bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional Characterization of Baxter's Recombinant Human ADAMTS13 Drug Candidate.
Authors: Rottensteiner Hanspeter , Plaimauer Barbara , Schrenk Gerald , Schmidt Michaela , Gruber Bernadette , Schreiner Jutta , Turecek Peter L , Scheiflinger Friedrich 
Published: October 2019

Abstract
Abstract 2235
Baxter has developed a human recombinant (r) ADAMTS13 for treatment of patients with hereditary TTP. Here we characterize preclinical and clinical lots of rADAMTS13 with respect to their functional properties.
The ability of rADAMTS13 to degrade human full-length rVWF under moderate denaturing conditions was analyzed by two functional assays (VWF:CB and VWF:RCo activity) and by gel electrophoresis (multimer analysis and immunoblot analysis). In all assays, the extent of rVWF degradation served as a direct measure for ADAMTS13 activity.
VWF:CB activity of rVWF was reduced upon incubation with rADAMTS13, with only minimal differences between the individual batches. VWF:RCo activity of rVWF also declined after exposure to rADAMTS13, with no relevant differences between rADAMTS13 batches. Likewise, VWF multimer analysis demonstrated the disappearance of high molecular weight multimers upon incubation with rADAMTS13. Non-reducing SDS-PAGE followed by immunostaining using a polyclonal anti-human VWF antibody clearly showed the appearance of the C-terminal and N-terminal VWF fragments, with no visible differences in the intensity of these bands between preclinical and clinical Phase I rADAMTS13 batches.
Proteolytic activity of rADAMTS13 towards its multimeric VWF substrate was confirmed in two flow-based assays using full-length rVWF as substrate. One assay was based on the VenaFlux platform technology and determined the rADAMTS13 concentration-dependent decrease of the surface coverage of fluorescently-labeled platelets that had been perfused together with red blood cells and rVWF over an adhesive surface of a microcapillary. The other assay measured the extent of VWF cleavage product generation after subjecting a reaction mixture consisting of multimeric rVWF, lyophilized platelets and rADAMTS13 to fluid shear stress on a vortex mixer. Both assays revealed a high comparability between preclinical and clinical batches.
All assays thus demonstrated consistency between rADAMTS13 batches over different production stages. Importantly, comparability was also shown between the ADAMTS13 activity measured by the assays using full-length VWF as substrate and FRETS-VWF73 assay used for potency assignment of rADAMTS13.

Disclosures:
Rottensteiner: Baxter Innovations GmbH: Employment. Plaimauer:Baxter Innovations GmbH: Employment. Schrenk:Baxter Innovations GmbH: Employment. Schmidt:Baxter Innovations GmbH: Employment. Gruber:Baxter Innovations GmbH: Employment. Schreiner:Baxter Innovations GmbH: Employment. Turecek:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment.
FDG-PET/CT Early After 90Y-Ibritumomab Tiuxetan Therapy Predicts Outcome in Relapsed or Refractory Indolent B-Cell Lymphoma
Authors: Okada Masaya , Fujimori Yoshihiro , Oku Naohiko , Tamekane Akira , Takafuta Toshiro , Nakajima Toshiyuki , Tokugawa Tazuko , Sawada Akihiro , Ishii Shin-ichi , Kaida Katsuji , Ikegame Kazuhiro , Soma Toshihiro , Ogawa Hiroyasu 
Published: October 2019

Abstract
Abstract 3648

Background:
Radioimmunotherapy (RIT) with 90Y-ibritumomab tiuxetan has been used for the treatment of relapsed or refractory indolent B-cell lymphoma. Early prediction of response to the therapy may offer the potential to identify patients who will benefit this therapy. We evaluated the efficacy of fluorine 18 fluorodeoxyglucose (FDG) combined positron emission tomographic-computed tomographic (FDG-PET/CT) imaging for assessment of therapy and predicting outcome in 90Y-ibritumomab tiuxetan radioimmunotherapy.

