bluuebunny/crossref_metadata_2025_split huggingface dataset:
Total Body Irradiation Causes Residual Bone Marrow Injury by Induction of Persistent Oxidative Stress in Murine Hematopoietic Stem Cells.
Authors: Wang Yong , Liu Lingbo , Pazhanisamy Senthil Kumar , Meng Aimin , Zhou Daohong 
Published: October 2019

Abstract
Abstract 3209
Poster Board III-146
Ionizing radiation (IR) and/or chemotherapy cause not only acute tissue injury but also have late effects including long-term bone marrow (BM) suppression. The induction of residual BM injury is primarily attributable to induction of hematopoietic stem cell (HSC) senescence. However, neither the molecular mechanisms by which IR and/or chemotherapy induce HSC senescence have been clearly defined, nor has an effective treatment been developed to ameliorate the injury, which were investigated in the present study using a total body irradiation (TBI) mouse model. The results showed that exposure of mice to 6.5 Gy TBI induced a persistent increase in reactive oxygen species (ROS) production in HSCs only for up to 8 weeks, primarily via up-regulation of NADPH oxidase 4 (NOX4). This finding provides the foremost direct evidence demonstrating that in vivo exposure to IR causes persistent oxidative stress selectively in a specific population of BM hematopoietic cells (HSCs). The induction of chronic oxidative stress in HSCs was associated with sustained increases in oxidative DNA damage, DNA double strand breaks, inhibition of HSC clonogenic function, and induction of HSC senescence but not apoptosis. Treatment of the irradiated mice with N-acetyl-cysteine (NAC) after TBI significantly attenuated IR-induced inhibition of HSC clonogenic function and reduction of HSC long-term engraftment after transplantation. These findings suggest that selective induction of chronic oxidative stress in HSCs by TBI leads to induction of HSC senescence and residual BM injury and that antioxidant therapy may be used as an effective strategy to mitigate IR- and chemotherapy-induced residual BM injury.

Disclosures
No relevant conflicts of interest to declare.
Expression of FLT3 Internal Tandem Duplication in Pediatric Patients with Acute Myeloid Leukemia and Its Correlation with Multidrug Resistance.
Authors: Qiao Zhenhua , Zhao Jiangning , Xu Lianrong , Lu Quanyi , Niu Xiaoqing , Zhang Peng , Wang Zhao 
Published: October 2019

Abstract
Abstract 4427
FLT3 Internal Tandem Duplication is a kinase mutation frequently observed in cases of adult acute myeloid leukemia (AML). This study was aimed to investigate the expression of FLT3 internal tandem duplication (FLT3-ITD) in pediatric patients with acute myeloid leukemia (AML) and to analyse the clinical features of patients with mutations and the relation of FLT3-ITD with multidrug resistance gene 1 (mdr1). Samples were analysised from eighty-one new diagnosed pediatric patients with AML. The diagnosis was based on French-American-British (FAB) criteria. Immunophenotyping was done by flow cytometry. For each patient, several clinical and biological characteristics were analyzed (age, WHO performance status, WBC count at diagnosis, bone marrow blasts, FAB subtypes, immunologic phenotype, and cytogenetics). The expressions of FIT3-ITD and mdr1 gene in bone marrow samples was determined by RT-PCR. patients were treated with uniform chemotherapy. Statistical analysis were carried by SAS. The results indicated that the FLT3-ITDs were detected in 8 out of 81 pediatric patients (9.88%) and all mutations detected were hybrid, while less frequently this mutation was detected in adult patients. Although they were irrelevant with sex and immunophenotypes, the mutations seemed predominant in older pediatric patients. The average age is 14-year-old in the patients with mutations, but 9-year-old in those without mutation (P=0.039). The leukocyte counts and bone marrow blast cell counts in pediatric patients with FLT3-ITD at diagnosis were higher than those in pediatric patients without FLT3-ITD (median of 58.4×10∧9/L versus 19.49 ×10∧9/L, p = 0.001 and median of 78.5% versus 54.4%,p = 0.041 respectively). The normal chromosomes were found in most pediatric patients with FLT3-ITD, although no significane in the stastistics. The patients with FLT3-ITD had lower induction remission rate (only 25%), but the patients without FLT3-ITD had higher remission rate (76.1%). According results detected by RT-PCR, the mdr1 gene was found in 27 pediatric patients, but only 3 out of 8 pediatric patients with FLT3-ITD were detected to express both FLT3-ITD and mdr1. It is concluded that the FLT3-ITD is a frequent mutation in pediatric patients with AML, especially in the elder pediatric patients. It is related with higher leukocyte counts and bone marrow blast cell counts, which may due to the continual activation of Flt3 tyrosine kinase. The prognosis of these patients with mutations is worse and the induction remission rate is lowe. But the FLT3-ITD not relates with the mdr1, which suggests that the low induction rate is not resulted from the multidrug resistance, at least not from the P-glycoprotein (Pgp) activity. So the common MDR modulators may be uneffective for therapy of the patients with FLT3-ITD.

