bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biweekly Bendamustine Monotherapy for Relapsed or Refractory Indolent B-Cell Non-Hodgkin Lymphoma and Mantle Cell Lymphoma: A Rabbit-14 Trial
Authors: Igarashi Tadahiko , Wakita Hisashi , Tsujimura Hideki , Aotsuka Nobuyuki , Masuda Shinichi , Utsu Yoshikazu , Murata Naoya , Irisawa Hiroyuki , Tsukasaki Kunihiro , Itoh Kuniaki 
Published: October 2019

Abstract
[Background]
Bendamustine has demonstrated high response rates in non-Hodgkin lymphomas (NHL). However, standard administration schedule frequently shows delayed hematological recovery resulting in the discontinuation of treatment. Here we designed a novel treatment schedule that could be more tolerable and conducted randomized phase II study (UMIN000008702).
[Methods]
Patients (pts) with relapsed/refractory(R/R) indolent B-cell NHL and mantle cell lymphoma were randomly assigned to standard arm (120mg/m2 on day1 and 2, every 3 weeks) or Benda-14 arm (120 mg/m2 on day1 and 15, every 4 weeks) of bendamustine monotherapy. Each arm was repeated to 6 cycles and the accomplishment rate (AR) of all scheduled treatment was analyzed as primary end point.
[Results]
A total of 46 pts were enrolled into the study. Baseline characteristics were: median age 64 years (range 46-78); 48% male; 76% follicular lymphoma; 33% ECOG PS ≥1; 50% having one previous regimen. 65% stage III/IV. 24% bone marrow positive. 33% with bulky mass (>6cm). Using random allocation, twenty two and 24 pts were assigned to standard and Benda-14 arm and the AR of 6 cycles in each arm was 41 and 38%, respectively. The median number of cycles was 4.5 in both arms. Eleven (50%) in standard and 10 (42%) in Benda-14 arm withdrew from protocol due to mainly prolonged hematological toxicities. Three withdrew due to disease progression. Two withdrew due to adverse events (AE). Grade 4 non-hematological AE was observed in one. Overall response rate (ORR) in the standard arm was 77% (95% confidence interval [CI], 59 to 95), including a 50% complete response (CR) compared with 83% (95% CI, 68-99), including a 46% CR in Benda-14 arm.　After a median follow-up time of 16 months, the median event-free survival (EFS) in the standard arm and Benda-14 arm was 14.6 months (95% CI, 8-26) and 15 months (95% CI, 11 - not reached), respectively. There was no significant difference between two arms in AR and in EFS (p=0.431). The overall survival (OS) in both arms was the same of 89% at 15 months.
[Conclusions]
Although this study did not confirm the superiority of Benda-14 to complete 6 cycles of treatment, Benda-14 arm appears to be equally tolerable and active as the present standard therapy. Benda-14 could be a study arm of next trial that determines better practical strategy for this disease population.

Disclosures
Igarashi: Zenyaku-Kogyo Inc.: Research Funding. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding.
Phase II Study of Epigenetic Therapy with Hydralazine and Valproate in Cutaneous T-Cell Lymphoma
Authors: Espinoza Ramiro , Aguilar Rodríguez Manuel , Zapata Nidia P. , Torres Jorge Carlos , Nolasco Diana Berenice , Alarcon Barrios Silvia Eugenia , Cervera Eduardo , Candelaria Myrna , Lozano Valentin , Sosa Alejandro , Espinoza Javier , Vieyra Magnolia , Gutierrez Jorge , Sosa Luis Mario , González Reynaldo , Oñate Luis , Labardini Juan 
Published: October 2019

