bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multicentre Retrospective Analysis of Rituximab Use in the Treatment of Steroid Resistant Autoimmune Haemolytic Anaemia in Ireland,
Authors: Maung Su Wai , O'Keeffe Denis , Leahy Maeve , O'Leary Hilary M , Khan Irfan , Cahill Mary , Galligan Oonagh , Murphy Philip , Krawczyk Janusz , McPherson Suzanne , Jackson J F , Ryan Mary , Hennessy Brian , Burke Aine C , Enright Helen , McHugh Johnny 
Published: October 2019

Abstract
Abstract 3171
Autoimmune haemolytic anaemia (AIHA) is characterised by severe haemolysis due to development of auto antibodies directed against patient's own red cells. Rituximab is a chimeric monoclonal antibody that specifically depletes B cells by targeting CD20 on both immature and mature B lymphocytes We evaluated the use of Rituximab in patients with AIHA who are refractory to conventional Immunosupression in 5 centres in ireland.

Methods:
24 cases of AIHA from five centres in the Republic of Ireland were identified who were treated with Rituximab at the standard dose of 375mg/m2 weekly for four weeks. All patients had received prior therapy with steroids and 50% of patients received two or more courses of Immunosupression. One patient had splenectomy prior to Rituximab. Five patients had an underlying lymphoproliferative disorder and two had a myeloproliferative neoplasm. Response was assessed at 1,3,6,12,36, 48 and 60 months. Medium duration of follow up was 34 months. Response was defined as normalisation of Haemoglobin concentration and haemolytic parameters reticulocyte count, bilirubin and lactate dehydrogenase (LDH).
Overall response to Rituximab was 83.3% at 28 days post treatment. Four patients responded to Rituximab in combination with other Immunosupression such as Azathioprine or low dose steroids. Medium response duration was 11.5 months. Sustained response at 1 year, 2 years and 4 years post treatment were 60%, 55% and 30% respectively. Rituximab was well tolerated without significant complications in the majority of patients. One patient developed neutropenic sepsis. One patient received second course of Rituximab after relapse within a year and had sustained response of over two years after the second course.

Conclusion:
Rituximab is a safe and effective treatment for patients with AIHA who are resistant to steroids.The majority of patients will initially respond but a significant number will gradually relapse over time. Re-treatment with rituximab maybe considered on relapse.

Disclosures:
No relevant conflicts of interest to declare.
The Presence of An Internal Tandem Duplicate of FlT3 Receptor (ITD) Is An Unfavorable Prognostic Factor on the Outcome of Adult Patients with Acute Myeloid Leukemia (AML) Autografted in First Remission (CR1) Only in the Absence of An NPM1 Mutation,
Authors: Gorin Norbert C. , Labopin Myriam , Meloni Giovanna , Pigneux Arnaud , Esteve Jordi , Sanz Miguel A. , Bosi Alberto , Arcese William , Milone Giuseppe , Polge Emmanuelle , Mohty Mohamad 
Published: October 2019

Abstract
Abstract 4139
The prognosis of patients with AML harboring the FlT3 ITD is known to be poor in those patients treated with chemotherapy alone. However, it remains uncertain whether this abnormality has also an impact on outcome following high dose intensification and autologous stem cell transplantation (ASCT).
We addressed this question using the EBMT data base: we initially reported on a total of 134 patients in 2010 (Blood 2010, 3356a). Following further queries, we have now extended our study to a total of 357 patients with AML autografted in CR1 between January 2000 to December 2009, and in whom the information on the presence or the absence of FlT3ITD was available. 258 (136 with a normal karyotype) patients were ITD negative and 99 (63 with a normal karyotype) were ITD positive. 96% of the patients received peripheral blood as a source of stem cells. The median follow up was 30 m. (range, 1–118).
Patients who were ITD positive had higher white cell counts at diagnosis (54 vs. 12.5 109/L; p<0.0001) and had a higher proportion of slow remitters (needing more than one induction course to achieve CR) (22% vs. 11%; p=0.04). Interestingly, patients who were ITD positive were more frequently found to be NPM1 mutated (59% vs. 40%; p=0.03).
In the univariate analysis, Leukemia-Free Survival (LFS) at 3 years was significantly lower in patients who were ITD positive (34±5% vs. 52±4%; p=0.001) and the relapse incidence was higher (58±5% vs. 42±4%; p=0.002). The Non-Relapse Mortality (NRM) rate was similar (8±3% vs. 6±1%; p= 0.7).
By multivariate analysis, the only unfavorable prognostic factors for outcome were failure to achieve CR with more than one induction course (slow remitters), and the presence of an ITD, which were associated with higher relapse incidence (p= 0.006; p=0.03) and lower LFS (p=0.05; p=0.005).
In this series, it was interesting to observe that the only group with a significantly lower LFS in univariate analysis, was the group of patients who were FlT3ITD positive without NPM1 mutation (23±11% vs. 56±6% for FLT3ITD negative/NPM non-mutated, 46±8% for FLT3ITD negative/NPM mutated and 48±13% for FLT3ITD positive /NPM mutated; p=0.03).
We conclude that in the context of autografting for AML in CR1, the presence of a FLT3ITD is an unfavorable prognostic factor only in less than 50% of the patients corresponding to those with the absence of a NPM1 mutation. This study helps to better define the population of patients with AML that would benefit most from intensification with autologous stem cell transplantation.

