bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concomitant Radiochemotherapy In The Treatment Of Refractory Or Locally Relapsed Diffuse Large B-Cell Lymphoma: A Single Center Retrospective Study
Authors: Gyan Emmanuel , Villate Alban , Lissandre Severine , Benboubker Lotfi , Delain Martine , Colombat Philippe 
Published: October 2019

Abstract

Introduction
Primary refractory Diffuse Large B-Cell Lymphoma (DLBCL) as well as relapse after salvage therapy displays a poor prognosis. Salvage radiation therapy alone does not provide sufficient disease control on locally chemoresistant DLBCL. Autologous stem cell transplantation (ASCT) provides the best progression-free survival when salvaged patients are transplanted in Complete Response (CR). The objective of this study was to assess the effectiveness of CCR in locally relapsed or refractory DLBCL, followed by ASCT in responding patients.

Material and methods
We report the outcome of consecutive patients with locally relapsed or refractory lymphoma for which a decision of CRC was taken in a single institution. Each patient has been assessed by CT or PET-scan. The CRC regimen consisted in 3 cycles of Rituximab (375 mg/m² day 1), CDDP (30 mg/m² 3 days 1-3) and VP16 (120 mg/m² days 1-3) at 21 days intervals, with concomitant radiotherapy delivered to the residual disease sites, administrated in 2 Gy fractions per day to a total dose of 30 Gy, starting on day 1 of the second cycle. Responding patients received ASCT with a BEAM conditioning at the end of the procedure. Extra-hematological toxicity was ranked according to the Common Terminology Criteria for Adverse Events. Tumor response was evaluated according to IWG 1999 at 1 month after the last cycle of CRC, three months after ASCT if performed and during a quarterly follow-up.

Results
We identified 13 patients with localized chemoresistant DLBCL from January 2002 to April 2011 including 12 primary refractory forms. The median age was 56 years (20-76), 12 of 13 patients had received at least two lines of chemotherapy before inclusion with anthracycline and cisplatin. 11 patients achieved a partial response (85%) and 4 of them (31%) a complete response after the CRC. 8 (61.5%) patients were transplanted 1 month after the last cycle of CRC. 7 patients have relapsed within 6 months after the end of treatment. After a median follow-up of 37 months (range 21-125) for the surviving patients, 7 patients are alive and free of disease. The overall survival is 54%, and all surviving patients had been transplanted. No severe toxicity was reported.

Conclusion
CRC should be considered as an option in the therapeutic arsenal in refractory or locally relapsed DLBCL, especially in patients eligible for ASCT. Further research on CRC is warranted.

Disclosures:
No relevant conflicts of interest to declare.
Phase II Trial Of Bortezomib In Combination With Fractionated Cyclophosphamide and Rituximab (BCR) For Relapsed/Refractory Mantle Cell Lymphoma (MCL)
Authors: Romaguera Jorge E , Fanale Michelle A. , Samaniego Felipe , Fayad Luis E , Hagemeister Fredrick B , McLaughlin Peter , Rodriguez Maria Alma , Weaver Pam , Hartig Kim , Badillo Maria , Kwak Larry W. , Younes Anas , Pro Barbara , Wang Michael 
Published: October 2019

Abstract

Background
MCL is incurable. Bortezomib has shown single agent activity of 33% in relapsed MCL. Pre-clinical published data shows additive/synergistic activity of BCR.

Materials and methods
MCL pts ages 18 through 85, with adequate organ function unless due to lymphoma, and without HIV-1 infection or any significant medical/mental condition, were treated under an IRB-approved study, consisting of Bortezomib 1.3 mg/m2 IV given on days 1, 4, 8, and 11 (dose on day 11 omitted early on study); fractionated cyclophosphamide 300 mg/m2 q 12 hrs days 1, 2, and 3, and rituximab 375 mg/m2 day 1. Cycles were repeated every 21 days for a total of 6 or less if a response was achieved and patient qualified for SCT.

Results
From 9/2009 to 8/2012, twenty-one patients were entered in the study. Their clinical characteristics are as follows:
Overall response (OR)/CR rates: 71%/53%.
One patient had stable disease and 4 patients progressed. With a Median follow-up of 31 months, the median TTP was 15.8 months and the median OS was 36.4 months.
Toxicity was mainly hematologic. With 77 cycles given, grade 3 anemia was 5%, grade 3 / 4 neutropenia was 16%/9%, and grade 3 / 4 thrombocytopenia was 19%/8%. Early in the study, day 11 dose of bortezomib was omitted because of low counts by day 11 of cycle. Non-hematologic toxicity included grade 3 neutropenic fever (1%), and grade 3 fatigue (3%). No patient developed sensory neuropathy grade ¾.

