bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bendamustine In Combination With Rituximab As First-Line Treatment For Indolent Non-Hodgkin Lymphoma: Retrospective Analysis Of An Spanish Registry
Authors: Solorzano Silvia , Martinez-Chamorro Carmen , Panizo Carlos , Quero Cristina , Deben Guillermo , Paz Jose , Batlle Ana , Serrano Alfons , Muentes Zayda , Gutierrez Antonio , Tomas Jose Francisco 
Published: October 2019

Abstract

Introduction
Indolent lymphomas represent 40% of all subtypes of non-Hodking's lymphoma, of which follicular lymphoma (FL) is the most frequent. Bendamustine is a dual alkylating agent with demonstrated high efficacy and low toxicity profile in reported clinical trials. We present the preliminary results from the experience of Spanish compassionate use registry of this agent as first-line treatment for indolent lymphoma.

Methods
Retrospective multicenter analysis of patients with indolent non-Hodgkin lymphomas (iNHL) treated as frontline with Bendamustine plus Rituximab (BR) in compassionate use. Clinical efficacy was evaluated according to Cheson criteria (2007) and toxicity according to CTCAE v3.0 scale. This study has been approved by local ethical committees.

Results
Patients’ characteristics: There are 96 patients registered (9 centers), with the following diagnoses: FL: 62 (64.5%), marginal zone 24 (25%), Waldenström macroglobulinemia 7 (7.3%) and mantle NHL 3 (3.1%). The main clinical features of the series are: 45% males, median age 64 years (range 36-84), 87.1% ECOG≤ 1, 63% Ann Arbor stage IV, 50.5% high risk FLIPI and 43.7% CIRS ≥ 4. Extranodal involvement was present in 79.1% of the patients, bone marrow involvement in 52% and 11 patients (11.9%) had bulky disease. Treatment consisted in 6 cycles of BR (B-90 mg/m2 D1-2, R-375mg/m2 D1) in 95% patients. Median number of cycles administrated was 6 (range 1-8). G-CSF support was administered in 16.1% of cycles. Response and Safety: Overall response rate was 95%, with 65.5 % CR, 13.1% uCR and 16.4% PR in the 61 evaluable patients. Progression was documented in 4.9% of patients. Three exitus ocurred due to aspergillosis, progression and other not related with LNH. Median follow-up period was 14 months (3-47). In general, treatment was well tolerated; over 461 cycles registered, the most common adverse event was hematological toxicity with grade 3-4 neutropenia in 10.4%, grade 3-4 leucocitopenia in 6.9% and grade 3-4 anemia in 1.9% of the cycles. Other toxicities included all grades infections in 3.2% of patients, gastrointestinal in 3.4%, asthenia in 3.2%, chills in 1.1%, and mucositis 0.4%. Only 9 hospitalizations due to febrile neutropenia were reported.

Conclusion
Bendamustine plus rituximab was an effective and well tolerated regimen for newly diagnosed patients with indolent NHL.

Disclosures:
No relevant conflicts of interest to declare.
Risk Factors For Radiation Pneumonitis In Patients With Lymphoma Treated With Chemotherapy and Photon Or Proton Radiotherapy
Authors: Mesina Anna , Grover Surbhi , Mesina Carmen , Nasta Sunita D. , Svoboda Jakub , Plastaras John P. 
Published: October 2019

Abstract

Introduction
As volume-based radiotherapy planning has become a more standard part of combined modality therapy for lymphomas, dose-volume based constraints for organs-at-risk are needed for treatment planning. Conformal techniques such as intensity modulated radiation therapy and proton radiotherapy may achieve lower doses to certain organs like the heart, but may result in higher doses to other tissues like the lungs and breasts. We sought to define the dosimetric risk factors that are associated with development of radiation pneumonitis (RP).

Methods
This is a single-institution retrospective analysis of patients with thoracic lymphomas treated with combined modality therapy between 1999 and 2013 who had at least 4 months of follow-up after radiotherapy. Univariate analyses (UVA) were performed using Fisher exact and Wilcoxon rank-sum tests.