Methods:
Radioimmunotherapy with 90Y-ibritumomab tiuxetan was preformed in 52 patients with relapsed or refractory indolent B cell lymphoma (follicular lymphoma, 45; mucosa-associated lymphoid tissue lymphoma, 5; lymphoplasmacytic lymphoma, 2) at Hyogo College of Medicine Hospital from June 2009 through August 2012. FDG-PET/CT scanning was performed at two weeks and the later after 90Y-ibritumomab tiuxetan therapy.

Results:
In FDG-PET at 2 weeks after 90Y-ibritumomab therapy, 26 (50%) showed complete response (defined as early CR), 20 (38%) showed partial response (PR-2W) and 6 (12%) showed non response (NR-2W). Further follow-up revealed 10 later CR (8 CR out of 20 PR-2W and 2 CR out of 6 NR-2W), showing 69 %(36) of overall CR rate. Relapse was occurred in 4(17%) of 26 early CR and in 6 (60%) of 10 later CR, indicating significantly low relapse late in early CR (P= 0.0074, by Chi-square test). Patients with early CR (CR in 2 weeks after the RIT) showed significantly better progression free survival than those with later CR (P=0.0046, by Logrank test). In contrast, analysis at six weeks after the RIT showed 36 CR patients (10 of which eventually relapse), but failed to discriminate patients who had high risk of relapse.

Conclusion:
Our results suggest that CR assessed by FDG-PET/CT at 2 weeks after 90Y-ibritumomab tiuxetan therapy discriminates good responder to the RIT and predicts better progression free survival in relapsed or refractory indolent B cell lymphoma.

Disclosures:
No relevant conflicts of interest to declare.
Clinical Phase II Study of a Non-Anthracycline-Based Immunochemotherapy Regimen(R-GemOx) As First-Line Treatment in Elderly Patients with Diffuse Large B-Cell Lymphoma
Authors: Fan Lei , Wang Li , Xu Ji , Zhang Run , Wang Rong , Xu Wei , Li Jianyong 
Published: October 2019

Abstract
Abstract 3667

Introduction:
Anthracycline-based regimen(CHOP and CHOP-like regimens) is still the most widely used treatment of elderly patients with diffuse large B-cell lymphoma (DLBCL), but because of low rates of the overall response, high incidence of co-morbidities and treatment-related adverse effects, the prognosis of these patients remain dismal. Our aim was to develop a non-anthracycline-based immunochemotherapy regimen, rituximab combination with GemOx (gemcitabine and oxaliplatin) for elderly patients with DLBCL and investigate the safety and preliminary efficacy of this regimen.

Design and Methods:
This study was a prospective, single-arm clinical trial. Eligible patients was previously untreated, CD20 positive DLBCL patients diagnosed by biopsy, ≥70 years of age or ≥60 years with ECOG PS of ≥2. Therapeutic protocol of R-GemOx regimen was as follows: rituximab 375 mg/m2 i.v. on day 1; gemcitabine 1 g/m2 i.v. on day 2; oxaliplatin 100 mg/m2 i.v. on day 2, each cycle of treatment was administered every 14 to 21 days according to recovery of toxicities. Patients who responded to the treatment and did not have disease progression received up to six cycles of R-GemOx treatment.

Results:
15 patients were enrolled between July 2010 and April 2012 and 12 patients were eligible to evaluate. Patients were 41.7% (5/12) male with median age 73(range: 61–85 yrs), three patients (25.0%) were <age 70. ECOG PS ≥2 was 11/12 and the international prognostic score (IPI) enrolled to study was low risk group (0–1 score) 0/12, low intermediate group (2 score) 4/12, high intermediate (3 score) 2/12 and high risk group (4–5 score) 6/12. Evaluation of response was according to response criteria for lymphoma: The overall response rate (ORR) among treated pts was 75.0% (CR/CRu, 5; PR, 4); one patient (8.3%) had SD and 2 patients (16.7%) had PD. With a median follow-up of 7 (4–26) months, the median overall survival (OS) and the progression-free survival (PFS) have not been achieved. In terms of toxicities, most treatment related adverse events (AEs) were mild or moderate in severity. The most common grade ≥3 AEs were bone marrow depression (25.0%) and gastrointestinal complications (16.7%), no impairment of kidney and heart were observed.