Disclosures:
No relevant conflicts of interest to declare.
Health Care Resource Utilization and Cost in Patients with Chronic Myeloid Leukemia in a Privately Insured Patient Population in the United States,
Authors: Iyer Shrividya , Trask Peter C , Siu Gordon , Mardekian Jack 
Published: October 2019

Abstract
Abstract 4220

Objective:
To estimate health care resource use and related costs in patients with chronic myeloid leukemia (CML).

Methods:
A retrospective cohort analysis was conducted using the Thomson Reuters MarketScan Commercial Claims and Encounters and Medicare Supplemental databases, which is composed of medical and pharmacy claims for approximately 43 million beneficiaries. Cases with at least 2 medical claims associated with a diagnosis of CML (ICD-9-CM code: 205.1) between Jan 1, 2002 and Dec 31, 2009 were extracted from the database. Index date was defined as the date of the first diagnosis of CML. A minimum of six months pre-index and 12 months post index enrollment was required. Disease and non-disease related utilization and costs were estimated. Resource utilization was calculated from index date to last available claims data point and then annualized per patient.

Results:
A total of 2583 patients were identified with an average follow up of 2.7 years. The mean age of the cohort was 59 years, and 45% were female. Proportions of patients having at least one inpatient, outpatient, and ER CML related visit were found to be 32.4%, 94.9%, and 15.1%, respectively. The average number of visits (standard deviation [SD]) per patient year was found to be 1.3 (1.4) and 1.6 (2.4) for inpatient and ER visits, respectively, among patients who had at least one visit. Average number (SD) of outpatient and office visits per patient year was found to be 40.6 (34.5) and 15.3 (11.6), respectively. Average number of prescriptions filled for CML was 3.3 per patient year. Disease-related health care costs ($23,166) constituted 36% of the total health care costs ($64,441) per patient year. Inpatient ($24,462 ± 77,429), outpatient ($24,391 ± 48,439), and prescription drug costs ($15,588 ± 18,327) accounted for 38%, 38%, and 24% of the total health care costs, respectively. CML drug costs accounted for 73% of the prescription drug costs.

Conclusion:
Cost burden of chronic myeloid leukemia are substantial. Effective disease management could help reduce resource utilization and cost while improving overall disease outcomes.

Disclosures:
Iyer: Pfizer: Employment. Trask:Pfizer Inc (at time of work completion): Employment; Sanofi: Employment. Mardekian:Pfizer Inc: Employment, Equity Ownership.
Nelarabine Is Safe and Effective In Adult Relapsed or Refractory T Cell Acute Lymphoblastic Leukemia (T-ALL) and Lymphoblastic Lymphoma (T-LBL): The Bologna Experience
Authors: Papayannidis Cristina , Iacobucci Ilaria , Abbenante Mariachiara , Lonetti Annalisa , Guadagnuolo Viviana , Ferrari Anna , Ottaviani Emanuela , Testoni Nicoletta , Baldazzi Carmen , Curti Antonio , Parisi Sarah , Clissa Cristina , Baccarani Michele , Martinelli Giovanni 
Published: October 2019

Abstract
Abstract 4250

Background.
Nelarabine (N) is approved for the treatment of T-ALL and T-LBL that have not responded to or has relapsed after treatment with at least 2 chemotherapy regimens.
Aim. To evaluate safety profile and efficacy of N as savage therapy in 16 adult relapsed or refractory T-ALL or T-LBL.

Methods.
After obtaining an informed consent, 16 patients (median age 33 years, range 19–45, M/F= 13/3) affected by T-ALL (n=10) and T-LBL (n=6) received savage therapy with N (median cycle=1, range 1–3), administered at standard adult dosage (1500 mg/sqm on days 1, 3 and 5, every 21). Four patients were primary resistant to induction treatment, 7 patients were relapsed after two previous chemotherapy regimens (including allogeneic BMT in 4 cases and autologous SCT in 1 case); the remaining 6 patients had a molecular relapsed disease (MRD positive). Molecular characterization was performed, including NOTCH and WT-1 genes mutational status. GEP analysis, according to Ferrando A. stratification (Cancer Cell 2002), is still ongoing.

