bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rituximab With Or Without Chlorambucil For The Treatment Of Extranodal Marginal Zone B-Cell Lymphoma (MALT Lymphoma) Results From a Monocentric Study
Authors: Rigacci Luigi , Puccini Benedetta , Benelli Gemma , Kovalchuk Sofia , Fabbri Elisa , Bosi Alberto 
Published: October 2019

Abstract

Introduction
Standard therapy of MALT lymphomas is not defined apart from H Pylori eradication for gastric localization.

Aim
This study was designed to evaluate the use of Rituximab (R) alone or in combination with Chlorambucil (RC) in the treatment of patients with diagnosis of MALT.

Patients and methods
All patients with histologically confirmed diagnosis of MALT lymphoma were selected from our data base. Only patients treated with R or RC were analysed and evaluated. The scheme: rituximab 375 mg/sqm weekly for 4 doses, then monthly for 4 infusions alone or in combination with chlorambucil at the dosage of 0,1 mg/Kg/die for 45 days, then on days 1 to 15 monthly for 4 months.

Results
From January 2000 to December 2012, 136 patients were diagnosed and treated in our Institution, 76 were selected because of uniformly treated with R or RC. The median age at diagnosis was 68 years (range 32-85). In 20 patients the disease was localized in conjunctiva; 17 in the stomach; 14 in the lung; 13 in salivary glands; 3 intestine; 2 respectively in lacrimal gland, liver, skin; 1 in breast, cheek and tongue. Stage was IA in 63 patients (83%), IB in 1, IIA in 5 patients and IIB in 1, IIIA in 1 patient, IVA in 4 patients and IVB in 1. Bone marrow biopsy was negative in 59 patients, positive in 5 and not performed in 12 patients. The proliferative index was evaluated in 50 patients with Mib1 monoclonal antibody: 42 patients showed less than 30% of positivity and 8 had more than 30% of positivity. The diagnosis of MALT in 4 patients was associated with Sjogren Syndrome, in 4 patients with a positive HCV and in 1 with scleroderma. According to treatment 61 patients were treated with the combination of Rituximab and Chlorambucil and 15 were treated with Rituximab alone. At the end of treatment 69 patients (91%) obtained a complete remission and 7 (9%) a partial remission with an overall response rate of 100%. With a median observation period of 54 months (range 1-160) the overall survival was 89%. Eight patients died 5 for progression of disease (2 after a relapse) and 3 for causes not related to the lymphoma. Ten patients (14%) relapsed, 8 of these patients were retreated with Rituximab and obtained a new complete remission.

Conclusions
After a long follow-up the combination of Rituximab and Chlorambucil or Rituximab alone proved to be low toxic, feasible and effective therapy for MALT lymphomas.

Disclosures:
No relevant conflicts of interest to declare.
Obinutuzumab (GA101) More Potently Engages Phagocytic-Lineage Cells Resulting In Enhanced Monocyte and Macrophage Activity When Compared To Rituximab and Ofatumumab
Authors: Herter Sylvia , Klein Christian , Umana Pablo , Bacac Marina 
Published: October 2019

Abstract
Therapeutic antibodies possess several clinically relevant mechanisms of action including cell death induction, perturbation of tumor cell signaling, activation of complement dependent cytotoxicity (CDC), antibody dependent cellular cytotoxicity (ADCC), antibody dependent cellular phagocytosis (ADCP) and induction of adaptive immunity. Obinutuzumab (GA101) is a novel humanized, glycoengineered Type II anti-CD20 monoclonal antibody engineered for displaying enhanced FcγRIIIa (CD16) binding affinity and characterized by stronger induction of ADCC and direct tumor cell death when compared to wild-type, Type I anti-CD20 antibodies rituximab and ofatumumab. In light of the important role of phagocytic lineage cells in the mechanism of action of therapeutic antibodies, we compared GA101, rituximab and ofatumumab for their ability to trigger FcγR-dependent monocyte and macrophage effector functions. We show that, due to glycoengineering, GA101 displays superior CD16-dependent binding to monocytes, M1 and M2c macrophages in presence of nonspecific, competing, human endogenous IgGs, a situation that more closely mimics physiological conditions. Subsequently, GA101 more strongly engages monocytes and macrophages and leads to significantly higher elimination of CD20-expressing tumor cells as shown by assays detecting total antibody activity (ADCP, ADCC and direct effects). In support of the stronger GA101 activity, higher nitric-oxide (NO) levels are also detected in supernatants of tumor/macrophage co-cultures treated with antibody. Taken together, our data show that in addition to stronger NK-cell mediated ADCC and direct cell death induction due to Type II CD20 binding, GA101 more potently engages phagocytic-lineage cells resulting in enhanced monocyte and macrophage activity under conditions that more closely resemble physiological settings.