Results
Of the 89 patients analyzed, 13 (14.6%) were diagnosed with RP (at least Grade 1, Common Toxicity Criteria v4.0). Patients were predominantly female (62%) and never smoked (67%). Diagnoses were grouped as Hodgkin lymphoma (62.9%) or non-Hodgkin lymphoma (37.1%), and 18.5% were also treated with autologous stem cell transplants. UVA showed that RP was more commonly associated with a diagnosis of non-Hodgkin lymphoma (38%) than Hodgkin lymphoma (8%), despite exposure to bleomycin in the majority of patients with Hodgkin lymphoma. Higher lung doses were significantly associated with RP using multiple lung dose-volume parameters: mean lung dose (12.3 vs. 16.7 Gy, p=0.002), volume of lung receiving 20 Gy (27.3% vs. 39.1%, p=0.0009), and volume of lung receiving 5 Gy (51% vs. 66.8%, p=0.004). The majority (67%) of patients who developed RP had mean lung doses of over 15 Gy, whereas only 24% of those who did not develop RP had mean lung doses above 15 Gy, see Figure. Heart dosimetric parameters were also significantly associated with RP, including mean heart dose (13.3 vs. 21.5 Gy, p=0.004), volume of heart receiving 20 Gy (25.4% vs. 48.3%, p=0.003), and volume of heart receiving 5 Gy (57.6% vs. 81.1%, p=0.04). There were not enough events to determine if heart and lung parameters were independently associated with RP, but they were strongly correlated (R=0.75).
Gender, smoking history, and autologous transplant were not significantly associated with RP. None of the 13 patients treated with proton radiotherapy developed RP. In general, patients treated with proton radiotherapy had lower mean heart doses (9.4 vs. 15.4 Gy) and mean lung doses (9.6 Gy vs. 13.5 Gy).

Conclusions
Higher doses to lung and heart are associated with increased risk of RP, and doses to these critical structures should be considered carefully during volume-based consolidative radiotherapy using advanced techniques.

Disclosures:
No relevant conflicts of interest to declare.
Dose Of Vincristine didn’t Predict Outcome Of Treatment For Elderly DLBCL Patients Introductions
Authors: Miyata Yasuhiko , Nakamura Hiroyuki , Yamamoto Hideyuki , Kojima Yuki , Iida Hiroatsu , Nagai Hirokazu 
Published: October 2019

Abstract

Introductions
Diffuse large B-cell lymphoma (DLBCL) is one of the aggressive type of non-Hodgkin lymphoma (NHL) and is known to have a good drug-sensitivity and prognosis. More than 40% of patients with DLBCL are older than 70 years old at diagnosis, and age is known as a poor prognostic factor. However, dose modification is frequently necessary due to their comorbidities and organ function decline, and this leads to poor outcome of their treatment. Therefore, it is important to optimize treatment strategy and chemotherapy for the elderly with DLBCL to improve their outcome.

Aims
The aim of this study is to unveil underlying problems in the treatment against elderly patients with DLBCL and develop a new therapeutic approach to overcome them.

Methods
The medical records of all new elderly patients (70 years old< ) with DLBCL between 2003 April and 2011 October at Nagoya Medical Center were reviewed for a retrospective analysis , to identify characteristics and treatment response of those patients. Survival of patients intensively treated (82 pts) was evaluated using Kaplan-Meier method, and analyzed using Log-rank test.

Results
We experienced new 93 patients aged over 70 years (41.9 % of all DLBCL cases). Median observation period of was 52.7 months. R-CHOP and R-CHOP-like regimes were administrated into 78 and 4 patients respectively. Four patients treated without rituximab due to patients’ decision. CR was obtained in 70 patients (CR rate 85.3%), and 3-yr OS and PFS were 72.2% and 72.1% respectively. Eleven patients died during induction chemotherapy or didn’t obtain CR and eventually died. The median doses of ADR, CPM, and VCR were 69.51±15.2%, 70.23±20.0% and 59.1±28.1% of original regimen, respectively.% of VCR to original CHOP regimen was significant different between age 70-79 and age more than 80 (p<0.0001), but OS by % of actual dose VCR to original CHOP was not different (50%< vs. ≧50%, p=0.62), suggesting that dose of VCR didn’t predict outcome of treatment. It might suggest that dose of VCR could be reduced with keeping treatment outcome to improve QOL of survivors who suffer from peripheral neuropathy.

