bluuebunny/crossref_metadata_2025_split huggingface dataset:
Confirmation of Safety, Efficacy and Response Duration in Non-Hodgkin Lymphoma Patients Treated with 60 μg/m2/d of BiTE® Antibody Blinatumomab.
Authors: Nagorsen Dirk , Zugmaier Gerhard , Viardot Andreas , Goebeler Mariele , Noppeney Richard , Schmidt Margit , Klappers Petra , Baeuerle Patrick A , Kufer Peter , Bargou Ralf C 
Published: October 2019

Abstract
Abstract 2723
Poster Board II-699
Indolent and mantle cell lymphoma (MCL) are predominantly treated with chemotherapy or a combination of chemotherapy with monoclonal antibodies. Despite high initial response rates, eventually almost all patients however relapse, leaving the disease incurable. Moreover, with increasing numbers of regimens administered, the responsiveness of patients is reduced. Blinatumomab is a single-chain bispecific antibody construct with specificity for CD19 and CD3, belonging to the class of bispecific T cell engager (BiTE®). Here, we report on patients in an ongoing phase 1 trial treated at a dose of 60 μg/m2/d for 4–8-week by continuous i.v. infusion with single-agent blinatumomab. In total, 12 patients with indolent mainly follicular lymphoma or MCL were treated at 60 μg/m2/d during the first treatment cycle. 11/12 patients showed an objective response (7 PR and 4 CR). As of July 2009, median response duration was 12 months with 6 out of 11 responses still ongoing. The single non-responding patient experienced a reversible, neurological adverse event leading to early discontinuation of treatment. Of the 11 responders, one patient developed a port infection and 4 patients showed neurological symptoms, which were all fully reversible. In order to mitigate neurological adverse events during first dosing, which can occur in a defined subset of patients, patients were treated for 1–2 weeks with a lower initial dose (5 and/or 15 μg/m2/d) followed by a maintenance dose of 60 μg/m2/d. A lower starting dose appeared to ameliorate initial adverse events to an extent that treatment could be continued without interruption. Taken together, our data confirm a high single-agent activity of 60 μg/m2/d blinatumomab infused for 4–8 week with long lasting remissions and a favorable risk/benefit profile. The confirmed dose will be considered for further clinical development of blinatumomab in follicular lymphoma and MCL. New data on patients treated with a dose of 90 μg/m2/d will be presented.

Disclosures:
Nagorsen: Micromet: Employment, Equity Ownership. Zugmaier:Micromet: Employment, Equity Ownership. Schmidt:Micromet: Employment, Equity Ownership. Klappers:Micromet: Employment, Equity Ownership. Baeuerle:Micromet: Employment, Equity Ownership. Kufer:Micromet: Employment, Equity Ownership, Patents & Royalties. Bargou:Micromet: Consultancy, Patents & Royalties.
Infectious Complications in Advanced Relapsed/Refractory Multiple Myeloma Patients Treated with Lenalidomide (Revlimid +/- Corticosteroids).
Authors: Kukreti Vishal , Masih-Khan Esther , Dean Saima , Kumar Deepali , Mikhael Joseph R. , Trudel Suzanne , Reece Donna E. , Chen Christine 
Published: October 2019

Abstract
Abstract 2876
Poster Board II-852
Multiple myeloma (MM) patients (pts) are immunosuppressed given the underlying disease, previous treatments and myelosuppression seen on lenalidomide (Revlimid, Rev). We evaluated the infectious complications seen on Celgene's Expanded Access Rev program at Princess Margaret Hospital. We have treated 75 pts who had progressed after at least one prior therapy as part of a national study in Canada. At entry, pts were required to have a neutrophil count of ≥1.0 ×109/L. The median age was 61 yrs (range 35-79); 52% were males. Prior therapy included stem cell transplant in 65, thalidomide in 54 and bortezomib in 24. Number of lines of prior therapy were as follows: 24 (one), 29 (two), 16 (three), 8 (four) and one (five). Neupogen was used liberally (63%) after a patient had a dose delay on trial due to neutropenia. Patients were treated with full dose lenalidomide at entry onto clinical trial and were maintained on full dosing unless platelet counts were <30×109/L or ANC was <1.0×109/L. No other dose adjustments were made for renal dysfunction.

