bluuebunny/crossref_metadata_2025_split huggingface dataset:
Late Cardiotoxicity of Intensive Modified Program NHL-BFM-90 in Adult Poor Prognosis Patients with Diffuse Large B-Cell Lymphoma
Authors: Dorokhina Elena , Magomedova Aminat Umaraskhabovna , Shevelev Alexander , Kulikov Sergei M , Gitis Michael , Vedernikov Alexey , Vedernikov Alexey , Vorobiev Andrey , Kravchenko Sergey , Savchenko Valeri G 
Published: November 2019

Abstract
Aim. To evaluate late cardiotoxicity of intensive modified program NHL-BFM-90 (mNHL-BFM-90) in adult poor-prognosis patients with diffuse large B-cell lymphoma (DLBCL).
Materials and methods. The data of ECG and echocardiography of 40 patients DLBCL wich received mNHL-BFM-90 protocol in the Hematology Reserch Center in the period from 2002 to 2009 years was analyzed . Group consisted of 20 men, 20 women, aged from 31 to 76 years, median age - 56.5 years at the time of the survey, the median period after therapy- 6 years. Individual cumulative dose of doxorubicin - 150 to 300 mg / m2. Comparison group included 19 patients, 8 men and 11 women, aged from 39 to 78 years, mediana- 70 years at the time of the survey, who received therapy to CHOP / R-CHOP. The median period after therapy - 5.5 years. Individual cumulative dose of doxorubicin - 200 - 400mg / m2. ECG and echocardiography studies were performed before and after 5 or more years after the end of chemotherapy. Clinical cardiomyopathy was defined by the presence of clinical signs of congestive heart failure. Subclinical cardiomyopathy was defined by the presence of characteristic changes by echocardiography and ECG study without clinical signs of CHF.
Results. From 40 patients DLBCL wich received mNHL-BFM-90, signs of subclinical cardiomyopathy were detected in 24 (60%) patients, clinical heart failure was not defined in any patient. In comparison group signs of subclinical cardiomyopathy were detected in 14 (74%) patients. Clinical heart failure was not defined in any case. Summar index of cardiotoxicity was significantly dependent on age (p=0.03), the presence of cardiac disease in anamnesis (p=0.3), and significantly higher (p = 0.05) in the group of patients after CHOP / R-CHOP therapy. A risk of subclinical cardiomyopathy revealing was significantly higher in group with cardiac disease in anamnesis (p = 0.05).
Conclusion. Late cardiotoxicity of high-dose program mNHL-BFM 90 does not exceed the toxicity of standard CHOP / R-CHOP. Patients with ischemic heart disease, hypertension, diabetes in anamnesis had the most severe sings of subclinical cardiomyopathy after chemotherapy according to examination data. Clinically significant heart failure in any patient was identified.

Disclosures
No relevant conflicts of interest to declare.
Autologous Stem Cell Transplantation (AutoSCT) in First Remission of Follicular Lymphoma (FL) "Save" Patients (pts) with Poor Prognosis. Results of the First Russian Prospective Study
Authors: Nesterova Ekaterina , Kravchenko Sergey , Baryakh Elena , Misyurina Anna , Mangasarova Yana , Vorobyev Vladimir , Gaponova Tatyana , Gemdzhian Eduard , Vorobyev Andrey , Savchenko Valeri 
Published: November 2019