Conclusions:
This is the first clinical study to investigate the safety and efficacy of R-GemOx regimen in elderly patients with DLBCL. Rituximab combination with GemOx appears highly active and favorable toxicity profiles in elderly patients with DLBCL requiring treatment, the encouraging preliminary data suggest R-GemOx is a promising first-line regimen for this subgroup of patients, and further evaluation is required.

Disclosures:
No relevant conflicts of interest to declare.
Bortezomib + DA-EPOCH-R Induction Therapy Followed by Maintenance Bortezomib Versus Observation in Newly Diagnosed Mantle Cell Lymphoma
Authors: Dunleavy Kieron , Grant Cliona , Hessler Julieanne , Miller Barry W. , Steinberg Seth M. , Pittaluga Stefania , Roschewski Mark , Jaffe Elaine S. , Wiestner Adrian , Wilson Wyndham H. 
Published: October 2019

Abstract
Abstract 3672

Background:
Bortezomib, a proteasome inhibitor, is effective in relapsed/refractory mantle cell lymphoma (MCL) and achieves responses in up to 50% of patients. While its mechanisms of action are broad, in MCL, brotezomib causes cell cycle arrest and induces apoptosis through oxidative/ER stress-mediated up-regulation of noxa. DA-EPOCH-R is an effective platform in MCL. We set out to assess the efficacy of bortezomib in combination with DA-EPOCH-R in newly diagnosed MCL and to assess the efficacy of maintenance bortezomib following induction.

Methods:
Treatment was divided into three parts: Part A - bortezomib (1.3 or 1.5 mg/m2) on days 1, 4, 8 and 11 for one cycle; Part B - bortezomib (1.3mg/m2) on days 1 and 4 of DA-EPOCH-R (as previously described) for 6 cycles; Part C patients in CR or PR after Part B and without significant neurotoxicity were randomized to maintenance bortezomib (1.3 mg/m2 d 1, 4, 8 and 11 q 8 wks for 18 mos) or observation.

Results:
Patient characteristics (n=43): median (range) age 58 (41–75); 45% were aged 60y or over; male sex 32 (73%); stage IV disease 100%. At 48 months (with 57 months median potential follow-up), PFS is 50% and OS is 80%. Twenty-four patients randomized to maintenance bortezomib (13) or observation (11) had a similar PFS (p=0.41) (see attached curve). Overall, 50% of patients had at least grade 2 neurotoxicity. At the recommended 1.3mg/m2 dose of bortezomib, 33% of patients required a dose reduction or discontinuation of drug. Other significant toxicities were neutropenic fever/infection in 8% of cycles and grade 3 or 4 thrombocytopenia in 34% of cycles.

Conclusions:
Bortezomib in combination with DA-EPOCH-R is an effective strategy in patients of all ages with MCL. Maintenance bortezomib (versus observation) does not improve the PFS. However, compared to our historical patients treated with DA-EPOCH-R alone, patients who received DA-EPOCH-R and bortezomib have a significantly better PFS at 48 months (50% versus 19%, respectively). These preliminary results suggest that bortezomib with immunochemothearpy may improve PFS. Accrual continues and responses will be correlated with translational end-points on biopsied tissue sampled before and after bortezomibalone (Part A).

Disclosures:
No relevant conflicts of interest to declare.
Phase I/II Study of Myeloablative Anti-CD20+ Radioimmunotherapy with I-131-Rituximab in High-Risk CD20-Positive Non Hodgkin Lymphoma
Authors: Schwarz Kathleen , Julia Wagner , Schreiber Susanne , Schmidt Burkhard , Hoellein Alexander , Verbeek Mareike , Schwaiger Markus , Peschel Christian , Scheidhauer Klemens , von Schilling Christoph , Keller Ulrich 
Published: October 2019

Abstract
Abstract 3700

Background:
Radioimmunotherapy (RIT) has been successfully used to treat primary and relapsed/refractory CD20+ Non-Hodgkin-Lymphoma (NHL). Myeloablative anti-CD20 RIT allows delivering high radiation doses to lymphoma sites when followed by autologous stem cell infusion (autoSCT). However, RIT is infrequently used at present and long-term data is lacking.

