bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterizing Frailty in Myeloproliferative Neoplasms: Baseline Results from the Orchid Study
Authors: Jackson Chornenki Nicholas L , Karampatos Sarah , Leong Darryl , Siegal Deborah M , Hillis Christopher M. 
Published: November 2020

Background: Contemporary treatment of Myeloproliferative Neoplasms (MPNs) has altered their natural history. Frailty, a state of reduced physiologic reserve is prevalent among older individuals, and increases risk for cardiovascular disease (CVD) and other adverse health outcomes. However, little is known about frailty in MPNs. An improved characterization of frailty may inform MPN treatment goals including the impact of treatment on frailty and CVD.
Methods : We utilized the ORCHID database, a multi-centre prospective observational registry of MPN patients. Frailty-related factors collected included: unintentional weight loss (&gt;4kg lost in prior year); grip strength (below 20th percentile for age and sex); Timed Up and Go test (TGUG) greater than 13.5 seconds (indicative of high fall risk); self-reported exhaustion; and cognitive frailty measured by the Digit Symbol Substitution test (DSST). Baseline information on cardiovascular event history was also collected.
Results: In total, 150 patients were included (56 CML, 28 ET, 14 PMF, 52 PV). Baseline information and past medical history are detailed in Table 1. Cardiovascular events prior to diagnosis were most common in patients with PV (7.7% MI and 5.8% stroke). Past medical history of Venous Thromboembolism (VTE) was more common in Ph-negative MPNs (15.3% PV, 21.4% PMF, 21.4% ET) compared to CML where VTE history was absent. Hypertension and dyslipidaemia were overall the most common cardiovascular comorbidities. The burden of depression was highest in PMF with 30.7% of patients reporting a PHQ-9 score ≥ 10. Frailty related outcomes are detailed in Table 2. All four MPNs had high rates of frailty in every domain at baseline. Among Ph- MPNs (ET, PV, and PMF), ET and PV patients generally had a lower burden of frailty compared to PMF patients in most measurements. A high risk of falls as determined by a prolonged get-up-and-go test was present in approximately 20% of PV, CML, and ET patients and 42% of PMF patients. ET patients had the lowest self-reported exhaustion, with less than 40% reporting they ever felt "everything was an effort" or that they "just couldn't get going". PMF patients had the highest self-reported exhaustion. The proportion of patients with low DSST scores was greater in PMF (38.5%) and PV patients (24.3%) than ET (20%) and CML (15%) patients. Unintentional weight loss was common across MPN patients (33.9% to 50%).
Conclusion: There is a high rate of baseline frailty among patients with MPNs with domains differing between diseases. In this cohort, cardiovascular event history at diagnosis was highest among PV patients and lowest in CML patients.

Disclosures
Siegal: Leo Pharma: Honoraria; Novartis: Honoraria; Portola: Honoraria; Bayer: Honoraria; BMS Pfizer: Honoraria. Hillis:Roche: Honoraria.
Predictors of All Cause Post Operative Bleeding in Patients with Left Ventricular Assist Device
Authors: Elkayam Natalie , Gegechkori Nana , Bernstein Aryeh , Lipshitz Jay 
Published: November 2020

Background:Patients with implanted left ventricular assist device (LVAD) have been shown in multiple studies to have significantly increased bleeding rates, and yet independent risk factors for such complications remain poorly characterized.
Objective:This study sought to assess factors associated with increased bleeding risks after LVAD implantation.
Methods: The case-control study was represented by a retrospective electronic medical chart review for all adult patients above age 18, who had the LVAD implanted at Maimonides Medical Center from 2013-2018. The study comprised of a follow up period of 24 months after the LVAD implantation.
84 adult patients with implanted LVADs at Maimonides Medical Center were included in the study. The predictors among patients with any late postoperative bleeding (&gt;7 days post-surgery) within the study period were compared to those without any events of interest. The outcome measure was a composite variable reflecting any bleeding event, such as upper and lower gastrointestinal (GI) bleed, intracranial hemorrhage or hemorrhage in any other organ. Patients were considered to have GI bleed if they had one or more of the following symptoms: guaiac-positive stool with hemoglobin drop &gt;2g/dL, hematemesis, melena, active bleeding or blood within the GI tract at the time of endoscopy or colonoscopy. Intracranial or other organ bleeding was defined as appropriate clinical presentation and findings on imaging with hemoglobin levels reduced by more than or equal to 2 g/dl with no alternative explanation for anemia.
Logistic regression was used to create a multivariable model to identify predictors associated with an increased risk of all cause bleeding within 24 months after LVAD implantation.
Results: The study population consisted of 43 cases and 41 controls. Baseline characteristics were similar in both groups. A total of 43 (51%) patients had at least 1 episode of any type of bleed within study period.
Multivariable analyses showed that blood urea nitrogen (BUN) &gt;20 before LVAD implantation and Creatinine &gt;1.2 at the time of bleeding were significantly associated with all cause bleeding risk within 24 months after surgery with odds ratio (OR): 4.46, 95% confidence interval (CI): 1.78 to 11.15 and OR 3.55, 95% CI 1.13 to 11.15 respectively.
Conclusions: Perioperative BUN &gt;20 (p=0.001) and postoperative Creatinine &gt;1.2 (p=0.03) are associated with higher incidence of all cause bleeding within 24 months after surgery among patients with LVAD. Future studies should evaluate whether there are other factors accurately predicting bleeding events in order to improve outcomes.

