bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peripheral Blood Progenitor Cell Mobilization of CD34+ Cells with Combine G-CSF and GM-CSF in Pediatric Patient Outcome and Economic Advantage
Authors: Garcia Heidy lyz 
Published: November 2020

Background: Clinical trials to mobilize PBPC for autologous and allogeneic harvesting prior to high dose chemotherapy/radiotherapy include chemotherapy, cytokines, or chemotherapy combine with cytokines. PBPC mobilized by G-CSF or GM-CSF reduces the hematological toxicity and supportive care requirements in recipients of autologous and allogeneic transplants, in our study we combined G-CSF and GM-CSF to mobilize PBPC for transplantation.
Methods: We selected 63 patients with different cancers to participate in the study and 7 healthy donors. We utilize to mobilize in all the patient the combination of G-CSF and GM-CSF (10μg/Kg/day each) administered for 5 consecutive days. Then we proceed it to harvest the PBPC until we obtain a threshold of 2.0 x 10^6/Kg CD34+ cells. A total of 31 PBPC transplants were performed (27 autologous and 8 allogeneic). Neutrophil engraftment was defined as ANC&gt; 500/mm³ and, platelet engraftment was defined as a platelet count &gt; 30,000/mm³ (transfusion independent) for more than 48 hours.
Results: Data on PBC 24, 48, 72, and 96hrs. For the 31 PBPC autologous transplant patients, the median days to ANC&gt;500 was 10.6 days; 11 days for the allogeneic. None of the subject's experience bone pain, headache, flu like side effects or a documented or proven infection. Median days to platelet engraftment following infusion CD34+ cells, was 13.2 for the autologous PBPC; 13 days for the allogeneic.
Conclusions: The combination the G-CSF and GM-CSF (10μg/kg/day x 5 days) was well tolerated. We can appreciate that there is a reduction in the duration and severity of neutropenia as well of thrombocytopenia in both types of transplant (autologous/allogeneic). The GVHD incidence were not increase by the use of G-CSF and GM-CSF. We conclude that this procedure is cost effective and a suitable way to mobilize an average number of PBPC (from 1-3 apheresis) in a shorter amount of time indicating an economic advantage. It is proven to be less expensive than other agent used to mobilize stems cells for transplant.

Disclosures
No relevant conflicts of interest to declare.
Influencing Factors of Non-Genetic Factors Influencing the Overall Survival of Multiple Myeloma Patients
Authors: Gui Lin , Wang Fei , Shi Jinning , Chen Baoan 
Published: November 2020

Objective: To explore the non-genetic prognostic factors in patients with multiple myeloma (MM).
Methods: Kaplan-Meier survival curve, Log-rank test and Cox regression model were used to carry out univariate and multivariate analysis on clinical and laboratory parameters of 51 MM patients who were newly diagnosed with MM and had complete follow-up data in the Department of Hematology, Jiangning Hospital Affiliated to Nanjing Medical University, Nanjing From November 2011 to October 2012.
Results: Of the 51 patients, 29 were male and 22 were female. Followed up to December 2019, 21 died and 30 survived. The univariate analysis showed the prognosis was influenced by factors including age, disease stage, standard treatment, new drugs, maintenance treatment, hypercalcemia, globulin, albumin, hemoglobin. Patients aged &lt;65 years, with ISS stage I and II, with standardized treatment, with new drugs, with normal or below normal blood calcium, with normal or below normal globulin, with albumin ≥ 35g/L or patients with hemoglobin ≥100g/L have longer survival time. The multivariate analysis showed that maintenance treatment, hypercalcemia and hemoglobin were independent risk factors influencing the prognosis of MM patients.
Conclusion: Patients with blood calcium ≥ 2.6mmol/L, hemoglobin &lt;100g/L and those who do not undergo regular maintenance therapy have a poor prognosis.
Key words multiple myeloma; overall survival; non-genetic; prognostic factors