Disclosures:
Herter: Roche: Employment. Klein:Roche Glycart AG: Employment. Umana:Roche: Employment, Equity Ownership. Bacac:Roche: Employment.
ONO-4059, A Novel Bruton’s Tyrosine Kinase (Btk) Inhibitor: Synergistic Activity In Combination With Chemotherapy In a ABC-DLBCL Cell Line
Authors: Yasuhiro Tomoko , Yoshizawa Toshio , Birkett Joseph TP , Kawabata Kazuhito 
Published: October 2019

Abstract

Purpose
Bruton’s tyrosine kinase (Btk) is a key regulator of the B-cell receptor (BCR) signaling pathway and abberant BCR signaling has been implicated in the survival of malignant B-cells. Recent studies indicate that targeting Btk is effective in the treatment of B-cell malignancies. ONO-4059 is a highly potent and selective oral Btk inhibitor with an IC50 in the sub-nmol/L range. The activated B-cell-like (ABC) sub-type of diffuse large B-cell lymphoma (DLBCL) correlates with poor prognosis and a substantial unmet need still exists. The standard treatment with Rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) for ABC-DLBCL in particular being associated with a poorer outcome. The combination of ONO-4059 with the Bcl-2 inhibitor, ABT-263 has demonstrated greater apoptosis in ABC-DLBCL cell lines than that seen with single agent treatment (Ryohei K. et al., EHA 2013 meeting). To explore rational combinations, ONO-4059 combined with chemotherapy drugs was evaluated in a ABC-DLBCL cell line.

Methods
ABC-DLBCL cell line (TMD-8) was incubated with ONO-4059 monotherapy (1-1000 nmol/L) and in combination with various agents that target various pathways thought to be involved in DLBCL. Cell viability was determined by the CellTiter-Glo Luminescent Cell Viability Assay. Apoptosis was determined by AnnexinV-FITC/7AAD (AnnV+/7AAD-) staining.

Results
ONO-4059 inhibited the TMD-8 cell growth and Btk phosphorylation in a concentration-dependent manner, with an IC50 of 3.59 for 72 hr and 23.9 nmol/L for 4 hr respectively. Furthermore, the decrease in Btk phosphorylation subsequently down-regulated Erk phosphorylation. At the 48 hr time-point, 7% of apoptosis occurred in TMD-8 cells at 10 nmol/L, an earlier time-point than that observed for dead cell. After the combination of 10 nmol/L of ONO-4059 with 25 nmol/L of doxorubicin, 500 nmol/L of etoposide, 1.5 nmol/L of vincristine and 1000 nmol/L of dexamethasone, the increased apoptosis ratio was observed, 25, 20, 17 and 29%, respectively. Synergy was observed when ONO-4059 was combined with the CHOP regimen.

Conclusion
Recent studies indicate that targeting Btk induces BIM expression, the pro-apoptotic protein, following inhibition of Erk phoshphorylation. Our results demonstrate that treatment with ONO-4059 in combination with chemotherapy results in a synergistic effect, inducing apoptosis and is more effective compared with respective monotherapies. ONO-4059 is currently being developed in a Phase I clinical trial for the treatment of B-cell malignancies. Additional combination studies are underway using the TMD-8 xenograft model, testing ONO-4059 in combination with various agents.

Disclosures:
Yasuhiro: Ono Pharmaceutical Co., Ltd.: Employment. Yoshizawa:Ono Pharmaceutical CO., Ltd: Employment. Birkett:Ono Pharma UK: Employment. Kawabata:Ono Pharmaceutical Co., Ltd.: Employment.
CD20-Specific Engineered Toxin Body Demonstrates Direct Cell Kill Of Multiple B-Cell Non-Hodgkin's Lymphoma Types
Authors: Rajagopalan Sangeetha , Wirth Rachel , Erdman Jennifer , Brieschke Brigitte , Null William , Liu Jensing , Willert Erin , Higgins Jack 
Published: October 2019