Patients, Design and Methods:
23 patients with relapsed/refractory CD20+ NHL who did not achieve a complete response to salvage chemotherapy were enrolled in this Phase I/II trial to evaluate RIT with 131I-labelled Rituximab (131I-R) in a myeloablative setting between January 2000 and October 2004. Biodistribution and dosimetry studies were performed in all patients to determine 131I activity required to induce a total body dose of 21 to 27 Gy to the critical organs lung and kidney. In 6/23 patients RIT was combined with high dose chemotherapy (HD-CTx) followed by autoSCT. 8/23 patients received a sequential HD-CTx with a second autoSCT. The median follow-up is 9.5 years.

Results:
188–525 mCi 131I were delivered to achieve the limiting organ dose. No grade 3/4 non-hematologic toxicity was seen with RIT alone. Significant grade 3/4 toxicity (mucositis, neutropenic fever, pneumonia, sepsis) including one therapy related death was observed in all patients treated with RIT combined with HD-CTx/autoSCT. The overall response rate was 87% (64% complete response rate). The median progression free (PFS) and overall survival are 47.5 and 101.5 months. After long-term follow up, 9 patients are progression free and 10 patients are alive. An elevated (>1) international prognostic index (IPI) was most predictive for overall survival.

Conclusion:
Myeloablative 131I-Rituximab RIT followed by autoSCT is feasible, well tolerated and effective in high risk CD20+ NHL and prolongs PFS compared to last standard chemotherapy. Patients additionally treated with high dose chemotherapy experienced significantly increased toxicity. Long-term results for progression free survival and overall survival in this trial are encouraging.

Disclosures:
No relevant conflicts of interest to declare.
Long-Term Follow-up of Chronic Phase Chronic Myeloid Leukemia Patients Who Failed Interferon Alpha and Switched to Imatinib
Authors: Breccia Massimo , Loglisci Giuseppina , Salaroli Adriano , Serrao Alessandra , Zacheo Irene , Latagliata Roberto , Alimena Giuliana 
Published: October 2019

Abstract
Abstract 3742
Few data were reported about the long-term outcome of patients treated with imatinib after interferon-alpha (IFN) failure. Recently, MDACC group reported a 10-year survival rate of 68%. We report here the outcome of 134 adult Ph+ CML patients who switched to imatinib after IFN failure. Response criteria used are in accordance to ELN guidelines; survival was calculated from start of imatinib until death for any cause, progression-free survival (PFS) was calculated from start of imatinib to advent of accelerated/blastic phase or death for any cause and event-free survival (EFS) was calculated from start of therapy to development of any event leading patient to discontinue the drug. There were 74 males and 60 females, median age was 47 years. Median follow-up was 96 months. Sokal score identified 66 patients as low risk, 49 patients as intermediate and 17 as high risk, whereas Eutos score identified 107 patients as low risk and 10 patients as high risk. Overall, 103 patients (76.8%) achieved a CCyR as their best cytogenetic response and 68 (51%) achieved a MMR, after a median time of 52 months. Complete molecular remission (CMR, undetectable transcript according to ELN recommendations) was achieved as the best response in 60 patients after a median follow-up of 76 months. The estimated 9-year overall survival rate was 74%, the PFS rate was 71% and the EFS was 54%. Progression to accelerated/blastic phase was detected in 19 patients. Due to resistance or intolerance to imatinib, 22 patients switched to dasatinib (12 patients for cytogenetic resistance, 5 patients for intolerance, 2 for molecular resistance and 3 for BC) and 17 patients switched to nilotinib (11 patients for cytogenetic resistance and 6 for molecular resistance): 18 patients (64%) achieved or maintained CCyR and 11 patients (35%) achieved MMR. Achieving at 12 months a CCyR or an MMR was associated with a significant better OS in the long-term (82%) as compared to less than PCyR (70%) or only CHR (12%). Baseline factors that correlated with a poor OS were clonal cytogenetic evolution, higher percentage of basophils and blast cells in peripheral blood, high Sokal and Eutos score, whereas age did not correlate with a worse OS. The results of our study support the validity of rescuing with imatinib patients failing IFN, with an estimated 9-year survival rate of 74% that is similar to that reported in other recent studies.

