bluuebunny/crossref_metadata_2025_split huggingface dataset:
Status of Minimal Residual Disease Determines Outcome of Autologous HSCT in Adults with High-Risk Acute Lymphoblastic Leukemia.
Authors: Giebel Sebastian , Stella-Holowiecka Beata , Krawczyk-Kulis Malgorzata , Goekbuget Nicola , Hoelzer Dieter , Doubek Michael , Mayer Jiri , Piatkowska-Jakubas Beata , Skotnicki Aleksander , Dombret Herve , Ribera Josep-Maria , Piccaluga Pier Paolo , Czerw Tomasz , Sadus-Wojciechowska Maria , Kyrcz-Krzemien Slawomira , Holowiecki Jerzy 
Published: October 2019

Abstract
Abstract 2321
Poster Board II-298
The role of autologous hematopoietic stem cell transplantation (autoHSCT) in the treatment of adult acute lymphoblastic leukemia (ALL) is a subject of controversies as several prospective studies failed to prove its advantage over maintenance chemotherapy. Those studies, however, did not take into account the status of minimal residual disease (MRD), which is now recognized a potent predictor for relapse among patients treated with conventional-dose chemotherapy. The goal of this analysis was to determine the impact of MRD on outcome of autoHSCT.
Data on 123 autoHSCT recipients collected from 6 study groups cooperating in the European Leukemia Net were analyzed. Median age of 77 B-lineage and 46 T-lineage high-risk ALL patients was 31 (16-59) years. Ph+ ALL was recognized in 20 cases. All patients were in first complete remission (CR) lasting 6 (1.5-22) months. Peripheral blood was used as a source of stem cells in 67 patients whereas bone marrow, in 56 cases. Conditioning was based on chemotherapy alone (n=76) or total body irradiation (n=47). MRD was evaluated in bone marrow with the use of either multiparametric flow cytometry (n=79) or molecular techniques (n=44). MRD level of 0.1% bone marrow cells was used as a cut-off point for the purpose of this study. At the time of autoHSCT MRD was &0.1% in 93 patients and ≧0.1% in 30 cases.
With the median follow up of 5 years, the probability of leukemia-free survival (LFS) at 5 years for the whole group equaled 48% (+/-5). Three patients died of transplantation-related complications. The LFS rate was significantly higher for patients with the MRD level at transplantation &0.1% compared to those with MRD ≧0.1% (57% vs. 19%, p=0.0002). The difference was particularly pronounced for peripheral blood HSCT (66% vs. 20%, p=0.0006) and for T-lineage ALL (62% vs. 8%, p=0.001). In a multivariate analysis adjusted for other potential prognostic factors (age, CR duration, Ph+ ALL, immunophenotype, source of stem cells, type of conditioning), the MRD status &0.1% remained the only independent factor associated with increased LFS (HR=2.5, p=0.0009).
CONCLUSIONS: MRD status is the most important predictor for LFS after autoHSCT in adults with ALL. More than half of patients with high risk disease and low MRD level at the time of transplantation may be cured. This observation may contribute to re-evaluation of the role of autoHSCT in the therapy of adult ALL.

Disclosures:
No relevant conflicts of interest to declare.
Rituximab Maintenance Following Chemoimmunotherapy Improves Outcome in B-Cell Chronic Lymphocytic Leukemia.
Authors: Del Poeta Giovanni , Del Principe Maria Ilaria , Ragusa Dario , Maurillo Luca , Buccisano Francesco , Ottaviani Licia , Giannì Laura , Luciano Fabrizio , Bulian Pietro , Rossi Francesca Maria , Venditti Adriano , de Fabritiis Paolo , Gattei Valter , Amadori Sergio 
Published: October 2019