Disclosures:
No relevant conflicts of interest to declare.
Up Regulation Of Peroxiredoxin 2 Which Is Correlated With Disappearance Of Philadelphia Chromosome In CML Cells Might Have Therapeutic Applications During Imatinib Therapy
Authors: Yoo Eun-Sun , Mun Yeung-Chul , Ahn Jee-Young , Huh Jung-Won , Lee Kyoung Eun , Nam Eunmi , Lee Soon-Nam , Seong Chu-Myong 
Published: October 2019

Abstract

Background
BCR/ABL oncogenic tyrosine kinase is known to induce high levels of intracellular ROS which may further induce genomic instability with malignant transformation and even imatinib (IM) resistance. There are several lines of evidence that the production of reactive oxygen species (ROS) and the expression and activity of antioxidant enzymes make up the primary redox control of leukemia cells and cell survival. Therapies targeting the redox environment such as over-expression of antioxidants or antioxidant treatment, could inhibit tumor cell growth even resistant cells. In this study, we investigated the change of peroxiredoxin (Prx), which have a function of protection against oxidative stress, and survival of BCR-ABL positive cells during IM therapy.

Methods
BCR-ABL1 positive cell lines were cultured using 20% IMDM medium. We evaluated cell growth by MTT assay, and also evaluated BCR/ABL expression by western blot analysis. We also evaluated changes of intracellular ROS level and antioxidant enzymes, by immunoblot assay. siRNAs against Prx2 (100-200nM) were transfected into K562 cells using HiPerFect transfection Reagent (Qiagen) according to manufacturers’ protocol. During siRNA transfection, 1uM of imatinib was treated for 48hours. 72 hours after siRNA transfection, expression of BCR/ABL and Prx2 were detected by western blot assay and proliferation was determined by MTT assay method. Intracellular ROS was measured by flow cytometry after 10uM DCF-DA staining for 20mins.

Results
During IM treatment, we observed the significant decrease of cell viability and decrease of intracellular ROS level in BCR-ABL1 positive cell lines. These finding were well correlated with eradication of BCR/ABL oncogene by western blot results. The expression levels of Prx2 was restored with IM treatment and restoration of redox enzymes is correlated with reduction of BCR-ABL protein in Philadelphia positive cells. siRNAs transfected cells were not decreased cell survival even though eradication of BCR/ABL oncogene during IM treatment.

Conclusion
Significant change of ROS and Prx2 levels according to IM treatment are closely correlated with bcr/abl kinase level in both BCR-ABL1 positive cell lines. This finding was correlated with restoration of the level of PRX2. Those results has been implicated the possibility of therapeutic application by modulation redox system. Strategy of over-expression of Prx2 might be able to control sensitivity of the BCR-ABL1 positive cells to drug-induced apoptosis. Understanding the molecular mechanisms of changes on ROS and redox enzymes may be potential tools to develop more potent new drugs in Ph+ CML or Ph+ ALL patients especially for IM resistant.

Disclosures:
No relevant conflicts of interest to declare.
Hypoxia Regulates Eph/Ephrin-Facilitated Adhesion and Proliferation Of Chronic Myeloid Leukemia Cells
Authors: Zhou Xuan , Xiaoli Liu , Xu Na , Xiao Yajuan , Yi Zhengshan , Gao Guanlun , Zhang Jinfang , Huang Bintao , Du Qingfeng 
Published: October 2019

Abstract

Background and Objective
Recently, hypoxia has been demonstrated to be correlated with metastasis. The cellular response to oxygen deprivation involves a series of metabolic and biosynthetic events associated with adaptation to a hypoxic environment. Meanwhile, eph receptors and their ligands (ephrins) have also been proved to play a very important role in regulating the migrationand proliferationof leukemia cell in our early study. Therefore, we performed the experiment to address the hypothesis that hypoxia might be an important mediator linking Ephs/ephrins expression to chronic myeloid leukemia cell adhesion and proliferation.

Methods
K562 cells were cultured in a hypoxia environment with different density of oxygen (1%, 5%, 20%). The expression of HIF-1α, EphA5, EphB4, EfnA1, EfnB2 and signaling pathway proteins like p-FAK, p-Src, p-Paxilin, p-p130, p-cofilin, p-Akt, cyclin D3, cyclin E, p-Rb of K562 cells in different hypoxia environment were determined by real-time PCR and Immunoblot analysis. The K562 cells adhesion to endothelial cells and bone marrow stromal cells were tested with the adhesion assay kit. K562 cell proliferation, apoptosis and cell cycle were also detected with immunofluorescence analyses. After knocked down HIF-1α gene in K562 cells, the related protein levels and adhesion ratio were determined by the same methods.

