bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 1b Study Of Otlertuzumab (TRU-016), An Anti-CD37 ADAPTIR™ Protein, In Combination With Rituximab In Patients With Previously Untreated Chronic Lymphocytic Leukemia (CLL)
Authors: Maddocks Kami , Pagel John M. , O'Brien Susan , Byrd John C. , Stromatt Scott , Awan Farrukh T 
Published: October 2019

Abstract

Background
CD37 is a tetraspanin protein expressed on the surface of normal and transformed B-cells across a wide range of maturational stages and demonstrates death signaling via SHP1. Otlertuzumab is a CD37-specific therapeutic protein built on the ADAPTIR™(modular protein technology) platform that has shown significantly greater direct killing of CLL cells than rituximab and higher levels of Fc-mediated cellular cytotoxicity of CLL cells than either alemtuzumab or rituximab in pre-clinical models. This phase 1b trial was conducted to evaluate the safety and efficacy of otlertuzumab in combination with rituximab in patients with previously untreated CLL.

Methods
Patients with untreated CLL that required treatment, had adequate organ function, ECOG ≤2, and absolute neutrophil count ≥800/μL were eligible. Patients were ineligible for chemotherapy as first-line therapy due to patient age, comorbidity, or patient refusal of chemotherapy Patients received otlertuzumab (20 mg/kg) weekly by IV infusion for two 28-day cycles then once a month for 4 months. Rituximab (375 mg/m2 the first dose then 500 mg/m2) was administered after otlertuzumab by IV infusion on the same schedule. Safety was evaluated using CTCAE and IWCLL 2008 Grading scale for Hematologic Toxicity in CLL Studies. Response was determined using the 1996 NCI and the 2008 IWCLL Criteria.

Results
24 patients have been treated. Patient characteristics and adverse events are shown in the table. The majority of the patients have not completed 6 cycles of therapy. The preliminary response by investigator assessment using NCI criteria at the last assessment is an ORR 88% (21/24); 2 patients have had PD. Six patients have had CT scans and bone marrow assessments 3 months after their last dose of study drug; by IWCLL criteria 1 has a CR, 4 have a PR and 1 has SD. The patient with a CR was MRD negative by five color flow cytometry of bone marrow aspirate. One patient discontinued therapy for a systemic inflammatory response. Severe (Grade 3 or 4) neutropenia was reported in 13% of patients; the incidence of severe infections was low (8%). Serious adverse events were reported for 4 patients: pneumonia, systemic inflammatory response, and deep vein thrombosis in 1 patient; and lymph node pain, worsening sinusitis, and fever in 1 patient each.

Conclusions
The preliminary response rate with otlertuzumab in combination with rituximab is promising. Follow-up is ongoing and the IWCLL response rate will be presented.

Disclosures:
O'Brien: Emergent Product Development: Research Funding. Stromatt:Emergent Biosolutions: Employment. Awan:Lymphoma Research Foundation - Research Funding: Research Funding, Speakers Bureau; Spectrum Pharmaceuticals, Inc. - Speakers bureau: Research Funding, Speakers Bureau.
Microrna-150 Inhibits Tumor Invasion and Metastasis By Targeting The Chemokine Receptor CCR6 In Advanced Cutaneous T-Cell Lymphoma
Authors: Ito Mitsugu , Teshima Kazuaki , Ikeda Sho , Watanabe Atsushi , Nara Miho , Kitadate Akihiro , Yamashita Junsuke , Oshima Koichi , Sawada Kenichi , Tagawa Hiroyuki 
Published: October 2019