Disclosures
No relevant conflicts of interest to declare.
IL-6 Deficiency Reverses Leukemic Transformation in an MDS Mouse Model
Authors: Mei Yang , Liu Yijie , Han Xu , Yang Jing , Ji Peng 
Published: November 2020

Myelodysplastic syndromes (MDS) are a group of age-related myeloid malignancies that are characterized by ineffective hematopoiesis and increased incidence of developing acute myeloid leukemia (AML). The mechanisms of MDS to AML transformation are poorly understood, which is partially due to the scarcity of leukemia transformation mouse models. Recently, we established a mDia1/miR146a double knockout (DKO) mouse model mimicking human del(5q) MDS. DKO mice present with pancytopenia with aging due to myeloid suppressive cell (MDSC) expansion and over-secretion of pro-inflammatory cytokines including TNF-a and interlukine-6 (IL-6). In the current study, we found that most of the DKO mice underwent leukemic transformation at 12-14 months of age. The bone marrow of these mice was largely replaced by c-Kit+ blasts in a background of fibrosis. Flow cytometry analysis and in vitro colony formation assay demonstrated that hematopoietic stem progenitor cells (HSPCs) in DKO bone marrow were dramatically declined. The leukemic DKO mice had elevated white blood cell counts and circulating blasts, which contributes to the myeloid cell infiltration in non-hematopoietic organs including liver and lung. Moreover, the splenocytes from DKO old mice efficiently reconstitute the hematopoiesis, but led to a 100% disease occurrence with rapid lethality in gramma irradiated recipient mice, suggesting the leukemic stem cells enriched in DKO spleen were transplantable. Given the significant roles of the inflammatory cytokines in the pathogenesis of the DKO mice, we crossed DKO mice with IL-6 knockout mice and generated mDia1/miR-146a/IL-6 triple knockout (TKO) mice. Strikingly, the TKO mice showed dramatic rescue of the leukemic transformation of the DKO mice in that all the aforementioned leukemic phenotypes were abolished. In addition, IL-6 deficiency normalized the cell comparts and prevented leukemic transplantation ability in TKO spleen. Single cell RNA sequencing analyses indicated that DKO leukemic mice had increased monocytic blast population with upregulation of Fn1, Csf1r, and Lgals1, that was completely diminished with IL-6 knockout. Through a multiplex ELISA, we found IL-6 deficiency attenuated the levels of multiple inflammatory cytokines in TKO serum. In summary, we report a mouse model with MDS leukemic transformation during aging, which could be reverted with the depletion of IL-6. Our data indicate that IL-6 could be a potential target in high risk MDS.

Disclosures
No relevant conflicts of interest to declare.
Remission in Patients with Acute Promyelocytic Leukemia Treated with Arsenic Trioxide (varitrinox) As the First Line in Colombia
Authors: Milone Gustavo , Sarmiento Doncel Samuel , Agudelo Rico Carol , Vizcarra Reyes Fabiola , Diaz Mosquera Gina Alejandra , Duque Ortega Juan Guillermo , Cortes Bernal Javier Mauricio , Meza Cadavid Francisco Javier 
Published: November 2020

