after drug initiation. Indefinite discontinuation of the immunotherapy was the mainstay of treatment resulting in resolution of complications in the majority (74.5%) of the patients. Two patients were re-challenged with the same checkpoint inhibitor and one experienced a relapse of immune cytopenia (autoimmune hemolytic anemia).
Conclusion:
Immune-mediated hematologic complications associated with checkpoint inhibitors are rare. They are usually reversible after discontinuation of such treatment. Relapses may occur with re-challenge.

Disclosures
No relevant conflicts of interest to declare.
Neutrophil KLF2 Regulates Arterial and Venous Thrombosis
Authors: Nayak Lalitha V. , Lapping Stephanie , Maiseyeu Andrei , Schmaier Alvin H. , Jain Mukesh 
Published: October 2019

Abstract
Experimental, clinical and pathological studies support an important link between inflammation and thrombosis. Although accumulating evidence suggests that cells of the innate immune system contribute to the thrombotic process, the identity of nodal molecular determinants operative in immune cells remains poorly understood. Our previous work in mice bearing global deletion of the transcription factor KLF2 identifiedthis factor as a critical mediator of thrombosis). Here, using cell-specific KLF2 deleted murine models (endothelial, platelet, and myeloid- deleted KLF2) we identify myeloid KLF2 as the major determinant of thrombosis. Complete blood counts and coagulation assays in myeloid KLF2 deleted mice (MY-K2-KO) were similar to those in control LysM cre mice. Using two models of vascular thrombosis (carotid artery thrombosis assay, Rose Bengal model and complete inferior vena cava ligation model of venous thrombosis) we observed a robust prothrombotic phenotype in the MY-K2-KO mice as compared to control Cre mice. As LysM Cre deletes in both neutrophils and monocyte/macrophages, we next sought to determine whether one subset was dominantly responsible for the observed phenotype. Adoptive transfer of KLF2-KO neutrophils in control mice conferred both the arterial and venous pro-thrombotic phenotype. Conversely, neutrophil depletion with Ly6G antibody (>90% depletion achieved) reversed the prothrombotic phenotype in MY-K2-KO mice. By contrast, depletion of monocytes/macrophages using clodronate liposome injection did not affect arterial or venous thrombosis. Next, we evaluated the effect of KLF2 deficiency on critical neutrophil functions that may contribute to the pro-thrombotic phenotype. As compared to controls, MY-K2-KO neutrophils demonstrated more pronounced recruitment to the endothelium. In microflow chamber assays, MY-K2-KO neutrophils showed decreased rolling and increased P-selectin induced adhesion. The importance of this was affirmed by the observation that adoptive transfer of MY-K2-KO neutrophils incubated with PSGL-1 antibody was unable to generate a prothrombotic phenotype in control mice. In addition, MY-K2-KO neutrophils demonstrated enhanced neutrophil extracellular traps generation associated with increased myeloperoxidase and neutrophil elastase expression. And finally, MY-K2-KO neutrophils (but not monocytes) demonstrated increased tissue factor expression and activity. Collectively, these studiesidentify neutrophil KLF2 as a critical determinant of both arterial and venous thrombosis and suggest that modulation of neutrophil KLF2 may be a fruitful approach to the management of thrombosis.

Disclosures
Schmaier: Alnylam: Research Funding; Biomotiv: Consultancy; Cleveland Clinic Foundation: Research Funding; Temple University: Patents & Royalties; Enzyme Research Laboratories: Honoraria; Shire: Consultancy, Honoraria, Research Funding.
Sequential Infusion of Anti-CD22 and Anti-CD19 Chimeric Antigen Receptor T Cells Following Autologous HSCT in Patients with B-NHL
Authors: Cao Yang , Wang Na , Wang Gaoxiang , Xiao Yi , Huang Liang , Li Chunrui , Xiao Min , Zhang Tongcun , Zhang Yicheng , Zhou Jianfeng 
Published: October 2019

