bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survival of Patients with Relapsed Diffuse Large B-Cell Lymphoma In a Community Hospital
Authors: Mirault Jaclyn , Milani Arash Ghanbari , Ghetia Ditina , Yeboah Isaac , Sharma Puja , Colmer Jonas , Cotler Samantha , Topilow Arthur A. 
Published: October 2019

Abstract
Abstract 4902
Introduction: Of the various subtypes of non-Hodgkin's lymphoma, Diffuse Large B-cell Lymphoma (DLBCL) is the most prevalent, making up 30 percent of all non-Hodgkin's lymphoma cases. Information from community hospitals regarding the treatment and survival of relapsed patients is scarce. The study was done to obtain the survival data of patients with a relapse of DLBCL, treated with and without transplant at our center.
Patients and Methods: The tumor registry data at Jersey Shore University Medical Center between 2000–2008 was reviewed. 41 patients had been diagnosed with DLBCL. Of these, the diagnosis in 13 pts represented a relapse of DLBCL. Review of the hospital records showed that the treatments for these relapsed patients had been radiation, rituximab -based chemotherapy, and/or autologous stem cell transplant. Eight were female and five were male, with a median age of 66 years at initial diagnosis (range: 51 to 81 years). The median age was 68 at the time of relapse (range: 52 to 82 years). Survival was measured from the time of the diagnosis of relapse until death from any cause or the date when lost to follow up. Information on the duration of time from initial diagnosis to relapse was also obtained.
Results: Of the 13 patients who relapsed, 3 underwent stem cell transplant, one of whom died at 43 weeks and two are alive after 70 and 336 weeks. Of the 10 who did not have transplant, 6 died at 2, 8, 15, 19, 19 and 38 weeks. The 4 remaining non-transplant patients are alive at 37, 61, 167, and 221 weeks. Of the 13 patients who relapsed, at primary diagnosis, one had been stage I, 3 had been stage II, 3 had been stage III, and 5 had been stage IV. One was of unknown stage. The average time from diagnosis to relapse was 80 weeks.
Conclusion: Although our numbers are small, it does appear that there is a role for second-line treatments in those patients with a relapse of large cell lymphoma that are not undergoing stem cell transplant. Further study of the treatment of non-transplanted patients with relapsed DLBCL appears warranted.

Disclosures:
No relevant conflicts of interest to declare.
The Anti-CD20 Monoclonal Antibody GA101 Displays More Robust Anti-Tumor Activity Versus Rituximab In Waldenstrom's Macroglobulinemia (WM)
Authors: Yang Guang , Hanzis Christina , Verselis Sigitas , Xu Lian , Hunter Zachary , Ioakimidis Leukothea , Sheehy Patricia , Patterson Christopher , Fox Edward , Treon Steven P. 
Published: October 2019

Abstract
Abstract 4904

Background:
Rituximab is an IgG class CD20-directed monoclonal antibody used in the treatment of B-cell malignancies, including WM. We and others have previously demonstrated dependence for IgG class therapeutic antibodies on polymorphisms at FcγRIIIA-158. Approximately half of WM patients express V/V or V/F, and the remainder half express F/F at this polymorphic locus. Patients with WM expressing FcγRIIIA-158 V/V or V/F show improved rituximab single agent activity, as well as attainment of deeper responses (VGPR or CR) with combination Rituximab therapy. GA101 is a novel humanized anti-CD20 antibody with a glyco-engineered Fc domain that exhibits increased Fcg receptor binding and ADCC activity.

Methods:
In this study, we examined the in vitro activity of GA101 and Rituximab against WM cells, and also examined the activity of these antibodies in context of FcγRIIIA-158 polymorphisms. ADCC activity for GA101 and Rituximab was assessed using genotyped healthy donor derived NK cells against BCWM.1 WM cells, as well autologous NK cells against the patient's own lymphoplasmacytic cells. In vitro B-cell depletion and direct cell death induction assays were also performed.

Results:
We observed significantly greater ADCC activity against WM cells for GA101 versus Rituximab in both healthy donor, as well as autologous NK cell assays. GA101 mediated ADCC activity was particularly more robust versus Rituximab in patients expressing FcγRIIIA-158 F/F versus V/V or V/F (Figure 1). In addition, GA101 induced significant direct cell death against WM lymphoplasmacytic cells, as well as in vitro B-cell depletion assays in comparison to Rituximab, which exhibited little direct cell death induction activity. Nuclear translocation of apoptosis inducing factor (AIF) was observed following GA101 by immunofluorescence microscopy.