Results:
There were 32 pts (43%) who had a clinically evident infection; the majority (91%) was on prophylactic antibiotics (septra/ciprofloxacin) at the time. There were two deaths due to infection and 23 pts (72%) required hospitalization (range 2-27 days). The majority of infections occurred within the first 4 cycles of treatment (26 pts) and seemed to occur more in pts with several lines of prior therapy – 7/24 (29%) with 1 prior therapy, 14/29 (48%) with 2, 9/16 (56%) with 3 and 2/8 (25%) with 4 prior therapies. Sixteen were neutropenic of which 7 had febrile neutropenia (9%). The types of infections were: respiratory in 14 (1 with pneumocystis pneumonia), cellulitis in 4, herpes simplex and herpes zoster in 2 pts each. These included streptococcus pneumoniae (1), staphylococcus aureus (3), respiratory syncitial virus (1) and mycobacterium chelonae (1). Rev was held during the infection in 23 pts (72%).

Conclusions:
1) Infections are frequent in this patient population (43%) and often lead to hospitalization (72%); respiratory infections accounted for a large majority (43%).
2) Early aggressive growth factor support and broader antibiotic prophylaxis may be of benefit especially in heavily pretreated patients.
3) Dose reduction of Rev in the context of serious infections should be further evaluated.

Disclosures:
Kukreti: Celgene: Honoraria. Trudel:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria. Chen:Celgene: Honoraria.
Odds of Venous Thromboembolims (VTE) Associated with Hospitalization, Surgery, and Cancer Among Nursing Home Residents: A Population-Based Study.
Authors: Leibson Cynthia L. , Heit John A. , Bailey Kent R. , Petterson Tanya M. , Ashrani Aneel 
Published: October 2019

Abstract
Abstract 2984
Poster Board II-960
In previous studies of venous thromboembolism (VTE) among all residents of Olmsted County, MN, the odds of VTE associated with surgery, medical hospitalization, or active cancer were extremely high (Univariate odds ratio [OR] =14.6; 4.6, and 8.4 respectively). We also showed that nursing home (NH) residency was an independent risk factor for VTE (OR =5.6).
From a clinical practice perspective, it is important to identify which NH residents are at risk of VTE. While it might be assumed that, similar to estimates for the population generally, surgery, medical hospitalization, and cancer are associated with increased risk of VTE within the NH population, the answer remains unclear.
We took advantage of the previous identification of all Olmsted County, MN residents who met research criteria for incident VTE 1998-2005 (N=1168). We then determined which individuals were resident of a local NH at time of symptom onset, regardless of location of symptom onset (i.e., for purposes of this study, individuals whose VTE occurred in-hospital having been admitted from a NH were considered NH residents). For each such NH VTE case (N=96), we identified 2 same sex Olmsted County residents of similar age and duration-of-medical-history who were resident of a local NH at the time of the case's VTE event (i.e., index date) (N=192). The detailed provider-linked medical records of NH VTE cases and NH non-VTE controls were reviewed for 3 months before index for surgery or medical hospitalization and for 6 months surrounding index for active cancer. Using conditional logistic regression, we tested and estimated the odds ratio associated with each of these potential risk factors.
The proportions of NH VTE cases and NH non-VTE controls with surgery (33%, 28%), medical hospitalization (44%, 46%), and active cancer (12%, 9%) were similar. Univariate odds ratios (95% confidence intervals) and p values for surgery, medical hospitalization, and active cancer were 1.5 (0.7-3.1), p=0.30; 1.1 (0.6-2.1), p=0.74; and 1.4 (0.6-3.2), p=0.46 respectively.
Compared to the entire Olmsted County population, the odds of VTE associated with surgery, hospitalization, and cancer are surprisingly much lower for NH residents. Additional investigation is needed to characterize the subset of NH residents at increased risk of VTE.

Disclosures:
No relevant conflicts of interest to declare.
Hemoglobin Bound Von Willebrand Factor (HbVWF) Multimers Are Hyperactive and More Prevalent in Patients with Sickle Cell Disease.
Authors: Zhou Zhou , Han Hyojeong , Udden Mark M. , Cruz Miguel A. , Dong Jing-fei , Guchhait Prasenjit 
Published: October 2019