Abstract
Abstract 2364
Poster Board II-341

The treatment goal of B-cell chronic lymphocytic leukemia (B-CLL) has already shifted from symptom palliation to the attainment of maximal disease control combining purine analogs with monoclonal antibodies. This immunochemotherapeutic approach resulted both in more complete responses (CR) and longer response duration, often remaining only a minimal residual disease (MRD) detectable by flow cytometry. We treated in first line 120 B-CLL symptomatic patients (pts), median age 62 years, with six monthly courses of intravenous or oral fludarabine at conventional doses and then, after a median time of 31 days, with four weekly doses (375 mg/sqm) of rituximab (rtx). Fourteen pts had a low Rai stage, 103 an intermediate stage and 3 a high stage. We defined as high risk pts having at least two of these markers: unmutated IgVH, CD38>30%, ZAP-70>20%, intermediate unfavorable cytogenetics (trisomy 12 or del11q or del17p). Based on NCI criteria, 92/120 (77%) pts achieved a CR, 24/120 (20%) a partial remission (PR) and 4/120 (3%) no response or progression. Ten pts underwent grade 3 (WHO) infective lung toxicity, 1 patient acute fatal B hepatitis and 2 pts progressed towards Richter's syndrome. Hematologic toxicity included mainly neutropenia (grade 3 and/or 4 in 56 pts) and thrombocytopenia (grade 3 and/or 4 in 8 pts). Fifty-four pts either in CR with B-CLL bone marrow cells >1% (MRD+, n=16 pts) or in CR MRD negative, but with B-CLL peripheral cells going up >1000/microl within 1 year after induction (n=22 pts) or in PR (n=16 pts), underwent consolidation and maintenance therapy with four monthly cycles of rtx at 375 mg/sqm followed by twelve monthly low doses of rtx (150 mg/sqm). The median follow-up duration was 50 months. All treated pts experienced a long progression-free survival from the end of induction treatment (40% at 9 years). On the other hand, global overall survival (OS) was 54% at 10 years. Nevertheless, CLL pts undergoing consolidation and maintenance therapy (n=54) showed a longer response duration vs MRD+ not consolidated pts (n=16; 75% vs 9% at 4 years; P<0.00001, Figure). Noteworthy, persistently MRD negative (>1 year) pts (n=43) showed a very long response duration (79% at 6 years, Figure). Moreover, OS was shorter in MRD+ not consolidated pts (0% vs 79% at 15 years; P=0.0007). Noteworthy, within the high risk subset (n=48), consolidated pts (n=17) showed a longer response duration (56% vs 0% at 2.5 years, P=0.003) vs MRD+ not consolidated pts (n=11). Therefore, rituximab consolidation and maintenance immunotherapy improve response duration in B-CLL, thus potentially increasing OS, also within the high risk subset.

Disclosures:
No relevant conflicts of interest to declare.
Dramatic Reduction of Chronic Lymphocytic Leukemia (CLL) Cells Following Adoptive Transfer of Cord Blood (CB) Natural Killer (NK) Cells Using CB-Engrafted NOD-SCID IL2Rγnull (NSG) Mice as a Model.
Authors: Xing Dongxia , Ramsay Alan G. , Decker William , Li Sufang , Robinson Simon , Yang Hong , Shah Nina , Hosing Chitra , Bollard Catherine M. , Gribben John G. , Shpall Elizabeth J. 
Published: October 2019

Abstract
Abstract 2370
Poster Board II-347
Adoptive transfer of NK cells in human B-CLL has been limited by the lack of suitable animal models to test the clinical efficacy of this immune therapy strategy. Primary patient B-CLL cells are difficult to engraft in NOD-SCID mice as these mice lack an immune microenvironment that provides essential accessory cells for tumor development. In the current study, we utilize a novel 2-step engraftment protocol using NOD-SCID γnull mice (NSG). Firstly, human cord blood (CB) derived CD34+ stem cells were engrafted to generate humanized chimeric mice capable of supporting B-CLL cells. By week 12, the human engraftment level reached 30% to 60% as detected in peripheral blood. Secondly, these mice were infused with human primary B-CLL cells labeled with CFSE. Our results show that following tail vein injection of 5E7 primary patient CLL cells, chimeric mice exhibited proliferation of CFSE+CD5+ B cells in the spleen and bone marrow, with disease development resembling human CLL. This allowed us to investigate the efficacy of ex vivo IL-2 expanded CB NK cell therapy using this novel mouse model system. As early as 24 hours post-infusion of IL-2 expanded human CD56+CD3- CB NK cells (10E7 per mouse) there was a detectable reduction of CD5+ leukemia cells in the peripheral circulation of CLL-engrafted mice by flow cytometry analysis. Moreover, by day 7 there was a dramatic 99.5 % reduction of CD5+ B-CLL cells in the blood, bone marrow, and spleen of experimental animals compared to the non-treated control group (P<0.001). Of note, expanded CB-NK cells exhibited high anti-leukemic specificity as healthy B cells from the original CB transplant were spared post-infusion. Overall, our studies suggest that the chimeric NSG mouse has utility as an in vivo model for testing immunotherapeutic strategies in aggressive B-CLL. Here, our results highlight the strong anti-leukemic response of infused ex vivo expanded CB-NK cells.