Abstract
Objectives: To evaluate the therapeutic response to treatment with transcriptional therapy that combines hydralazine / valproate(Transkrip) in cancer patients with cutaneous T-cell lymphoma
Determine toxicity, duration of response and time to progression of epigenetic therapy with hydralazine / valproate in patients with T-cell lymphomas
Material and methods
an open-label, phase II, prospective and longitudinal in the National Cancer Institute of Mexico was carried out, recruiting patients diagnosed with Cutaneous T based on WHO classification 2008, newly diagnosed untreated, demographic data were analyzed and vital and somatometry signs, assessment of efficacy was established according to the therapeutic response in lymphomas measured at each visit at the affected sites for each patient, using the m-SWAT system sorted in complete response (CR), partial response (PR ), stable disease (SD) and progression (PE) and is considered response to patients with complete or partial response, these data were collected in the form of case report at baseline in the first consultation, during treatment and at the end the study at each visit to the doctor. Statistical analysis was performed with SPSS version 13.0 software.
results
16 patients were selected with diagnosis of cutaneous T-cell lymphoma, one patients discontinued the study at baseline and 4 patients had disease progression during the first months of the study, a total of 10 patients who completed 18 months of study continuing the compassionate use treatment.
The median age of patients was 45.8 years analyzed (18-83 years) of which 8 are women (53%) and 7 men (47%) with an ECOG 1 in 93.3% of patients, with an average weight of 72.5 ± 15.99 kg, height 1.6 ± 0.1 m, body mass index 28.3 ± 5.7 kg / m2, 46.7% of overweight patients, systolic blood pressure an average of 116.2 ± 14.3 mmHg and diastolic 75.1 ± 11.04 mmHg with respiratory rate 19.43 ± 1.74 resp / min and 77.8 ± 12.3 cardiac beats / min. Of the 10 patients who completed the study, 100% had complete or partial response itching to 6 month continuing unchanged at month 18, the dream as an adverse event occurred in 33% of patients, this being more frequent, adverse events attributed to the drug were known, expected and mild. From 6 months of treatment, the percentage of partial response and complete response of m-SWAT and pruritus were greater than 90% of patients.
conclusions:
Hydralazine/Valproate (Transkrip) is a medication that offers patients with cutaneous T-cell lymphoma, both first-line and refractory, a therapeutic alternative with high efficiency and good safety profile.

Disclosures
No relevant conflicts of interest to declare.
Dual SYK/JAK Inhibition Overcomes Ibrutinib Resistance in Chronic Lymphocytic Leukemia
Authors: Wang Yue Lynn , Lu Pin , Coffey Greg P , Pandey Anjali , Guo Ailin 
Published: October 2019

Abstract
Ibrutinib (a BTK inhibitor) has generated remarkable responses in CLL. However, the drug, to a large extent, does not cause cell death directly and does not eradicate CLL malignant clones. Inability to eradicate CLL has fostered resistance generation. Once patients become resistant, they do poorly with a median survival of 3-4 months. Novel therapeutic strategies are needed to prevent resistance, improve treatment outcome and ultimately cure the disease. Herein, we explore dual targeting of the BCR and JAK-STAT pathways with a novel single agent, cerdulatinib, which selectively inhibits both SYK (a BCR component) and JAK kinases. We demonstrated that cerdulatinib delivered potent tumor inhibition in 60 primary CLL patient samples, especially in those with poor prognostic indicators. Importantly, cerdulatinib, but not ibrutinib, is able to overcome the support of microenvironment and induces CLL cell death at clinically achievable concentrations. Further, cerdulatinib blocked proliferation of ibrutinib-sensitive and ibrutinib-resistant primary CLL cells and of BTKC481S-transfected cells. These anti-tumor effects are correlated with the inhibition of BCR and JAK-STAT signaling and downstream inhibition of the functions of AKT, ERK and NFκB. Collectively, our results show that simultaneous targeting of BCR and JAK-STAT pathways is a more effective strategy relative to single BTK inhibition.

Disclosures
Coffey: Portola Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding. Pandey:Portola Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding.
Targeting ß-Catenin Signaling in DLBCL with ICG-001 and PAM-1 Suppresses Cell Proliferation and Induces Apoptosis
Authors: Fachel Angela A. , Muley Ashlesha Shrikant , Meydan Cem , Agirre Xabier , Cerchietti Leandro , Melnick Ari , Richards Kristy L. 
Published: October 2019