Acute promyelocytic leukemia (APL) is a subtype of Acute Myeloid Leukemia (AML) in which a chromosomal translocation t (15; 17) (q22; q12) is generated by fusing produces a hybrid PML / RARα gene, generating an altered signal . The combination of transretinoic acid (ATRA) plus arsenic trioxide (ATO) has been shown to be superior to ATRA plus chemotherapy in the treatment of newly diagnosed standard risk patients with acute promyelocytic leukemia (APL) in several countries.
The objective of the present study is to describe the frequency of remission in patients with acute promyelocytic leukemia who were administered as a first line Arsenic Trioxide (varitrinox) during the period from November 2017 to June 2020 in Colombian patients.
Methods: Retrospective observational and descriptive study of 12 patients diagnosed with acute promyelocytic leukemia treated with ATO Arsenic trioxide (Varitrinox) as first line, the source of information was provided by the treating hematologists (medical records) by filling out the technical concept format. Active pharmacovigilance scientist in Colombia, this format keeps the identification information of the patient anonymized and the confidentiality of the data is guaranteed as well as compliance with the rules of good clinical practice.
Results: Twelve patients with age range between 22 and 69 years with a median age of 34.0 were analyzed. It was found in the analysis that 100% had induction hematologic remission with a median of 45 days. 75% of patients received ATO + ATRA and were at low and intermediate risk, the remaining 25% received ATRA + ATO + Chemotherapy and were at high risk, and intermediate risk. 91.7% of molecular remission in consolidation was obtained and it was measured in cycle 3 by means of PCR (undetectable), 8.3% (n = 1) was positive 3% and is finishing consolidation. Regarding the most frequent adverse events, intravascular coagulation (n = 9), neutropenia (n = 6) and thrombocytopenia (n = 6) were observed. 75% of patients are disease-free, 16.7% are on maintenance (they received ATO + ATRA + Induction chemotherapy) and 8.3% are on consolidation. So far, none of the patients under study have died.
Conclusions: Our results support the use of ATO (Varitrinox) in newly diagnosed APL patients (as first line), as a care strategy for low, intermediate and high risk patients. The role of ATRA-ATO is guaranteed in other studies where they manage patients of different risks.
Key words: Arsenic trioxide, leukemia promyelocytic acute, leukemia myeloid acute, remission induction, tretinoin.

Disclosures
No relevant conflicts of interest to declare.
Tet2 Inactivation Enhances the Anti-Tumor Activity of Tumor-Infiltrating Lymphocytes (TILs) to Curtail Melanoma Growth
Authors: Lee Minjung , Li Jianfang , Fang Shaohai , Zhang Joanna , Vo Anh Tran Tram , Han Wei , Zeng Hongxiang , Isgandarova Sevinj , Moczygemba Margarita Martinez , Zhou Yubin , Li Jia , Sun Deqiang , Huang Yun 
Published: November 2020

Inactivation of tumor infiltrating lymphocytes (TILs) is one of the mechanisms mitigating anti-tumor immunity during tumor onset and progression. Epigenetic abnormalities are regarded as a major culprit contributing to the dysfunction of TILs within tumor microenvironments. In this study, we used a murine model of melanoma to discover that Tet2 inactivation significantly enhances the anti-tumor activity of TILs, with the efficacy comparable to immune checkpoint inhibition imposed by anti-PD-L1 treatment. Single-cell RNA-seq analysis further revealed that Tet2-deficient TILs exhibit effector-like features. Transcriptomic and ATAC-seq analysis further demonstrated that Tet2 deletion reshapes the chromatin accessibility and favors the binding of transcription factors geared toward CD8+ T cell activation. In summary, our study establishes that Tet2 constitutes one of the epigenetic barriers contributing to dysfunction of TILs, and that Tet2 inactivation could benefit anti-tumor immunity to boost tumor suppression.

Disclosures
No relevant conflicts of interest to declare.
A Retrospective Analysis of Brentuximab Vedotin and Pembrolizumab Combination As Salvage Treatment for Patients with Relapsed or Refractory Hodgkin Lymphoma
Authors: Massaro Fulvio , Meuleman Nathalie , Bron Dominique , Maerevoet Marie 
Published: November 2020