Abstract
Background: FL is one of the most frequent types of lymphomas: it consists about 22% of non-Hodgkin lymphomas in Russia. 20 % of pts have an aggressive tumor after standard therapy.
In FL pts with unfavorable prognosis (FLIPI-1 III-IV, fast growth of tumor mass, B-symptoms, third cytological grade of tumor, bulky, absence of tumor response after first line R-CHOP-21 therapy) autoSCT allows to increase the overall (OS) and progression-free survival (PFS).
Aim: To estimate an efficacy of HDT (high dose therapy) with following autoSCT in front-line therapy of FL pts with factors of poor prognosis.
Patients and Methods: Since 2000 to 2015 years in National Research Center for Hematology were treated 39 FL pts with poor prognosis. All pts received R-CHOP-21 induction therapy. In 24 patients (62%) who hadn't partial response or poor prognosis patients with partial response after 4-6 courses autoSCT was performed. This group consists of 17 males and 7 females with median age 46 years old (31-68). Majority of pts (23/24) had IV stage of disease according to Ann Arbor. In 16/24 (66%) cases pts had bulky disease. 3/24 pts had phenomenon of leukaemization. Basing on FLIPI-1 criteria all pts were divided into 3 groups: low risk - 5/24, intermediate - 3/24, high - 16/24. B-symptoms were in majority of cases (18/24). 18/24 pts were diagnosed with I-II cytological grade of FL, 6/24 - III A/B. Basing on tumor growth pattern there was following ratio: nodular tumor growth revealed in 6/24 pts, nodular-diffuse tumor growth - in 15/24, diffuse tumor growth - in 3/24. Immunochemical analysis of serum and urine proteins was performed in 20/24 cases, among them increased level of serum β2-microglobulin was diagnosed in 10/20 pts. Increased activity of lactate dehydrogenase (LDH) was revealed in 16/24 pts. Bone marrow involvement at the time of disease onset was diagnosed in 18/24 pts.
Results: After induction R-CHOP-21 chemotherapy pts underwent HDT which included two courses R-DHAP, following high-dose cyclophosphamide with rituximab, then high dose etoposide with rituximab. As condition regimen R-BEAM was performed. All 24 FL pts, who underwent autoSCT, continue to be in complete remission. Median follow-up was 31 months (7-178).
Conclusions: Preliminary results of the first prospective study of intensive therapy of FL in Russia demonstrate that autoSCT in front line therapy provides to achieve a complete remission in pts with poor prognosis and allows to increase an overall and disease-free survival.

Disclosures
No relevant conflicts of interest to declare.
Single Agent Gemcitabine As a Salvage Regimen in Patients with Relapsed/Refractory Hodgkin's Lymphoma after Autologous Stem Cell Transplantation
Authors: Ozdemir Evren , Aslan Alma , Turker Alev , Barista Ibrahim , Kars Ayse 
Published: November 2019

Abstract
The aim of this study was to evaluate the efficacy and safety of gemcitabine as a salvage regimen in patients with relapsed or refractory Hodgkin's lymphoma after autologous stem cell transplantation (ASCT). Fifteen patients were enrolled. All patients had received ≥ 2 prior chemotherapy regimens, had an ECOG performance status ≤ 2, had adequate organ function and had undergone ASCT. Patients received intravenous gemcitabine (1000 mg/m2) on days 1 and 15, every 4 weeks. The median age was 26 years (range, 18-44) and 8 (53%) were female. Eight (53%) had primary refractory disease. All had previous platinum-based salvage chemotherapy (IIVP, 7; ICE, 5; DHAP, 3). All (100%) had relapsed/refractory disease following ASCT as their last treatment. Eleven (73%) had refractory/progressive disease after ASCT. None had previous brentuximab vedotin treatment. Median number of previous lines of chemotherapy was 2 (range, 2-3). Median number of gemcitabine cycles administered to the patients was 4 (range, 2-6). Treatment response was assessed with PET-CT in majority of the patients before and 2-3 cycles after gemcitabine, and those patients who demonstrated a response continued to receive a maximum of 6 courses of gemcitabine or bridged to allogeneic SCT. Of 15 patients, 1 (7%) had complete response, 5 (33%) had partial response and the remaining patients had refractory/progressive disease with an overall response rate of 40%. The median time to progression for responding patients was 3 months (range, 2-7 months). Two patients were successfully bridged to allogeneic SCT. Main toxicity was hematological. Grade ≥ 3 hematologic toxicity occurred in 8 patients: thrombocytopenia (40%), neutropenia (33%) and anemia (7%). Three patients had grade 4 thrombocytopenia and 2 had grade 4 neutropenia. Dose reduction was necessary in 3 patients and treatment cycle postponed in 2 patients because of hematological toxicity. Five patients (33%) needed G-CSF support. Two patients developed febrile neutropenia. No treatment-related deaths occurred. Gemcitabine was shown to be an active salvage regimen in patients with relapsed/refractory Hodgkin's lymphoma after ASCT, producing an overall response rate of 40%. Although, the median PFS time was short, some patients can be bridged to allogeneic SCT. Hematological toxicity was common.