Abstract
The B-cell membrane protein CD20 is expressed by both benign and neoplastic lymphocytes. It has been a superb target for immunotherapies targeting B-cell derived diseases. There are several anti-CD20 antibodies which have been developed for B-cell lymphoma therapy. The most successful example of this targeted approach is rituximab, which is approved for front and second line therapy of Non-Hodgkin lymphoma (NHL). However, rituximab has limited direct cell-kill effects, acting primarily through indirect immune responses induced by antibody-dependent cell-mediated cytotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC). While CD20-targeted radiotherapeutics have shown promise, their administrative challenges have curtailed their clinical utility. Thus, a therapeutic approach with direct cell-kill activity against CD20-expressing cells would be clinically useful. We have developed an engineered toxin body (ETB) comprising a CD20 specific scFv and a modified Shiga-like Toxin A (3F7) capable of specifically recognizing and killing CD20 expressing cells. 3F7 is selectively cytotoxic against B-cell NHL cell lines and against NHL cells obtained from patients. It demonstrated potent cytotoxicity against Burkitt’s lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma with IC (50) values ranging from 1.4 nM to 12 nM. Through immunofluorescent tracking, 3F7 internalizes within one hour after binding to CD20 (+) B cells. Consistent with the in vitro activity, 3F7 demonstrated anti-tumor efficacy in mice bearing Raji xenograft tumors. These results show that 3F7 is a promising targeted therapeutic agent against CD20 positive B-cell lymphomas and is currently under further development.

Disclosures:
Rajagopalan: Molecular Templates: Employment. Wirth:Molecular Templates: Employment. Erdman:Molecular Templates: Employment. Brieschke:Molecular Templates: Employment. Null: Molecular Templates: Employment. Liu:Molecular Templates: Employment. Willert:Molecular Templates: Employment. Higgins:Molecular Templates: Employment.
Progression Of Large Lymphoma Is Significantly Impeded With a Combination Of Gemcitabine Chemotherapy and Dendritic Cells Intra-Tumor Vaccination
Authors: Zhu Xue-Jun , Yang Zhong-Fa , Wang Li-Xin , Rosmarin Alan G. 
Published: October 2019

Abstract
Relapsed, refractory Hodgkin’s or non-Hodgkin’s lymphoma remains to be a challenge and lacks efficient treatment. A small number of tumor cells that escape from treatment become resistant or unresponsive to chemotherapeutic agents. These cells grow rapidly and soon regenerate into large tumors. Immune vaccination with dendritic cells (DCs) efficiently inhibits growth of small size tumor only. The progression of tumors induces accumulation of Gr-1+CD11b+ myeloid derived suppressor cells (MDSCs) in the lymphatic organs and vicinity of tumor cells. MDSCs enable tumor cells to escape from host or exogenous immune cells mediated surveillance and attack. Gemcitabine is the chemotherapeutic agent used for lymphoma treatment. Gemcitabine has been reported to selectively eliminate MDSCs in tumor bearing animals. Thus, gemcitabine not only eliminates the majority of tumor to leave fewer resistant cells, it also reduces MDSCs to improve the immune environment favorable for the subsequent tumor vaccination. In this presentation, we used A20 cells to establish a large size, murine B-cell lymphoma model. We confirmed the accumulation of MDSCs in the spleen of lymphoma-bearing mice. Gemcitabine induced increased apoptosis in isolated, cultured MDSCs. In vivo injection of gemcitabine eliminated the majority of MDSCs in the spleen of lymphoma-bearing mice. Gemcitabine treatment combined with intratumoral injection of DCs markedly reduced the size of tumor, and significantly improved the survival of the lymphoma-bearing mice. We demonstrated that intra-large-size-lymphoma injection with inactivated DCs in combination with gemcitabine chemotherapy enhanced the therapeutic efficacy of either DC-based vaccination or chemotherapeutic reagent alone. Together with other studies, our report supports the hypothesis that gemcitabine-mediated reduction in MDSCs significantly reduces the immune suppression in tumor-bearing animal environment. This study established novel experimental foundation for the combination of immune-chemotherapy to treat relapsed or refractory lymphoma in large size with enhanced efficacy.