Disclosures:
No relevant conflicts of interest to declare.
Severe Early-Onset Inflammatory Bowel Disease Caused by IL10 Receptor Deficiency Can Be Cured by Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Boztug Kaan , Kotlarz Daniel , Glocker Erik , Gertz Mike E , Schäffer Alejandro A , Noyan Fatih , Perro Mario , Diestelhorst Jana , Allroth Anna , Murugan Dhaarini , Hätscher Nadine , Pfeifer Dietmar , Sykora Karl-Walter , Sauer Martin , Kreipe Hans , Lacher Martin , Nustede Rainer , Woellner Cristina , Baumann Ulrich , Salzer Ulrich , Koletzko Sibylle , Shah Neil , Segal Anthony , Sauerbrey Axel , Buderus Stefan , Snapper Scott , Grimbacher Bodo , Klein Christoph 
Published: October 2019

Abstract
Abstract 713
In spite of recent genome-wide association studies, the molecular pathophysiology of many human auto-inflammatory diseases such as enterocolitis remains largely unknown.
Here, we discover the first fully penetrant monogenetic defect causing inflammatory bowel disease (IBD) in humans. Using homozygosity mapping and candidate gene sequencing, we identified three distinct, homozygous mutations in IL10RA, encoding the IL10R1 protein, and IL10RB, encoding the IL10R2 protein, in patients with severe and refractory enterocolitis. IL10R1 is a specific receptor for IL10, whereas IL10R2 is a shared cytokine receptor unit for IL10, IL22, IL26, and IFNλ. The striking similarity of the clinical phenotype between patients with IL10RA and IL10RB deficiency, respectively, suggests that defective IL10-mediated signaling, and not IL22, IL26, or IFNλ dependent effects, is the critical reason for disease.
Deleterious missense mutations in IL10RA abrogate IL10-induced signaling, as shown by deficient phosphorylation of STAT3 at the residue tyrosine 705 in primary patient cells and in HeLa cells engineered to express mutant IL10R1. Mutations in IL10RB introduced a premature stop codon. Defective expression of IL10R2 on the cell surface and deficient STAT3 signaling could be reconstituted by lentiviral gene transfer. As a consequence of defective STAT3 signal transduction in response to IL10 stimulation, IL10R-deficient primary cells showed increased secretion of TNFαa and various other proinflammatory cytokines unresponsive to IL10-dependent negative feedback regulation (TGFβ1, IL1αa, IL1β, IL2, IL6, IL6sR, RANTES, MCP1, MIP1αa, and MIP1β). We are currently assessing whether other IBD patients with early-onset IBD show defects in IL10-mediated signal transduction.
In view of the therapy refractory course of disease and the critical role of IL10 signaling on cells of the hematopoietic system, we have successfully treated two IBD patients with IL10 receptor deficiency by hematopoietic stem cell transplantation (HSCT) without overt side effects. This proof-of-principle suggests that allogeneic HSCT may represent a novel therapeutic approach to treat defined subgroups of IBD patients.
In summary, our results suggest that IL10 receptor defects constitute monogenetic causes for severe, early-onset IBD patients, proving that a lack of IL10-mediated negative feedback signaling perturbs homeostasis of the intestinal immune system.