Disclosures:
No relevant conflicts of interest to declare.
Incidence of Late Chronic Anemia in Newly Diagnosed Patients with Chronic Myelogenous Leukemia Responsive to Imatinib
Authors: Volpicelli Paola , Latagliata Roberto , Breccia Massimo , Vozella Federico , Finsinger Paola , Carmosino Ida , Loglisci Giuseppina , Santopietro Michelina , Salaroli Adriano , Diverio Daniela , Mancini Marco , Tafuri Agostino , Alimena Giuliana 
Published: October 2019

Abstract
Abstract 3769
Anemia has been reported in about 5–8% of newly diagnosed patients with Chronic Myelogenous Leukemia (CML) treated with imatinib in the first 6 months of therapy, and has been generally regarded as transient like neutropenia and thrombocytopenia: in patients responsive to imatinib, however, it is still unclear if the prolonged treatment could induce the appearance of a late chronic anemia. To highlight this issue, we revised 104 CML patients (M/F 54/50, median age at diagnosis 58.0 years, interquartile range 43.3 – 70.2) treated at our Institution with 1st line imatinib therapy for at least 36 months and in stable complete cytogenetic response (CCyR). At the 36th month of imatinib treatment, a late chronic anemia (defined as Hb levels < 11 g/dl for > 6 months) was present in 16/104 patients (15.4%): the anemia was severe (Hb < 10 g/dl) in 10 patients (9.6%) and moderate/mild (Hb ≥ 10 < 11 g/dl) in 6 patients (5.8%). Clinical features at diagnosis of patients who had late chronic anemia at the 36th month compared to the remaining 88 patients without late anemia are shown in the Table:
Hb < 11 g/dl at the 36th month Hb ≥ 11 g/dl at the 36th month p M/F 6/10 48/40 0.209 Median age (yrs) (IR) 68.0 (58.9 – 75.4) 56.6 (43.1 – 69.1) 0.016 Sokal Score: Low 3 44 0.002 Int 8 39 High 5 5 Median Hb (g/dl) (IR) 11.6 (10.4 – 13.3) 12.7 (11.2 – 13.8) 0.098 Median WBC (× 109/l) (IR) 79.0 (33.2 – 136.6) 60.5 (31.8 – 112.4) 0.423 Median PLTS (× 109/l) (IR) 624 (299 – 835) 412 (296 – 557) 0.122
All patients with late chronic anemia had a low reticulocyte count and 7/16 a condition of iron deficiency with reduced serum ferritin but no clinical and instrumental sign of chronic blood loss: in this latter group, oral iron supplementation was always ineffective. Four out 16 patients (25%) needed 1 or more red cell transfusions during the follow-up. At landmark analysis from the 36th month of imatinib treatment, there was no significant difference in the cumulative 4-year overall survival for patients with and for those without late chronic anemia (80%, 95% CI 44.8 – 100%, vs 94%, 95%CI 85.8 – 100%, respectively; p=0.068). In conclusion, the occurrence of a late chronic anemia during long-lasting treatment with imatinib has been observed in > 15% of our responsive patients and was severe in about 10% of cases: its occurrence seems more common in elderly patients with higher Sokal score at diagnosis. Late chronic anemia does not seem to affect OS, but the real impact should be evaluated on a large cohort of patients.