Disclosures:
No relevant conflicts of interest to declare.
ABC Expression As Additionally Marker To Monitoring Response In CML - A Preliminary Study
Authors: Alves Raquel , Gonçalves Ana Cristina , Freitas-Tavares Paulo , Couceiro Patrícia , Rodrigues-Santos Paulo , Sarmento-Ribeiro Ana Bela 
Published: October 2019

Abstract
Chronic myeloid leukemia (CML) is a mieloproliferative disorder characterized by the presence of the BCR-ABL gene fusion, which encodes an oncoprotein with a deregulated tyrosine kinase activity. This oncoprotein became the main therapeutic target of the disease with the introduction of specific tyrosine kinase inhibitors (TKIs). Additionally, the fusion gene expression level is used as a monitoring tool to determine the molecular response of each patient. However, several patients show incomplete or loss of response and even in some cases resistance to the TKI therapy. Leukemia stems cells, as normal stem cells, could present ABC transporters to protect them-self against therapeutic agents which could contribute to therapeutic failure. One of the most described ABC transporters is PgP and Imatinib and other TKIs are substrates for these efflux transporters. The precise link between ABC transports and response to therapy in CML is not fully understood.
The aims of this work were to evaluate the expression levels of ABC transporters, namely PgP and BCRP, in CML patients and to correlate them with the BCR-ABL levels.
We examined in CD34+ cells obtained from peripheral blood of 46 patients with CML, the expression levels of PgP and BCRP by flow cytometry using monoclonal antibodies. The BCR-ABL quantification was determined according to the international guidelines for CML management and at the time point of the study 26 patients (56,5%) present a positive quantification of BCR-ABL while the remain 20 patients (43,5%) were BCR-ABL negative. The median patient age at diagnosis was approximately 48 years (24–88), gender M/F=24/22, and 95% of the patients are under treatment with TKIs.
Our preliminary results show that patients with no detectable BCR-ABL mRNA (negative) present a higher percentage of CD34+ cells than patients positive for this fusion gene. Furthermore, 80% of these negative patients (n=16) expressed PgP and/or BCRP in cell membrane and 56,2% of these patients would present a positive quantification of BCR-ABL levels in the first 6 months and 75% at the end of one year.
These results suggest that the presence of ABC transporters in CD34+ cells of patients without detectable levels of BCR-ABL could constitute an earlier marker of loss of response and may be an additional tool for monitoring response in CML patients. However, further analysis should be performed, namely an increased number of patients, to confirm our results and the clinical relevance.

Disclosures:
No relevant conflicts of interest to declare.
Clinical Observation Of Decitabine Treatment In Selected Patients With Lower Risk Myelodysplastic Syndromes
Authors: Chang Chunkang , Zhang Zheng , Zhao Youshan , Li Xiao 
Published: October 2019

Abstract

Purpose
To assess the efficacy and tolerability of lower and conventional dose regimens of decitabine in patients with selected lower risk myelodysplastic syndrome (MDS).

Patients and Methods
The patients recruited in this study, in addition to having an IPSS score ≤ 1.0, also had to have at least one of the following indicators (with the tendency of malignant clonal expansion): (1) more than 2% marrow blasts, or more than 2% of CD34+ cells in CD45 positive subset. (2) poor karyotype by IPSS scoring, (3) unfit for immunosuppressive treatment(IST), (4) not benefited from best supportive care. The tested patients received decitabine by two different regimens: group A: 15mg/m2×5 days every 28 days , and group B: 20mg/m2×5 days every 28 days. Primary efficacy end point was overall response rate (ORR), complete remission [CR], marrow CR [mCR], CR without platelet recover [CRp], hematologic improvement [HI] or marrow CR plus hematologic improvement [mCR+HI]), cytogenetic response, hematological adverse effects .Secondary end points were progression free survival (PFS) and overall survival (OS).

Results
Total 34 patients were treated by decitabine（Group A, n = 23; group B, n=11）.
The median time of the 34 patients from MDS diagnosis to treatment was 6 months and 100% of them were de novo MDS. The total ORR and CR rate for the 34 patients were 70.6% (24/34) and 26.5% (9/34) respectively. ORR was 69.6% for group A and 72.7% for group B, and CR was 30.4% and 18.2% for group A and B respectively. The cytogenetic response in group A and group B were 55.6% (5/9) and 100%(1/1) respectively. All the difference was statistically insignificant. Also, no statistically differences were observed in secondary end points, OS from the diagnosis of MDS was 43 months in group A and not reached in group B respectively. And PFS were 44 months in group B and not reached in group A respectively. There were no difference between two groups in incidence of grade 3-4 neutropenia and thrombocytopenia. No therapy related death occurred in the 34 patients.

Conclusion
Decitabine is effective and safe in selected patients with lower-risk MDS. Lower and conventional dose of decitabine showed the same efficiency and safety in these patients.