Disclosures
No relevant conflicts of interest to declare.
Comparative Efficacy of First-Line Chemotherapy-Free Combinations in Chronic Lymphocytic Leukemia (CLL): A Network Meta-Analysis
Authors: Haddad Philip A , Ganey Nowell , Gallagher Kevin M. 
Published: November 2020

Introduction:
Chronic Lymphocytic Leukemia (CLL) is an incurable B-cell malignancy which disproportionately affects the elderly. Although first-line chemoimmunotherapy (CIT) improved CLL clinical outcomes, recent randomized trials revealed superior outcomes with novel chemotherapy-free combinations (CFC) incorporating anti-CD20 monoclonal antibodies and inhibitors of BTK or Bcl-2. So far, these CFC have not been compared head-to-head. We conducted this network meta-analysis to evaluate their relative efficacy to each other.
Methods:
A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language; diagnosis of CLL; trials that explored the efficacy of first-line CFC with Obinutuzumab (O), Rituximab (R), Ibrutinib (IB), Acalabrutinib (ACAL), Venetoclax (VEN) compared to standard CIT that included Chlorambucil (CHLOR) with either R or O, Bendamustine+Rituximab, or Fludarabine+ Cyclophosphamide+R; and phase 3 randomized studies reporting responses, progression, death, and adverse (AE) events. A frequentists network meta-analysis was conducted using netmeta package and random-effects model.
Results:
Five studies comprising a total of 2,272 participants were included. When O-based CFC data was analyzed, only ACAL-O had a significant lower relative risk (RR) of progression and death (P&D). There were no significant differences with respect to overall response rates (ORR), complete remission (CR), minimal residual disease (MRD), or grade &gt;3 adverse events (Grd3+) among O-based CFC. When R-based CFC data was analyzed, IB and IB-R were not different with respect to RR of P&D, ORR, CR, MRD, or Grd3+. When the data was analyzed as CFC versus combined CIT, only ACAL-O was found to be significantly superior to other O- and R-based CFC with respect to RR of P&D. ORR and Grad3+ rates of O- and R-based CFC were not significantly different. While ACAL-O, IB-O, and VEN-O had superior CR and MRD rates compared to other CFC, there were no significant differences among each other.
Conclusions:
This network meta-analysis is the first to compare and rank first-line CFC therapies in CLL. It indicates that ACAL-O has a superior profile having the lowest RR of P&D without significant difference in Grd3+ among CFC.

Disclosures
No relevant conflicts of interest to declare.
The Asia-Pacific Myeloma and Related Diseases Registry: Preliminary Results of Real-World Treatment Patterns and Clinical Outcomes
Authors: Huynh Kim , Aoki Naomi , Kim Kihyun , Chng Wee Joo , Gan Gin Gin , Min Chang-Ki , Lee Je-Jung , Goh Yeow Tee , Wellard Cameron , McQuilten Zoe , Moore Elizabeth M. , Wood Erica M. , Spencer Andrew 
Published: November 2020