Results.
Currently, 12 out of 16 patients are evaluable, due to a too short follow up in the other 4 cases. Seven out of 12 patients obtained a complete remission (CR) (5 T-ALL 2 T-LBL);a partial remission (PR) was documented in 2 cases, with an overall response rate (ORR) of 75%. Median duration of CR was 10 weeks (range 2.8–54+). Among these, 2 out of 4 patients in molecular relapse reached a molecular CR and underwent an allogenic BMT (currently in CR after a median follow up of 12 months). Extra- hematological toxicity, not clearly related to the drug, occurred in 3 cases, determining, a complete and irreversible paraplegia, a condition of mental confusion, and a peripheral neuropathy, respectively.

Conclusions.
N showed a strong efficacy also in cases with low levels of residual disease, in addition to a good safety profile. Neurological toxicity needs to be strictly monitored.

Acknowledgments.
European LeukemiaNet, AIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, PRIN 2008, PRIN 2009, Ateneo RFO grants, Project of integrated program (PIO), Programma di Ricerca Regione – Università 2007 – 2009.

Disclosures:
Baccarani: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Martinelli:Pfizer: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.
Lycorine Modulates the Expression of p21 Via a p53-Independent Pathway in HL-60 Cells
Authors: Liu Jing , Wang Shu-Ling , Fang Lin , Ye Mao , Sun Zhi-Wei , Li Lv , Wang Zi , Yan Hui-Wen , Luo Sai-Qun , Chen Hui-Yong , An Xiuli , Hu Wei-Xin 
Published: October 2019

Abstract
Abstract 4297
Leukemia is one of the most life-threatening cancers today, and acute promyelogenous leukemia is a common type of leukemia. We have previously shown that lycorine, a natural alkaloid extract from Amaryllidaceae, exhibited anti-leukemia effects in vitro and in vivo. Lycorine treatment of HL-60 cell arrested cell cycle at G2/M phase and induced apoptosis. In the present study, we sought to explore the molecular mechanisms for the anti-leukemia action of lycorine. Gene chip analysis revealed that lycorine treatment of HL-60 cells induced more than 9 fold increase of p21, a cyclin-dependent kinase inhibitor, whose expression is mainly regulated by p53. Since HL-60 cells are p53 null, the above findings suggest that lycorine activates p21 expression through p53-independent pathway. To further explore the alternative pathways for the activation of p21 induced by lycorine, we examined the effect of lycorine on the expression of Rb, pRb, E2F, c-Myc and HDACs which have shown to regulate p21 expression. We show that expression of pRb (ser780) and c-Myc was down-regulated, Rb and E2F were up-regulated, while the expression of HDAC1 and HDAC3 was not changed. Together these findings suggest that lycorine exerts its anti-leukemia effect by activating p21 expression via pRb/E2F and c-Myc pathways.

Disclosures:
No relevant conflicts of interest to declare.
Artificial Antigen Presenting Cells Expand NY-ESO-1 Antigen-Specific CD8+ T Cells From Patients with Melanoma
Authors: Maus Marcela V. , Riviere Isabelle , Borquez-Ojeda Oriana , Wang Xiuyan , Yuan Jianda , Merghoub Taha , Plotkin Jason , O’Reilly Richard J. , Wolchok Jedd D , Sadelain Michel 
Published: October 2019

Abstract
Abstract 4309
The NY-ESO-1 antigen is an attractive prototype cancer-testis (CT) antigen because it is expressed in a wide variety of tumors, including myeloma, melanoma, and synovial cell sarcoma, among others, but has restricted expression in normal tissues (testis and placenta). Based on our previous experience with 3T3-based artificial antigen presenting cells (AAPCs) in expanding influenza and CMV-specific T cells, we hypothesized that AAPCs expressing the NY-ESO-1 antigen and optimal costimulatory molecules would efficiently expand NY-ESO-1 specific T cells for potential use as adoptive immunotherapy. Accordingly, AAPCs were transduced to express the common MHC allele HLA-A*0201, beta2-microglobulin, and the full-length NY-ESO-1 protein, together with the T cell costimulatory ligands CD58, CD54, and CD80. These A2/NY-ESO-1 AAPCs expanded NY-ESO-1 specific T cells from normal donors after prolonged culture (4 weeks). In patients with melanoma who had detectable NY-ESO-1 antibodies, AAPC stimulation of PBMC expanded NY-ESO-1 antigen-specific CD8+ T cells approximately 3–4 logs in 3 weeks. These expanded T cells were functional in that they lysed peptide-pulsed targets (T2 cells) and native melanoma tumor targets (SK Mel 37). Expanded CD8+ T cells also produced interferon-gamma, MIP-1 beta, TNF-alpha and CD107a (but not IL-2) in response to antigen, indicating a polyfunctional response. We are currently performing scale-up experiments and pre-clinical validations of these AAPCs to embark on a clinical trial of adoptive cell therapy of NY-ESO1-specific T cells in patients with NY-ESO1-expressing tumors.