Abstract

Salvage chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) is the standard treatment for the patients with chemotherapy sensitive relapsed or refractory B-NHL. However, more than half of patients will ultimately relapse. To improve long-term remission rate, we administered adoptive T-cell immunotherapy after HSCT. Based on the findings that CD19/CD22 dual antigen targeting have been demonstrated to be a promising approach for overcoming antigen escape relapse, we conducted an open-label, single-center and single-arm pilot study of sequential infusion of anti-CD22 and anti-CD19 CAR-T cells following autologous HSCT. We aimed to evaluate its safety and efficacy in patients with relapsed, refractory and high-risk B cell lymphoma. This trial is registered with ChiCTR, number ChiCTR-OPN-16009847.
Between December 2016 and March 2018, 20 patients were enrolled in this clinical trial, with a median age of 33 years (range, 24-61 years). Of these 20 treated patients, 2 had PMBCL, 4 had tFL,14 had DLBCL, 70.0% (14/20) had received at least three previous therapies. 50.0% patients (8/16) harbor a TP53 mutation. At baseline assessment (prior to conditioning), 3 participants had a CR, 8 had a PR, 8 had a PD, 1 had a SD. All patients received bis-chloroethyl nitrosourea, etoposide, Ara-C, and melphalan, CD22 and CD19 CAR T cells were infused 2 to 7 days after stem cell infusion. The median anti-CD22 and anti-CD19 CAR-T cells dose per kilogram of body weight were 4.0× 106 (range, 1.0-10.0×106) and 4.2× 106 (range, 1.8-10.0×106) respectively. Normal HSCT-associated neutrophil engraftment within 20 days in all 20 patients was observed. 11/20 (50.5%) patients experienced cytokine release syndrome and no patient had severe CRS (grade 3-4). Neurologic events occurred in 2 (10.0%) patients. At 3 months, there was a 90.0% remission rate (95% CI ,68.3-98.8) with 85.0 % complete remissions (CRs) and 5.0% partial remissions (PRs) accessed by PET-CT. The duration of responses currently ranges from 3.7 months to19.1 months. All patients (17/20) who achieved CRs are ongoing, and the current median duration of all CRs is 13.2 months.
Our results indicated that patients with relapsed, refractory and high-risk B cell lymphoma who received sequential infusion of anti-CD22 and anti-CD19 CAR-T cell therapy following HSCT had high rates of durable remission, with safety profile. Anti-CD22 and Anti-CD19 CAR-T cell therapy following HSCT may become a useful treatment approach for relapsed , refractory B cell lymphoma and high-risk B cell lymphoma.

Disclosures
No relevant conflicts of interest to declare.
Compound Application of Thalidomide and Recombinant Human Interferon-α-1b, Interleukin-2 in Different Disease Status of Acute Myeloid Leukemia a Multi-Center Prospective Study of a New Combination of Old Drugs
Authors: Chen Lin , Mi Ruihua , Wei Xudong , Ying Qingsong , Yuan Fangfang , Liang Lijie , Li Mengjuan , Liu Delong , Song Yongping 
Published: October 2019

Abstract
Objectives: The aim of this study was to investigate the therapeutic effects of combinational application of thalidomide and recombinant human interferon-α-1b, interleukin-2 (the ITI scheme) in treating acute myeloid leukemia (AML) in different settings.
Methods: AML patients with different disease states were categorized into three groups and received treatments following the ITI scheme. Group A consisted of relapsed or refractory AML patients (R/R-AML) and primary AML patients who were unable to receive chemotherapy. Group B included patients with morphologically complete remission (CR) and consistently positive minimal residual disease (MRD). Group C is composed of AML patients with initial complete remission and negative MRD. The CR rate, partial remission rate, MRD status, quality of life, and long-term survival were observed accordingly. ITI scheme is administrated as: IFNα-1b 60ug/d qod ih, IL-2 1001 million units/d qod ih, Thalidomide 200mg qn po. the Compound Salvia Tablets were recommended orally taken in order to prevent deep venous thrombosis.
Results: a. With a total response rate of 30% in 60 AML patients of Group A, 4 CR, 6 CRi and 8 PR, who maintained good quality of life with no transfusion with red blood cells or platelet components any more (Table1).The MRD of 13 cases (72.2%) turned negative among 18 patients in Group B. MRD levels turned unmeasurable in seven patients receiving a conventional dose of ITI regimen, and MRD levels significantly decreased in three patients. MRD levels turned unmeasurable after receiving a higher dose of ITI regimen in two patients, and one patients MRD level decreased. Five patients failed to this regimen and suffered a hematologic recurrence. The efficacy is positively correlated with level of MRD level before ITI administration. 81.8% (9/11) patients responded to ITI regimen in whose MRD level ≤1.0%. However, only 57.1% (4/7) responded in whose MRD≥1.0%. 3 patients responded to a extra dose of ITI after no response to a normal dose. Indicated that the efficacy of this regimen is positively correlated with the dose of the regimen.(Table 2)In group C of 88 patients, 11 patients failed to maintain MRD negative, and the relapse rate was 12.5% (Table 3and figure 1).
Conclusions: The ITI scheme can provide a new, effective, and affordable treatment option for AML patients that are intolerant to conventional chemotherapy, including R/R-AML patients, patients with CR status but MRD positive, and patients after initial CR.