Background and Aims: The Asia-Pacific (APAC) Myeloma and Related Diseases Registry (MRDR) collects data on epidemiology, treatment and outcome trends for patients with multiple myeloma (MM) in participating regional countries. Prevalence of MM is expected to continue to increase with ageing populations and improvements in survival. Although some MM data are available for Asia, very few exist at regional level. Generation of 'real world evidence' on practice and outcomes is important to complement data from clinical trials. In the APAC MRDR, regional clinical experts provide local clinical context and registry oversight, and participating hospitals obtain local ethics approval and manage patient recruitment and data collection.
Methods: The APAC MRDR prospectively collects observational data on patient characteristics, diagnosis, medical history, treatment (including supportive therapies), and outcomes (overall and progression-free survival, and quality of life using the EQ-5D-5L) on newly diagnosed MM (NDMM), plasma cell leukaemia, plasmacytoma, and MGUS patients via a secure, country-specific, web-based database. Participants are reviewed 4-monthly for a minimum of 2 years. Preliminary data from October 2018 to June 2020 were analysed.
Results: 20 hospitals have ethics approval to participate and patient recruitment has commenced at 14 hospitals in Korea, Singapore, and Malaysia. Sites in Taiwan will also start recruitment in 2020, and sites in China have been identified. To date, a total of 469 patients (419 NDMM) have been enrolled, of which, data from 348 (83%) NDMM participants from Korea, Singapore, and Malaysia were available for analysis. Results are presented in Table 1.
Summary and Conclusions: The APAC MRDR is now successfully established and expanding. As data mature, these will provide important new information on the epidemiology and treatment of MM across the APAC region, and provide opportunities for regional benchmarking and collaborative research.

Disclosures
Spencer: Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding; Secura Bio: Consultancy, Honoraria; Pharmamar: Research Funding; Roche: Honoraria; Servier: Consultancy, Honoraria, Research Funding; HaemaLogiX: Consultancy, Honoraria, Research Funding.
Clinicopathological Features of Hematological Malignancies Presenting As Breast Lesions on Mammography: The Mount Sinai Medical Center Experience
Authors: Galarza Fortuna Gliceida , Dvir Kathrin , Febres-Aldana Christopher , Delgado Ruben , Gonzalez Ferrua Maria , Poppiti Robert , Sriganeshan Vathany 
Published: November 2020

Background:Breast involvement by hematological malignancies is extremely rare and encompasses approximately 1% of all breast tumors. In this retrospective data review, we aimed to evaluate the clinical, pathological and radiographic characteristics of hematological malignancies involving the breast.Methods:Our database was searched for "leukemia", "lymphoma" and "myeloma" in reports of breast biopsies, obtained between August 2009 and August 2019. A total of 13 cases met inclusion criteria.Results:A total of 13 breast biopsies with the diagnosis of leukemia or lymphoma were identified. All samples were obtained through ultrasound guided core needle biopsy. All 13 patients were females, 61.54% Caucasian, 15.38% Black, 15.38% Hispanic and 7.7% Asian, with median age of 71 years. In 8/13 patients (61.54%), a palpable breast lesion prompted the imaging study, while the remaining 5/13 patients (38.46%) were detected on routine screening mammography. Average lesion size was 2.7cm (±2.47cm, SD). On mammogram, 61.5% of cases were described as BIRADS 4, 30.8% as BIRADS 0 and 7.7% as BIRADS 5. Pathological evaluation revealed all cases (100%) were lymphomas. The commonest lymphoma subtype was marginal zone B-cell Lymphoma (MZL) (38.48%), followed by diffuse large B cell lymphoma (DLBCL) (15.38%) and small lymphocytic lymphoma (SLL) (15.38%). Burkitt's lymphoma (7.69%), follicular lymphoma (7.69%), hairy cell leukemia (7.69%) and lymphoplasmacytic lymphoma (7.69) were also identified. Primary breast lymphoma (PBL) was identified in 4/13 patients (30.77%), while in 9/13 (69.23%) the breast lesion were secondary breast lymphomas (SBL). Treatment options for patients with PBL consisted of local radiation in two patients, R-CHOP chemotherapy in one patient and immunotherapy with rituximab plus radiation in one patient. Patients with SBL received systemic chemotherapy. None of the patients were treated surgically.Conclusion:Hematological malignancies involving the breast can present as a palpable or subclinical lesions with a high BIRADS on mammography. MZL was the predominant subtype, followed by DLBCL and SLL. PBL can be a localized disease suitable for conservative management.

Disclosures
No relevant conflicts of interest to declare.
Safety and Efficacy of Purine Analogs for Treatment of Waldenstrom Macroglobulinemia
Authors: Dar Abdul Jabbar , Khurshid Qasim , Ahmad Muhaddis Ejaz , Mirza Muhammad Ali , Khalid Farhan , Tayyeb Muhammad , Abdullah Syed Maaz , Farooqi Muhammad Saad , Khan Sana Irfan , Kashyap Richi , Javed Saad , Faizan Unaiza , Anwer Faiz 
Published: November 2020