Abstract
Abstract 3058
Poster Board II-1034
Elevated levels of von Willebrand factor (VWF), especially the ultra-large multimers, play a significant role in the pathogenesis of vascular occlusion in sickle cell disease (SCD) by promoting cell adhesion to the endothelium. Investigating the pathophysiology of vaso-occlusion and thrombosis in SCD, we have recently observed that excessive extracellular-hemoglobin (Hb) in plasma significantly inhibited ADAMTS-13 proteolysis of VWF by binding directly to the enzyme cleavage-site on VWF. Here, we further show that subpopulations of VWF multimers, which are bound to extracellular-Hb, exist in plasma. We have successfully isolated the Hb-bound VWF (HbVWF) multimers from SCD patients' plasma using the Ni-NTA column and quantified by commercial kit. The HbVWF multimers exist in 5 to 6-times less quantity than the Hb-free multimers as measured in SCD patients. Purified HbVWF multimers are mostly uncleavable by recombinant ADAMTS-13 in vitro. These HbVWF multimers are hyper active in agglutinating platelets as detected by ristocetin cofactor (RCof) activity assay, and also hyper adhesive to collagen type-III compared to the Hb-free multimers. The HbVWF multimers exists in about 2-fold more quantity in SCD patients than normal individuals [mean percent level ± SE, 8.1±1.8 (individual mean 6 – 11) vs. 16.6±3 (12 – 21), P <0.001; n=10]. Using another sandwich-ELISA assay we have reexamined the HbVWF levels, which showed a similar pattern as above. Further, the increased level of HbVWF multimers exists parallely with an elevated RCof activity of plasma VWF [mean percent activity ± SE, 100.4±15.1 (78 – 124) vs. 132.9±11.4, (109 – 149), P <0.001] and high extracellular-Hb levels [mean mg/L ± SE, 59±6.5 (42 – 96) vs. 281.5±71.7 (184 – 410), P <0.001] in plasma of SCD patients compared to normal individuals. Therefore, we believe that these hyperactive HbVWF multimers play a crucial role in cell adhesion, vascular occlusion and thrombosis in SCD. Also, we speculate that this mechanism is not only limited in SCD, but also occurred in other pathophysiological conditions associated with severe intravascular hemolysis.

Disclosures
No relevant conflicts of interest to declare.
Genetic Polymorphism of NAD(P)H:Quinine Oxidoreductase 1 Is Associated with An Increased Treatment-Related Mortality in Patients Undergoing Allogeneic Transplantation.
Authors: Koldehoff Michael , Beelen Dietrich W. , Elmaagacli Ahmet H 
Published: October 2019

Abstract
Abstract 3342
Poster Board III-230

Introduction:
The widely expressed detoxification enzyme NAD(P)H:quinine oxidoreductase 1 (NQO1) is involved in the cellular response to oxidative stress and irradiation and protects cells against the mutagenicity from free radicals and toxic oxygen metabolities. NQO1 is subject to a genetic polymorphism (C609T) leading to a change in its amino acid sequence. Heterozygous individuals C/T have intermediate activity and homozygotes T/T are NQO1 deficient. Never before the influence of genetic polymorphisms of NQO1 on patients who underwent allogeneic transplantation, was evaluated.

Methods:
Here we genotyped in a retrospective study 198 patients (and their donors) for NQO1 expression that underwent allogeneic transplantation for various diseases and analyzed their outcome. Genotyping of NQO1 was performed by real-time PCR using subsequent melting curve analysis.

Results:
145 patients (73.2%) were genotyped as homozygous wild-type gene C/C, 48 patients (24.2%) were genotyped as heterozygous genotype C/T and five patients (2.5%) were genotype as homozygous gene mutation T/T. From the donors 147 donors (74.2%) were C/C, 50 donors (25.3%) were C/T, and one donor (0.5%) had a homozygous gene mutation T/T. Calculated genotype frequencies did not differ from that reported earlier by other studies for Caucasians. Five-year estimate for treatment-related mortality (TRM) was highest in genotype C/T- and T/T-patients with 39% ±11% compared to homozygous wild-type gene C/C-patients (21% ± 3.9% [p<0.045]), whereas the five-year estimate for relapse or overall survival (OS) were not statistically different between the groups. No differences for five-year estimates for TRM, relapse rate, or OS were seen in recipients with either genotype C/C-, C/T- or T/T-donors. No statistic differences were found in the incidence of acute GVHD grade 2-4 within the study groups. NQO1 C/T, T/T genotypes were not associated with elevated bilirubin or creatinin levels regarding on recipient or the donor side, even after stratification based on HLA disparity.

Conclusions:
These results suggest that patients with genetic polymorphism of NQO1 do have an increased TRM after transplantation. Genotyping for NQO1 (C609T) might help to identify patients with higher risk for TRM.