Disclosures:
No relevant conflicts of interest to declare.
Discontinuation of Imatinib Therapy After Achieving a Molecular Response in Chronic Myeloid Leukemia Patients.
Authors: Mahon Francois-Xavier , Rea Delphine , Guilhot Francois , Huguet Francoise , Nicolini Franck Emmanuel , Legros Laurence , Charbonnier Aude , Guerci Agnes , Varet Bruno R. , Etienne Gabriel , Aton Emilie , Reiffers Josy , Rousselot Philippe 
Published: October 2019

Abstract
Abstract 859

Background
Imatinib (IM) has greatly improved survival rates in chronic myeloid leukemia* (*CML). However, all patients (pts) must continue treatment for an unknown period of time.
A pilot study of the first pts who discontinued IM therapy was previously reported (Rousselot et al. Blood 2007;109:58–60). The multicentre study Stop Imatinib (STIM) was initiated in July 2007 in order to evaluate the persistence of complete molecular remission (CMR) after stopping IM, and to determine the factors that could be associated with CMR persistence.

Methods
Inclusion criteria were IM treatment duration of at least 3 years and sustained CMR. Sustained CMR was defined as BCR-ABL/ABL levels below a detection threshold corresponding to a 5-log reduction (undetectable signal using RQ-PCR) for at least 2 years. Molecular relapse, defined as RQ-PCR positivity, was taken into account if confirmed in two successive assessments. In cases of molecular relapse, pts were re-challenged with IM at 400 mg daily.

Results
From the pilot study, 8 among 15 patients are still in CMR with a median follow up of 42 months (range 37-49). The number of patients enrolled in the STIM study was 69. 34 patients had received interferon alpha (IFNa) prior to IM and 35 pts were de novo. Median follow-up (range) was 17 months (6-24). 37 pts relapsed (loss of CMR) within the first 6 months and two patient relapsed after more than 6 months (M7 ,M18). At M12, the probability of remaining in CMR was 45% (95% CI: 33-56%). For previously treated with IFN (n=34) this probability was 44% (95% CI: 27-59%) versus 46% (95% CI: 29-61%) for de novo pts (p=0.93, overall). All patients in molecular relapse were sensitive again after imatinib re-challenge (decreasing BCR-ABL level, achievement CMR again). Male pts had a better probability of survival without molecular relapse (p=0.02) and a trend was observed for the low Sokal risk group (p = 0.06). Peripheral NK cells counts prior to IM discontinuation were significantly lower in relapse pts (mainly cytotoxic cells CD56dim) as compared to the non relapse pts(p=0.005).

Conclusions
We have confirmed that CMR can be sustained after discontinuation of imatinib with a long follow-up, particularly in male patients and in pts with cytotoxic NK cells in their peripheral blood. Using stringent criteria, it is possible to stop treatment in patients with sustained CMR, even in those treated with IM as a single agent.
(ClinicalTrials.gov number, NCT00478985 [ClinicalTrials.gov])

Disclosures:
Mahon: Amgen: Honoraria; Novartis Pharma: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria. Guilhot:Novartis Pharma: Consultancy, Honoraria; BMS: Consultancy, Honoraria.
R-HCVAD/R-MTX-Arac (R-HCVAD) Overcomes Risk Features Associated with Inferior Outcomes In the Treatment of Newly Diagnosed, High-Risk Diffuse Large B-Cell Lymphoma (DLBCL).
Authors: Mato Anthony R , Feldman Tatyana , Zielonka Tania , Bhattacharyya Pritish K. , Campaiola Alexandria , Shah Rina P , Rosario Maria , Bejot Coleen , Stives Susan , Curtin Mary , Vicioso Rosalba , Goldberg Stuart L , Pecora Andrew L , Goy Andre 
Published: October 2019