Conclusion
Bortezomib can be safely combined with cyclophosphamide and rituximab and results in high rates of overall/complete responses in patients with relapsed/refractory MCL.

Disclosures:
Off Label Use: Gemcitabine, fludarabine and melphalan for transplant conditioning. Younes:Seattle Genetics, Inc.: Advisory/Scientific Board Membership Other, Honoraria, Research Funding. Pro:Seattle Genetics, Inc.: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Travel expenses Other.
Can Polymorphisms In Oxidative Stress Related Genes Be a Risk Factor For CML?
Authors: Gonçalves Ana Cristina , Alves Raquel , Freitas-Tavares Paulo , Teixeira Adriana , Mota-Vieira Luísa , Nascimento-Costa José Manuel , Sarmento-Ribeiro Ana Bela 
Published: October 2019

Abstract
Oxidative stress (OS) is recognized to be a evident feature in cancer development and progression. Indirect evidences suggest a role for oxidative stress (OS) in Chronic Myelogenous Leukemia (CML) etiology and pathogenesis. OS, resulting from an imbalance between Reactive Oxygen Species (ROS) production and antioxidant defenses, contributes to cell damage, apoptosis and ineffective hematopoiesis. The antioxidant enzymes superoxide dismutases (SOD) and catalase (CAT) are important components of cell defense against OS, and polymorphisms in the genes may contribute to differences in susceptibility of individuals to oxidative damage since it can lead to reduced protection against OS.
In the present study we set to investigate the influence of polymorphisms of oxidative stress related genes, namely SOD1 (A251G), SOD2 (Ala16Val), COX2 (G-765C), CAT (C-262T) and NADPH oxidase p22 phox (C242T), as a risk factor for CML development and also as a prognostic risk marker in CML patients.
Our study population consisted of 48 patients diagnosed with CML and the same number of healthy controls. Diagnosis was set according to international criteria. The genetic polymorphisms of SOD1 (A251G), SOD2 (Ala16Val), COX2 (G-765C), CAT (C-262T) and NADPH oxidase p22 phox (C242T) were assessed by RFLP-PCR. The patient group median age was 51 years (18-86), gender M/F=27/21. The strength of association between polymorphisms and CML risk was assessed by odds ratio (OR) with the corresponding 95% confidence interval (CI95%) and Kaplan-Meier survival analysis will be assessed to investigate the prognostic importance of these polymorphisms.
Our preliminary results show a higher wild type allelic frequency of SOD1 (94%), COX2 (80%), CAT (82%) and NADPH oxidase p22 phox (67%) polymorphism and a higher variant allelic frequency SOD2 (52%) in CML patients, compared to controls. In these patients the predominant genotype was AA (88%), CG (52%), GG (67%), CC (73%) and CT (46%), respectively for SOD1, SOD2, COX2, CAT and NADPH oxidase p22 phox. Besides that, individuals with CC genotype of NADPH oxidase p22 phox and with TT genotype of CAT have an increase risk for CML about 2,3636-fold (CI95% 1,0346-5,3997; p=0,032) and 12,368-fold (CI95% 1,5151-100,9687; p=0,0076), respectively.
These preliminary results show that CAT (C-262T) and NADPH oxidase p22 phox (C242T) genetic polymorphisms might be related with CML development and may be a novel genetic markers for CML susceptibility.

Disclosures:
No relevant conflicts of interest to declare.
Megakariocytic Hypoplasia Due To TKIs In a CML Patient Can Be Overcome By TPO Receptor Agonist Eltrombopag
Authors: Dolata, MD Wojciech K. 
Published: October 2019

Background
Patients who develop severe thrombocytopenia while treated with TK inhibitors may be forced to stop them, face a worse prognosis, and eventually require a treatment with a bone marrow transplant.
Eltrombopag is a TPO receptor agonist that stimulates megakaryocytic proliferation.