Disclosures
Off Label Use: Gemcitabine in Hodgkin's Lymphoma.
A Combination of Lenalidomide and Rituximab (ReRi) As Salvage Therapy in Elderly Patients Affected By Diffuse Large B Cells (DLBCL) Lymphoma Relapsed and Refractory
Authors: Gini Guido , Bocci Caterina , Sampaolo Michela , Trappolini Silvia , Cacciagiù Sonia , Olivieri Jacopo , Olivieri Attilio , Offidani Massimo , Rupoli Serena , Poloni Antonella , Scortechini Anna Rita , Capelli Debora , Montanari Mauro , Scortechini Ilaria , Leoni Pietro 
Published: November 2019

Abstract
BACKGROUND
The incidence of non Hodgkin's lymphoma (NHL) increases with age, over one third of NHL cases involves elderly patients >70 years of age.
As a matter of fact, many elderly patients (pts) are not enrolled in controlled studies because they do not meet the inclusion criteria. This is the reason why the data from trials on elderly cases are not representative for the whole elderly population. Consequently, many of these patients do not benefit of new therapeutic progresses and the treatment is not yet adequate.
Moreover in case of relapse, salvage therapy in the elderly is virtually absent, and the prognosis is extremely poor.
Lenalidomide is an immunomodulatory drug with anti-angiogenetic and anti-neoplastic action on cancer cells and also has other anti-tumor activity by acting on the neoplastic microenvironment. Both monotherapy and combination of Lenalidomide with rituximab have shown efficacy in terms of overall response rate (ORR, Overall Response Rate) in the setting of salvage therapy in relapsed/refractory DLBCL, with an acceptable rate of hematologic and extra-hematological toxicities
PATIENTS AND METHODS
In the period 2013-2014 we consecutively treated 12 elderly patients affected by advanced DLBCL relapsed/refractory.
Median age at the start of treatment was 79 years (yrs) (62-86), 5 out 12 was over 80 yrs and 4 out 12 over 75 yrs. The median number of previous treatment was 3 (2-4), 3 pts were transplanted and 4 patients was refractory to previous line of therapy.
The treatment scheme included at first cycle: Rituximab 375 mg/m2 i.v. days 1, 8, 15, 22, Desametasone 5 mg p.o. days 1, 8, 15, 22 and Lenalidomide 15 mg/die p.o. from day 2 to 22. From the second to the sixth cycle we administered Rituximab 375 mg/m2 i.v. days 1, 14, Lenalidomide 20 mg/die p.o. from day 2 to 22
RESULTS
The overall response rate has been 75% (CR,PR,SD), 3 patients out 12 (25%) achieved a CR and 3 PR (25%).
The median PFS was 6 months and with a median follow up of 1 year the overall survival is 25%.(fig.1)
All deaths are due to lymphoma progression and the 3 patients in CR are still alive in CCR.
CONCLUSIONS
In this elderly and heavily pretreated group of patients our scheme containing Lenalidomide-Rituximab has shown an high rate of response with a good rate of CR and a promising trend in overall survival.
The treatment appears feasible and safe also in this particular group of frail patients and even if we need more data to confirm we think it will be possible to extend this therapy in frail elderly patients in a most precocious line of treatment.
Figure 1. Figure 1.