Disclosures:
No relevant conflicts of interest to declare.
Antitumor Activity of Small-Molecule SYK Inhibitor R788 and Fludarabinin Mono- and Combined Therapy in a Human B-CLL Xenograft Model.
Authors: Schüler Julia , Buchner Maike , Fiebig Heinz-Herbert , Veelken Hendrik , Zirlik Katja 
Published: October 2019

Abstract
Abstract 2378
Poster Board II-355
B cell chronic lymphocytic leukemia (B-CLL), one of the most common leukemia in adults, is characterized by the accumulation of mature B cells expressing CD19 and CD5. Improved understanding of CLL has lead to new prognostic tools and therapeutic options. The protein kinase Syk as a key mediator of proximal B-cell receptor (BCR) signalling is constitutively phosphorylated in CLL B cells. For these novel therapeutics, functional in vivo models are highly valuable. We have established a cell line-based, disseminated B-CLL model in NOD/SCID-IL2-receptor-gamma-chain-/- (NSG) mice. In the current study, SYK inhibitor R788 (60mg/kg/day (d); applied daily) was evaluated in mono- and in combined therapy with Fludarabin (8mg/kg/day; applied 5 consecutive days in two cycles) as a well established compound in B-CLL treatment regimens in comparison with a control group. Equal parts of MEC1 cells were injected intravenously and into the peritoneal cavity of NSG mice and respective therapies were started 7 days after implantation. Tumor growth was monitored with flow-cytometry (FACS), daily monitoring of B-CLL symptoms and fluorescence-based in vivo imaging (FI). Tumor inhibition was calculated as the proportional reduction of mean B-CLL cell infiltration at the respective compartment of the test- compared to the control-group (in %). MEC1 cells engrafted predominantly in bone marrow (BM; take rate = 100%), but were as well detectable in spleen (33%) and peripheral blood (PB; 8%). At the respective doses and schedules the examined compounds were well tolerated in tumor-bearing mice. No acute toxicity could be observed and maximal body weight loss was below 15% in mono- and combined therapy. Tumor development was clearly reduced by R788 (optimal T/C of 48% on day 18), albeit to a lesser extend then standard anticancer agent Fludarabin (optimal T/C of 19% on day 18). Combined therapy induced no synergistic effects showing an optimal T/C value of 42% on day 19. Thus, MEC1 engraftment into NSG mice is a valuable in vivo model for B-CLL which exhibits high reproducibility and take-rates in relevant compartments closely mimicking the clinical situation. Collection of whole-body FI data proved to be a time- and animal-saving analysis that allows to closely monitor B-CLL growth. Further investigations will optimize the very promising antitumor activity of R788 and evaluate the potentially synergistic effect of R788 with additional well-established B-CLL therapeutics.

Disclosures:
No relevant conflicts of interest to declare.
Oversulfated Chondroitin Sulfate Does Not Cause Augmentation in HIT Antibody Mediated Heparin-Induced Platelet Aggregation (HIPA).
Authors: Iqbal Omer , Plamoottil George , Sadeghi Nasir , Hoppensteadt Debra , Fareed Jawed 
Published: October 2019

Abstract
Abstract 2417
Poster Board II-394

Heparin is one of the widely used anticoagulants for the prophylaxis and treatment of thrombotic disorders. Heparin, a linear polysaccharide belonging to a family of glycosaminoglycans (GAGS) consists of repeating disaccharide units of 1-4 linked iduronic acid and glucosamine residues. Heparin is a mixture of low, medium and high molecular fractions and is heterogeneous not only in terms of molecular weight but also sites and degree of sulfation. Oversulfated chondroitin sulfate, one of the important toxic contaminants in certain batches of heparins manufactured during 2007 to 2008 resulted in deaths of some patients following intravenous administration that led to the recall of these heparins by the FDA. An increased incidence of heparin-induced thrombocytopenia (HIT) and thrombosis syndrome (HITTS) was reported as a result of contaminated heparins. It was hypothesized that OSCS interacts with heparins and other LMWHs increasing their HIT/HITTS potential. In order to validate this hypothesis blood was drawn from healthy volunteers (n=5) and mixed with 3.2% sodium citrate solution (9 parts of whole blood to 1 part of citrate). The citrated blood samples were centrifuged at 800 rpm to obtain platelet rich plasma (PRP) and further centrifuged at 3000 rpm to obtain platelet poor plasma (PPP). Apheresis fluid was collected from confirmed cases of HIT and pooled. The platelet aggregometers (Biodata) were blanked with individual PPP. The PRP (300ml) was mixed with HIT positive pooled apheresis fluid (200ml) and platelet aggregation was recorded using Gentium Heparin, Enoxaparin, and Bemiparin at a final concentration of 10mg/ml, either alone or in mixtures of 10%, 20% and 30% OSCS. The Heparin-induced platelet aggregations (HIPA) were run for a period of 30 minutes and the tracings obtained. While OSCS alone at a final concentration of 10 mg/ml caused an average of 29.5% platelet aggregation, it did not cause an augmentation of platelet aggregation in 10%, 20% and 30% mixtures with Heparin, Enoxaparin, Bemiparin and AVE 5026 (see table). This data suggests that drugs like heparin, and low molecular weight heparins such as Enoxaparin, and Bemiparin did not augment HIT/HITTS response when combined in various proportions with OSCS. Based on HIPA the reported increase in HIT response may therefore be due to in vivo interactions of the OSCS with platelets and endothelial cells. Corroborative evidence from clinical studies are warranted to validate these preliminary results.