Abstract
Abstract 1782

Background:
Chemo immunotherapy (R-CHOP) has improved outcomes of both GC (germinal center) and ABC (activated B-cell) subtypes of DLBCL. However outcomes in DLBCL patients treated with R-CHOP with ABC subtype (vs. GC) and/or with poor-risk features (High IPI, high Ki-67) remain inferior. These patients might benefit from more dose-intensive or high-dose therapy approaches. In our practice at The John Theurer Cancer Center, we have employed a risk-adaptive strategy with R-HCVAD to treat patients with DLBCL with aggressive features.

Methods:
Utilizing Kaplan Meier (KM) survival and Cox regression analyses, we conducted a retrospective cohort study to describe the outcome of patients treated with R-HCVAD in the 1st-line setting with the following high-risk features: high Ki-67 (MIB-1), high IPI, multiple extra-nodal (EN) sites, bulky disease or immunohistochemistry (IHC) staining patterns (GC vs. non GC by Hans’ model). The primary study endpoints were PFS and OS. The proportional hazards assumption was met for this analysis.

Results:
45 patients (median age 57, range 34–71 yrs) with newly diagnosed DLBCL treated with R-HCVAD (median 6 cycles, range 1–8) were available for this analysis, representing 1010 total months of follow up at-risk. Baseline characteristics included: stage III-IV (90%), IPI ≥ 3 (52%), median Ki-67 (80%, range 10–100%), median EN sites (2), non-GC subtype (34%), bone marrow (BM) involvement (38%), EBER positive (14%), HIV negative (100%). With 17 months (range 9–64 months) median follow up, median OS and PFS (graph) are not yet reached. 2-yr PFS and OS were 80% (95% CI 61–91%) and 78% (95% CI 61–88%) respectively. In Cox regression analysis, survival outcomes were not adversely affected by: patient age > 60 (HR .8, p=.18), LDH > ULN (HR 2.3, p=.3), non-GC IHC pattern (HR .5, p=.5), BM involvement (HR 1.9, p=.4), Ki-67 ≥ 80% (HR 1.7, p=.6) or EN sites ≥ 2 (HR 4.7, p=.15).

Conclusions:
This analysis represents the largest reported cohort of DLBCL patients treated with R-HCVAD. These data suggest that R-HCVAD can overcome traditional poor-risk features such as high IPI, high Ki-67 and non-GC IHC pattern. Future work will focus on identifying molecular markers for failure in DLBCL patients treated with dose-intensive regimens. A randomized trial comparing R-HCVAD to R-CHOP in selected high-risk patients is warranted.

Disclosures:
No relevant conflicts of interest to declare.
Interim Results of a Phase 1 Trial of An Oral Histone Deacetylase Inhibitor Belinostat In Patients with Lymphoid Malignancies.
Authors: Zain Jasmine M. , Foss Francine M , de Bono Johann S. , Narwal Ameet , Neylon Ellen , Blumenschein George , Lassen U. , Knoblauch Poul , Diefenbach Catherine S. , O'Connor Owen A. 
Published: October 2019

Abstract
Abstract 1787

Background:
Belinostat (Bel) is a histone deacetylase inhibitor with broad preclinical activity. A phase I study of oral Bel in patients (pts) with solid tumors found a recommended dose for day (d) 1–14, q3w, of 750 mg QD, with allowance for intra-patient dose escalation if limited toxicity. The current study was initiated to assess if the same dose could be utilized in pts with lymphoma.

Objectives:
safety and efficacy assessments of oral Bel in cohorts of 3–6 pts (A 750; B 1000; C 1250; D 1500, E 1750; F 2000), treated d 1–14, q3w in pts with relapsed/refractory non-Hodgkin lymphoma (NHL) or Hodgkin's disease (HD) with evaluable disease and acceptable organ functions.