Disclosures
Offidani: Celgene, Janssen: Honoraria.
The BET Inhibitor OTX015 (MK-8628) Shows in Vivo Antitumor Activity in Combination with Additional Targeted Agents in Diffuse Large B-Cell Lymphoma (DLBCL)
Authors: Gaudio Eugenio , Cascione Luciano , Ponzoni Maurilio , Tarantelli Chiara , Bernasconi Elena , Riveiro Maria Eugenia , Cvitkovic Esteban , Zucca Emanuele , Bertoni Francesco 
Published: November 2019

Abstract
OTX015 (MK-8628) has shown anti-lymphoma activity in both the preclinical and clinical settings (Boi et al, CCR 2015; Stathis et al, EORT-NCI-AACR 2014). Here we report in vivo data on OTX015 in combination with four targeted compounds in DLBCL.
Methods. NOD-Scid (NOD.CB17-Prkdcscid/NCrHsd) mice were subcutaneously engrafted with the activated B-cell like DLBCL cell line SUDHL2 (15 x106 cells) and then divided into 10 groups (6 mice each). Treatment with OTX015 was started 3 days after the graft, and treatments with other drugs were initiated when mice developed palpable tumors (100 mm3). Tumor size was measured two times per week using digital calipers. Tumor volumes were calculated using the equation V = [length x width2]/2 (width and length are the shortest and the longest diameters of each tumor, respectively). Tumor specimens were collected at the end of treatment and necrosis was semi-quantitatively defined on the total amount of neoplastic tissue.
Results. Xenografts of SU-DHL-2 were treated with control or OTX015 (50 mg/kg once daily; QDx7/w x5w), the BTK-inhibitor ibrutinib (5 mg/kg; QDx2/w x5w), the mTOR-inhibitor everolimus (1 mg/kg, Qdx2/w x5w), the HDAC-inhibitor vorinostat (15 mg/kg; QDx2/w x5w), the anti-CD20 monoclonal antibody rituximab (3 mg/kg; QDx1/w x5w) as single agents or in OTX015-containing combinations. No weight loss was reported. OTX015, in accordance previously published data (Boi et al, CCR 2015), as single agent delayed tumor growth. Almost complete eradication of tumors was observed in mice treated with OTX015 combinations (p<0.001) (Figure 1). Three tumors for each group were H&E stained and necrosis percentage evaluated. Only control and vorinostat-treated tumors showed no or minimal (<5%) necrosis, which appeared higher in tumors treated with all the other drugs as single agents and in the combinations.
Conclusions. OTX015-containing combinations with everolimus, ibrutinib, vorinostat and rituximab showed very promising in vivo activity in an ABC-DLBCL model, providing the rationale for future clinical studies.
Figure 1. In vivo treatment of ABC-DLBCL SU-DHL-2 xenografts with MK-8228 as single agent and in combination with other targeted drugs. Figure 1. In vivo treatment of ABC-DLBCL SU-DHL-2 xenografts with MK-8228 as single agent and in combination with other targeted drugs.

Disclosures
Riveiro: Oncology Therapeutic Development: Employment. Cvitkovic:Oncology Therapeutic Development: Employment, Membership on an entity's Board of Directors or advisory committees. Bertoni:PIQUR Therapeutics AG: Research Funding; Oncology Therapeutic Development: Research Funding.
Establishment and Characterization of a Patient-Derived Model of ALK-Positive Anaplastic Large Cell Lymphoma
Authors: Wick Michael J , Helman Elena , Vaught Teresa L , Farley Monica , Rasco Drew W , Smith Lon , Tolcher Anthony , Patnaik Amita , Clark Michael , Papadopoulos Kyriakos P 
Published: November 2019