Results
The results showed that the mRNA levels of HIF-1α were enhanced after 10 h of hypoxic exposure (1% O2), compared with normal exposure (P<0.05), as well as the mRNA levels of EphA5, EphB4, EfnA1, EfnB2 and related signaling pathway proteins were enhanced after 24h of hypoxic exposure (P<0.05). The protein levels of HIF-1α, EphA5, EphB4, EfnA1, EfnB2 and signaling pathway proteins like p-FAK, p-Src, p-Paxilin, p-p130, p-cofilin, p-Akt, cyclin D3, cyclin E, p-Rb also increased after 24h of hypoxic exposure (1% O2). After knocked down HIF-1α, the expression of Eph/ephrin didn’t enhance after 72h of hypoxic exposure(1% O2) ,which proved HIF-1α regulate Eph/ephrin expression. The adhension to endothelial cells was signiﬁcantly up-regulated (1.6 to 2-fold, P<0.05) after 36 h of hypoxic exposure (1% O2), the apoptosis cells down-regulated (1.3 to 1.5 fold, P<0.05).

Conclusions
We concluded that Eph receptors and ephrins were closely correlated with chronic myeloid leukemia cell adhesion and proliferation, and this process was regulated by hypoxia. Our findings shed new light on the regulation of this intriguing receptor/ligand family and present evidence for the role of Ephs/ephrins in chronic myeloid leukemia cells.

Disclosures:
No relevant conflicts of interest to declare.
Effective Targeting Of Chronic Myeloid Leukemia Initiating Activity With The Combination Of Arsenic Trioxide and Interferon Alpha
Authors: El Eit Rabab , Ahmad Iskandarani , Saliba Jessica , Jabbour Mark , Mahfouz Rami , Bitar Nizar , ElAyoubi Hanadi , Zaatari Ghazi , Mahon Francois-Xavier , de Thé Hugues , Bazarbachi Ali , Nasr Rihab 
Published: October 2019

Abstract
Imatinib is the standard of care in the treatment of Chronic Myeloid Leukemia (CML) patients. However, imatinib is not curative since most patients who discontinue therapy will relapse, stressing the need for novel therapies that target leukemia initiating cells (LIC). Arsenic trioxide induces complete remission in patients with acute promyelocytic leukemia (APL). We previously demonstrated that, through full degradation of PML-RARA, the combination of arsenic and retinoic acid eradicates APL LICs and cures the disease. Interferon alpha (IFN) induces hematologic and cytogenetic remissions and interestingly, improved outcome was reported with the combination of interferon and imatinib. We investigated the effects of arsenic and IFN on human CML cell lines or primary cells and the bone marrow retroviral transduction/transplantation murine CML model. In vitro, the combination of arsenic and IFN inhibited proliferation and activated apoptosis. Importantly, arsenic and IFN synergistically reduced the clonogenic activity of primary bone marrow cells derived from CML patients. Moreover, in a murine transplantation model of CML, we show that arsenic/IFN prolonged survival of primary leukemic mice and sharply diminished transplantation of CML cells in secondary recipients, pointing to exhaustion of CML LICs. Our results also suggest that IFN/arsenic may clear LICs independently from oncoprotein catabolism. Interestingly, arsenic/IFN effect on CML LIC activity was significantly superior to that of imatinib.These studies plea for a clinical exploration of this combination, knowing that IFN and arsenic have both shown clinical activity in CML, alone or in combination with imatinib.

Disclosures:
No relevant conflicts of interest to declare.
A Translocation (9;22)(p24;q11.2) In a Patient With CML
Authors: Abreu Daniele Costa , Castilho, Bachelor Ana Paula , Niewiadonski, Bachelor Vivian Dionísio , Drummond Mauricio , Gaburo Nelson 
Published: October 2019

Abstract

Introduction
In January 2013 was received in our lab service a bone marrow sample for cytogenetic analysis. The 61 years old female patient presents an elevated white blood cell count (118,000 x10³/mm³) and clinical diagnosis as Chronic Myeloid Leukemia (CML). According the medical information the treatment began with hydroxyurea 3g daily and allopurinol 300mg daily.

Methods
We proceeded with cytogenetic examination of the patient’s bone marrow aspirate by conventional G-banding analysis performed on unstimulated short-term cultures (24 hrs). FISH for BCR/ABL translocation was tested using a dual fusion dual color probe. Because of the sample stability we were unable to performed RT-PCR test.

Results
Chromosome analysis showed the translocation (9;22)(p24;q11.2) as a sole abnormality in 100% (20/20) of analyzed metaphases. Chronic myeloid leukemia presents as a specific chromosomal abnormality the Philadelphia chromosome, t(9;22)(q34;q11) which is different from the results obtained where the region of translocation of chromosome 9 was p24 instead of the classic q34. This result suggests it is BCR/JACK2 translocation. The FISH analysis showed the presence of a complex Ph chromosome: ABL con BCRx1 (one fusion) and BCRx2;ABLx2.