Case
62-year-old man presented in October 2008 with splenomegaly and leukocytosis. The bone marrow biopsy was diagnostic of CML. Imatinib was started at 400 mg daily resulting in hematological response and resolution of splenomegaly, but severe thrombocytopenia necessitated 50 % dose reduction. Thrombocytopenia was not responsive to Prednisone, and a trial of platelets transfusions with the standard dose of Imatinib had to be stopped because of thrombocytopenia below 10 K and the risk of bleeding – reducing the dose of the TKI was improving the platelet count.
Treatment with Dasatinib and with Nilotinib also necessitated 50 % dose reductions because of thrombocytopenia.
These reduced TKI dosing resulted in the best Quantitative RT-PCR for bcr/abl product reduction level at – 1.01. Bone marrow biopsy in December 2010 showed no morphologic evidence of CML, and no dysplasia; it was normocellular marrow with erythroid hyperplasia and megakaryocytic hypoplasia. Cytogenetic analysis and FISH showed presence of the Philadelphia chromosome rearrangement. The patient declined the treatment with a Bone marrow transplant.
In April 2011 a TPO agonist Eltrombopag 50 mg daily was started, given on two weeks on two weeks off schedule. As platelets remained adequate since then, the Nilotinib was escalated to the full dose of 400 mg twice daily. The patient tolerated the treatment well.

Results
The patient required about half-a-year support with Eltrombopag; after that it was discontinued as the platelet count remained above 40 K. No dose reduction of Nilotinib was necessary. In January 2012 the patient reached the milestone of Complete Cytogentic Response with the level of bcr/abl transcript minus 2 or less, which continued to decrease and now the patient is achieving a Major Molecular Response.

Conclusion
Treatment of CML with Tyrosine Kinase Inhibitors – Imatinib, Dasatinib, or Nilotinib in our patient – can be complicated by severe thrombocytopenia. These patients’ next treatment option may be a Bone marrow transplant.
Limited use of Eltrombopag can improve thrombocytopenia, and allow these patients to continue TKIs with attainment of the treatment milestons.

Disclosures:
Off Label Use: Eltrombopag. It is used in thrombocytopenia, in ITP. In this presentation it was used to treat thrombocytopenia secondary to Thyrosine Kinase Inhibitors in Chronic Myelogenous Leukemia.
Interferon-Alpha (IFN-a) Is Able To Maintain Complete Molecular Response (CMR) In Chronic Myeloid Leukemia (CML) Patients Who Maintain Undetectable disease After Imatinib (IM) Discontinuation
Authors: Carella Angelo Michele , Beltrami Germana , Ghiggi Chiara 
Published: October 2019

Abstract
Cytotoxic lymphocytes (CTLs) which recognize distinct antigenic peptides on CML cells, contributed greatly to the eradication of leukemic cells after allografting. Previously, BCR-ABL specific peptides and the PR1 non-apeptide, were found to elicit a CML-specific CTL response. PR1 is a peptide derived from myeloblastin (MBN), also known as proteinase 3. MBN is abundantly expressed in azurophil granules of normal myeloid cells and is substantially overexpressed in certain immature myeloid leukemia cells where it may be important for the maintenance of a leukemic phenotype. PR1-specific CTLs (PR1-CTLs) lyses and inhibits the proliferation of CML cells but not of normal myeloid precursors. The association between the emergence of PR1-CTLs and the response to IFN-a in vivo strongly implied that IFN-a can induce remissions via induction of a CML-specific PR1-CTLs response. Therefore IFN-a, given to CML patient with undetectable disease achieved with IM, might enable its discontinuation.
Ten consecutive CML patients, who were in stable CMR for at least one year after IM therapy, discontinued IM and received IFN-a. This drug was given at the dose of 3M/U/m2 weekly. The median duration of IM therapy before discontinuation was 60 (range, 31-76) months. At a median follow-up of 40 months (range, 26-58 months), five patients still have undetectable level of BCR-ABL transcript. Five patients relapsed at a median of 8 months (range, 3 – 11 months) but all except one, achieved a new CMR after reintroduction of IM. Grade 2 intolerance (muscle pain, fever) to IFN-a developed in 6/10 patients. The details of patients characteristics will be discussed during the presentation. These preliminary results demonstrate that treatment with low dose IFN-a offered to CML patients with undetectable disease is feasible and this approach may become an attractive alternative to TKI discontinuation alone.

Disclosures:
No relevant conflicts of interest to declare.
Is EUTOS Score Predictive Of Outcome In Patients With Early Chronic Phase Chronic Myeloid Leukemia Treated With Imatinib? Preliminary Data From The National Protocol Of The Chilean Cooperative Group Panda
Authors: Zelada Javier , Aida Capurro Marisa Pia , Rojas Bernardita , Pilleux Lilian M , Aspillaga Augusto , Intriago Marvila , Rosas Jeanette , Graver Diego , Undurraga Soledad S. 
Published: October 2019

Abstract

Background
Before the Tirosine Kinase Inhibitors (TKI) era, the SOKAL and HASFORD scores have been used to predict outcome in chronic myeloid leukemia (CML) patients. The recently reported European Treatment and Outcome Study (EUTOS) score is a simple formula created to identify patients with significantly lower probabilities of responding to therapy and survival. The MD Anderson group didn´t validate this score.