Abstract
MicroRNA (miRNA)s are a class of small regulatory RNA molecules that play important roles in tumor development by pairing with the 3' untranslated region (UTR) of target messenger RNAs to repress their productive translation. Thus although the genes responsible for T-cell lymphomas remain largely unknown, in some lymphoma subtypes, miRNA dysregulation may contribute to tumorigenesis. For example, altered expression of various oncRogenic or tumor suppressive miRNAs has been identified in lymphomas/leukemias and solid tumors We show here that a tumor suppressive miRNA, miR-150, is significantly downregulated in advanced cutaneous T-cell lymphoma (CTCL), and that the downregulation is strongly associated with tumor invasion and metastasis. Inoculation of cutaneous T-cell lymphoma cell lines into NOD/Shi-scid IL-2γnul mice led to CTCL cell migration to multiple organs, but this invasion/metastasis was substantially reduced in miR-150-transfected CTCL cells due to direct downregulation of CCR6, a specific receptor for the chemokine CCL20. MiR-150 thus appears to negatively regulate the interaction between CCL20 and CCR6 in CTCL cells, thereby inhibiting autocrine CTCL cell metastasis. CD4+ T helper cells are divided into TH1, TH2, TH17, and TH22 subsets. Among these, the TH22 subset produces only IL-22, while TH17 cells produce both IL-17 and IL-22. Normally, IL-22 activates CCL20 transcription by binding to the IL-22RA1/IL-10RB receptor, which is not expressed in lymphoid organs or lymphocytes. In the present study, we further found that both IL-22 and its receptor subunit, IL-22RA1, are aberrantly overexpressed in advanced CTCL, but IL-17 is not expressed, suggesting CTCL is derived from the TH22 subset. In the presence of continuous upregulation of CCR6 accompanied by downregulation of miR-150, IL-22 activation could lead to continuous CCL20-CCR6 interaction in CTCL cells and, in turn, autocrine metastasis to distal organs. This is the first report demonstrating an invasion/metastasis mechanism in advanced CTCL.

Disclosures:
No relevant conflicts of interest to declare.
EZH2 Inhibitor DZNep Induces Apoptosis In Adult T-Cell Leukemia/Lymphoma Cells By BCL2 Suppression Via Regulation Of Mir-181a
Authors: Daisuke Sasaki , Hiroo Hasegawa , Hiroaki Taniguchi , Imaizumi Yoshitaka , Naoki Uno , Yoshitomo Morinaga , Miyazaki Yasushi , Katsunori Yanagihara 
Published: October 2019

Abstract

Background
Adult T-cell leukemia/lymphoma (ATL) is a mature T-cell neoplasm originating from human T-cell leukemia virus type-1 (HTLV-1) infected cells. Its clinical behavior differs among patients and is sub-classified into 4 sub-types: smoldering and chronic as indolent subtypes, and acute and lymphoma as aggressive subtypes. Prognosis for patients with the aggressive subtypes is very poor with standard chemotherapy, thus a new therapeutic approach is urgently needed. Previously, we reported that EZH2, a part of the PRC2 complex, not only methylates histone, but also serves as a recruitment platform for DNA methyltransferases that methylate the promoter regions of target genes (tumor suppressor gene and miRNAs) and is overexpressed in ATL cells. We found that ATL cell lines were sensitive to DZNep (3-deazaneplanosin A), which has been shown to deplete EZH2 expression, and their proliferation was attenuated. In the present study, we clarified which target genes and miRNAs are involved in DZNep-induced ATL cell death.

Results
We performed microarray analyses using the ATL cell lines KK1, SO4, LMY1, and KOB to compare their gene expression profiles between cells treated and untreated with DZNep. The results showed that BCL2 transcripts in ATL cell lines were commonly suppressed by DZNep. In accordance with those findings, quantitative PCR analysis revealed that BCL2 transcripts were suppressed in DZNep-treated as compared to untreated ATL cell lines. We also confirmed that EZH2 and BCL2 protein expressions were clearly suppressed in the ATL cell lines by DZNep. These findings indicated that DZNep suppresses BCL2 expression at the transcriptional level in ATL cells. In addition, we performed another set of microarray analyses for miRNA expression profiles using primary ATL cells obtained from ATL patients and CD4 positive T-cells from healthy volunteers. The ATL cells showed decreased expression levels of several miRNAs, such as miR-101, miR-126, and miR-181a. Importantly, miR-181a has been shown to be regulated by EZH2, while miR-181a is a candidate negative regulator of BCL2 expression. Quantification of miR-181a transcripts to determine whether miR-181a is induced by DZNep showed that miR-181a was up-regulated in ATL cells by DZNep. These results strongly support the notion that miR-181a is suppressed by EZH2 and that BCL2 expression is regulated by miR-181a in ATL cells. Together, our findings indicate a unique apoptotic pathway of BCL2 suppression via miR181a and that the EZH2 inhibitor DZNep may become a novel therapeutic agent for ATL.