Abstract
Introduction: DLBCL is a fast-growing, aggressive form of NHL and ~30% of the patients are not cured with the current treatment regimens. Recently Wnt/ ß-catenin signaling has been identified as a new target pathway for lymphoma. To specifically target B-catenin we picked two drugs that act downstream of the Wnt/B-catenin pathway. ICG-001 inhibits TCF/β-catenin mediated transcription by competing specifically with β-catenin for CREB binding protein (CBP), but not for p300. PAM-1 is a p21-activated kinase 4 (PAK4) allosteric modulator acting as a nucleo-cytoplasmic shuttling protein. PAK4 interacts with and phosphorylates β-catenin on Ser675, promoting TCF/B-catenin transcriptional activity and stabilizing β-catenin through inhibition of its degradation. We conducted a pre-clinical study with ICG-001 and PAM-1 ß-catenin inhibitors on 16 ABC and GCB DLBCL cell lines and provided a molecular rationale for Wnt/ß-catenin directed therapy.
Material & Methods: RNAseq data from DLBCL cell lines, patient and normal B-cell samples were used to profile transcript abundance of the Wnt pathway in DLBCL. Western blotting was used to measure ß-catenin expression in 16 ABC and GCB DLBCL cell lines. Pharmacological inhibition of ß-catenin-signaling was tested using ICG-001 and PAM-1 compounds. A metabolically active cellular assay (CellTiter Glo) and flow cytometry with annexin V staining were used to determine cell viability and apoptosis. To address the specificity of the drug response, DLBCL cells were transduced with a ß-catenin/TCF pathway reporter, knocked down for ß-catenin, and canonical Wnt target expression was assessed using quantitative real-time (qRT-PCR) and Western blot.
Results: ß-catenin is expressed on all DLBCL cell lines at different levels that do not correlate with the ABC/GCB classification. The ß-catenin inhibitors ICG-001 and PAM-1 significantly reduced viability in all ABC and GCB DLBCL cell lines, regardless of DLBCL subtype. The EC50 after 48h of treatment ranged from 1.4 μM to 6.3 μM for ICG001 and from 80 nM to 870 nM for PAM-1. Both compounds suppressed cell proliferation, induced apoptosis, and reduced Wnt/ß-catenin transcriptional activity.
Conclusions: Our data indicate that targeting ß-catenin pathway with ICG-001 and PAM-1 could be therapeutically beneficial to DLBCL patients.

Disclosures
Melnick: Janssen: Research Funding.
Copy Number Variations in Cytochromes and Glutathione-Transferases As Early Predictors of the Efficacy of Tyrosine Kinase Inhibitors in CML
Authors: Lavrov Alexander V , Ustaeva Oksana A , Adilgereeva Elmira P , Smirnikhina Svetlana A , Chelysheva Ekaterina , Shukhov Oleg , Shatokhin Yuriy V , Mordanov Sergey V , Turkina Anna G , Kutsev Sergey 
Published: October 2019

Abstract
Chronic myeloid leukemia (CML) is characterized by the presence of the chimeric tyrosine kinase BCR-ABL in all leukemic cells. This non-specific enzyme promotes uncontrolled cell proliferation and genome instability. Tyrosine kinase inhibitors (TKI) help most of the people to achieve long standing remission, however up to 20% of patients develop slow response or even primary resistance to the therapy. In this work we focused on copy number variation (CNV) in glutathione transferases (GSTs) and cytochromes (CYPs) as possible predictors of the response rate to TKI. Thirty one CML patient with optimal response and 16 with therapy failure were enrolled in the study. Patient were grouped according to ELN2013 recommendations: BCR-ABL<1% and/or Ph+ 0% for optimal response and BCR-ABL>10% and/or Ph+ >35% at 6 months of TKI therapy for the failures. We found that these two groups of patients had differed frequencies of wild type and mutated genes: CYP1A2, CYP2A6, CYP2C19, CYP2C9, CYP2D6, CYP2E1, CYP3A4, CYP3A5, GSTM1, GSTP1, GSTT1 (p< 0.0013). Validation in the additional group of 15 CML patients showed that the test allows to predict failures and responders (p=0.02) with high accuracy: positive and negative predictive value 83% and 78%; sensitivity and specificity 71% and 88%.

Disclosures
Chelysheva: Novartis: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Shukhov:BMS: Honoraria; Novartis Pharma: Honoraria. Turkina:BMS: Honoraria; Novartis Pharma: Honoraria; Pfizer: Honoraria. Kutsev:Novartis: Speakers Bureau; Pfizer: Speakers Bureau.
Experience with Pegylated Interferon α-2a in 30 Patients Diagnosed with Hematologic Neoplasms
Authors: Bahcecioglu Adile Begum , Etgul Sezgin , Aslan Tuncay , Aydın Muruvvet Seda , Malkan Umit Yavuz , Okay Mufide , Ozdemir Evren , Ciftciler Rafiye , Goker Hakan , Buyukasik Yahya 
Published: October 2019