Results:
21 pts, sex (9 F, 12 M) - median age 48 (range 21 – 81), prior regimens, median 5 (range 1 – 13), 12 had BM transplants, including 3 pt with allogeneic have been enrolled. Diagnoses included Mantle Cell lymphoma (MCL; 5 pts), HD (7 pts), other NHL (9 pts).
Median number of Belinostat cycles 3 (range 1–29) 1 pt remains on trial. In 21pts evaluable for tox the most frequent adverse events (regardless of attribution or grade) were: Diarrhea and fatigue (each in 18pts), vomiting (14 pts), cough and constipation (each in 12 pts), anxiety and decreased appetite (each in 11pts). Non-hem gr 3/4 events: 6 pts had gr 3 diarrhea – no dose dependency, – (1 grade 3 diarrhea at 1500-mg dose resulting in hospitalization - DLT) Gr 3 Abdominal pain; cholelithiasis; DVT; hyperthyroidism (each seen in 1 pt;), only gr 4 event was respiratory distress (1 pt in cohort C). Gr 4 Thrombocytopenia (2 pts - Cohort C and E) gr 3 Thrombocytopenia (4 pts - Cohorts, D, E, F) Gr 4 anemia (1 pt - cohort B) Gr 3 anemia (2 pts - Cohort C and D) Leucopenia grade 3 or 4 was not seen-. In 16 pts evaluable for efficacy, stable disease have been noted in 12 pts, including 4- pts with MCL, 4 pts with NHL and 4 with HD. 1 pt with HD had CR after C2 and was treated with additional 2 cycles.

Conclusions:
Oral Bel can be administered safely with a d 1–14, q3w schedule in pts with lymphoma at a daily dose higher than what has been established for pts with solid tumors. Protocol defined DLTs have been encountered in the dose range 750 – 2000mg in pts with lymphoma. Cohort D at 1500 mg was expanded due to 1 DLT (diarrhea). Cohort E at 1750 mg was tolerated without DLT and cohort F 2000 mg is currently being investigated. Final evaluation will include additional pts and possible dose escalation. The safety profile and early tumor shrinkage noted in MCL and HD warrants continued evaluation of Bel, especially in combination with other active compounds.

Disclosures:
Foss: Allos Therapeutics, Inc.: Consultancy, Speaker. Neylon:Allos Therapeutics, Inc.: Honoraria. Knoblauch:TopoTarget: Employment. O'Connor:Allos Therapeutics, Inc.: Research Funding.
Targeting Chronic Lymphocytic Leukemia with Cord Blood NK Cells In NSG Model
Authors: Xing Dongxia , Decker William , Li Sufang , Robinson Simon , Shah Nina , Yang Hong , Champlin Richard E. , Parmar Simrit , Gribben John G. , Bollard Catherine M , Shpall Elizabeth 
Published: October 2019