Disclosures:
No relevant conflicts of interest to declare.
Interim Analysis on a Dutch HOVON Multicenter Randomized Open Label Phase II Trial on 3 Rituximab Dosing Schemes In Chronic ITP Patients:
Authors: Zwaginga Jaap Jan , van der Holt Ronnie , Biemond Bart J. , Boekhorst Peter A.W. te , Levin Mark , Vreughdenhil Art , Huijgens P.C. , Brand Anneke , van der Griend Rene , Luten Marleen , Pruijt Hans , Weerdt Okke de , van Pampus Elisabeth , Zweegman Sonja , Hollestein Rene , Koene Harry R. 
Published: October 2019

Abstract
Abstract 2514
The overall short term effectivity of Rituximab in the treatment of ITP is reported to be around 50%. In most studies the traditional CD20 dosing scheme of 4 weekly interspaced 375 mg/m2 doses is used although other single-arm studies suggest comparable effectivity of lower doses. To investigate alternative dosing schemes, we conducted an open label phase II multicenter trial and randomized 156 ITP patients that were refractory for corticosteroid treatment, between three schemes. Questions were: are higher CD20 peak levels of value and is dose saving a feasible approach in early responding patients? The treatment arms were: A) 375 mg/m2 once a week for 4 weeks, B) 750 mg/m2 once a week for 2 weeks and C) 375 mg/m2 once a week for 2 weeks, in early and sustained responding patients (= within 15 days and still responding at 43 days) and another 2 × 375 mg/m2 to patients not fulfilling these criteria. In retrospect, seven of the 156 patients appeared ineligible at randomization and were therefore excluded from all analyses. Here we report on the best response within 71 days as primary end point for the first 105 patients that were included, i.e. 35 per treatment arm
Arm A (n=35) 4 × 375 mg/m2 Arm B (n=35) 2 × 750 mg/m2 Arm C (n=35) 2 or 4 × 375 mg/m2 Patient characteristics Male/female, % 37/63 49/51 43/57 WHO 0/1/2/not reported, % 86/6/–/9. 77/20/3/– 91/9/–/– Age in years, median (range) 56 (19–77) 56 (17–82) 41 (18–80) On stable corticosteroid, % 36 29 46 Splenectomized, % – 15 11 Baseline plt count × 109/l, median (range) 16 (3–31) 15 (1–30) 19 (2–30) Treatment outcome, % Early responses in Arm C 26 All best responses within 71d 46 42 51 CR: >150 × 109 plt/l 20 14 14 GR: >50 × 109 plt/l 20 14 23 MR: >30 × 109 plt/l AND >2 × baseline 6 14 14 No response 54 58 49 Treatment failure at 6 months, % (standard error) 57 (8) 60 (8) 54 (9)
So far, on the basis of the within 71 days overall response data, no superior dosing scheme of CD20 can yet be discerned.

Disclosures:
No relevant conflicts of interest to declare.
Angiopoietin-Like 3 Affects Homing Ability of Hematopoietic Stem Cells.
Authors: Umikawa Masato , Zheng Junke , Huynh HoangDinh , Zhang Chengcheng 
Published: October 2019

Abstract
Abstract 2632
Angiopoietin-like proteins (Angptls) are a seven-member family of secreted glycoproteins that share sequence homology with angiopoietins. It is known that several members of the Angptl family including Angptl3 support ex vivo expansion of hematopoietic stem cells (HSCs). However, the physiological role of Angptls in the hematopoietic system is not well known. Here we show that Angptl3 is expressed by both bone marrow stromal cells and HSCs. To study the intrinsic effect of Angptl3 in mouse HSCs, we isolated the same number of HSCs from wild-type and Angptl3-null mice and performed reconstitution analysis. Adult bone marrow Angptl3-null HSCs showed decreased repopulation compared to wild-type HSCs, suggesting that Angptl3 has cell-autonomous effect on HSC activity. By contrast, HSCs isolated from liver of the null mice had enhanced HSC repopulation activity than their wild-type counterparts. To study whether this effect is caused by difference in homing, we injected CFSE labeled wild-type HSCs and Angptl3 null HSCs into lethally irradiated mice, and checked the homing to bone marrow, spleen, and liver. While homing of these two types of cells to bone marrow or spleen was not significantly different, Angptl3 null HSCs homed better to the liver than the wild-type HSCs. Our result suggests that Angptl3 is important for the retention of HSCs in the bone marrow, and the absence of Angptl3 leads HSCs to move to extramedullary organs such as liver.