Conclusions:
GA101 is associated with enhanced ADCC activity relative to Rituximab by NK cells, particularly for those subjects expressing FcγRIIIA-158 F/F. In addition, GA101 demonstrated direct cell death in WM lymphoplasmacytic cells through an AIF mediated caspase-independent pathway. These studies provide the framework for the investigation of GA101 in WM, and suggest particular benefit for those patients who express FcγRIIIA-158 F/F.

Disclosures:
No relevant conflicts of interest to declare.
Rituximab in Lymphoma Associated Auto-Immune Haemolytic Anemia
Authors: Bhargava Amit , Banerjee Nirupma 
Published: October 2019

Abstract
Abstract 4923
The association of Autoimmune hemolytic and Non Hodgkin's lymphoma is a known phenomenon. Cold hem agglutinin disease (CHD), is an uncommon Autoimmune hemolytic anemia, mediated by cold reactive auto antibodies that bind to erythrocyte carbohydrate antigen causing hem agglutination and complement mediated hemolysis. Cold agglutinin–mediated hemolysis occurs at low temperature which may be severe and difficult to treat.
CHD may be primary when it is idiopathic or secondary as in lympho-proliferative disorder of bone marrow associated with clonal proliferation of CD20 B cells that produce monoclonal 1g M cold agglutinin (kappa /lamda). Rituximab has been used as an as a novel treatment option in Autoimmune hemolytic anemia. Rituximab is a genetically engineered chimeric monoclonal antibody that targets the CD20 antigen on B cells.
Rituximab in autoimmune conditions possibly acts by destruction of CD20_clonotypic precursor B cells and/or CD20 plasma cells, thus is effective in controlling immunoglobulin-mediated diseases of B lymphocytes.
We analysed four patients of lymphoma with severe CHD who were successfully treated with the chimeric anti-CD20 monoclonal Rituximab (375mg/ m2) intravenously every three weeks for four to six cycles, till the Agglutinins disappeared from the serum.

Patient and method
In this study patients diagnosed with lymphoma associated CHD were treated with Rituximab with a dose of 375mg/ meter square given every three weeks for four to six cycles, till the primary aim was achieved. The primary aim was correction of anemia, disappearance of cold hem-agglutinins from serum, assessed by complete blood counts and measuring cold agglutinins in serum.
Four such patients were studied, all of them had NHL-DLBCL (IHC proven), with severe hemolysis and jaundice with Hemoglobin <5 gm/ dl. All had presence of cold agglutinins in the serum and were positive for direct and indirect coomb's test.

Response
All the patients showed significant improvement in the symptoms due to anemia and there was a rise in hemoglobin detected within the first week of Rituximab treatment. They achieved normal levels of hemoglobin with four to six weeks of treatment and in three patients cold agglutinins disappeared after completion of five cycles and the fourth patients had it after the sixth cycle. None of the patients was given any transfusion because of incompatibility issues.

Conclusion
Our experience with Rituximab was excellent in this indication and patients had a good overall outcome. Further trials need to be done for more evidence in this regard.

Disclosures:
No relevant conflicts of interest to declare.
Prognostic Factors Associated with Progression of Myelodysplastic Syndromes (MDS) to Acute Myeloid Leukemia (AML) In Patients (pts) Treated with Decitabine
Authors: Fullmer Amber , Garcia-Manero Guillermo , Borthakur Gautam , Kadia Tapan , Kantarjian Hagop , Jabbour Elias 
Published: October 2019

Abstract
Abstract 4956

Background:
About 50% of pts with MDS ultimately progress to AML with no clear pattern in underlying parameters leading to progression. This analysis sought to identify predictive factors in pts with MDS that are associated with progression to AML after treatment with decitabine.

