bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recent Updates on Blinatumomab: A Bispecific T-Cell Engaging Antibody in Relapsed and Refractory B-Cell Acute Lymphoblastic Leukemia
Authors: Saleem Tabinda , Rafae Abdul , Wahab Ahsan , Ehsan Hamid , Neupane Karun , Rehman Mohammad Ebad Ur , Pachika Pranali , Ali Rabia , Ali Sundas , Anwer Faiz 
Published: November 2021

Abstract
Introduction: Blinatumomab is a bispecific T-cell engaging antibody that binds and allows CD3 cytotoxic T cells to recognize and eradicate CD-19 positive malignant B cells. Blinatumomab is currently under study for relapsed and refractory B-cell acute lymphoblastic leukemia (RR B-ALL).
Methods: A comprehensive literature search was conducted across various data sets, including PubMed, Cochrane, and Embase, and presented data in ASH and ASCO. A review of the most recent data is summarized in this abstract.
Results: Eight clinical trials are currently under various phases of the study evaluating blinatumomab in RR B-ALL. In the phase 1/2 trial by Locatelli et al., 110 patients treated with blinatumomab showed complete remission (CR) with &lt;5% blast cells of 62.7% at a dose of 5-15 µg/m 2. In phase 1b trial by Horibe et al., nine Japanese children received blinatumomab at a dose of 5 µg/m 2/day for week 1, followed by (f/b) 15 µg/m 2/day for week 2-4 and showed an CR in 56% patients.
In a phase II study, Martinelli et al., treated 45 patients at a dose of 9 µg/day in week 1, f/b 28 µg/day; 36% of the patients achieved CR. In another phase II trial by Gokbuget et al., a 15 µg/day dose in 20 patients resulted CR in 50% pts. Topp et al. reported CR of 43% in 39 patients, and Stein et al. reported 45% CR in 64 patients treated with a similar regimen.
In phase III trials, Rambaldi et al., reported 36% CR in 119 patients and, Kantarjian et al. reported CR of 43.9% in 271 patients treated with blinatumomab at a dose of 9 µg/day during week 1 and 28 µg/d onwards for up to 3 and 6 cycles, respectively.
In all the trials, blinatumomab was given via 4-week continuous IV infusion followed by 2-week treatment-free interval per cycle. The most common grade 3 and 4 adverse effects are listed in the table 1.
Conclusion: Blinatumomab is showing promising results in RR B-ALL with a good side effect profile. However, the final results of these trials are awaited.
Figure 1 Figure 1.

Disclosures
Anwer: Janssen pharmaceutical: Honoraria, Research Funding; Allogene Therapeutics: Research Funding; BMS / Celgene: Honoraria, Research Funding; GlaxoSmithKline: Research Funding.
Limited Role of Antithrombin Deficiency in Hypercoagulopathy Associated with Nephrotic Syndrome
Authors: Abdelghani Eman , Waller Amanda P. , Wolfgang Katelyn J , Kerlin Bryce A. 
Published: November 2021

Abstract
Background: Nephrotic syndrome (NS) is associated with an acquired hypercoagulopathy that drives venous thromboembolic comorbidities. The molecular mechanisms underlying NS-associated hypercoagulopathy are incompletely understood, however previous studies proposed marked urinary loss of antithrombin (AT) as a primary etiology. We have previously demonstrated, in rodent NS models, that there is no correlation between AT antigen and thrombin generation, which we have previously used to characterize the hypercoagulopathy. The objective of this study is to examine the association between AT antigen, AT activity, and hypercoagulopathy along with NS disease severity markers (proteinuria and plasma albumin) in 2 cohorts that include both pediatric and adult NS patients.
Methods: Plasma samples were obtained from both cohorts as follows: (1) Samples were obtained on presentation from 147 adult and pediatric patients participating in the NEPTUNE prospective observational cohort study (2) Samples were obtained on presentation and after 7 weeks of glucocorticoid therapy (GC) in steroid sensitive and steroid resistant pediatric patients participating in the PNRC study. AT antigen and activity assays were performed using ELISA and chromogenic assays, respectively. Thrombin generation assay, plasma albumin, and urine protein-to-creatinine ratio were determined as previously described.
Results: There was no significant relationship between AT antigen or AT activity and thrombin generation parameters. AT antigen and activity also did not correlate with NS severity markers (plasma albumin and proteinuria) in the NEPTUNE cohort (Figure1). In PNRC pediatric cohort, no significant correlation was found between AT antigen and thrombin generation or other disease severity markers. However, AT activity was significantly associated with both plasma albumin and endogenous thrombin potential at presentation (Figure 2) and at follow-up. Interestingly, GC therapy significantly improved AT activity in steroid-sensitive but not steroid-resistant NS patients (Figure 3). A comprehensive literature review and meta-analysis was also performed which revealed that clinically significant AT deficiency (&lt;0.7 IU/mL) is uncommon in both pediatric and adult NS patients.
Conclusion: AT antigen does not correlate with thrombin generation-defined hypercoagulopathy in adult or pediatric NS patients. AT activity does correlate with hypercoagulopathy in pediatric NS patients and improves significantly with successful remission inducing therapy. These data suggest that pediatric NS patients may have a qualitative, but not quantitative, AT deficiency that is responsive to therapy. The mechanism underlying this qualitative deficiency should be characterized in future studies.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Modulating Endothelial Cells with EGFL7 to Diminish aGVHD after Allogeneic Bone Marrow Transplantation in Mice
Authors: Guimond Martin , Moutuou Moutuaata , Goda Chinmayee , Sell Nathalie , Kaylan Sonu , Karunasiri Malith , Kulkarni Rohan SUDHIR , Goulard Marie , Kovovich Sofia , Naumann Eric , Ackaoui Antoire , Bigras Charles-Etienne , Daudelin Francis , Ruddich Alex , Garzon Ramiro , Ranganathan Parvathi , Dorrance Adrienne M. 
Published: November 2021