Abstract
Introduction:
Interferon (IFN-α) is frequently used in various hematologic neoplastic disorders either at failure of first-line treatment or as first-line therapy in selected patients. IFN-α has shown significant activity in treatment, but the therapy is handicapped by high dropout rates due to side effects and cumbersome dosing schedules. Pegylated (peg) IFN- α is formulated by the covalent binding of one 40 kDa branched PEG-polymer to a lysine side chain of IFN- α. This modification prolongs serum half-life and patient exposure to medicine, decreases renal excretion, thus allowing for weekly administration, acceptable toxicity, tolerability and activity profiles.
The results of peg-IFN in polycythemia vera (PV) and essential thrombocythemia (ET) in phase 2 studies are encouraging, with molecular responses in some patients. There is at least one phase 3 study of hydroxyurea versus peg-IFN as first-line cytoreductive therapy for PV. In spite of ongoing international efforts to evaluate peg-IFN in PV, there is limited experience on peg-IFN use in other hematologic neoplasms.
Method: <>All patients who were put on peg-IFN in our center were found in our institutional electronic database. The patients had been recorded prospectively. All patients who had been treated with peg-IFN had been approved by national health authority and all patients had given informed written consent. Responses were evaluated by ELN (chronic myeloid leukemia), IWG-MRT (PV and ET), EUMNET (myelofibrosis), Nordic proposal criteria (hypereosinophilic syndrome), modified consensus criteria (systemic mastocytosis) (Am. J. Hematol 2009;84:790), Cheson criteria (lymphomatoid granulomatosis) and PET response criteria (Erdheim Chester disease) standardized criteria. Adverse effects were classified according to Common Terminology Criteria for Adverse Events (CTCAE4.0). Categorical and continuous data were expressed as ratio (%) and median (range). Statistical analyses were done by SPSS v17 (Chicago, IL).
Results:
There were 30 patients with 8 different hematologic neoplasms: 12 PV, 6 ET, 2 chronic myeloid leukemia (CML), 3 systemic mastocytosis (SM), 4 Erdheim-Chester disease (ECD), 1 primary myelofibrosis (PM), 1 hypereosinophilic syndrome (HES), and 1 lymphomatoid granulomatosis (LG). Detailed descriptive data, toxicity and treatment results are presented in table 1. Responses were observed in all disease categories. Toxicities were frequent in PV/Et, including significant autoimmune disorders (nephritic syndrome, autoimmune hepatitis)
Conclusion:
Peg-IFN is effective in many hematologic neoplastic disorders. Unfortunately, toxicity is a major concern in this treatment.

Disclosures
No relevant conflicts of interest to declare.
Extramedullary Hematopoiesis in Patients with Primary Myelofibrosis Rare and Serious Complications
Authors: Yassin Mohamed A. , Nashwan Abdulqadir , Mohamed Shehab 
Published: October 2019

Abstract
Extra Medullary Hematopoiesis refers to the presence of hemopoietic elements in locations other than the bone marrow medullary space,It may be seen in many conditions, including chronic hemolytic anemias like thalassemia Intermedia or major. The common sites of involvement are the liver, spleen and the lymph nodes. Less common sites include the central nervous system, adrenal gland, kidney, perirenal soft tissues, breast, peritoneum and gastrointestinal tract the paraspinal region is a relatively uncommon location for these hemopoietic deposits. There are a few case reports of EMH occurring in the spineMost cases have been reported in connection with thalassemia, although it has also been described in patients with sickle cell anemia, polycythemia vera ,myelodysplastic syndrome and myelofibrosis. To the best of our knowledge, there are very few documented case reports in the literature of patients with myelofibrosis who developed cord compressive symptoms due to EMH in the spine from 1958 till 2016 only 15 cases were reported, In reported cases male to female ratio 7:1 with age range between 30 and 75 year old Paraprasesis are the most common presenting symptoms Thoracic region is the most affected site The degree of anemia and bone marrow fibrosis does not correlate with the occurrence of EMH since it was reported in cases with early fibrosis or mild anemia. Correlation between molecular markers like JAK2 and CALR, MPL is not described
No definite guidelines have as yet been formulated for the treatment of such patients with EMH. Excision and decompression, radiotherapy, hypertransfusion and hydroxyurea alone or in combination have been proposed as well as lack of consensus about what is complete remission is it clinical or clinical and radiological and what is partial response is it any reduction of the mass lesion or any degree of clinical improvement in conclusion there is necessity to establish consensus for treatment and definition of CR, PR or No response in EMH with MF.