Aims
To validate the EUTOS score in our population treated in the public health hospitals in Chile with a single protocol of the cooperative group PANDA.

Methods
Patients were selected from the data base of the CML 2007 PANDA protocol. All patients were adults (>15 years old) in early chronic phase and received first-line treatment with imatinib-based regimes and had a minimal follow up of twelve months. Event was defined as not reaching complete cytogenetic response in the first year of treatment, death from any cause at any time, loss of complete hematologic response, loss of major cytogenetic response, or progression to accelerated or blast phase. Overall survival (OS) was defined as death of any cause at any time. Event free survival (EFS) was defined as time from diagnosis to any event.

Results
A total of 78 patients were selected from the 330 patients of the data base. The rest had incomplete data. The median age was 48 (range 16 to 79 years old), 47 men and 31 women. Patients with low EUTOS score were 49 (63%) and 29 (37%) were high. The sensitivity of EUTOS was 46% , the specificity was 71% and the negative predictive value was 68%. There was no significative difference in EFS and OS in both EUTOS groups.

Conclusions
EUTOS score was not predictive of outcome in our patient population. Nevertheless it showed a good negative predictive value meaning that it can only identify low risk patients. This could be used in developing countries to select patients that could use lower cost TKI in first line treatment.

Disclosures:
No relevant conflicts of interest to declare.
Improved Prognostic Assessment Of Patients With MDS By IPSS-R and MDS-CI
Authors: van Spronsen Margot , van Spronsen Margot , de Loosdrecht Arjan van , Chamuleau Martine ED 
Published: October 2019

Abstract

Purpose
Myelodysplastic syndrome (MDS) is a broad spectrum of bone marrow failure syndromes characterized by diversity concerning clinical behavior, influence on patient’s outcome and risk for leukemic evolution. For more accurate prognostic assessment, the International Prognostic Scoring System (IPSS) has been recently revised. The purpose of this single-center study was to validate the r-IPSS and to compare this model with the MD Anderson Risk Model Score (MDAS), the IPSS and the (revised) WHO classification-based Prognostic Scoring System (WPSS(-R)). Furthermore, the predictive value of the MDS-Specific Co-morbidity Index (MDS-CI) as several other prognostic factors were analyzed.

Methods
Data were retrospectively collected from 222 MDS patients diagnosed at the VUmc between January 2000 and 2013. Selection was based on informative cytogenetics and the availability of peripheral blood and bone marrow counts. The MDAS, (r-)IPSS, (r-)WPSS and MDS-CI were applied and the impact of individual prognostic factors on patients’ outcome was investigated. Kaplan-Meier method was used for estimating survival and the value of prognostic models was determined by Cox’s multivariate regression method.

Results
Of our study population, 25 (11%), 83 (38%), 51 (23%), 37 (17%) and 25 (11%) patients were classified according to the IPSS-R as very low, low, intermediate, high and very high risk with, respectively, median overall survival (OS) of 129 (95%CI 96-161), 89 (95%CI 73-105), 43 (95%CI 30-57-61), 31 (95%CI 20-42) and 19 (95%CI 7-31) months (P < 0.000). Compared to the MDAS, IPSS, WPSS(-R) and MDAS, the IPSS-R had a higher predictive power for OS. The MDS-CI was of significant predictive value additional to IPSS-R (P < 0.003). Low risk MDS-CI patients who underwent stem cell transplantation (SCT) had a significantly higher mean overall survival (OS), respectively 104 versus 43 months (P < 0.038). However, mean OS of intermediate and high risk MDS patients who received SCT was not better.

Conclusion
Our data confirm the predictive value of the IPSS-R and show the additional value of the MDS-CI. Combined application of these models refines the prognostic assessment and identifies co-morbidity among MDS patients, which may assist and influence clinical decision making.