Abstract
Acute graft versus host (aGVHD) is the second cause of death after allogeneic-hematopoietic stem cell transplant (allo-HSCT) underscoring the need for novel therapies. Based on previous work that endothelial cell dysfunction is present in aGVHD and that epidermal growth factor-like domain 7 (EGFL7) plays a significant role in decreasing inflammation by repressing endothelial cell activation and T cell migration, we hypothesized that increasing EGFL7 levels after allo-HSCT will diminish the severity of aGVHD. Here, we show that treatment with recombinant EGFL7 (rEGFL7) decreases aGVHD severity and improves survival in recipient mice after allogeneic transplantation with respect to controls without affecting graft versus leukemia effect. Histopathology analysis revealed higher amount of leukocyte infiltration in both large intestine and liver of PBS group compared to rEGFL7-treated mice. Furthermore, damage to the gut was reduced in EGFL7 treated mice. Finally, we showed that rEGFL7 treatment results in higher thymocytes, T, B and dendritic cells in recipient mice after allo-HSCT. This study constitutes a proof of concept of the ability of rEGFL7 therapy to reduce GHVD severity and mortality after allo-HSCT.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
LC3-Associated Phagocytosis in Bone Marrow Macrophages Suppresses AML Progression through Mitochondrial DAMP Induced Sting Activation
Authors: Moore Jamie A , Mistry Jayna J , Hellmich Charlotte , Horton Rebecca H , Wojtowicz Edyta , Jibril Aisha , Wileman Tom , Jefferson Matthew , Beraza Naiara , Bowles Kristian M , Rushworth Stuart A 
Published: November 2021

Abstract
The bone marrow (BM) microenvironment regulates acute myeloid leukemia (AML) initiation, proliferation and chemotherapy resistance. Following cancer cell death, a growing body of evidence suggests an important role for uncleared apoptotic debris in regulating the immunologic response to, and growth of, solid tumors. LC3-associated phagocytosis (LAP) maintains tissue homeostasis by regulating immune responses, such as tumor immunity. Here we investigate the role of LAP in macrophage within the BM microenvironment of AML.
We find that depletion of BM macrophages via clodronate liposomes increased AML growth in-vivo. We show that LAP is an important pathway in BM macrophage to process dead and dying cells in the AML microenvironment. We used two syngeneic leukemia models (HOXA9/Meis1 and MN1) to investigate the role of LAP on AML proliferation. AML cells were injected into LAP deficient (Atg16L1 E230-) and wild-type (Atg16L1 E230+) mice. Targeted inhibition of LAP leads to accumulation of apoptotic cells (AC) and apoptotic bodies (AB) in the tumor microenvironment resulting in accelerated leukemia growth and decreased animal survival.
Mechanistically, we show, via cytokine arrays and gene analysis, that the phagocytosis of AML derived AB via LAP in BM macrophage resulted in STING pathway activation in the phagocytic cells. Furthermore, through inhibition of STING using H-151 STING inhibitor, we show that STING activation in vivo supressed leukemia growth. STING activation can lead to a type I IFN response and to recruitment of cytotoxic T-cells. We saw no increase in CD8 + T-cell numbers or activation, however, via ex vivo analysis found that STING activation is required for phagocytic functions in macrophages.
Next, we found that leukemic AB can induce a STING response in BM derived macrophages and that leukemic AB have increased mitochondria content that are processed by macrophages. Moreover, we identify that mitochondrial damage associated molecular patterns (DAMPs) from leukemic AB are processed by BM macrophages via LAP. Additionally, the depletion of mitochondrial DNA (mtDNA) in AML derived AB identified that the mtDNA from leukemic AB is responsible for the induction of STING signalling in BM macrophages.
In summary, we report that LAP in BM macrophage of apoptotic debris in the AML microenvironment suppresses leukemic growth, through mechanisms stimulated by AML apoptotic bodies which contain mtDNA in the BM microenvironment. This process is mediated by the activation of the STING pathway.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Ridd Is Required for the Prevention of Chronic Gvhd By Targeting IRE-1a/Xbp-1s Signaling
Authors: Choi Hee-Jin , Tang Chih-Hang Anthony , Tian Linlu , Wu Yongxia , Sofi Mohammed Hanief , Schutt Steven Douglas , Hu Chih-Chi Andrew , Yu Xue-Zhong 
Published: November 2021

Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is an effective therapeutic procedure to treat hematological malignancies. However, the benefit of allo-HCT is limited by a major complication, chronic graft-versus-host disease (cGVHD). Since transmembrane and secretory proteins are generated and modified in the endoplasmic reticulum (ER), the ER stress response is of great importance to secretory cells including B cells. By using conditional knock-out (KO) of XBP-1, IRE-1α or both specifically on B cells, we demonstrated that the IRE-1α/XBP-1s pathway, one of the major ER stress response mediators, plays a critical role in B cell pathogenicity on the induction of cGVHD in murine models of allo-HCT. Endoribonuclease activity of IRE-1α not only activates XBP-1s transcription factor by converting unspliced XBP-1 (XBP-1u) mRNA into spliced XBP-1 (XBP-1s) mRNA but also cleaves other ER-associated mRNAs through regulated IRE-1α-dependent decay (RIDD). Besides, it is known that ablation of XBP-1s production leads to unleashed activation of RIDD. Therefore, we hypothesized that RIDD plays an important role in B cells during cGVHD development. In this study, we found that B cells deficient for XBP-1s reduced ability to induce cGVHD, which however was reversed by inactivation of IRE-1α, highlighting the role of RIDD in controlling cGVHD (Fig. A). Activation of RIDD targets IgM mRNA of (Fig. B), a contributor to organ damage and fibrosis in cGVHD, which correlated with dysregulated expression of MHC II and costimulatory molecules such as CD86, CD40, and ICOSL in B cells (Fig. C). Alloreactive T cells need to be primed by APCs to initiate GVHD, and specifically, CD86 and CD40 mediated-costimulation from APCs has been demonstrated to play an essential role in eliciting cGVHD. We demonstrated that alloreactivity of T cells, especially CD4 T cells, can be recovered by suppressing RIDD in XBP-1s-deficient B cells (Fig. D). Since IRE-1α carrying a S729A mutation shows ablated RIDD activity without effect on splicing XBP-1 mRNA, we investigated the contribution of B cells from S729A knock-in mice to confirm the role of RIDD in B cells. We found that B cells from S729A mice increased GVHD severity (Fig. E). S729A B cells showed significant increases in IgM secretion (Fig. F), GC cell differentiation (Fig. G), and the expression levels of MHCII and co-stimulatory factors (Fig. H). In conclusion, these results provide a novel insight on how ER stress response regulates B cell activity after allo-HCT and suggest RIDD is an important mediator for reducing cGVHD pathogenesis.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Outcomes of High Grade B- Cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements: An Atlantic Canadian Centre Perspective
Authors: Kelly Erica , Forward Nicholas Allen , Keating Mary-Margaret 
Published: November 2021