Introduction:
There are about 1500 cases every year in the United States of America and while the disease is incurable but it is treatable. Purine analogs are anti-metabolites that mimic the structure of metabolic purines and are used for the treatment of Waldenstrom macroglobulinemia (WM).
Methods:
We performed a comprehensive literature search on articles following PRISMA guidelines. Beginning with articles published after 1995, we used databases like PubMed, Embase, Clinicaltrials.gov, Cochrane Library and Web of Science. Total 580 articles were identified initially and after detailed screening, we finalized 16 studies involving patients with Waldenstrom macroglobulinemia.
Results:
The total number of patients in the studies involving regimens based on purine analogs were 1211. The doses of Fludarabine ranged from 25-30 mg/m2 and that of Cladribine ranged from 0.1-0.5 mg/kg. The complete response (CR) observed ranged from 2-15% and the partial response (PR) ranged from 11-67%. The overall response rate (ORR) ranged from 38-95%.
Fludarabine:
In the study Dhodapkar et al., N=231, the highest CR and ORR was observed, 4% and 66% respectively. In the study Zinzani et al., the PR was 41%.
Fludarabine and Cyclophasphamide:
In the study Dimopoulos et al., the PR was 55% and the progression free survival (PFS) was 24 months.
Fludarabine, Cyclophosphamide and ofatumumab:
In the study Gavriatopoulou et al., the PR was 67% and very good partial response (VGPR) was 17% and the PFS was 23 months.
Fludarabine, rituximab and cyclophosphamide:
In the study Tedeschi et al., the CR was 11.60%, ORR was 79% and the PR was 41.8%.
Fludarabine and Rituximab:
In the study Treon et al., the CR was 4.6%, VGPR was 32.5%, PR was 48%, and ORR was 95.3% with PFS of 51.2 months.
Cladribine:
In the study Liu et al., the CR was 5% and PR was 50%. In the studies Dimopoulos et al., 1994 the highest CR was observed, 11.5% with an ORR of 85%. The PR was also the highest, 73%.
Conclusion:
There is limited literature on regimens containing both Fludarabine and Cladribine, which are used for the treatment of WM. Despite heterogenicity in WM patients and various regimens used in literature. Purine analogs containing regimens are a remarkably effective treatment with overall response rates reaching up to 79%. Neutropenia and thrombocytopenia were the main side effects. There is a paucity of phase 3 randomized trials demonstrating a clinical benefit of anyone regimen over another. We recommend future randomized prospective trials better to understand the efficacy and safety profile of regimens containing purine analogs.

Disclosures
Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.
Clinical Characterization and Risk Factors Associated with Cytokine Release Syndrome Induced By COVID-19 and Chimeric Antigen Receptor T-Cell Therapy
Authors: Hong Ruimin , Zhao Houli , Wang Yiyun , Chen Yu , Cai Hongliu , Hu Yongxian , Wei Guoqing , Huang He 
Published: November 2020

Background: An excessive immune response during coronavirus disease (COVID-19) can induce cytokine release syndrome (CRS), which is associated with life-threatening complications and disease progression.
Methods: This study was aimed to investigate the differences and similarities between CRS induced by COVID-19 and CAR-T therapy, then provide valuable experiences for early identification and controlling CRS progression in COVID-19. We retrospectively evaluated the clinical characteristics of severe CRS (sCRS, grade 3-4) induced by COVID-19 (40 patients) or chimeric antigen receptor T-cell (CAR-T) therapy as a comparator (41 patients).
Results: Grade 4 CRS was significantly more common in the COVID-19 group (15/40 [35.7%] vs. 5/41 [12.2%], P=0.008). CAR-T group had more more dramatic increase in cytokine than COVID-19 group (Figure1), including IL-2 (7.3pg/mL [IQR: 2.0-12.7] vs.1.7 [0.7-2.7], P&lt;0.001), IL-6 (7120.6 pg/mL [1066.8-15 136.4] vs. 110.3 [41.7-728.1], P&lt;0.001), IL-10 (174.5pg/mL [61.7, 434.6] vs. 10.1 [6.3-20.6], P&lt;0.001) and IFN-γ (1308.5pg/mL [296.6, 3108.2] vs .35.0 [16.9-60.8], P&lt;0.001). Interestingly, COVID-19 group had significantly higher levels for TNF-α (31.1 pg/ml [16.1-70.0] vs. 3.3 [1.8-9.6], P&lt;0.001).The correlations between viral load/ tumor burden and various cytokine levels were shown in Figure 2. Lg viral loads were correlated with lg IL-6 (R2=0.101; P&lt;0.001) and lg IL-10 (R2=0.105; P&lt;0.001) .In CAR-T group, LDH was a common indicator related to tumor burden among patients with ALL, NHL, and MM. The lg LDH concentration was correlated with the lg serum concentration of IL-6 (R2=0.161; P=0.01). The independent risk factors for COVID-19-related sCRS were hypertension history (OR: 7.167, 95% CI: 2.345-21.903; P=0.001) and minimum platelets &lt;100×109 /L during disease course (OR: 9.237, 95% CI: 2.544-33.546; P=0.001).
Conclusion: Our study demonstrated that there were similar processes but different intensity of inflammatory responses of sCRS in COVID-19 and CAR-T group. The diagnose and management of COVID-19 related sCRS can learn lessons from treatment of sCRS induced by CAR-T therapy.
Keywords: Cytokine release syndrome, COVID-19, Chimeric antigen receptor T-cell therapy
Figure 1