Disclosures
No relevant conflicts of interest to declare.
Not All Polyps Are Created Equal: Multiple Myeloma in the Gut
Authors: Akella Divya , Aparna Fnu , Pekez Marijeta , Nathan Nirmala S. , Ramberan Hemchand , Thakur Kshitij 
Published: October 2019

Abstract
Background: Multiple myeloma is a neoplastic proliferation of plasma cells producing a monoclonal immunoglobulin usually restricted to the bone marrow. Recent literature confirms increased extramedullary involvement of skin, liver and lymph nodes but gastrointestinal multiple myelomas remain rare.
Case: We report a case of 57-year-old female with a past medical history of progressive multiple myeloma IgA lambda on elotuzumab, lenalidomide and dexamethasone therapy, who presented with generalized weakness and black stools for approximately one week. Initial laboratory work demonstrated a hemoglobin of 6.7 grams per deciliter and heme positive stools consistent with anemia secondary to presumed gastrointestinal blood losses. Esophagogastroduodenoscopy (EGD) was unremarkable. Colonoscopy revealed 6 colonic polyps scattered throughout the distal transverse, cecal and descending colon which were excised and sent for pathology. Pathology of the polyps showed plasma cell myeloma with anaplastic features. Immunohistochemistry demonstrated cells that were positive for CD-138 and negative for keratin staining, confirming plasma cell origin. Furthermore analysis was positive for lambda light chain, but negative for kappa light chain. The patient was managed with packed red cell transfusion with no further evidence of recurrent bleeding.
Conclusion: Gastrointestinal multiple myeloma are rare, but as our case demonstrates, they must be considered in the differential diagnosis of patients with gastrointestinal bleeding, particularly those with multiple myeloma. The endoscopic appearance of multiple myeloma polyps may be similar to other more common conditions, making pathological and immunohistochemical analysis of biopsies essential for making a correct diagnosis.

Disclosures
No relevant conflicts of interest to declare.
Clinical Implications of Spliceosome Mutations: Epidemiology, Clonal Hematopoiesis, and Potential Therapeutic Strategies
Authors: Walter Matthew J. , Graubert Timothy A. 
Published: October 2019

Somatic mutations in genes that are involved in pre-mRNA splicing (i.e., spliceosome genes) occur in ~50% of patients with myelodysplastic syndromes (MDS). Commonly mutated spliceosome genes (e.g., SF3B1, SRSF2, and U2AF1)have variable prognostic significance in patients with myeloid malignancies. For example, SRSF2 and U2AF1 mutations are associated with worse and SF3B1 mutations with better clinical outcomes compared to patients without a spliceosome gene mutation. While multiple groups have shown that RNA splicing is altered in patients with spliceosome gene mutations, the contribution of these alterations to disease pathogenesis is largely unknown. Several groups have recently reported that RNA splicing and hematopoiesis are altered in mutant expressing mouse models, providing direct evidence that spliceosome gene mutations contribute to some MDS phenotypes. Spliceosome gene mutations have also been detected in the blood cells of healthy elderly individuals with clonal hematopoiesis who are at an increased risk of developing hematopoietic cancer, further implicating these mutations as early genetic drivers in MDS. Consistent with this possibility, spliceosome gene mutations tend to occur in the founding clone (i.e., present in every tumor cell in a patient) of myeloid malignancies. Collectively, these observations indicate that targeting mutant cells could have a large clinical impact. Several observations indicate that spliceosome gene mutations may create a genetic vulnerability in cells that could be exploited therapeutically. Spliceosome gene mutations are typically heterozygous and mutually exclusive of each other in patients, implying either a redundancy in pathogenic function of mutant genes or that a cell cannot tolerate two spliceosome perturbations at once. Accumulating evidence now suggests that heterozygous mutant cells require appropriate expression levels of the non-mutant residual allele or other splicing factors to maintain cell viability. Therefore, we and others hypothesize that cells harboring spliceosome mutations will have increased sensitivity to pharmacological perturbation of the spliceosome, providing a new treatment approach for patients with these mutations. To examine this, we used sudemycin compounds that bind the SF3B1 protein to modulate pre-mRNA splicing. We show that treatment of U2AF1 mutant mice with sudemycin results in attenuation of mutant-associated hematopoietic progenitor cell expansion compared to control treated mice. Collectively, data from our group and others suggest that cells expressing mutant spliceosome genes have an increased sensitivity to pharmacologic perturbation of splicing. Clinical trials are being designed to treat spliceosome mutant hematological cancers with splicing modulator compounds.

Disclosures
No relevant conflicts of interest to declare.