Disclosures:
No relevant conflicts of interest to declare.
Evidence That High-Mobility Group A2 (Hmga2) Expression Contributes to the Ontogeny-Dependent Properties of Fetal Hematopoietic Stem Cells.
Authors: Copley Michael R. , Kent David G. , Benz Claudia , Rowe Keegan M. , Woehrer Stefan H. , Eaves Connie J. 
Published: October 2019

Abstract
Abstract 2634
Fetal and early neonatal hematopoietic stem cells (HSCs) are distinct from their adult counterparts by their rapid turnover and expansion rates in vivo. However, the mechanisms underlying the regulation of these properties are poorly understood. In previous studies using serial limiting-dilution competitive repopulating transplant assays, our lab has shown that the rapid expansion phenotype of fetal HSCs is at least partially intrinsically determined since significantly more daughter HSCs are produced from fetal as compared to adult HSCs when similar numbers are transplanted into the same type of irradiated adult host. Additionally, we have observed a conversion of fetal HSCs to the adult regeneration phenotype that occurs within six weeks of transplantation in the primary host. To facilitate a comparison of highly-purified subsets of fetal and adult HSCs identified by an identical phenotype, we adopted the use of the CD45+EPCR+CD150+CD48− (E-SLAM) phenotype which we found gave HSC purities of 20–50% for hematopoietic tissues from early fetal to aged adulthood. We then used comparative gene expression analysis to identify candidate regulators of the fetal HSC high self-renewal program. This gave 20 candidate genes whose transcript levels were measured by quantitative real time PCR in E-SLAM cells isolated from E14.5 fetal liver (FL) and adult bone marrow (ABM). Of these genes only Hmga2 and Smarcc1 showed significant differences (p<.05) in expression between fetal and adult HSCs and only Hmga2 maintained this differential expression when the same cells were stimulated to divide for 48 hrs in vitro. To test the hypothesis that high expression of Hmga2 is a necessary and sufficient factor in determining the fetal HSC self-renewal program, purified adult E-SLAM HSCs were transduced with Hmga2-overexpressing or control lentiviruses and the kinetics of transduced vs untransduced hematopoietic cells in a congenic serial-transplantation model were then analyzed. Interestingly, when BM cells from the primary repopulated mice (transplanted 6-weeks earlier) were injected into secondary animals and the peripheral blood was analyzed for donor-type %Y/GFP chimerism, the Hmga2-overexpressing cells were observed to have a competititve advantage and exhibited an ∼6-fold expansion relative to the untransduced cells. In contrast, the control virus-infected BM cells were found to be equally competitive. These findings support the hypothesis that high expression of Hmga2 may be a critical mediator of the high self-renewal phenotype of fetal HSCs.

Disclosures:
No relevant conflicts of interest to declare.
Recovery of KIR Expression After Allogeneic Stem Cell Transplantation in Multiple Myeloma Patients
Authors: Stuebig Thomas , Lioznov Michael , Fritsche-Friedland Ulrike , Alchalby Haefaa , Wolschke Christine , Ayuk Francis , Bacher Ulrike , Zander Axel R. , Kroeger Nikolaus 
Published: October 2019

Abstract
Abstract 4555

Introduction:
Activating and inhibitory killer immunoglobulin like receptors (KIR) are predominantly expressed on natural killer (NK) cells. KIR mismatch allogeneic stem cell transplantation (alloSCT) has been reported to provide beneficial effects for Multiple Myeloma (MM). However, their recovery in MM patients remains poorly understood. We, therefore, analysed KIR recovery in 90 MM patients after alloSCT.

Methods:
KIR expression (CD158a/h, CD158b/b2, CD158e1/e2) on NK cells and T cell subsets was measured by flow cytometry at different time points after alloSCT.

Results:
During the first 90 days after alloSCT NK cells represent the largest lymphocyte subset. Activating receptors like NKp30 and NKp44 showed a fluctuating expression while members of the KIR family were expressed at a constant rate (20% of NK cells). There was no significant difference in the early post transplantation period (day 0–90) compared to later time points (day 360).
In contrast, T cells showed increased KIR expression during the first 30 days after alloSCT, which was highly significant for CD158e (p=0,0001). After 30 days the expression declined to baseline. Furthermore, T cell activation marker HLA-DR reached its highest expression between days 60 and 90 when KIR receptors were expressed at their lowest level (27% vs. 8%, p < 0,0001).

Conclusions:
We conclude that KIR receptors were differentially expressed on NK and T cells. Because KIR receptors are constantly expressed by NK cells and NK cells are the most frequent lymphocyte populations early after alloSCT, NK cells may be useful for KIR mismatch cellular therapy.

Disclosures:
No relevant conflicts of interest to declare.