Disclosures
No relevant conflicts of interest to declare.
Abnormal Coagulation Function in Chimeric Antigen Receptor T Cell Treatment of Hematologic Malignancies
Authors: Qi Kunming , Cheng Hai , Cao Jiang , Chen Wei , Qiao Jianlin , Zeng Lingyu , Li Zhenyu , Xu Kailin 
Published: October 2019

Abstract
Chimeric Antigen Receptor T cell( CAR-T) is an effective treatment for refractory recurrent hematologic malignancies nowdays. However, CAR T cells can potentially damage normal tissues by specifically targeting a tumor-associated antigen that is also expressed on those tissues. Cytokine release syndrome (CRS), a systemic inflammatory response caused by cytokines, is the most common type of toxicity, including fever, hyoxemia, pain and so on. In our study, we found 6 cases abnormal coagulation function which was not very common complication after CAR-T infusion. 4 cases relapsed/refractory acute B lymphoblastic leukemia(B-ALL), including 2 female 53 and 45 years old, 2 male 20 and 6 years old. 1 case multiple myeloma(MM), female 65 years old and 1 case relapsed/refractory diffuse large B-cell lymphoma (DLBCL), male 17 years old. After conditioning chemotherapy with fludarabine and cyclophosphamide, CAR-T cells were infused into patients. In these cases, female 65 years old B-ALL patient had the most severe cytokine release reactions, multiple organ function damage, and abnormal coagulation function that prothrombin time (PT) and activated partial thromboplastin time (APTT) were prolonged and reached a peak (Too long to detect) on the 14th day after CAR-T infusion, while fibrinogen (FIB) was reduce d (peak on the 14 day, 0.328g/L) and D-Dimer, fibrinogen degradation products (FDP) significantly increased (peak on the 12th day, 28.7ug/mL and more than 10mg/L respectively). After positive hemostasis and other treatments with amperenic acid, vitamin K1 and so on, the level of PT, APTT, FIB, etc were returned to normal on the 19thday. The other 5 patients went through the same process, only slightly. Patients with severe abnormal coagulation function were prone to bleed and even life-threatening, and giving active treatment, finally they all recovered. For the first time, we reported the abnormal coagulation function after CAR-T infusion in hematologic malignancies.

Disclosures
No relevant conflicts of interest to declare.
Synergic Effect of Histone Deacetylase Inhibitor Chidamide with Doxorubicin on Diffuse Large B-Cell Lymphoma with Double BCL2/MYC Expression
Authors: Fang Ying , Liu Feng , Zhao Wei-li 
Published: October 2019

