bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adding Slow Release Tetracosactide Acetate to Eltrombopag Improves Haematological Response in ITP Patients with Platelet-Count Fluctuation
Authors: Iuliano Francesco , Iuliano Eleonora , Rossi Marco 
Published: October 2019

Abstract
Background and aim
Tetracosactide Acetate (SR-TA) stimulates the release of corticosteroids such as cortisol from the adrenal gland. It is absorbed on to a zinc phosphate complex which ensures the sustained release of the active substance from the intramuscular injection site. SR-TA is currently used in the management of ulcerative colitis and Crohn's disease, juvenile/adult rheumatoid arthritis and osteoarthrosis. However, its properties indicate that this compound may be particularly useful in patients unable to tolerate oral glucocorticoid therapy or where normal therapeutic doses of glucocorticoids turned to be ineffective. Eltrombopag is an oral, non-peptide thrombopoietin receptor agonist that has been shown efficacy and safety in chronic immune thrombocytopenia (ITP) patients not responding to previous therapy. Based on these premises, we treated with a combination of Eltrombopag and SR-TA selected ITP patients undergoing a platelet count fluctuation despite a standard eltrombopag dose was given .
Material and methods
A total of 6 adult patients, female (60%),median (range) age 37 (28 - 54) years, median (range) baseline platelet count 31 (28 - 46) × 109/L, median of 3 (2 - 4) prior ITP therapies, received a combo of Eltrombopag 50 mg by mouth daily and SR-TA 1 mg intramuscularly daily until the target platelet count of 50× 109/L was reached, then a dose of 1mg of SR-TA was given every 3 days; in responding patients , i.e. without platelet count fluctuation, the dose was further reduced to 1mg per week.
Results
5 out of six patients responded to treatment reaching and maintaining the platelet count between 50× 109/L and 100× 109/L. After a median follow-up of 6 months with combo treatment, all patients maintained their response. Self-administration was started by 100% of patients (6/6). No adverse events have been observed.
Our experience has shown that eltrompopag/SR-TA combo is effective and safe in maintaining the platelet count above 50x109/L in those patients not reaching this target with the TPO mimetic alone.

Disclosures
No relevant conflicts of interest to declare.
Loss-of-Function Mutation in tet2 in Zebrafish Leads to Early MDS like Phenotype
Authors: Rajan Vinothkumar , Woodside Rachel , Prykhozhij Sergey V , Berman Jason 
Published: October 2019

Abstract
Myelodysplastic syndrome (MDS) is a pre-leukemic state characterized by the failure of the bone marrow to produce mature and functional blood cells. Nearly one-third of MDS patients progress to acute myeloid leukemia (AML). AML is the most common form of acute leukemia in adults and accounts for a high level of mortality in pediatric leukemia.
Loss-of-function mutations in the Ten-11 Translocation 2 (TET2) gene are implicated in MDS and AML, but evidence that TET2 mutations are also found in healthy individuals as a result of clonal hematopoiesis calls into question the contribution of TET2 to leukemogenesis. Many studies have tried to mutate the DNA binding domain in TET2 both in mouse and zebrafish, but the blood phenotypes observed have been inconsistent.
We created a tet2 zebrafish mutant using CRISPR-Cas9 technology, where we deleted 2.1 kb from exon 2, confirmed by cDNA analysis. A recent publication suggests the importance of Ser99 in the stability of the TET2 protein (Wu et al., 2018) and this conserved serine residue is contained in the region of deletion in our zebrafish tet2 mutant.
These tet2 mutant fish were incrossed to create a maternal-zygotic mutant with no tet2 expression. Importantly, quantitative PCR demonstrated that there was no compensatory effect from tet1 and tet3 in the context of tet2 loss.
Whole mount in situ hybridization performed on 24-48h tet2 mutant zebrafish embryos provided evidence of a significant reduction of early and mature myeloid and erythroid cells through staining for spi1/pu.1 (myeloid), gata1 (erythroid) myeloperoxidase (mpx; neutrophils), carboxypeptidase A5 (cpa5; mast cells) and l-plastin (lcp1; macrophages). The stem cell compartment was not impacted, as shown by wild-type runx1/c-myb expression. Further, o-dianisidine staining revealed low hemoglobin content in tet2 mutants compared with control embryos. Overall, the early embryos elucidate a refractory anemia like phenotype.
Flow cytometry analysis of kidney marrow from 3-month-old adult tet2 mutant fish similarly demonstrated a decrease in the myeloid and erythroid compartments, in keeping with characteristics typical of low stage MDS. We are currently employing RNAseq and MeDIP analysis on blood cell populations from tet2 mutants to determine the genetic and epigenetic signatures associated with this mutation.
This zebrafish model of tet2 loss uniquely provides with a dynamic phenotype that starts with refractory anemia with progression through low stage MDS. Thus this model will be beneficial in elucidating the mechanisms underlying how tet2 contributes to MDS and AML and provide a preclinical platform to screen for therapeutic interventions.