Disclosures:
No relevant conflicts of interest to declare.
Interim and Post-Treatment Positron Emission Tomography-Computed Tomography Scan Status Is Highly Predictive Of Outcome In Diffuse Large Cell Lymphoma Patients Treated With R-CHOP21
Authors: Huang Honghui , Xiao Fei , Chen Fangyuan , Han Xiaofeng , Zhong Lu , Zhong Hua , Xu Lan , Zhu Jianyi , Ni Beiwen , Liu Jia , Chen Tao 
Published: October 2019

Abstract

Background
Taking a step forward from the international prognostic index, attention is focused on the role of 18F-fluorodeoxyglucose positron-emission tomography-Computed Tomography scan (PET) as a tool for guidance in risk stratification in patients with diffuse large B-cell lymphoma (DLBCL). Here, we analyzed the predictive value of interim and post-treatment PET in patients with DLBCL.

Methods
In our retrospective study, we analyzed a homogeneous cohort of newly diagnosed DLBCL patients treated with R-CHOP21 who underwent PET scan at diagnosis, after three cycles of chemotherapy and at the end of treatment. For interim PET, images were interpreted by computing maximum standardized uptake value between PET performed at baseline and after three cycles of immuno-chemotherapy (¦¤SUVmax). The images of post-treatment PET were interpreted visually according to the International Harmonization Project criteria. The primary study endpoints were progression-free survival (PFS) and overall survival (OS).

Results
Thirty-eight patients with DLBCL with PET data were identified. The median follow-up was 28 months. At interim PET evaluation, optimal cutoff to predict progression was 66% for ¦¤SUVmax. ¦¤SUVmax analysis (≥66% vs< 66%) identified patients with significantly different 2-year PFS (90.7% vs 38.9%; P =.000) and 2-year OS (95.5% vs 62%; P=.016) (Fig1). Post-treatment PET status (negative vs positive) was statistically significantly associated with 2-year PFS (91% vs 45.5%; P =.001) and 2-year OS (100% vs 72.7%; P =.012) (Fig2).

Conclusions
These data support the prognostic utility of PET in interim and post-treatment settings in patients with DLBCL treated with R-CHOP21. An interim PET scan after three cycles of treatment can effectively predict the outcome by using quantitative assessment of ¦¤SUVmax and allows clinicians to design a risk-adapted therapeutic strategy. A positive PET after the completion of therapy identifies a patient subset with an inferior PFS and OS.

Disclosures:
No relevant conflicts of interest to declare.
Multicentric Bone Involvement As Presentation Of Late Relapse In a Patient With Hairy Cell Leukemia (HCL)
Authors: Hyppolito Joyce E , Perini Guilherme Fleury , Campregher Paulo Vidal , da cunha Pasqualin Denise , Filho Reynaldo Jesus Garcia , Hamerschlak Nelson 
Published: October 2019

Abstract

Introduction
Hairy Cell Leukemia (HCL) is a lymphoproliferative disease, recently defined molecularly by mutations in the BRAF gene. It has an indolent course, and usually presents with massive splenomegaly, progressive pancytopenia and rare circulating tumor cells. Extranodal involvement, except for liver, is rare in HCL.

Methods
We described the case of a 46 year old female patient diagnosed with HCL in 2008. At that time, patient presented for medical assistance due to pancytopenia (Hb: 8,4g/dL, Leukocytes: 1200uL, Platelets: 29.000). A bone marrow biopsy showed extensive infiltration by lymphocytes positive for CD20, CD11c, CD25 and kappa, compatible with HCL. At that time, biopsy-proven involvement of a mediastinal node was also documented. The patient was treated with Cladribine 0.1mg/kg for 7 days, and achieved complete response.
Five days later, the patient presented with left hip pain. A MRI of the left leg showed nodular involvement of the acetabulum, with edema and bone fissures. A biopsy was consistent with HCL relapse. A PET-CT showed additional lesions in left tibia and right humerus.

Conclusion
Bone involvement in HCL is a rare event, and is usually restricted to one lesion. We present a case of multicentric involvement at relapse.