Disclosures:
No relevant conflicts of interest to declare.
Clinical Grade Generation of T-Helper-1-Driven Polyclonal T-Cell Populations for Adoptive Immunotherapy Against Tumor Associated Antigens
Authors: Kayser Simone , Boß Cristina , Icheva Vanya , Stevanovic Stefan , Lang Peter , Handgretinger Rupert , Feuchtinger Tobias F. 
Published: October 2019

Abstract
Abstract 4314
Adoptive T cell therapy has been shown an option to treat patients with malignancies. In contrast to vaccinations, T cells for adoptive T-cell therapy are generated ex vivo to be re-infused into the recipient. This enables treatment of immunocompromized hosts and use of allogeneic T cells to exploit graft versus tumor effects. Adoptive T-cell therapy involving CD4+ T-helper cells (Th cells), intends to induce sustained T-cell responses in vivo. The Th1 cytokine interferon-gamma (IFN-γ) has not only an effect in orchestrating cytotoxic T-cell reponses, IFN-γ by itself has antitumor effects. Transferring T cells in a lymphopenic host furthermore eliminates regulatory T cells (Tregs) and offers access to homeostatic cytokines. The aim of our study was the translation of preclinical data into a GMP conform clinical scale protocol to generate specific T cells for adoptive T-cell therapy against tumor associated antigens. Large scale generations of NY-ESO-1 specific T cells was performed according to current GMP regulations in a GMP facility. In brief, peripheral blood mononuclear cells from healthy donors were primed with an overlapping NY-ESO-1 15-mer peptide mix. The priming was done in the presence of IL-7 and IL-2. T cells were enriched using IFN-γ capture technique and expanded for two weeks in autologous culture conditions with IL-7, IL-15 and IL-2. T-cell specificity, function and proliferation capacity was analyzed by flow cytometry. The T-cell products showed high numbers of specifically IFN-γ+, TNF-alpha+ T cells. Tolerance inducing cytokines like IL-10 were absent. Enrichment of Tregs was excluded. Both, CD4+ and CD8+ T cells with an effector memory phenotype proliferated in response to NY-ESO-1. CD107a assays demonstrated cytotoxic capacities of T cells. The T-cell product did not include alloreactive T cells. In summary GMP-conform generation of NY-ESO-1 specific T cells was established. Although tumor associated antigens are potential self antigens, it is possible to induce a functional Th1 response in peripheral blood T cells from healthy donors. Adoptive T-cell therapy against tumor associated antigens could have implications for multiple tumor entities in autologous as well as allogeneic treatment approaches.

Disclosures:
No relevant conflicts of interest to declare.
Which Patients Would Be Willing to Change Anticoagulation From Vitamin-K Antagonists to a New Oral Anticoagulant?
Authors: Harenberg Job , Marx Svetlana , Abou-Ayash Nadja , Kremer Christophe , Hoeing Vera , Schirk Katrin , Weiss Christel , Froelich Lutz 
Published: October 2019

Abstract
Abstract 4318
New oral anticoagulants have generated promising data on the prophylaxis of systemic and non-systemic embolism in patients with atrial fibrillation and treatment of acute venous thromboembolism and prolonged prophylaxis of recurrent events. For patients on chronic treatment with vitamin-K antagonists (VKA) we analysed the motivation and willingness to change the anticoagulation from VKA to new oral anticoagulants.
Patients (n=110) on stable treatment with VKA for at least 3 months (indication for anticoagulation: atrial fibrillation or VTE) completed a validated personality inventory (Freiburger Persönlichkeitsinventar FPI-R), and a self-developed questionnaire on general attitudes regarding anticoagulant therapy (Q1). Patients were divided in two groups according to the reply to the question weather they were willing to switch to a new oral anticoagulant. Out of these sets of questions 7 questions were identified by means of a logistic regression analysis for the willingness to change anticoagulation with VKA to a new oral anticoagulant. The same patients completed this shortened questionnaire (Q2) (n=85) thereafter.
Logistic regression analysis defined the 7 items of the FPI and Q1 questionaires as relevant for willingness of patients to change the medication. The probability to change medication was 98% using the 7 questions (Q2) compared to the 2 comlete questionnaires. The items were: extraversion – introversion scale on the FPI-R consisting of 14 questions, and from Q1: hope for a better quality of life with a new anticoagulant, no scepticism for new drugs, wish of a lack of routine monitoring for dose adjustment, relevance of the practitioners opinion, thoughts in the past of alternatives for anticoagulation, and difficulty to adjust the prothrombin time. Using Q2 85% of patients confirmed to be willing to change the anticoagulant drug compared to Q1 (chi square test p<0.0001).
Seven questions were identified and confirmed to identify patients for their willingness to change anticoagulation from VKA to a new oral anticoagulant.