Disclosures
No relevant conflicts of interest to declare.
Efficacy and Safety of Low-Dose Decitabine in Low- or Intermediate 1-Risk MDS
Authors: Cao Zhijian , Ma Jun 
Published: October 2019

Abstract
OBJECTIVES: Decitabine has been approved in China for treatment with high-risk Myelodysplastic syndromes (MDS) patients (pts) in 2008. However data of decitabine on efficacy and safety of low-dose decitabine in low- or intermediate 1-risk MDS was absence. Herein,3 years datas in our centre of low- or intermediate 1-risk MDS treated with decitabine were analysed to evaluate the efficacy and safety in two subgroups.
METHODS: Inclusion Criteria:Patients of age > 18; Patients with low-or intermediate 1-risk MDS. The IPSS is used to classify patients with MDS across disease subgroups. ECOG performance status ≤ 2. And normal hepatic,renal and cardiac function. Study Design: Decitabine 20mg/m2 intravenously (IV) over the course of one hour daily for 3 days. Courses were repeated every 28 days when possible. Dose reductions for grade 3 and 4 toxicities were allowed for decitabine (to 10 mg/m2 or 15 mg/m2). The primary endpoint was overall response rate (ORR).
RESULTS: In total, 37 patients were enrolled and treated from September 2014 to October 2017 in our center. The median follow-up was 26 months (range, 4-49 months). The median time from diagnosis to therapy with decitabine was 3 weeks (range, 1-52 weeks). Their F/M ratio was 16/21 and the median age of the enrolled population was 58 years (range, 40-71 years). More than 70% of patients had 2 to 3 cytopenias, and 43% were transfusion dependent at enrollment. Most patients had intermediate 1-risk MDS by IPSS (n=29). Next-generation sequencing was performed in 35 patients (90%). The most frequently detected mutations included TET2 (n=15; 41%), SF3B1 (n=7; 19%), ASXL1 (n=5, 13%), RUNX1 (n= 5, 13%), and SRSF2 (n=3, 8%). The ORR after 2 cycles of decitabine was 65% (24/37),with 35% of patients (13/35) achieving a CR. Hematologic improvement was seen in 19%(7/37). The median time to best response was 3 months (range, 1-12 months). The median number of cycles received was 5 (range, 1-13 cycles). 19% of patients (7/37) became transfusion independent. The EFS and OS were 68% and 78% respectively in 1 year. The treatment was well-tolerated, with most adverse events being of grade 1 to 2, Nausea (24%), Fatigue (14%), Infection/Neutropenic fever (19%), Constipation (6%), Diarrhea (6%). Grade 3 and higher nonhematologic adverse events were rare. Grade 3 adverse events were Infection/Neutropenic fever (6%), but rare, and no grade 4 adverse events were observed.
CONCLUSIONS: These data confirm that decitabine is a feasible and effective agent for low- or intermediate 1-risk MDS pts, and its need longer time to response (more than 2 cycles). Safety profile was acceptable and the most adverse events were Nausea, Fatigue, and Infection/Neutropenic fever.

Disclosures
No relevant conflicts of interest to declare.
Co-Transplantation of Mesenchymal Stem Cells Can Ameliorates Acute Gvhd and Viremia after Allogeneic Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia: A Multi-Center Retrospective Study of 119 Patients
Authors: Chen Minmin , Zheng Zhizhong , He Guangsheng , Lin Shengyun , Zhang Donghua , Hu Huijing , Liu Jia , Chen Zhizhe , Hu Jianda , Yang Ting 
Published: October 2019