Disclosures:
Tafuri: Sigma Tau Pharmaceuticals: Research Funding.
Identification of AADACL1 As a Novel Regulator of Human Platelets Via Chemoproteomics
Authors: Holly Stephen P. , Chang Jae Won , Niessen Sherry , Boulaftali Yacine , Smith Matthew C. , Phillips Ryan M. , Black Justin L. , Piatt Raymond , Li Weiwei , Weyrich Andrew S. , Bergmeier Wolfgang , Cravatt Benjamin F. , Parise Leslie V. 
Published: October 2019

Abstract
Abstract 381
A comprehensive knowledge of the platelet proteome is necessary for understanding important vascular pathologies such as myocardial infarction and stroke. To discover new signaling pathways in human platelets that may represent potential therapeutic targets, we took a combinatorial approach utilizing small library screening coupled with an innovative proteomics technique known as competitive activity based protein profiling (ABPP), a highly sensitive mass spectrometry (MS) technique that queries active enzymes from endogenous biological sources. Human platelets were pretreated with a novel carbamate library designed to interrogate enzymatically active proteins belonging to the serine hydrolase superfamily, which is estimated to represent 1% of the human proteome. Carbamate screening resulted in the identification of several novel inhibitors that reduced fibrinogen binding and P-selectin exposure on agonist-stimulated platelets. An endogenous protein target of the most selective inhibitor was identified by competitive ABPP as arylacetamide deacetylase-like 1 (AADACL1, also known as NCEH1), a lipid deacetylase implicated in cancer growth and atherosclerosis. Using highly selective second generation inhibitors of AADACL1 and MS-based metabolomics, we show that AADACL1 regulates platelet aggregation, Rap1 and PKC activation, lipid metabolism and fibrinogen binding. Elimination of AADACL1 protein levels via RNA interference in a megakaryocytic cell line that responds to platelet agonists also reduces inside-out signaling to αllbβ3. Furthermore, inhibition of AADACL1 reduces collagen-dependent thrombus growth under arterial shear conditions, suggesting that AADACL1 may be a relevant therapeutic target. Collectively, these data identify AADACL1 as a novel regulator of important signaling pathways in platelets and megakaryocytes and validate activity-based proteomics as a means to identify new classes of anti-platelet targets for thrombotic diseases.

Disclosures:
Parise: BD: Consultancy; Biogen-Idec: Consultancy; NIH: Research Funding; AHA: Research Funding; SCDAC-NIH: Membership on an entity's Board of Directors or advisory committees; BRI Milwaukee: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Eptifibatide, a glycoprotein IIb/IIIa inhibitor, was evaluated as treatment for acute pain episodes in patients with sickle cell disease.
A 15 Mg/M2/d Dose of Decitabine Confers Comparable Responses and Better Tolerance Than the Standard Regimen in MDS patients—results of a Multicenter Prospective Cohort Study
Authors: Li Xiao , Song Qiang , Chen Yu , Chang Chunkang , Wu Dong , Wu Lingyun , Su Jiying , Song Luxi , Zhang Zheng , Xu Feng , Hou Ming 
Published: October 2019

Abstract
Abstract 3832
To further optimize the decitabine schedule for the treatment of myelodysplastic syndrome (MDS), a multicenter, prospective cohort study was performed. Out of 80 MDS patients, 46 were treated with a reduced dose of 15 mg/M2/d of decitabine by daily intravenous infusion for 5 consecutive days every 4 weeks. The remaining 34 patients were treated with the standard dose of 20 mg/M2/d of decitabine for 5 days every 4 weeks. All of the clinical and experimental baselines, as well as the course number used, were statistically comparable for the two groups. The results showed that the patients receiving the reduced dose of decitabine achieved statistically comparable overall response rate (ORR) (63% vs 71%), complete remission (CR) (30% vs 26%), cytogenetic CR (50% vs 46%) and overall survival (OS) (20.5 vs 19.6 months) compared with the standard dosage group. The decitabine concentration in the blood at a fixed time point after drug intake was decreased in the reduced-dose group but showed a similar degree of p15ink4b grading for the responders in the two groups. A reduced dose caused less severe cytopenia, fewer cases of proven infection and a shorter median course interval (28 days vs 35 days in the standard-dose group). We concluded that a 15 mg/M2×5 day decitabine schedule yielded the same clinical benefit as the standard schedule and improved the bone marrow tolerance in this intermediate-sized cohort study. This trial was registered at www.clinicaltrials.gov as #ChiCTR-ONRC-12002004.

Disclosures:
No relevant conflicts of interest to declare.