Disclosures:
No relevant conflicts of interest to declare.
Stroma cells and Monocytes make Multiple Myeloma Cells Active In Bone Marrow Microenviroment
Authors: Ikeda Hiroshi , Ishida Tadao , Hayashi Toshiaki , Aoki Yuka , Shinomura Yasuhisa 
Published: October 2019

Abstract
The Bone marrow (BM) microenvironment plays crucial role in pathogenesis of multiple myeloma　(MM). Paracrine secretion of cytokines in BM stromal cells promotes multiple myeloma cell proliferation and protects against drug-induced cytotoxicity. In current study, monocytes, component of BM cells, can directly promote mesenchymal stem cells osteogenic differentiation through cell contact interactions. Down-regulation of inhibitors such as DKK1 drives the differentiation of mesechymal stem cells into osteoblasts. In this study, we examined the role of monocytes as a potential niche component that supports myeloma cells. We investigated the proliferation of MM cell lines cultured alone or co-cultured with BM stromal cells, monocytes, or a combination of BM stromal cells and monocytes. Consistently, we observed increased proliferation of MM cell lines in the presence of either BM stromal cells or monocytes compared to cell line-only control. Furthermore, the co-culture of BM stromal cells plus monocytes induced the greatest degree of proliferation of myeloma cells. In addition to increased proliferation, BMSCs and monocytes decreased the rate of apoptosis of myeloma cells. Our results therefore suggest that highlights the role of monocyte as an important component of the BM microenvironment.

Disclosures:
No relevant conflicts of interest to declare.
The Detection Of The Immunophenotyping Of Plasma Cells In Patients With Multiple Myeloma
Authors: Ouyang Jian , Li Ermin , Zhou Min , Chen Junhao , Xia Yongquan , Xu Xuejing , Wang Xian , Zhou Rong-Fu 
Published: October 2019

Abstract

Objectives
To study the immunophenotyping of plasma cells in patients with Multiple Myeloma(MM). To explore the antigen combination used to identify benign plasma cells from malignant plasma cells.

Method
Four-color flow cytometry (BD FACSCalibur )was respectively used to detect antigens expression rate of 44 diagnosed patients with MM and 25 normal controls (14 patients with nutritional iron deficiency anemia and 11 healthy bone marrow donators). The results were analyzed by the software of CellQuest. The positive expression rate of clusters of differentiation in cells surface is greater than twenty percent.

Results
The frequency of expression rate of clusters of differentiation among patients with MM are as fellows:CD138+(97.72%) ACD38+(100.00%) ACD56+(63.64%) ACD19-(84.09%) ACD20+(11.63%) ACD200+(77.27%) ACD28+(38.64%) ACD86+(54.55%). The frequency of expression rate among normal plasma cells of controls are CD138+(100.00%) ACD38+(100.00%) ACD56-(0.00%) ACD19+(96.00%) ACD20-(0.00%) ACD200+(0%) ACD28+(0.00%) ACD86+(4.00%).

Conclusions
Using the antigen combination of CD138 ACD38 ACD56 ACD19 ACD20 ACD200 ACD28 ACD86 is availably conducive to detect the phenotype of the malignant plasma cells of the patients with MM.

Disclosures:
No relevant conflicts of interest to declare.
Hemopoiesis Regulated Negatively In Aged Monkeys
Authors: Li Ming , Ikehara Susumu 
Published: October 2019

Biological aging is associated with a progressive loss of regulation of cellular, tissue and organ interaction, ultimately resulting in senescence. In humans, accelerated marrow adipogenesis has been associated with aging and several chronic conditions, including diabetes mellitus and osteoporosis. Studies of the hemopoietic system using nonhuman primates have provided important information for understanding the mechanism of human hemopoiesis. Excellent reconstitution of donor hemopoietic cells in a collagen gel group has been observed in the long term in mice. We therefore investigated whether the method would be helpful for reconstituting hemopoiesis in the fatty tibias of monkeys. Nine- to 11-year-old monkeys were used for this study to examine if hemopoiesis could be restored in the fatty marrow of old monkeys. Bone marrow cells were collected from the humerus using the perfusion method, mixed with cultured bone marrow stroma cells in collagen gel, and then injected into the tibia of the same monkey. Clot sections were made from the tibias 1, 2 and 6 weeks after the bone marrow transplantation. However, no bone marrow cells were observed at any of the time points. These results suggested that adipocytes negatively regulate bone marrow reconstitution.