Disclosures
No relevant conflicts of interest to declare.
Risk Mitigation Strategy for Concizumab Clinical Trials after Pause Due to Non-Fatal Thrombotic Events
Authors: Seremetis Stephanie Valer , Cepo Katarina , Skovgaard Rasmussen Josephine , Høyer Rose Trine , Tamer Søren , Porstmann Thomas , Haaning Jesper 
Published: November 2020

Introduction Concizumab, a humanized recombinant monoclonal antibody directed against the tissue factor pathway inhibitor, is under investigation as a subcutaneous prophylactic treatment for patients with hemophilia A or B (HA/HB) with and without inhibitors. In the concizumab phase 2 trials, treatment was well tolerated and a favorable safety profile was shown, with no deaths or thromboembolic events and no adverse events (AEs) leading to withdrawal. We describe the non-fatal thrombotic serious AEs (SAEs) that occurred during the pivotal phase 3 explorer7 (NCT04083781) and explorer8 (NCT04082429) concizumab trials and the risk mitigations incorporated in the explorer clinical trials.
Methods The explorer7 and explorer8 trials were initiated in late 2019 to evaluate the efficacy and safety of concizumab prophylaxis in HA/HB patients with/without inhibitors, respectively. Concizumab was administered subcutaneously with a 1.0 mg/kg loading dose (concizumab-naïve patients only) and a maintenance dose of 0.25 mg/kg daily from the second day onwards.
Results In March 2020, explorer7 and explorer8 were paused due to the occurrence of two arterial and three venous thrombotic SAEs in three patients with HA or HB with inhibitors. All three patients had thrombotic risk factors present at baseline and had used concomitant hemostatic medication on the day of, and in two cases in the days up to, event onset. Two of the patients were among those with the highest concizumab exposure measured during phase 3. Laboratory parameters in all three patients were as expected. Based on these analyses, risk mitigation plans were developed, including guidelines for the concomitant use of hemostatic agents in the management of bleeding episodes while on concizumab prophylaxis and updates to the concizumab dosing regimen.
Conclusion Novo Nordisk has assessed all available data and defined risk mitigation strategies and changes to the explorer trial protocols.

Disclosures
Seremetis: Novo Nordisk Ins: Current Employment, Current equity holder in private company. Cepo:Novo Nordisk: Current Employment. Skovgaard Rasmussen:Novo Nordisk: Current Employment. Høyer Rose:Novo Nordisk A/S: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Tamer:Novo Nordisk: Current Employment, Current equity holder in private company, Divested equity in a private or publicly-traded company in the past 24 months. Porstmann:Novo Nordisk Health Care A/G: Current Employment. Haaning:Novo Nordisk: Current Employment, Current equity holder in publicly-traded company.
ANGPTL2-Containing Exosomes from Vascular Endothelial Cells Promote Leukemia Development
Authors: Sun Guohuan , Huang Dan , Hao Xiaoxin , He Xiaoxiao , Zheng Zhaofeng , Chen Chiqi , Yu Zhuo , Xie Li , Ma Shihui , Liu Ligen , Zhou Bo , Cheng Hui , Zheng Junke , Cheng Tao 
Published: November 2020

Exosomes are functional messengers of certain cellular niches to permit non-contact cell communications. Whether niche-specific exosomes fulfill this role in cancer is unclear. Here, we show that blocking exosome secretion from endothelial cells (ECs), but not perivascular cells, megakaryocytes or spleen stromal cells, markedly delayed the progression of acute myeloid leukemia (AML). Notably, reducing exosome production from ECs had no effect on normal hematopoiesis. EC-derived exosomes contained a high level of ANGPTL2, which supported AML development via binding to LILRB2 receptor. Moreover, ANGPTL2 exosome released from ECs was governed by VPS33B. These findings demonstrate a role of niche-specific exosomes in cancer development and suggest that targeting ANGPTL2 exosomes from ECs might be a potential strategy to interfere AML.

Disclosures
No relevant conflicts of interest to declare.