Abstract
Background: Anaplastic large cell lymphoma (ALCL) is an uncommon, aggressive CD30-positive T-cell lymphoma exhibiting or lacking chromosomal translocation involving the Anaplastic Lymphoma Kinase (ALK) gene and expression of ALK protein. ALK positive ALCL (ALK+-ALCL) typically has an improved prognosis compared with ALK-negative; however, patients often respond favorably to standard chemotherapy and CD30-directed immunoconjugates only to progress and are left with few treatment options. To help identify additional treatment options, we collected tumor tissue and established, characterized and evaluated in vivo an ALK+-ALCL patient-derived xenograft (PDX) model from a thirty one year old Caucasian female with relapsed ALCL following initial therapy with a pediatric S-phase specific regimen.
Methods: The ST2698 ALK+-ALCL model was established in CB17 SCID mice using tissue collected from a lymph node tumor biopsy. Clinical tissue, patient blood and the PDX model were subjected to WGS sequencing using an augmented and content-enhanced exome. The augmented exome is optimized to detect major cancer mutations by enhancing coverage over known sequencing gaps and GC-rich regions across >1300 cancer and 200 miRNA genes. We also performed whole-transcriptome sequencing on the PDX model. All data were analyzed using a cancer bioinformatics pipeline optimized for high accuracy detection of small variants and indels, somatic copy-number aberrations, gene expression and fusions. Drug sensitivity studies were performed evaluating sensitivity of the model to patient's current clinical treatment and relevant targeted therapies; study endpoints included tumor volume and time from treatment initiation with tumor growth inhibition, delay and regression reported at study completion.
Results: Exome analysis identified several variants which were confirmed by transcriptome data. Efficacy studies confirmed model sensitivity to the patient's current clinical course (CHOP). In addition, ST2698 was found moderately sensitive to the IMiD lenalidomide (T/C=47%). However, treatment with the ALK-inhibitors crizotinib or ceritinib resulted in tumor regressions including durable complete responses in some mice.
Conclusion: We have established and characterized a patient-derived ALK+-ALCL xenograft model using DNA and RNA-based analysis. In addition we evaluated the model in vivo and confirmed sensitivity to the patient's current clinical course and identified two ALK inhibitors as active, including reported complete tumor regressions.

Disclosures
Rasco: Celgene: Research Funding; Asana BioSciences, LLC: Research Funding. Tolcher:Asana BioSciences, LLC: Consultancy, Research Funding; AbbVie: Consultancy; ArQule: Consultancy; Bayer: Consultancy; BioMed Valley Discoveries: Research Funding; Janssen R&D: Consultancy.
Ixazomib, an Oral Proteasome Inhibitor, Induces Rapid Mobilization of Hematopoietic Stem Cells in Mice
Authors: Ghobadi Armin , Rettig Michael P. , Holt Matthew , Ritchey Julie , Eissenberg Linda , DiPersio John F. 
Published: November 2019