Abstract
Background: High Grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (also known as Double-hit lymphoma (DHL)) is an aggressive B cell Non-Hodgkin lymphoma which has recently been recognized by the WHO as a distinct clinical entity from Diffuse Large B cell lymphoma (DLBCL). Compared to patients with DLBCL, patients with DHL have poor outcomes with standard R-CHOP chemoimmunotherapy, and the optimal treatment regimen for this high-risk lymphoma is unknown. Due to clinical and genetic overlap with Burkitt lymphoma (which shares translocations involving MYC), treatment of DHL with more intensive Burkitt lymphoma protocols is a common approach. However, these regimens are associated with significant toxicity, and the superiority of these regimens over standard R-CHOP remains uncertain. At our institution, R-CODOX-M/IVAC has been the preferred regimen for fit younger patients with DHL.
Objective: To review the outcomes of patients with DHL treated with R-CODOX-M/IVAC at our institution.
Methods: In this retrospective single-centre study, patients with DHL receiving R-CODOX-M/IVAC were identified by cross-referencing provincial cancer care data and hospital pharmacy data. All adult patients with a diagnosis of DHL and who were treated with R-CODOX-M/IVAC between January 2009 and January 2019 were included in the analysis. The primary outcomes is complete response (CR) per standard lymphoma response criteria. Secondary outcomes include median progression-free survival (PFS), overall survival at 1 year, and median overall survival. Kaplan-Meier analysis was used for survival analyses.
Results: 14 patients with DHL and meeting the inclusion criteria were identified and included in the analysis. The complete response rate was 35.7%. With a median followup time of 26 months, the median PFS was 31.8 months, and the median OS was 54.3 months. The overall survival at 1 year was 77%.
Conclusions: A previous meta-analysis demonstrated inferior outcomes for patients with DHL receiving RCHOP, with a median PFS of only 12.1 months. The optimal treatment of these patients remains to be defined. Dose-adjusted regimens have been associated with a significant improvement in PFS compared to RCHOP (21.6 months versus 12.1 months). Previous retrospective data suggests R-CODOX-M/IVAC results in more favourable outcomes 2 year PFS of 41% and 2 year OS of 53% (Sun et al., Clinical Lymphoma, Myeloma & Leukemia, 2015). Our data, although limited, that R-CODOX-M/IVAC may be associated with improved outcomes compared to published results with RCHOP. The limitations of this study include its retrospective design, lack of matched controls receiving RCHOP, and its small sample size. Nevertheless, this study adds to the small body of available evidence on this difficult to treat clinical entity.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Iron Chelation Therapy in Low- to Intermediate- Risk Myelodysplastic Syndrome Patients: A Systematic Review and Meta-Analysis
Authors: Yang Sarah , Zhang Ming Chan , Li Allen , Leong Russell , Mbuagbaw Lawrence , Crowther Mark 
Published: November 2021

Abstract
Background
Transfused patients with low- to intermediate-risk myelodysplastic syndromes (MDS) are known to suffer from iron overload. Iron chelation therapy (ICT) may improve outcomes, however, it remains to be thoroughly investigated.
Methods
We conducted a systematic review and meta-analysis to assess the benefit of ICT in patients with MDS. MEDLINE, EMBASE, and Cochrane CENTRAL were searched for studies on ICT for low- to intermediate-risk MDS that reported adjusted hazard ratios (aHR) or overall survival (OS). Two reviewers independently screened titles and abstracts and subsequent full texts for eligibility. Studies were extracted for general demographics, AML progression rate, incidence of cardiac injury, and median OS or aHR. aHR risk ratios were calculated using a random-effects model meta-analysis. Risk of bias was assessed using the Cochrane Risk of Bias tool for randomized controlled trials (RCTs) and Newcastle-Ottawa scale for non-randomized studies.
Results
The initial search yielded 1177 citations, of which we included 11 observational studies (n = total patient number) and one RCT (n = total patient number) for analysis. The heterogeneity was moderate (I 2=57%; P=0.02). There was a significant reduction in risk of mortality in patients with iron overload and low- or intermediate-risk MDS treated with ICT (aHR 0.43; 95% CI 0.32-0.57; P &lt; 0.00001) (figure 1). The median OS among patients receiving ICT and patients receiving no ICT was reported for nine studies. The median OS for patients receiving ICT was consistently longer than the median OS in the non-ICT group across all studies (figure 2).
Conclusion
Iron chelation therapy (ICT) is associated with a lower risk of mortality in low- to intermediate- risk myelodysplastic syndrome patients. Given the limited number of RCTs, more high-quality studies are required before ICT becomes a standard of care for this group of patients
Figure 1 Figure 1.

Disclosures
Crowther: Syneos Health: Honoraria; Precision Biologicals: Honoraria; Pfizer: Speakers Bureau; CSL Behring: Speakers Bureau; Bayer: Speakers Bureau; Hemostasis reference laboratories: Honoraria.
Prothrombotic Phenotype of a Protein S Mutant Lacking Anticoagulant Activity
Authors: Springborn Stephanie , Ghosh Sourav , Schulte Marie L , Rothlin Carla , Branchford Brian R 
Published: November 2021