Abstract
Introduction
Diffuse large B-cell lymphoma (DLBCL) represents the most common neoplastic disorder of B-lymphocytes. Although great progress has been made in the treatment of DLBCL, patients with double BCL2/MYC expression have been reported to be refractory to R-CHOP regimen. In our clincial trial (NCT02753647), we found that chidamide, a histone deacetylase inhibitor, plus R-CHOP elicits favorable outcome, especially for DLBCL patients with double BCL2/MYC expression. Therefore,we set out to investigate the underlying mechanism.
Methods
Core needle biopsy of tumor samples of DLBCL with double BCL2/MYC expression were transplanted into immunodecient (NOD-SCID) mice to establish patient-derived xenograft (PDX) models. Heterotopic PDX models were maintained by passaging tumor tissues from mouse to mouse. Chidamide and doxorubicin, either alone or in combination, were applied to PDX models with low passage numbers (<10) to preserve the genetic integrity of the parental tumors. The dose and administration schedule were as follows: doxorubicin 0.6mg/kg twice a week, chidamide 12.5mg/kg/day for two weeks. RNA-seq and ATAC-seq were performed to achieve an integrative transcriptomic and epigenomic anlaysis of PDX models on Day 7 and Day 14 of treatment. The study was approved by Shanghai Rui Jin Hospital Review Board and written informed consent were obtained from patients in accordance with the Declaration of Helsinki.
Results
We observed significant growth inhibition of xenografted tumors treated with chidamide combined with doxorubicin, as compared to those of the single treatment. RNA-seq analysis revealed that chidamide and doxorubicin synergistically regulate a set of genes associated with B-cell differentiation and multiple signaling transduction pathways involved regulation of BCL2 and MYC, including the IL6-JAK-STAT and PI3K-AKT-MTOR pathways. Furthermore, accessible chroamtin region profiling by ATAC-seq indicated that chidamide and doxorubin co-repress distal cis-regulatory elements (i.e. enhancers) associated with lymphocyte development.
Conclusions
As a histone deaceltylase inhibitor, chidamide is able to synergize with doxorubicin to inhibit the growth of DLBCL expressing high levels of MYC and BCL2 in PDX models. This is, in part, due to remodeling of the landscape of accessible chromatins in lymphoma cells. Our study provides insight into how epigenetic therapeutics can sensitize DLBCL with double BCL2/MYC expression to conventional chemotherapy.

Disclosures
No relevant conflicts of interest to declare.
Antiplatelet Therapy for Patients with Hemophilia after Percutaneous Coronary Intervention
Authors: Xie Peter , Malik Devin , Kuriakose Philip 
Published: October 2019

Abstract
Background:
The incidence of coronary artery disease is increasing in hemophilia patients as their life expectancy improves. However, there are limited evidence-based studies available, and most current guidelines for antiplatelet therapy in patients with hemophilia are largely based on expert opinions. The assessment of benefit and risk of using antiplatelet therapy in these patients remains a clinical challenge.
Aim:
This study reports our institution's clinical outcome of patients with inherited hemophilia who underwent antiplatelet therapy for percutaneous coronary intervention in the last 10 years.
Methods:
Retrospective chart review from a single hospital for 10 calendar years of patients with inherited hemophilia A or B and a diagnosis of coronary artery disease who received oral antiplatelet agents.
Results:
See data Table 1 below.
Conclusions:
The usage of antiplatelet therapy for coronary artery disease as well as dual-antiplatelet therapy post percutaneous coronary intervention in patients with Hemophilia A or B carries a realistic risk of bleeding. However, outside of one patient with traumatic laceration of the liver, we did not identify any life threatening bleeding events in our patients who were placed on antiplatelet therapy. Since all subjects had no more than mild to moderate factor deficiency, it would be important to see how patients with severe deficiency would do on such therapy. Further studies are needed in the future to provide evidence and clarify the overall risk versus benefit of antiplatelet therapy in hemophilia patients with coronary artery disease.

Disclosures
No relevant conflicts of interest to declare.
Most CD5+ B Lymphocytes Secrete IL-10 in Autoimmune Hemolytic Anemia/Evans Syndrome Patients
Authors: Xing Limin , Zhao Manjun , Zhu Hongli , Shao Zonghong 
Published: October 2019