Abstract
BACKGROUD:Mesenchymal stem cells (MSCs) are known to exhibit immunomodulatory, anti-inflammatory, and pro-angiogenic properties, and therefore have the potential to improve the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for severe aplastic anemia (AA).
OBJECTIVE: To explore the efficacy and safety of allo-HSCT by co-transplantation with MSCs in AA patients.
METHODS: We conducted a multi-center retrospective study to comparing the incidence and severity of acute GvHD, transplant-related complication and overall survival (OS) of allo-HSCT with or without co-injection of MSCs in AA patients. A total of 119 consecutive severe AA patients (64 males/55 females) undergoing allo-HSCT at 4 hospitals from January 2012 to February 2018 were analyzed. The median age of the patients is 23 (range 1-56 years). Patients received conditioning regimens based on cyclophosphamide or busulfan, among whom 50 (42%) were MSD-HSCT, 21(17.6%) MUD-HSCT and 48 (40.4%) haplo-HSCT. All patients received cyclosporine A with short course methotrexate for prevention of GVHD. 89 patients transplanted with donor HSCs only, and 30 patients transplanted with HSCs and MSCs .MSCs infusion dose was 0.5-3.0×106/kg, at -1~+1 days following HSCs infusion. None of these patients had severe infection or organ failure before HSCT.
RESULTS: The two groups were well matched demographically. All patients achieved successful engraftment within one month post transplant. There was no difference in time to leukocyte and platelet engraftment in the two groups. The incidence of aGVHD grade II-IV (7.9 % versus 6.7 %, P =1.000) was similar in the HSC versus MSC groups, but there was a trend to a lower incidence of aGVHD grade III-IV in the MSC group (3.4% versus 0%, P=1.0). Moreover, a lower incidence of viremia in the MSC group was observed (CMV: 26.7% vs 62.9%, P < 0.001; EBV: 50% vs 80.9%, P = 0.002).With a median follow-up time of 811 days (range:28-2348days),the 2-yr OS was similar in both groups (82.8% versus 71.1%, P =0.498). A combination of bone marrow and peripheral blood as the sources of stem cells co-transplanted with MSCs (n=9) demonstrated an improved survival benefit (2-yr OS=100%).
CONCLUSION: Co-transplantation with MSCs could ameliorate the challenges of aGVHD and viremia and facilitate survival in allo-HSCT for AA patients.

Disclosures
No relevant conflicts of interest to declare.
SLC2A5 Overexpression in Childhood Philadelphia Chromosome Positive Acute Lymphoblastic Leukaemia
Authors: Zhao Pan , Zheng Yuhuan , Niu Ting 
Published: October 2019

Abstract
To study glycolysis/glycogenesis-related genes expression in childhood B cell acute lymphoblastic leukaemia (B-ALL), we performed a microarray-based analysis using published gene expression profiles. We found that gene SLC2A5, which encoded fructose transporter GLUT5 that facilitated cell fructose uptake, was up-regulated in Philadelphia chromosome positive ALL (Ph+ALL). Microarray-based analyses also suggested that SLC2A5 expression was significantly down-regulated in childhood B-ALL with t(1;19) or 11q23 mutation. High SLC2A5 expression was found in the patients who had recurrence within 3 years, early relapse, shortened complete remission duration, and positive minimal residue disease (MRD) status after treatment. The overexpression of SLC2A5 at both mRNA level and protein level in Ph+ALL was confirmed in a validation cohort of childhood B-ALL. We also validated the correlation of SLC2A5 expression and MRD status. In a mechanistic study using a human Ph+ALL cell line, we found that BCR-ABL kinase might regulate GLUT5 expression via c-myc. The tyrosine kinase inhibitors imatinib and dasatinib repressed GLUT5 expression and the cell uptake of fructose. Fructose protected the tumour cells from nutrition deficiency and drug-induced cell death. Overall, our findings showed that SLC2A5 was up-regulated in childhood Ph+ALL. The expression of SLC2A5 correlated with childhood B-ALL clinical factors, such as MRD status. Since TKI was able to inhibit GLUT5 expression, repression of fructose utility after TKI treatment contributes to TKI-induced Ph+ALL cytotoxicity. Targeting GLUT5 might be promising in B-ALL treatment, especially for Ph+ALL patients with high expression of SLC2A5.

Disclosures
No relevant conflicts of interest to declare.
Encouraging Outcome of Using Sibling HLA-Matched Fresh Cord Blood for Children β-Thalassemia Major Transplantation
Authors: Wen Jianyun , Chen Libai , Liu Sixi , He Yuelin , Ruan Yongsheng , Pei Fuyu , Feng Xiaoqin , Li Chunfu , Wu Xuedong 
Published: October 2019