Disclosures:
No relevant conflicts of interest to declare.
Improved Engraftment without Graft-Versus-Host Disease After MHC-Mismatched Cord Blood Transplantation with Photochemically Treated Donor Lymphocytes.
Authors: Kanathezhath Bindu , Mizokami Myra , Neumayr Lynne , Guo Hua , Walters Mark C. , Kuypers Frans A. 
Published: October 2019

Abstract
Abstract 2425
Poster Board II-402

Introduction:
Unrelated cord blood transplantation (CBT) is associated with a risk of graft rejection due in part to a limiting cellular content of the CB unit. Increasing the cellular content of the CB unit mitigates the graft rejection risk, but methods to use adjuvant immuno-modulatory cell co-infusions have also been tested with some success. We have investigated the co-infusion of photochemically (psoralen S59) treated mature donor T lymphocytes in a major histocompatibility complex (MHC) [H2-haplotype] mismatched murine transplant model as a new method to facilitate engraftment of donor CB cells.

Methods:
We analyzed the rates of donor hematopoietic cell engraftment, graft versus host disease (GVHD), and long-term survival in H2 haplotype disparate (C57BL/6®AKR) mice after CBT. Three different experimental groups were transplanted after sublethal radiation. Group 1 received allogeneic full term newborn peripheral blood alone, group 2 was transplanted with the same donor cells and unmanipulated donor T cells, and group 3 was transplanted with the similar donor cells and psoralen (S-59) treated donor T cells.

Results:
We observed a low rate of donor engraftment after transplantation with cord blood alone (Group 1). There was better engraftment but a high rate of fatal GVHD after transplantation with cord blood and unmodified donor T-cells (Group 2). The best results were observed after transplantation with 3 × 106 nucleated cord blood cells and 9 ×106 S-59 treated T cells (Group 3b). The engraftment rate was 75% compared to 12.5% after transplantation with 6 × 106 CB cells alone (p=0.04). The long-term survival in group 3 was 100% and the rate and severity of GVHD were minimal. Engraftment observed after CBT with unmodified donor T-cells (group 2) was accompanied by severe GVHD and poor survival. Donor myeloid, B cells and T cells were documented in the spleen and bone marrow of Group 3 mice by 30 days after CBT, although full hematological recovery was delayed until 50-60 days after CBT.

Conclusions:
These results show improved cord blood engraftment kinetics across a disparate H2 haplotype by adding psoralen-treated donor T lymphocytes. Co-transplantation of psoralen treated lymphocytes with CB cells facilitated durable engraftment of donor MHC high/c-kit+ cells in the marrow and splenic compartments with complete but delayed hematopoietic recovery. The low GVHD risk and excellent long-term survival observed in this murine model suggests the potential for clinical application.

Disclosures:
No relevant conflicts of interest to declare.
Safety of Excluding Suspected Deep Vein Thrombosis with a Single Whole-Leg Compression Ultrasound: Systematic Review and Meta-Analysis.
Authors: Johnson Stacy A , Stevens Scott M , Woller Scott C , Lake Erica , Donadini Marco , Douketis James D 
Published: October 2019

Abstract
Abstract 243

Background:
In patients with suspected lower extremity deep vein thrombosis (DVT), compression ultrasonography (CUS) is typically used as the initial test to confirm or exclude DVT. Patients with a negative CUS and either a moderate-to-high probability and/or a positive D-dimer usually require repeat CUS testing after 5–7 days to exclude proximal propagation of distal DVT, reducing diagnostic efficiency. Whole-leg compression ultrasound may safely exclude proximal and distal DVT in a single evaluation.