Abstract
Protein S is a vitamin K-dependent protein that plays an important role in balancing pro- and anti-thrombotic responses to vascular injury. On one hand, it circulates bound to activated protein C, functioning as an anticoagulant complex that downregulates the activities of coagulation factors V and VIII. On the other hand, protein S is a ligand for platelet TYRO3 and MERTK, which, along with the third paralog AXL, constitute the TAM family of receptor tyrosine kinases that functions to potentiate the action of platelet-activating agonists, ultimately resulting in activation of the α IIbβ3 integrin. The relative importance of these two activities in vivo, however, is not known. To better understand the importance of the TYRO3/MERTK-stimulating ability of protein S and thus gain additional insight into its role in platelet activation, we used CRISPR/Cas9 technology to generate mice with a D136A mutant form of protein S that lacks the ability to bind protein C and function as an anticoagulant, while retaining its ability to bind platelet-activating TAM receptors - hereafter termed Pros1 D136A mice. Since homozygosity for this variant was embryonically lethal, all assays were carried out in wild-type animals and their heterozygous littermates comprising a wild-type Pros1 allele and an allele encoding Pros1 D136A. Though there was no significant difference between Pros1 D136A mice and their wild-type littermates in either a collagen/epinephrine-induced pulmonary embolism model or in tail vein bleeding times, platelets from Pros1 D136A mice accumulated at the injury site to a significantly greater degree following in vivo laser injury to the cremaster muscle microvasculature. Taken together with the embryonic phenotype of Pros1 D136A homozygous mice, these data support the notion that protein S can function to augment platelet responsiveness. Further studies on this and other ligands for the TAM family of receptor tyrosine kinases should provide additional insights into their roles in physiological platelet activation.

Disclosures
Branchford: Bio Products Laboratory: Honoraria; Novo Nordisk: Honoraria.
Bendamustine-Bortezomib-Dexamethasone in Heavily Pretreated Multiple Myeloma: Old PLUS New Drugs in NOVEL Agents' Era
Authors: Cerchione Claudio , Catalano Lucio , Nappi Davide , Pareto Anna Emanuele , Pane Fabrizio , Martinelli Giovanni 
Published: November 2021

Abstract
Bendamustine is an old bi-functional alkylating agent which has proved to be effective in relapsed, refractory and in new diagnosed Multiple Myeloma (MM). Thus, aiming to provide further insights in this field, also in novel agents'era, we present here a retrospective, real-life analysis of patients with relapsed/refractory MM (rrMM), who had received salvage therapy with bendamustine in combination with bortezomib and dexamethasone (BVD)
81 patients (44 M/37 F), with rrMM, median age at diagnosis 59.4 years (r. 36-82), median age at start of treatment 63.6 years (r.37-86) treated with several lines of treatments (median 6, r. 2-11), every refractory to all the drugs previously received (also Bortezomib), received BVD (B 90 mg/sqm days 1,2; V 1.3 mg/sqm days 1,4,8,11, D 20 mg days 1,2,4,5,8,9,11,12, Pegfilgrastim day +4) every 28 days, until progression.
All patients had previously received bortezomib-based and IMIDs-based treatments, and 32% (26/81) had also received radiotherapy. 69% (56/81) had undergone single or double autologous and three (2%) allogeneic stem cell transplant. All patients were relapsed and refractory to last therapies received before BVD.
Bendamustine was well tolerated, with grade 3-4 transfusion-dependent anemia in 56% (46/81) of patients, and 43% (35/81) grade 3-4 neutropenia (no ospedalization was required, no septic shocks were observed). No severe extrahematologic toxicity was observed, only grade 1 gastrointestinal side effect (nausea), treated by common antiemetic drugs.
According to IMWG, ORR was 63% (51/81: 7 CR, 18 VGPR, 15 PR, 11 MR) with 11 PD and 19 patients in SD, which can be considered as an impressive result in this subset of rrMM patients. In particular, for 11 patients, BVD was, after having achieved at least a PR, a bridge to second auSCT, and for two patients a bridge to alloSCT. Eight patients have surprisingly achieved a notable PR after failure of novel agents (i.e. Carfilzomib, Daratumumab and Pomalidomide).
Median time to response was 1.3 months (r.1-3), median OS from diagnosis was 67.3 months (r.6-151), median OS from start of Bendamustine was 9.6 months (r.2-36).
The triplet Bendamustine-Bortezomib-Dexamethasone has shown significant efficacy in a particularly severe setting of patients, relapsed and refractory to all available therapeutic resources, and, in particular cases, it could be considered as a bridge to a second autologous or allogenic SCT, also after failure of novel agents.

Disclosures
Martinelli: Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Daichii Sankyo: Consultancy; Celgene /BMS: Consultancy, Speakers Bureau; Roche: Consultancy; Pfizer: Consultancy, Speakers Bureau; Incyte: Consultancy; Stemline Therapeutics: Consultancy; Astellas: Consultancy, Speakers Bureau.