Conclusion
The patient took imatinib without answer. She is still in clinical monitoring with persistent hyperleucocytosis and the treatment is following with hydroxyurea 500mg daily and Interferon 5000 UI three times a week. Further molecular and cytogenetic tests will be performed in a second sample to contribute with evaluation of disease progression and monitoring treatment response.

Disclosures:
No relevant conflicts of interest to declare.
A Decade Of Imatinib As First-Line Treatment Of Chronic Myeloid Leukemia: A Single - Latin American Institution Experience
Authors: Garcia Alvaro Cabrera , Delgado Carolina Balderas , Kassack Ipiña Juan Julio , Ramos Peñafiel Christian Omar , Jaloma Juan Collazo , Tovar Adolfo Martínez , Gallardo Hermelinda , Castellanos Sinco Humberto Baldemar 
Published: October 2019

Abstract
Targeted therapy commenced against Chronic Myeloid Leukemia (CML) with the development of small-molecule tyrosine kinase inhibitors (TKIs), since its approval in 2001 as first-line therapy, imatinib has been effective in achieving high response rates and improving the prognosis. However, the excellent results of large clinical trials are not entirely reproducible in the “real world”, we want to share our experience of a decade of use as front-line treatment.
A total of 160 patients with previously untreated CML since 2002 were reviewed: 90% chronic phase (CP), 7% accelerated phase (AP), and 3% blast phase (BP). All were treated with standard-dose imatinib. In CP, overall survival (OS) at 75 months was 82% and progression-free survival 66%(PFS). Survival was worse in those over 60 years (P= < .001). 40% achieved and maintained Complete Cytogenetic Response (CCyR), 19 patients progressed to BP. 23.4% had some degree of hematologic toxicity that required a temporary suspension or reduction of the initial dose. 26.8% of patients with chronic phase treated at our institution were in the high EUTOS score. In this population, the EUTOS score was not predictive for outcome. Our study showed that imatinib is effective, and well tolerated by our patients and remains as a good strategy used as first-line therapy for patients with CML.

Disclosures:
No relevant conflicts of interest to declare.
The Depth Of ‘Complete’ Molecular Response Predicts Molecular Relapse In Chronic Myeloid Leukaemia Patients On Tyrosine Kinase Inhibitor Therapy
Authors: Thomas Heledd , Apperley Jane F , Szydlo Richard M , Gerrard Gareth , Marin David , Milojkovic Dragana , Foroni Letizia 
Published: October 2019

Abstract

Background
There is currently no universal definition of complete molecular response (CMR) in chronic myeloid leukaemia (CML). This has implications for studies of TKI withdrawal as CMR is the main criterion for entry into these trials. We aimed to assess the proportion of patients in our practice who achieved CMR by a variety of definitions. We hoped to identify a definition that was predictive of sustained CMR and could therefore be recommended to predict those patients who might be able to stop treatment in the longer term.

Methods
We conducted a retrospective analysis of a comprehensive CML database of serial RT-qPCR results of 215 patients achieving deep molecular responses on TKI therapy. The least stringent definition of CMR was defined as BCR-ABL1 transcripts <11 and ABL1 control value (CV)>10,000. The depth of CMR was categorised according to transcript number and CV. Probability of molecular relapse according to depth of CMR at 2 and 5 years from initial CMR (ICMR) was estimated using the Kaplan Meier method.

Results
Patients with 6-10 transcripts (any CV) were most likely to lose CMR by 2 years (86.4%) while patients with 0 transcripts (any CV) were least likely to do so (7.6%). There was no difference in the probability of molecular relapse between patients with 1-5 transcripts (CV>32,000) and those with 0 transcripts (any CV) (RR at 2 years=1 p=0.945, RR at 5 years=3.7 p = 0.114).

Conclusion
Depth of CMR predicts molecular relapse at 2 and 5 years from ICMR. CMR4.5 (<6 transcripts) is the least stringent response that is required to sustain CMR. Patients with <6 transcripts (CV>32,000) are equally as likely to sustain CMR as patients with 0 transcripts up to 5 years from ICMR. These patients may be suitable for a stopping trial.

Disclosures:
Apperley: Ariad: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria. Milojkovic:BMS: Honoraria; Pfizer: Honoraria; Ariad: Honoraria; Novartis: Honoraria.