Disclosures:
No relevant conflicts of interest to declare.
Cross Reactivity of Natural Hirudin Compared to the Recombinant Hirudins with Sheep Anti Hirudin Antibody
Authors: Paramatmuni Vijaya L , Hoppensteadt Debra , Setty Saayi , Litinas Evangelos , Sadeghi Nasir , Fareed Jawed 
Published: October 2019

Abstract
Abstract 4321
Recombinant versions of hirudin such as lepirudin (Refludan®) and desirudin (Iprivask®) are currently used as parenteral anticoagulants for various indications. The recombinant hirudin preparations differ from the natural hirudin in lacking a sulfate group on tyrosine at the 63rd position and a single amino acid substitution. It is hypothesized that these minor differences in the natural and recombinant versions of hirudins contribute to a differential immunogenic behavior. The purpose of this investigation was to compare the relative immunoreactivity of the three forms of hirudin to a sheep antin–hirudin antibody. Antibodies (anti-n-hirudin) were generated in sheep treated with natural hirudin isolated from the medicinal leech (Hirudo medicinalis ). SDS-PAGE immunoblot and Western transfer were conducted using the native hirudin and two recombinant hirudins against the sheep anti-n-hirudin IgG antibodies. Cross-reactivity was quantified by measuring total optical density of the bands using a UVP densitometric scanning system and chemiluminescence detection, by comparing the protein-antibody complex band density from the western blot showed a comparable behavior of the Desirudin and Lepirudin in contrast to the normal or native hirudin which exhibited a much higher band density (2-fold increase). Moreover, the native hirudin exhibited specific bands representing mono, di- and tetra-meric forms, whereas the two recombinant forms exhibited primarily monomeric and dimeric forms. Interestingly several other preclinical versions of recombinant hirudins exhibited fifferent immunoblotting patterns. Although, the structural differences and the molecular weight represent relatively minor variations in the natural and recombinant hirudins, these studies strongly suggest a differential behavior of natural and recombinant hirudins in terms of their cross-reactivity with anti-n-hirudin antibodies.

Disclosures:
No relevant conflicts of interest to declare.
Comparison of Prothrombin Time INR Derived From Point-of-Care and Laboraotry Test According to Fibrinogen Level
Authors: Kim Sue Jung , Kim Juwon , Song Jaewoo 
Published: October 2019

Abstract
Abstract 4325
Coumarin-derived anticoagulants such as warfarin inhibit the vitamin K expoxide reductase (VKORC1) and block vitamin K cycle rendering coagulation factors II, VII, IX, X left in functionally null state (PIVKAs). Because of the narrow therapeutic range of warfarin, prothrombin time standardized into international normalized ratio (INR) should be frequently measured to prevent unwanted bleeding or recurring thrombosis. Point of care (POC) tests for patient self monitoring of anticoagulation was developed with the intention that more frequent monitoring of would enhance the compliance of the patients and prevent overdose. The accordance between results derived from these POCs tests and clinical laboratory tests has been repeatedly reported and the patients self monitoring strategy is now generally accepted as a reliable way for maintaining safer anticoagulation therapy. However, we pointed out that the POC test, especially CoaguChek (Roche) wide in use domestically, can show different correlation pattern with laboratory tests according to fibrinogen level, because the assay principle of the POC test is basically measuring thrombin activity. We found negative bias of POC INR compared with laboratory test from specimen with fibrinogen level lower than 130 mg/dl while positive biases were observed from that with fibrinogen level higher than 130 mg/dl. The difference in INR range from −0.7 to 1.7 and the maximum differences in both directions were observed in specimen with INR above 3.0, that is exceeding therapeutic range. These results suggest that patient selection according to fibrinogen status should precede the implementation of patient self monitoring and periodic laboratory tests and comparison with POC results should be continued as before the initiation of self monitoring.

Disclosures:
No relevant conflicts of interest to declare.