Abstract
Background: Hematopoietic stem cell transplantation(HSCT) is currently the only curative treatment for thalassemia major (TM). Cord blood (CB) from a sibling has different characteristics from marrow and has potential advantages and disadvantages as a stem cell source.
Methods: We conducted a retrospective study of fresh cord blood transplantation (F-CBT) from the matched human leukocyte antigen (HLA)-identical sibling donors in 35 children (median age at transplantation: 4 years, range:1-7 years) with β-TM from June 2010 to December 2016. The conditioning protocol included intravenous busulfan, cyclophosphamide, fludarabine, and thiotepa.
Results:The median collected CB volume was 130ml (range: 79-209ml). The median infused total nucleated cell (TNC) dose was 9.38×107/kg (range: 2.73-18.91×107/kg). One patient had graft failure (GF) on +30day after F-CBT and one patient died from respiratory and heart failure that developed from a pulmonary infection. Of the 33 patients who had a successful engraftment, two patients developed grade II~III acute graft-versus-host disease(GVHD); and one with grade I extensive chronic GVHD was observed during the long-term follow-up period. The median time to neutrophil recovery was +27 days (range: +14 to +49days). The platelet and hemoglobin engraftment times were +33 days (range: +19 to +73 days) and +26 days (range: +11 to +74 days), respectively. All the patients were followed up by December 31, 2017; the median follow-up time was 45 months, and the estimated 5-year overall survival (OS) and TM-free survival (TFS) of F-CBT were 97.1% and 94.2%, respectively.
Conclusions: F-CBT from a matched HLA-identical sibling donor is an effective treatment option for β-TM in children with less GVHD.

Disclosures
No relevant conflicts of interest to declare.
Prognostic Value of Minimal Residual Disease before Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia
Authors: Pérez-López Olga , Caballero-Velázquez Teresa , Colado Enrique , Alonso Sara , González-Campos José , Prats-Martín Concepción , Rodríguez-Torres Nancy , Escamilla Gomez Virginia , Espigado Ildefonso , Pérez-Simón Jose Antonio 
Published: October 2019

Abstract
Introduction
Several studies have shown that the minimal residual disease (MRD) in acute myeloid leukemia (AML) patients has a prognostic value after induction and consolidation therapy. Nevertheless the relapse is the most important cause of treatment failure in these patients, although they achieved a negative MRD, and even after an allogeneic hematopoietic stem cell transplantation (allo-HSCT). Nowadays, the value of the MRD before allogeneic BMT is still controversial.
Method
Multicentric study where we have studied correlative AML patients who went under an allo-HSCT in a situation of complete response, between 2012 and April'18. The MRD was analyzed by 8-coloured multiparametric flow cytometry, at least with 2 tubes per patient and 1,000,000 events per tube. We evaluated the prognostic value of the MRD before allo-HSCT.
Results
Between January'12 and April'18 we have gathered 90 allogeneic BMT in AML patients who were in CR, with a median age of 45 years old (17 - 66). The pre-HSCT situation was 1st complete remission (CR) in 75 patients and 2nd CR in 15. In 45 patients the conditioning regimen was myeoablative. In the group of patients (67) where we could know the risk group at diagnosis, the distribution was: low risk 18%, intermediate risk 59.7% and high risk 22.4%. The 46.7% of the donors were not related. In the last follow-up after allo-HSCT 24 patients have suffered a relapse (26.7%) and 41 (45.5%) have died (17 cases of mortality related to the transplant and 24 not related). In the global analysis the median follow-up of the overall survival (OS) was 37.5 months. Among the 90 patients, MRD was valuable in 86. Ten of 59 patients (16.9%) with negative MRD relapsed vs 12/27 (44.4%) with positive MRD, p= 0.016. If we consider only patients in 1st CR, 9/50 (18%) patients with negative MRD relapsed vs 10/22 (45.5%) with positive MRD, p= 0.02. This statistically significant difference does not exist if we consider only patients in 2nd CR. The median follow-up of OS and event free survival (EFS) was not reached in the negative MRD group and 571 days and 299 days in the positive MRD group. OS and EFS at 2 years after transplantation were 65% and 64% in the negative MRD group and 42% and 37% in the positive MRD group, p= 0.03 and p= 0.008 respectively (figure 1).
Conclusions
The detected MRD by 8-colour multiparametric flow cytometry previous an allo-HSCT in patients with AML in 1st CR is a prognostic factor in terms of relapse. Patients with a positive MRD before the allo-HSCT have a poorer OS and EFS than the patients with a negative MRD.
Figure 1. Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Risk Factors for Induction Related Mortality in Adults Patients with Acute Lymphoblastic Leukemia: Report from a Hispanic Population
Authors: Inclan-Alarcon Sergio I , Bourlon Christianne , Fierro-Angulo Oscar Manuel , Garcia-Ramos Jesus A , Riviello-Goya Santiago , Demichelis-Gómez Roberta 
Published: October 2019