Methods:
In a combined analysis of MDS pts treated with either a 3- or 5-day dosing schedule of decitabine, pts were stratified on the basis of those who progressed to AML (P) versus those who did not (NP). CR rates by IWG2006 criteria for each of the baseline factors were compared by using the chi-square test. Factors that were significant in the univariate analysis (p<0.05) were included in a multivariate analysis. Logistic regression analysis was conducted for progression to AML. The following variables were identified as predictors of progression: study effect; age; secondary or de novo MDS; prior MDS treatment, including growth factor use only and prior chemotherapy; del 5Q or 7; time to diagnosis; baseline ANC (< 500, 500 – 1000, or >1000 U/L); baseline HGB, plt and BM blast count ≤20; FAB classification; ECOG status; and IPSS (low, int-1, int-2). A Cox proportional-hazards analysis was conducted for survival.

Results:
A combined analysis of prognostic factors for MDS was completed in 163 pts with a complete response to decitabine; 37 (22.6%) had progressed to AML and 126 (77.3%) had not. Baseline characteristics in pts that progressed had significantly less time since diagnosis (<3mos), more RAEB, RAEB-t and IPSS classification of Int-2 and high-risk, lower baseline HGB levels and fewer prior treatments. From the multivariate analysis, the following factors were selected as predictors of progression: No history of prior treatment, time from diagnosis of MDS <3 months, hemoglobin levels under 10 g/dL, and a 3-day schedule of decitabine (p=0.005, 95% CI 1.4, 6.8). Survival estimates were determined for Del 5q or 7, baseline HGB <10, plt <50 and the 3-day dosing schedule approached but did not achieve a significant effect (p=0.08).

Conclusions:
MDS pts with a deep anemia (HGB <10), thrombocytopenia (plts <50), and a cytogenetic risk profile that includes a del5 and/or 7 anomaly are at a statistically higher risk of transformation into AML and should be considered for additional treatment options.

Disclosures:
Borthakur: Eisai Inc.: Research Funding. Kantarjian: Novartis: Consultancy, Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding. Jabbour: Eisai Inc.: Editorial and statistical support, Honoraria.
Establishment and Characterization of a Novel Human Myeloma Cell Line, AMU-MM1, From a Multiple Myeloma Patient Involving Central Nerve System After Treatment with Bortezomib
Authors: Hanamura Ichiro , Goto Mayuko , Nagoshi Hisao , Taki Tomohiko , Imai Norikazu , Suganuma Kazuto , Goto Mineo , Mizuno Shohei , Takahashi Miyuki , Yamamoto Hidesuke , Hiramatsu Akihito , Wakabayashi Motohiro , Watarai Masaya , Shikami Masato , Imamura Akira , Mihara Hidetsugu , Iida Shinsuke , Ueda Ryuzo , Taniwaki Masafumi , Miwa Hiroshi , Nitta Masakazu 
Published: October 2019

Abstract
Abstract 4991
Bortezomib improved the survival in patients with multiple myeloma (MM), however, cannot cure this disease even when it is combined with autologous stem cell transplant(s) and other new drugs. Myeloma cells cannot be excluded completely from a patient due to drug refractoriness and/or inefficiency of drug delivery in extramedullary sites such as cerebrospinal fluid (CSF). Therefore, it is important to clarify the mechanisms of bortezomib resistance and invasion to central nerve system (CNS) of myeloma for the progress of myeloma therapy.
In this study, we established a novel human myeloma cell line from a myeloma patient involved with CNS and analyzed its characters including sensitivity to bortezomib. The patient had been treated with bortezomib for 1.5 years when her CNS was involved with myeloma. The cells from patient's CSF were cultured in RPMI 1640 supplemented with 20% heat-inactivated fetal bovine serum (FBS) and rhIL-6. After 3 months of culture, cell proliferation became continuous with 10% FBS and without rhIL-6. The cell line, named AMU-MM1 was established and negative for EBV. A doubling time of AMU-MM1 cells was about 48 hours. AMU-MM1 cells were positive for CD38, CD54, CD138 and cytoplasmic kappa chain and negative for CD19, CD20, CD33 and CD56 by flow cytometry analysis while those in patient's bone marrow were positive for CD56. AMU-MM1 showed hypo- and pseudodiploid karyotypes with t(4;14), t(8;13), t(1;19), del13q, amp1q21 and others but without del17p by cytogenetic analyses including FISH. The G322A mutation in the proteosome beta 5 subunit (PSMB5) gene, which is reported as a mutation found in bortezomib-resistant cell lines induced via repeated drug selection, was not detected in AMU-MM1 by direct sequencing. Apoptosis analysis using Annexin V/PI assay indicated that AMU-MM1 was sensitive to bortezomib. Our data suggest that AMU-MM1 was derived from the cells that invaded to CSF in which bortezomib concentration was very low and not resistant to bortezomib, and the downregulation of CD56 might play a role in the pathogenesis of CNS involvement as reported before. In addition, we are now focusing on new chimera or dysregulated genes in t(8;13), t(1;19) and other sites as well.
In conclusion AMU-MM1 is a useful cell line for analysis of mechanisms of CNS involvement and also possibly the acquired resistance to bortezomib.