Disclosures:
No relevant conflicts of interest to declare.
Rhodiola Rosea Extract Reduces Autophagy In Acute Myeloid Leukemia Transformed From Myelodysplastic Syndromes Tumor Xenograft Model
Authors: Torello Cristiane Okuda , Machado-Neto Joao , Veira Karla P. , Maso Victor , Calgarotto Andrana , Franchi-Junior Gilberto Carlos , Lazarini Mariana , Queiroz Mary L. S. , Saad Sara Teresinha 
Published: October 2019

Abstract
Myelodysplastic syndrome (MDS) encompasses a heterogeneous group of clonal hematopoietic stem cell disorders, characterized by ineffective hematopoiesis and a tendency to progress towards acute myeloid leukemia (AML). The autophagy process has been implicated in the pathophysiology of both disorders. MDS treatment usually focuses on reducing or preventing complications, and single-target drugs are ineffective. The identification of novel compounds with anti-leukemia activity, as well as understanding the molecular and cellular basis of the disease may provide new therapeutic opportunities for MDS. In this concern, natural compounds such as Rhodiola rosea are considered interesting for the development of drugs against various molecular targets. Phytochemicals analyses of R. rosea extracts (RRE) revealed the presence of several components including polyphenols. The aim of this study was to study RRE effects using human tumor xenograft model. A total of 2x106 P39 cells (AML transformed from MDS), were subcutaneously injected in dorsal region of NOD.CB17-Prkdcscid/J mice. Tumor volume was measured once every 7 days and RRE treatment initiated when tumors reached 100-200 mm3 (n=6). The dose of 250mg/Kg body was given once every day by oral route (gavage). Control group received vehicle only (n=6). After 14 days, mice were sacrificed; tumors were removed and autophagy-related protein expression was evaluated by Western blot. After 14 days treatment, there was reduction of approximately 30% in tumor volume compared to controls. We found increased expression of beclin-1 and STSQM1/p62, and also Bcl-2 expression. In conclusion, Rhodiola rosea extract treatment in AML transformed from MDS tumor xenograft model reduces tumor growth, with pronounced inhibition of autophagy process.

Disclosures:
No relevant conflicts of interest to declare.
FANCA Controls Mitotic Phosphosignaling Networks To Ensure Genome Stability During Cell Division
Authors: Enzor Rikki , Sater Zahi Abdul , Cerabona Donna , Sun Zejin , Park Su-jung , Hanenberg Helmut , Clapp D. Wade , Nalepa Grzegorz 
Published: October 2019

Abstract
Fanconi anemia (FA) is a heterogenous genome instability syndrome with a high risk of cancer. The FA proteins are essential for interphase DNA damage repair. However, it is incompletely understood why FA-deficient cells also develop gross aneuploidy and multinucleation, which are symptoms of error-prone chromosome segregation. Emerging evidence indicates that the FA signaling network functions as a guardian of the genome throughout the cell cycle, including chromosome segregation during mitosis. However, the mechanistic aspects of the critical role of the FA signaling in mitosis remain poorly understood.
We have recently shown that the FA signaling network localizes to the mitotic apparatus to control the spindle assembly checkpoint and centrosome maintenance (J Clin Invest 2013, in press). The spindle assembly checkpoint (SAC) is a complex tumor suppressor signaling network that prevents premature separation of sister chromatids by delaying the metaphase-to-anaphase transition until all the kinetochores are properly attached to the mitotic spindle. Since weakened SAC promotes stochastic chromosome segregation, mutagenesis and cancer, these findings shed new light on the role of FA signaling in maintenance of genomic stability. We found the subcellular localization of FA proteins to the mitotic apparatus is spatiotemporally regulated as cells divide.
Our new data revealed the pathways connecting the FANCA protein with canonical mitotic phosphosignaling networks. We have employed unbiased kinome-wide phospho-mass spectrometry to compare the landscape of abnormalities of mitotic signaling pathways in primary FANCA-/- patient cells and gene-corrected isogenic cells. These experiments led us to identify and quantify a wide range of phosphorylation abnormalities of multiple FANCA-dependent centrosome-, kinetochore- and chromosome-associated regulators of mitosis. Our data illuminated the role for FA signaling in three critical stages of cell division: (1) the spindle assembly checkpoint, (2) anaphase and (3) cytokinesis. Thus, we employed live phase-contrast imaging of primary FANCA-/- patient cells in comparison to gene-corrected cells to separately quantify aberrations in (1) chromosome congression and metaphase-anaphase transition (SAC malfunction), (2) execution of anaphase and (3) completion of cytokinesis.
Our findings further our understanding of human cell cycle control and provide new insights into the origins of genomic instability in Fanconi anemia by establishing mechanistic connection between the FANCA protein and key mitotic signaling networks. The identification of cell division pathways regulated by FANCA has implications for future targeted drug development in Fanconi anemia and FA-deficient malignancies in the general population.

Disclosures:
No relevant conflicts of interest to declare.