Disclosures:
No relevant conflicts of interest to declare.
Incidence and Survival Outcomes Of Myelodysplastic Syndrome In The United States: A SEER Analysis 2001 - 2010
Authors: Ravipati Hari Prasad , Annangi Srinadh , Kota Vamsi 
Published: October 2019

Abstract

Introduction
Myelodysplastic syndromes (MDS) are a group of hematological disorders leading to ineffective hematopoiesis and excess blast formation. We aimed to establish the incidence rates and median survival periods in MDS by gender, race and geographic location in a large population cohort.

Methods
We performed a retrospective analysis of the United States (US) SEER database for MDS cases diagnosed between 2001 and 2010 using ICD-0-3 histology codes 9980/3, 9982/3, 9983/3, 9984/3 and 9986/3. Incidence rates were calculated using the 2000 US standard population. Five-year relative survival rates were measured using the Kaplan-Meier method after excluding cases diagnosed by death certificate and autopsy.

Results
14,920 cases were identified of which 87.2 % (n = 13,009) were present in age group sixty years and above. Age-adjusted incidence rates (per 100,000) for males were 14.8, 10.0, and 12.7 for white, black and other races respectively. The rates for females were 7.7, 7.1, and 7.0. On US county wise MDS case analysis, 11296 (86.8%) of cases were diagnosed in metropolitan counties and 1694 (13%) cases in nonmetropolitan counties. Median relative survival for white, black and other males were 27 months, 36 months and 24 months respectively ; 35 months, 38 months and 37 months for females. Five-year relative survival for white, black, and other males were 32.5% (95% CI 30.7- 34.3), 36.1% (95% CI 28.3 - 43.9) and 30% (95% CI 24.2 - 36.0) vs. 36.2% (95%CI 34.1 - 38.3), 41.1% (95% CI 34.4 - 47.8) and 37.3% (95% CI 30.2 - 44.5) for females. Median relative survival for cases from metropolitan and non-metropolitan counties were 31 months and 31 months respectively. Five-year relative survivals were 35.1% (95% CI 33.7-36.5) and 32.6% (95% CI 29.1-36.0) for metropolitan and non-metropolitan counties MDS cases respectively.

Conclusion
The incidence of MDS was higher in males compared to females with the highest rate in white males. Survival rates were similar in both sexes. No significant difference in survival rates were seen among the racial groups. No significant difference in the median survival and five-year relative survival rates were noticed between metropolitan and non-metropolitan groups.

Disclosures:
No relevant conflicts of interest to declare.
Increased Population Of Myeloid-Derived Suppressor Cells In Patients With Myelodysplastic Syndromes Overexpress ARG1 and Mediate CD8+ T Cell Inhibition
Authors: Shao Zonghong , Jiang Huijuan , Fu Rong 
Published: October 2019

Abstract

Objective
To investigate the proportion and activation of myeloid- derived suppressor cells (MDSC) in bone marrow from patients with myelodysplastic syndromes (MDS).

Methods
The proportion of MDSC (Lin-HLA-DR-CD33+) in bone marrow of 30 MDS patients and 19 normal controls were measured by flow cytometry assay(FCM). MDSC and CD8+ T cell were isolated from bone marrow of 14 MDS patients and 14 normal controls among them by FCM and microbeads. The expressions of arginase 1(ARG1) and inducible nitric oxide synthase (iNOS) were analyzed by qPCR and western bolting. Co-cultures with CD8+ T cell were proved the MDSC-mediated inhibition of CD8+ T cell.

Results
MDS patient’s median MDSC were 7.29% which was higher than that of controls (2.91%). The expression of ARG1 and iNOS mRNA in MDSC of high-risk MDS patients was higher than that of low-risk MDS patients. But the protein of ARG1 was overexpressed rather than that of iNOS. After co-cultured, the apoptosis ratio of CD8+ T cells of MDS((64.17±4.86) %) was increased compared to pure CD8+ T cells ( (54.58±9.95)%). Further more, the production of IFN-γsecreted by CD8+ T cells co-cultured with MDSC ((551.94±47.39) pg/ml)was lower than that of pure CD8+ T cells ((586.04±46.65) pg/ml) There was no significant difference in level of TNF-βbetween co-cultured with MDSC and pure CD8+ cells.

Conclusion
The proportion of MDSC in bone marrow was increased significantly in MDS. MDSC overexpressed ARG1 in patients with MDS and correlated to the malignant degree of this disease. Further more, MDSC can increased the apoptosis ratio of CD8+ T cell, and inhibited the secretion of IFN-γ. These findings suggested MDSC mediated the response of immunosuppression in MDS.

Disclosures:
No relevant conflicts of interest to declare.