Abstract
Abstract 2453
The incompatibility between donor killer cell immunoglobulin-like receptors (KIRs) and their corresponding ligands has been reported to reduce the risk of relapse after haploidentical and human leukocyte antigen (HLA) mismatched hematopoietic stem cell transplantation in patients with acute myeloid leukemia. We tested this KIR-ligand mismatch hypothesis in the context of allogeneic cord blood NK cells as an adoptive transfer of lymphocytes treating residual chronic lymphocytic leukemia (CLL). As a model for targeting malignant B cells in CLL, we examined allogeneic cord blood NK cell function in NOD scid gamma (NSG) mice, which carry the null interleukin-2 receptor gamma chain mutation, as the mice developed leukemia. Positively selected CD56+ cord blood NK cells were expanded ex vivo with interleukin-2 for 14 days. CLL cells were established in the NSG model by infusion of CLL cells obtained from patients. The leukemia that develops in NSG mice resembles human CLL, with a proliferating CD19+CD23+CD5+ B-cell population detected in the bone marrow, spleen, lymph nodes, and peripheral blood. Subsequently, expanded cord blood NK cells (5 × 106 per mouse) were intravenously infused into NSG-CLL mice. The NK cells that were infused into the CLL mice were typed for HLA and KIR (four main KIRs: KIR2DL2, KIR2DL3, KIR3DL1, and KIR2DL1). The CLL patients' samples that had been used in the NSG models were genotyped for KIR ligands (HLA-C group or HLA-Bw4 group and HLA-A3). In the six pairs of cord blood NK and CLL cells typed, all were HLA mismatched. Five pairs were KIR-ligand mismatched; these mice showed robust NK cell–mediated killing of CLL cells 7 days after NK cell infusion. Of interest, although no KIR-ligand mismatch was seen between the cord blood NK cells and CLL cells in one pair, we still observed NK cell–mediated killing of CLL cells in the mice. In this instance, NK cell–mediated cell killing could have been attributed to possible lower expression of HLA ligands by leukemic cells. Overall survival was significantly improved in CLL-NSG mice that had received cord blood NK cell treatment compared with overall survival in untreated mice (Kaplan-Meier analysis, p < 0.03). These results showed that adoptive transfer of allogeneic cord blood NK cells can be effective in killing CLL, and will be explored in the clinic.

Disclosures:
Gribben: Roche: Consultancy; Celgene: Consultancy; GSK: Honoraria; Napp: Honoraria.
Leukemia-Induced Alterations of Bone Marrow Microenvironment Contribute to Leukemogenesis.
Authors: Shim Jae-Seung , Kim Myungshin , Lee Jong Wook , Oh Il-Hoan 
Published: October 2019

Abstract
Abstract 2597
The impact of microenvironment on the regulation of normal hematopoietic process is being unveiled, but their role during leukemogenesis have been poorly understood. In this study, to characterize the leukemic microenvironment, we have analyzed mesenchymal stromal cells (MSC) of bone marrows from 55 cases of acute myelogenous leukemia (AML), and 17 of AML in the remission. When the colonogenic activity of MSCs were compared, 43% of AML-derived BM exhibited defect in colony (CFU-F) formation, where no colony formation or premature growth arrest of colonies were observed, whereas only 11% of normal BM exhibited growth arrest of colonies. In the AML subtypes, M3 type (FAB classification) exhibited most profound loss of CFU-Fs, where none of them (n=9) exhibited normal growth of colonies. In addition, numbers of colony (CFU-F) in AML was significantly lower than normal BM (52 vs. 155 per each ml of BM, respectively for AML and normal, p<0.05). In contrast, BMs of AML in remission did not exhibit significant difference in the number of CFU-F compared to numbers of normal BM (88 vs. 71.4 per 5×106 MNCs, respectively for normal and remission), indicating that the quantitative loss of CFU-F is correlated to disease activity of AML.
We next examined the qualitative changes of MSCs in AML, i.e., 83% of MSCs in AML (5/6) exhibited poor osteogenic differentiation, and all examined AML MSCs (6/6) exhibited lower adipogenic differentiaton compared to normal MSCs. During in-vitro culture, MSCs from AML showed accelerated loss of colonogenic activity during passage cultures compared to normal MSCs and lower intensity levels of CD146 in the cell surface. Moreover, MSCs from AML showed significantly higher levels of senescence-associated beta-galactosidase without changes in telomere length, indicating that the MSC has undergone qualitative change during leukemogenesis. When co-cultured with umbilical cord blood-derived CD34+ cells, AML-derived MSCs inhibited proliferation of CD34+ cells and caused significantly lower levels of hematopoietic cell expansion compared to the levels from co-culture with normal BM-derived MSCs or stroma-free cultures, indicating that leukemic MSCs should contribute to the loss of normal hematopoietic cells in leukemia.
Taken together, our study shows that microenvironment of BM undergoes quantitative and qualitative alteration during leukemogenesis and that such leukemic microenvironment contributes to the pathology of leukemia.

Disclosures:
No relevant conflicts of interest to declare.