Background:The standard treatment for Hodgkin lymphoma (HL) patients presenting a relapsed/refractory (R/R) disease is salvage chemotherapy followed by autologous stem cell transplantation (ASCT). However, with commonly used chemotherapy combinations (such as DHAP, ICE, BEGEV), 25-30% of these patients fail to achieve a complete metabolic response (CMR) and to proceed to ASCT, with subsequently poor outcomes. Single agents brentuximab vedotin (BV) and pembrolizumab have shown efficacy in heavily pretreated HL patients, as reported in previous studies. The combination of BV with nivolumab has been explored in a phase 1/2 study as first salvage treatment for HL patients, showing a CR rate of 61% (Herrera et al 2018). We explored the outcome of BV and pembrolizumab combination as salvage treatment in a series of R/R HL patients.
Methods:We retrospectively collected data of seven HL patients presenting with a high-risk multi-refractory disease (two or more prior treatments) followed at Jules Bordet Institute between May 2019 and July 2020 and treated with a combination of BV and pembrolizumab. Patients were covered by special insurance conditions allowing treatment reimbursement. Treatment proposal was approved by a local multidisciplinary committee. Treatment consisted of 3-week cycles with a combination of BV (1.8 mg/kg IV) and pembrolizumab (200 mg IV fixed dose), an early PET-CT evaluation followed by high-dose chemotherapy and ASCT consolidation for those achieving a Deauville score ≤4. After ASCT, patients received BV as maintenance for a total of 16 administration (including pre-ASCT cycles).
Results:We included 7 patients, 6 male and 1 female, with a mean age of 27.4 (20.6-36.3) years. All patients presented with an advanced-stage disease, with a mean number of 2.56 (2-3) prior treatments. The median follow-up time was 9.7 months, while the average number of received cycles of treatment was 4.2 (range 2-7). Table 1 shows additional patients' characteristics. The overall response rate (ORR) was 87% and particularly a CR was achieved in five patients (72%), with a median time to response of two cycles. One partial response and one disease progression were also observed. Six patients proceeded to ASCT (86%) and subsequent BV maintenance, with one early disease progression. One patient, in complete molecular remission after 2 cycles, locally progressed after 6 cycles and received radiotherapy before ASCT.
Table 2 summarizes the outcome for each patient included in the series.
Conclusions:The BV and pembrolizumab combination is a very effective bridge treatment to ASCT for high-risk R/R HL patients.

Disclosures
No relevant conflicts of interest to declare.
Prophylactic Donor Lymphocyte Infusion Based on Two Different Time for Preventing Relapse in Advanced Acute Leukemia Undergoing Allo-HSCT: Comparison of Two Independent Prospective Cohorts
Authors: Su Qiongqiong , Fan Zhiping , Huang Fen , Xu Na , Nie Danian , Lin Dongjun , Guo Ziwen , Pengcheng Shi , Wang Zhixiang , Jiang Ling , Sun Jing , Jiang Zujun , Liu Qifa , Xuan Li 
Published: November 2020

Background: Prophylactic donor lymphocyte infusion (pDLI) can reduce relapse in advanced acute leukemia (AL) undergoing allogeneic hematopoitic stem cell transplantation (allo-HSCT), but the optimal timing of pDLI remains uncertain. Our previous study demonstrated that pDLI on day +60 post-transplant regardless of minimal residual disease (MRD) could reduce relapse, but the incidence and mortality of graft-versus-host disease (GVHD) were high. To reduce GVHD post-pDLI, we modified our pDLI strategy by delaying the time to day +90 unless MRD was positive on day +60.
Methods: This study population came from two prospective multicenter cohorts. In cohort 1, pDLI was given once on day +60 regardless of MRD for all patients without grade II/&gt;II acute GVHD (aGVHD), and then administered based on MRD and GVHD. In cohort 2, for patients who were MRD negative on day +60 and did not experience grade II/&gt;II aGVHD by day +90, pDLI was given once on day +90 and then administered based on MRD and GVHD. For patients with positive MRD on day +60, the application of pDLI was conducted according to cohort 1. The outcomes of pDLI at two different time were compared.
Results: A total of 161 advanced AL undergoing allo-HSCT from January 2012 to December 2017 were enrolled, including 83 from January 2012 to December 2014 in cohort 1 (74 receiving pDLI) and 78 from January 2015 to December 2017 in cohort 2 (69 receiving pDLI). The extensive chronic GVHD (cGVHD) incidence in cohort 2 was lower than that in cohort 1 (10.3% vs 27.9%, P=0.006) and GVHD-free/relapse-free survival (GRFS) in cohort 2 was superior to that in cohort 1 (55.1% vs 41.0%, P=0.042). The 2-year relapse rate, overall and leukemia-free survival were similar between the two cohorts (29.0% vs 28.2%, P=0.986; 63.9% vs 64.1%, P=0.863; 57.8% vs 61.5%, P=0.666). Multivariate analysis revealed that modified pDLI strategy was the only protective factor for GRFS (P=0.015, HR=0.470).