Disclosures:
No relevant conflicts of interest to declare.
A New Murine Model Of Chronic Graft Versus Host Disease
Authors: Huang Xin , Weng Jianyu , Wu Ping , Tong Jiaqi , Lai Peilong , Geng Suxia , Du Xin 
Published: October 2019

Abstract
Chronic graft-versus-host-disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), with highly variable clinical presentations. The pathophysiology of cGVHD remains to be further understood. The utilization of murine models to study cGVHD has contributed to the understanding of cGVHD, and highlights its mechanistic complexity. Here, we report a new murine cGVHD modle with obvious lung tissue damage in these mice resulted in the development of bronchiolitis obliterans (BO), which is pathopneumonic for cGVHD.
Recipients 8 weeks BALB/c (H-2d) female mice, which irradiated with 700cGy dose of linear accelerator, then were injected with bone-marrow cells (1×107) and spleen cells (5×106) from (C57BL/6 x BALB/c) F1 donors (H-2bd haplotype) male mice. The observed items post-transplantation included hematopoietic reconstruction, implant, and general condition. Clinical scores were assessed every 3 days after +14 d. At + 135 d, mice were killed to evaluate the pathological changes of major target organs.
Mice in transplantation groups were in hematopoietic reconstruction at +7 d, and all survived to the end point (+135 d). Chromosomes of recipient mice were in full donor chimera. Clinical scores of cGVHD group have been more than 0.6 since +90 d. These mice develop pathologic manifestations in several organs including lung, skin, and liver. Biopsy-proven BO incidence was 100%, and pathological scores of cGVHD group were 5.33±1.55, which significantly higher than those of transplantation control groups (P < 0.05).
To date, most models involve parent-into-F1 combinations the transfer of MHC-mismatched cells resulted in a phenotype that resembles clinical systemic lupus erythematosus (SLE), termed SLE-cGVHD. However, some of the models do not use any pretransplantation conditioning and no obvious lung tissue damage. We exchanged parent for recipients, and provide a total boby irradiation as pretransplantation conditioning. New MHC-mismatched murine cGVHD model was easily obtained, and more relevancy to the clinical features of cGVHD. This model provides an ideal study model of clinical cGVHD pathogenesis and treatment strategies.
NOTES: The project was sponsored by grants from National Natural Science Foundation (No. 81270648 and 30972790), National Public Health Grand Research Foundation (No.201202017), and Guangdong Natural Science Foundation (No. S2012010009560).

Disclosures:
No relevant conflicts of interest to declare.
T Cell Receptor Vbeta Repertoire Plays An Important Role In Graft-Versus-Leukemia Effect To Acute Lymphocytic Leukemia With TCF3-PBX1
Authors: Oka Yoko , Shirasaki Ryosuke , Matsuo Takuji , Tashiro Haruko , Ooi Jun , Shirafuji Naoki 
Published: October 2019

Abstract

Background and Aims
We recently reported that graft-versus-leukemia (GVL) effect was observed in acute lymphocytic leukemia (ALL) with TCF3-PBX1 (53rd ASH, and 15th ASGCT). To understand better the mechanism of this GVL effect, we analyzed blood T cell receptors (TCRs) obtained from ALL patients with TCF3-PBX1.

Materials and Methods
The institutional ethical committee approved our study using clinical materials. Three informed ALL patients with TCF3-PBX1 were eligible. Leukemic blasts, blood lymphocytes after underwent allogeneic hematopoietic stem cell transplantation to achieve and keep complete remission, and cells from pathologically GVHD-diagnosed organs (liver, and skin) were collected. Lymphocytes were co-cultured with the patient-derived ALL blasts that were priory irradiated at 20 Gray (GVL model) or GVHD-related cells (GVHD model) for 14 days with recombinant human interleukin-2. Then, TCR Valpha (Va) and Vbeta (Vb) usages were analyzed with RT-PCR. When the preferential usage of Va and Vb was observed, T cells underwent single-cell culture, and the clones showing ALL blast-killing activity and not GVHD effect were selected, and their TCR nucleotide sequences were analyzed.

Results
In GVHD model and GVL one, TCR Va and Vb were oligoclonally used, in which Vb 6, 10, and 14 were preferentially used in GVL model but not in GVHD. On Va no selective usage was demonstrated between GVL model and GVHD one. Furthermore, the obtained single cells with GVL effect had specific TCR Vb nucleotide-sequences.

Discussion
In GVL model TCR Vbs were preferentially used. Currently we isolate tcf3-pbx1-specific oligopeptide-antigen recognized by the isolated TCRs, and observe cytotoxic GVL effect with the isolated TCRs in vitro. We also validate in vivo implications of the isolated GVL-specific T cells to treat leukemic non-obese diabetes/severe combined immunodeficiency mouse generated by the injection of ALL-blast with TCF3-PBX1.

Disclosures:
No relevant conflicts of interest to declare.