Purpose:
To assess the safety of withholding anticoagulation in patients presenting with suspected lower extremity DVT following a single negative whole-leg CUS.

Methods:
MEDLINE, EMBASE, CINAHL, LILACS, Cochrane, Health Technology Assessments databases were searched from January 1970 to April 2009 without language restrictions. This search was supplemented by reviewing Google, Google Scholar, clinicaltrials.gov, meeting abstracts, conference proceedings, reference lists, and by contacting content experts.

Study Selection and Data Extraction:
Randomized controlled trials and prospective cohort studies of patients with suspected DVT with a negative whole-leg CUS, not treated with anticoagulation, and followed at least 90 days for occurrence of venous thromboembolism (VTE). Studies required objective confirmation of VTE events during follow-up. Two authors independently reviewed articles and extracted data.

Results:
Six studies were included totaling 4,229 patients with negative whole-leg CUS exams and not receiving anticoagulation. VTE or suspected VTE-related death occurred within the follow-up period in 24 (0.6%) patients. Of these 24 events, 9 (37.5%) were distal DVT, 7 (29.2%) were proximal DVT, 6 (25.0%) were non-fatal pulmonary embolism, and 2 (8.3%) were deaths, possibly related to VTE. Combined VTE event rate at 3 months was 0.46% (95% CI 0.22, 0.70).

Limitations:
Pretest probability assessment was not available for all analyzed patients.

Conclusions:
Withholding anticoagulation in patients with suspected DVT based on a single whole-leg CUS is associated with a low risk of VTE (0.46%) during 3 months of follow-up. This strategy represents a safe and efficient alternative to serial CUS testing in patients with suspected DVT.

Disclosures:
No relevant conflicts of interest to declare.
Prevalence of Venous Thromboembolism Across Ethnic Groups in the United States.
Authors: Deitelzweig Steven B , Lin Jay , Johnson Barbara H , Schulman Kathy L. 
Published: October 2019

Abstract
Abstract 2492
Poster Board II-469

Objective:
Understanding the overall prevalence of VTE is paramount in estimating the burden of illness associated with this disease. This study aims to assess the number of VTE cases in the United States across ethnic groups based on recent data.

Methods:
Data from the Marketscan® Medicaid database from Thomson Reuters (Jan 2002–Dec 2005) were extracted for patients aged ≥18 years. Patients were evaluated for VTE in each year, defined by the presence of a VTE diagnosis on an inpatient claim or on ≥1 outpatient claim with evidence of anticoagulant administration. Age-, sex- and race-specific VTE prevalence rates were derived by dividing the number of VTE cases identified by the number of individuals in the underlying MarketScan populations during that time. These rates were then multiplied by 100,000 to obtain a VTE prevalence rate per 100,000.

Results:
In 2002, there were 276 individuals with evidence of VTE per 100,000 plan enrollees. In 2005, that number grew to 358, a 30% increase. African American males had the highest overall observed prevalence rate of 584 per 100,000 enrollees in 2002, growing to 785 in 2005 (Table). Caucasian males had the next highest observed prevalence at 457 per 100,000 enrollees in 2002, growing to 643 per 100,000 in 2005. Females generally had lower observed prevalence of VTE than males, although Hispanic females had similar prevalence's to Hispanic males (94 vs 93 in 2002, 149 vs 154 in 2005). Following multivariate adjustment for comorbidities and conditions known to be strong risk factors associated with developing VTE, African Americans were at significantly increased risk for VTE than Caucasians (Odds Ratio 1.04, 95% CI 1.00–1.07, p<0.05).

Conclusions:
VTE prevalence increased during the study period for the overall US Medicaid population. African Americans had the highest rate of VTE, followed by Caucasians and Hispanics. There is a need for improved VTE awareness and prevention across all ethnic groups.

Disclosures:
Deitelzweig: sanofi-aventis: Honoraria, Research Funding, Speakers Bureau, The authors received editorial/writing support in the preparation of this abstract funded by sanofi-aventis U.S., Inc.; Bristol-Myers Squibb: Honoraria, Research Funding, Speakers Bureau; Scios: Honoraria, Research Funding, Speakers Bureau; Pfizer: Speakers Bureau. Lin:sanofi-aventis: Employment. Johnson:sanofi-aventis: Research Funding. Schulman:sanofi-aventis: Research Funding.