Conclusions:
Delaying pDLI to day +90 based on MRD for advanced AL undergoing allo-HSCT can lower extensive cGVHD incidence and improve GRFS but not increase leukemia relapse.

Disclosures
No relevant conflicts of interest to declare.
DISC-0974, a Novel, First-in-Class, Anti-Hemojuvelin Monoclonal Antibody Is Predicted to be Efficacious at Low Doses in Humans As Determined By Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling in Non-Clinical Studies
Authors: Hixon Mark , Blaustein Cecile , King Christopher , Nguyen Sophia , Savage Will , Beconi Maria G. 
Published: November 2020

DISC-0974 is a humanized monoclonal anti-HJV antibody with high binding affinity for human, rat and cynomolgus monkey HJV (100 pM, 240 pM and 110 pM Kd, respectively) [Kovac 2016]. DISC-0974 inhibits the interaction between HJV and the key hepcidin regulatory ligands, bone morphogenetic proteins (BMPs), leading to decreased SMAD phosphorylation (SMAD-P) and reduced hepcidin expression [Kovak 2016].
Elevated hepcidin is a hallmark of and plays a critical role in the pathogenesis of anemia of inflammation (and other forms of anemia) by reducing transferrin saturation and erythroid iron availability, leading to failure of erythropoiesis and decreased hemoglobin synthesis. DISC-0974 is being developed to reduce hepcidin synthesis and treat anemia in these patients. A critical early signal of therapeutic effect is the effect of DISC-0974 on transferrin saturation (TSAT). TSAT has therefore been used as the primary pharmacodynamic marker in a series of non-clinical studies to determine the relationship between drug exposure and pharmacological activity.
In non-human primates (NHP) DISC-0974 elicits a dose-dependent reduction in hepcidin levels leading to increases in serum iron and consequently TSAT. PK/PD responses were examined over 60 days for a single 6 mg/kg intravenous dose of DISC-0974 in three male NHPs and in repeat dose studies occurring at 14 day intervals administered 3 times (vehicle, 0.6 and 3 mg/kg) or two times (60 mg/kg). In these studies, the serum iron response saturated in an exposure-dependent manner over the 0.6-60 mg/kg dose range. The onset of iron elevation lagged compared to the DISC-0974 maximal plasma concentrations by 1- 4 days post dose and persisted beyond what could be predicted by DISC-0974 plasma concentration alone. The observed PD responses were well-described by a delayed response PK/PD model of serum iron which was fit globally to all studies.
We will present single and multiple dose simulations showing that low monthly doses of DISC-0974 are sufficient to elicit a biologically significant and controlled PD modulation (serum iron, TSAT, hepcidin) over a sustained period-of-time (Figure 1). DISC-0974 is under development for the treatment of anemia of inflammation associated with high hepcidin.

Disclosures
Blaustein: Disc Medicine:Current Employment, Current equity holder in private company.King:Disc Medicine:Current Employment, Current equity holder in private company.Nguyen:Disc Medicine:Current Employment, Current equity holder in private company.Savage:Disc Medicine:Current Employment, Current equity holder in private company.Beconi:Disc Medicine:Current Employment, Current equity holder in private company.
Effective Erythropoiesis from Human iPSC-Derived RBC in Immunodeficient Mice
Authors: Deng Jiusheng , Lancelot Moira M. , Jajosky Ryan , Deeb Kristin , Saakadze Natia , Gao Yongixng , Liu Senquan , Stowell Sean R. , Cheng Linzhao , Roback John D 
Published: November 2020