Abstract

Objective:
Autoimmune hemolytic anemia (AIHA)/Evans syndrome is a form of immune-related cytopenia characterized by autoantibodies directed against red blood cells. A subset of B lymphocytes expressing CD5 is found in patients with AIHA/Evans syndrome. Previous studies have shown that the number of CD5+ B lymphocytes is correlated with the severity of AIHA/Evans syndrome. IL-10 can be induced in various types of human B cells, including naive, memory, and CD5+B cells, following B-cell activation by Th-cell-dependent and TLR-dependent signals. This study is to investigate the secretion function of CD5+ B lymphocytes in AIHA/Evans syndrome (ES) patients.
Methods:
25 untreated AIHA/ES patients, 28 remission AIHA/ES patients and 25 healthy controls (HCs) were enrolled in this study. The quantity of CD5+B lymphocytes which produce interleukin-10 (IL-10) (CD5+IL-10+) were detected by flow cytometry. CD5+ B lymphocytes were sorted from Peripheral blood (PB) by CytoFLEX Flow Cytometer. The expression of IL-10 mRNA in CD5+ B cells were measured by real-time PCR (RT-PCR). The concentrations of IL-10 in serum were detected by Enzyme-linked Immunosorbent assay (ELISA).
Results:
The percentage of CD5+IL-10+B cells in CD5+ B lymphocytes in newly diagnosed patients was 82.18±14.78%, which being significantly higher than that of remission AIHA/ES patients (56.68±24.39%) and HC (51.90±22.95%)(p<0.05). The percentage of CD5+IL-10+ B cells in CD5+ B lymphocytes in newly diagnosed patients was negatively correlated with their serum level of hemoglobin, C3 (P<0.05) and positively correlated with their serum level of LDH, TBIL and IBIL (P<0.05).
The expression level of CD5+ B lymphocytes IL-10 mRNA in newly diagnosed patients (49.34±22.84) was higher than that of remission patients (3.97±3.83) and HC (1.78±1.66) (P<0.05).
The concentration of IL-10 in serum in newly diagnosed patients (4.01±1.54 pg/ml) was lower than that of remission patients (5.08±1.72pg/ml) and HC (5.70±1.60pg/ml) (P<0.05).
Conclusions:
Most CD5+ B lymphocytes secrete IL-10 in AIHA/Evans patients and are positively correlated with the severity of the disease. The increased quantity of CD5+IL-10+ B cells and the decreased cytokines-secreted level maybe involved in the occurrence of AIHA/Evans syndrome.

Disclosures
No relevant conflicts of interest to declare.
The Pan-PIM Kinase Inhibitor LGB321 Strongly Increases Ibrutinib Effects in CLL, By Blocking Anti-Apoptotic Pathways and Microenvironmental Interactions
Authors: Decker Sarah , Saleem Shifa , Kissel Sandra , Zwick Anabel , Aumann Konrad , Zirlik Katja , Duyster Justus , Dierks Christine 
Published: October 2019

Abstract
Despite remarkable anti-tumor activity of ibrutinib in CLL, some patients develop resistance due to acquired mutations. By adding drugs which target survival pathways and the CLL protective microenvironmental interactions, we aim to increase ibrutinib efficacy and to prevent ibrutinib resistance. The three PIM kinases are involved in important disease mechanisms in CLL, with PIM1 regulating CXCR4 surface expression impacting the interaction with the protective microenvironment, and PIM2/3 affecting the apoptotic machinery by regulating BAD.
Here, we investigated the effect of the Pan-PIM kinase inhibitor LGB321 in CLL in vitro and in vivo and its cooperative effect with ibrutinib. LGB321 was highly effective in inducing apoptosis in primary CLL cells, independent of prognostic factors or microenvironmental interactions, and reduced pBAD and total BAD protein levels in CLL. In vitro combination of ibrutinib and LGB321 demonstrated strong additive effects with doubled apoptosis rates compared to single treatment. Further, LGB321 treatment blocked the CXCR4/CXCL12 axis by dephosphorylating the CXCR4 receptor on Ser339, by reducing total CXCR4 protein levels, and by blocking the externalization of the CXCR4 receptor. Concordantly, LGB321 blocked CXCR4 functions regarding migration towards a CXCL12 gradient and homing of LGB321-pretreated primary CLL cells towards the bone marrow of NOG mice.
In vivo experiments confirmed the efficacy of LGB321 in 5 different CLL xenograft studies. Transplantation of primary CLL cells into NOG mice and treatment with LGB321 for 2 weeks strongly reduced WBC counts, spleen size and spleen infiltration with human CLL cells in all 5 CLL cases, and blocked BAD as well as CXCR4 phosphorylation also in vivo.
Xenograft studies combining ibrutinib with LGB321 demonstrated much faster reduction of WBC counts than ibrutinib single treatment and strongly reduced disease burden in the double treated mice, confirming the cooperative effects of those two inhibitors also in vivo.
Our results demonstrate that LGB321 might be an effective treatment option for CLL patients by impairing PIM2/3 mediated CLL-cell survival, and by blocking the PIM1/CXCR4-mediated interaction of CLL cells with the protective microenvironment. Furthermore, LGB321 enhances ibrutinib treatment effects and might help to increase its efficacy and to avoid the development of ibrutinib resistance.

Disclosures
No relevant conflicts of interest to declare.