Abstract
Introduction: Granulocyte colony-stimulating factor (G-CSF) is the most commonly used drug for stem cell mobilization. Unfortunately, 5-30% of patients fail to collect sufficient hematopoietic stem/progenitor cells (HSPCs) to proceed to transplant. New strategies are needed to increase HSPCs collection in these patients. We previously reported that bortezomib directly and rapidly mobilizes HSPCs in mice by modulating the VLA-4/VCAM-1 axis (Ghobadi A et al. Blood 2014, 124: 2742-2753). Ixazomib (MLN9708) is a next-generation small-molecule proteasome inhibitor that has several potential advantages over bortezomib including oral route of administration. Here we study the effect of ixazomib on stem cell mobilization in mice.
Methods: DBA mice were treated with: (1) ixazomib via oral gavage (o.g., 8 mg/kg), (2) a single intravenous (iv) dose of bortezomib (0.8 mg/kg), (3) AMD3100 (5 mg/kg) SC, and (4) control diluent for ixazomib (2-hydroxypropyl-β-cyclodextrin [HPBCD]). Blood was harvested at baseline and 12, 15, and 24 hours (h) after ixazomib and bortezomib administration and at 3 hours and 12 hours after AMD3100 administration. Harvested peripheral blood (PB) was plated on MethoCult media (Stem Cell Technologies) for colony forming unit-cells (CFU-C) enumeration.
Results: Compared to vehicle (ixazomib diluent, 2-hydroxypropyl-β-cyclodextrin [HPBCD]), ixazomib mobilized significantly more peripheral blood colony forming unit-cells (CFU-C) at 12 - 15 h after administration (mean peak CFU-C: 105/ml vs. 870/ml respectively, i.e., a 0.6 vs. 5-fold increase in CFU-C , P < 0.02; Figure 1A). The majority of CFU-Cs mobilized by ixazomib were CFU-GM (CFU-granulocyte and monocyte, Figure 1B). The magnitude and kinetics of HSPC mobilization in the single ixazomib oral gavage group was identical to a single dose of IV bortezomib (Figure 1C, mean peak of 870/ml vs. 975/ml respectively, P > 0.66). There was no statistically significant difference in peak HSPC mobilization between the ixazomib (12 h after ixazomib administration) and AMD3100 groups (3 h after AMD3100 administration) (mean peak of 870/ml vs. 1240/ml respectively, P = 0.36) suggesting that ixazomib is a potent HSPC mobilizing agent (Figure 1D) with intermediate mobilization kinetics compared to AMD3100 (2-3 hours) and G-CSF (5-6 days) and with identical kinetics to IV bortezomib (12-15 hours).
Conclusion: Ixazomib is a potent and modestly rapid HSPC mobilizer agent in mice. Kinetics and magnitude of HSPC mobilization by ixazomib is identical to bortezomib. Trials to assess proteasome inhibitors as mobilizing agents are currently underway at Washington University.

Disclosures
No relevant conflicts of interest to declare.
Correlation Between Tumor Microenvironment and the Inflammatory Factors in Lymphoma-Burdened Mice
Authors: Zhang Jun , Ni Jun , Xu Pei , Shi Qingqing , Gu Jian , Depei Wu 
Published: November 2019

Abstract
Introduction
Since Vichow proposed the hypothesis that chronic inflammation was closely related to tumor in 1863, experimental, clinical and epidemiological studies have shown that inflammation plays an important role in tumor progression, immune response, tumor therapy and prognosis. In this study, 38B9 cells were injected into BALB/c mice to establish lymphoma-burdened mice model. The expression of IL-10, TNF- and IL-6 were observed in plasma and tissues to study the effects of tumor inflammatory factors on tumor environment.
Methods
Ten 9-week-old BALB/c mice were randomly divided into the control group and the tumor-burdened group. Each mouse in tumor-burdened group was injected with 2×106/200μl 38B9 cells, while the control group was injected with 200μl PBS buffer solution. The establishment of B-cell lymphoma tumor-burdened mice model was confirmed by magnetic resonance information (MRI). The peripheral blood samples were collected before injection, after tumorigenesis and when sacrificed. The tumor tissues were also collected. The level of IL-6, IL-10, TNF-α in the plasm were detected by enzyme-linked immuno sorbent assay (ELISA) and the relative value of mRNA in tissues were measured by quantitative real-time polymerase chain reaction (qRT-PCR).
Results
1.Compared with the control group, the levels of IL-6 and TNF-α in the tumor-burdened group were increased after injected 14 days (P <0.05). However, the level of IL-10 showed no significant difference (P >0.05). After injected 19 days, the levels of IL-6, IL-10 and TNF-α of tumor-burdened group were decreased (P<0.05).
2. The expression of IL-10 mRNA in tumor tissues was lower than the control group (P <0.05), while the expression of IL-6 mRNA in borderline tissues was higher than the control group (P<0.05). Compared with tumor tissue, the expression of IL-10 mRNA was increased in borderline tissue (P <0.05). The level of IL-6 and TNF-α showed no significant difference (P>0.05).
Conclusions
1. The level of IL-6, IL-10 and TNF-α in the tumor tissues and plasma were significantly higher after tumorigenesis.
2. The increased expression of inflammatory factors is related to tumor-induced inflammatory microenvironment.

Disclosures
No relevant conflicts of interest to declare.