Transfusion of red blood cells (RBCs) was the earliest developed form of cell therapy and is still a highly effective life-saving treatment for many patients. Induced pluripotent stem cells (iPSC) can differentiate into RBCs (iPSC-RBCs) and may provide a novel source for blood transfusion and a cellular model for erythroid differentiation. Here we developed a murine model to investigate the in vivo properties of human iPSC-RBCs. Human iPSC were generated from peripheral blood mononuclear cells of healthy donors by transfection of plasmids containing OCT4, SOX2, MYC, KLF4 and BCL-XL genes. iPSC lines expressed TRA-1-60, SSEA4 and Nanog markers, and showed a normal karyotype. iPSCs were induced to differentiate along the erythroid lineage using a 3-stage culture system requiring 33 days. At the end of the culture period, iPSC-RBCs were CD34-CD235a+CD41+CD43+CD71low; about 10% of cells were enucleated (CD235a+DRAQ5-). iPSC-RBCs were harvested and transfused into immunodeficient NSG mice which had been pretreated with clodronate liposomes and cobra venom factor (CL/CVF). CL/CVF treatment of NSG mice markedly promoted the survival of transfused human iPSC-RBC in vivo, which could be detected with anti-human CD235a antibodies for at least 7 days, although the numbers progressively decreased with time. Interestingly, a large number of transfused iPSC-derived cells homed to bone marrow of NSG mice. In NSG mice that were repetitively treated with CL/CVF every 3 days, nucleated iPSC-derived cells were still detectable in the bone marrow 4 weeks after transfusion. Furthermore, at 3 weeks after transfusion, human iPSC-RBCs reappeared in the peripheral circulation. These circulating iPSC-RBCs were &gt; 90% enucleated and were present at levels more than 4-fold higher than at 1 hour after transfusion. These results suggest that iPSC-RBCs which homed to the bone marrow of NSG mice retained the capability to complete differentiation into enucleated erythrocytes and egress the bone marrow into the peripheral blood. The results offer a new model using human peripheral blood iPSC and CL/CVF-treated NSG mice to investigate the development of human erythroid cells in vivo.

Disclosures
Jajosky: Biconcavity Inc.: Other: CEO and partial owner; BioMarin Pharmaceuticals: Current equity holder in publicly-traded company; Magenta Therapeutics: Current equity holder in publicly-traded company.
Major Infections after Blood Transfusion in Isolated Coronary Artery Bypass Surgery Patients: A Meta-Analysis
Authors: Mosalem Osama , Kherallah Shouq , Mujer Mark , Agarwal Priyal , Treasa Varghese Merryl , Elshafie Ahmed , Garces Christopher C , Abdelsamia Mahmoud , Rayamajhi Supratik 
Published: November 2020

BACKGROUND
Blood transfusion in patients undergoing coronary artery bypass surgery (CABG) remains high despite advances in perioperative blood conservation. Several studies have shown poorer clinical outcomes in isolated CABG patients who receive blood products, including an increased rate of renal failure, non-fatal myocardial infarction, and death. Our study sought to determine the impact of blood transfusion on sternal wound infections and other major infections in patients who undergo isolated CABG.
METHODS
We performed a systematic search using PubMed, Google Scholar, EMBASE, SCOPUS, and ClinicalTrials.gov without language restriction until May 15, 2020. A random-effects model was utilized to calculate risk ratio (RR) and mean difference (MD) with 95% confidence interval (CI).
RESULTS
In patients undergoing isolated CABG, sternal wound infections [RR 1.73 (95% CI: 1.35 to 2.20; p&lt;0.0001)] and overall major infections [RR 1.70 (95% CI: 1.39 to 2.08; p&lt;0.0001)] were significantly higher in those who received a periprocedural blood transfusion. Thirty-day mortality was lower in patients who did not receive any transfusion [RR 2.46 (95% CI: 1.09-5.56;p=0.03)]. The test of heterogeneity was low for clinical outcomes aside from 30-day mortality.
CONCLUSION
Periprocedural blood transfusion is associated with an increased risk of sternal wound infections and major infections and higher 30-day mortality in patients who undergo isolated CABG

Disclosures
No relevant conflicts of interest to declare.