Abstract
Introduction
Acute lymphoblastic leukemia (ALL) represents 20-30% of acute leukemia in adults. Higher incidence and inferior outcomes in Hispanic population have been described. In Latin Americans induction mortality (IM) is a major cause of death representing 20-50% vs.7-11% in developed countries. Our aim was to determine risk factors (RF) related to IM in ALL Hispanic adult patients.
Methods
We retrospectively analyzed clinical data of ≥18yo patients with ALL diagnosed and treated at our institution within 2009 and 2016.
Results
A total of 170 patients were included. Median age was 29 years (16-70), 64% were AYA, 96.8% had B-cell ALL, and 62.3% received Hyper-CVAD.
IM rate was 13.4%. In 64.1% IM was related to an infectious cause. The most frequent infection was pneumonia (39.8%). Gram-negative etiology was more prevalent (35.5% vs. 10.2%), however, IM rate was higher in gram-positive infections (26.3% vs .13.6%; p=.028).
RF related to IM in univariate analysis were: CNS involvement (OR4.6,95%IC2.8-9.5;p=<.001), tumor lysis syndrome (TLS) (OR 5.6, 95% CI 2.2-14.1; p=<.001), need for dialysis (OR 28.9, 95% CI 5.3-157.1; p=<.001), primary hypertension (OR 3.5, 95% CI 1.0-12.7; p=.052), shock status (OR 10.3, 95% CI 3.9-27.3; p=<.001), ECOG³2 (OR 1.9, 95% IC 1.1-3.4; p=.022), T-ALL (OR 2.2, 95% IC 1.1-4.3; p=.026), Hyper-CVAD (OR 1.9, 95% IC 1.1-3.8; p=0.51), ventilation assistance (OR 7.7, 95% IC 2.8-21; p=<.001), and vasopressor use (OR 7.6, 95% IC 2.8-20.6; p=<.001). In multivariate analysis TLS, need for dialysis and shock, kept statistical significance.
Conclusions
To our knowledge, this is the largest study that evaluates the impact over IM of biological, social, and economic factors in Hispanic adult patients with ALL. We identified factors not previously described such as hypertension and need for dialysis. Multicenter prospective studies most be urged to asses and validate these RF, and design a bedside prognostic score that can predict an increased risk of IM at ALL diagnosis.

Disclosures
No relevant conflicts of interest to declare.
STAT3 Inhibition Enables TLR9-Driven Differentiation of Cbfb/Myh11 acute Myeloid Leukemia Cells to Antigen-Presenting Cell Phenotype In Vivo
Authors: Kortylewski Marcin , Duttagupta Priyanka , SU Yu-Lin , Adamus Tomasz , Marcucci Guido 
Published: October 2019

Abstract
STAT3 transcription factor is persistently activated in cancer cells and in diverse tumor-associated immune cells being an important oncogene and an essential immune checkpoint regulator. It is a highly desirable but challenging therapeutic target for pharmacological intervention. We previously demonstrated that ligand for the intracellular receptor TLR9 (CpG oligonucleotide) allows for the uptake and cytoplasmic delivery of decoy oligodeoxynucleotides (dODNs) to inhibit transcriptional activity of STAT3 in a variety of human and mouse acute myeloid leukemia (AML) cells. Here, we demonstrate that CpG-STAT3dODN injected intravenously to mice engrafted with Cbfb/MYH11 AML, dramatically altered leukemic cell morphology, by reducing nucleus-cytoplasm ratio and increasing mitochondria size, and also resulting in metabolic shift from glycolysis to oxidative phosphorylation, resulting in increased mitochondrial ATP production. The transcriptional profiling of AML cells isolated from spleens of mice treated using CpG-STAT3dODN vs control CpG-scrODN or PBS, revealed the increased expression of genes regulating myeloid cell differentiation (Irf8, Cebpa, Gadd45a) and antigen-presentation (B2m, CIIta, IL-12a, Ifng), with decrease of leukemia-related regulators Runx1and Run1t1. Thein vivodifferentiation of leukemic cells was confirmed using flow cytometry by detecting appearance of the population of AML-derived CD11b+/MHCII+/CD86+myeloid cells after CpG-STAT3dODN but not control treatments. Furthermore, we confirmed that the differentiated AML cells have immunogenic effects, which drive expansion of Th1 effector T cell responses in Cbfb/MYH11 as well as C1498 AML models. Overall, our studies suggest that STAT3-inhibition can unleash immune-stimulatory potential downstream of TLR9 signaling transforming AMLcells into antigen-presenting cells. These findings support development of CpG-STAT3dODN strategy as a new bi-functional agent for AML immunotherapy.
This project described was supported by the National Cancer Institute of the National Institutes of Health under award number R01CA213131 to M.K.

Disclosures
Kortylewski: N/A: Patents & Royalties: I am an inventor on the US patent 9,976,147.