Disclosures:
No relevant conflicts of interest to declare.
Imatinib Treated Chronic Myelogenous Leukemia Concomitant with Multiple Myeloma. Is There a Relationship?
Authors: Kutner Jose Mauro , Bley Claudia , Perini Guilherme Fleury , Santos Fabio , Rodrigues Morgani , Ribeiro Andreza Alice Feitosa , Hamerschlak Nelson 
Published: October 2019

Abstract
Abstract 5005
Chronic myelogenous leukemia (CML) and multiple myeloma (MM) are hematological neoplasms with involvement of distinct hematopoietic cell lineages. The simultaneous occurrence of CML and MM is an extremely rare event. We report the case of a 46-year-old asymptomatic patient who was diagnosed with CML after an abnormal white blood cell count (90×109 u/L) was found on a routine complete blood cell count. Physical examination showed only splenomegaly. At diagnosis, a monoclonal protein peak was observed on electrophoresis (0.82g/dL). Bone marrow (BM) biopsy was characterized by granulocyte hyperplasia without clonal plasmacytosis. Karyotype showed t(9;22)(q34.1;q11.2) and a BCR/ABL mRNA transcript was detected by RT-PCR. Cytoreduction was initiated with hydroxyurea for 20 days until imatinib 400 mg/day was initiated. Patient achieved a major molecular response (MMR) after 7 months of treatment and remains in MMR. After 12 months from diagnosis, the patient persisted with monoclonal peak, and a new BM biopsy showed 15% monoclonal plasma cells, compatible with IgG lambda Myeloma. No end-organ damage was found, and there was no indication for therapy. Karyotype was 46, XX and a FISH analysis was positive for IgH rearrangement and for del 13q. At the time of this report the patient persists in MMR for CML with a monoclonal peak of 1.2 g/dL. No evidence of MM progression has been observed. These findings indicate coexistence of CML in chronic phase and monoclonal gamopathy of uncertain significance (MGUS), progressing to smoldering MM IgG lambda during IM treatment. At this moment, the association of CML and MM has been considered coincidental, but it is possible that imatinib may induce changes in phenotype of plasma cells which might lead to progression of multiple myeloma.

Disclosures:
No relevant conflicts of interest to declare.
NT-ProBNP and VEGF Serum Evaluation In AL Amyloidosis
Authors: Saltarelli Francesca , Moscetti Alessandro , Bianchi Maria Paola , Bruno Guglielmo , Salerno Gerardo , Corsetti Maria Teresa , Cardelli Patrizia , Ferranti Giovanna , La Verde Giacinto 
Published: October 2019

Abstract
Abstract 5008
AL amyloidosis is a plasmacellular dyscrasia in which fibrillary deposits containing monoclonal immunoglobuline light chains infiltrate tissues causing their dysfunction and failure. Amyloidosis could be classified into rare localized or more frequent systemic forms such as AL amyloidosis. Cardiac dysfunction is a very frequent feature in AL amyloidosis patients. To evaluate heart involvement both in systemic and localized AL amyloidosis, serum levels of pro-BNP (peptide NT-proBNP; 76 amino acids) and VEGF were investigated. NT-proBNP has been described as an useful marker for heart dysfunction and its role as a prognostic factor for patients with systemic AL amyloidosis has been validated. VEGF is a signaling protein that stimulates new blood vessel formation and showed to be a mitogen for vascular endothelial cells. Serum NT-proBNP and VEGF levels were performed in systemic or localized AL amyloidosis patients to evaluate if there is any correlation between them. Blood samples were collected from 8 patients with systemic amyloidosis and from 4 patients with localized amyloidosis. To analyze the results of NT-proBnp and VEGF, Mann-Whitney test and Spearman correlation were performed. Serum NT-proBNP values were significantly increased in systemic disease (p=0.004). VEGF serum levels were also significantly higher in patients with systemic disease compared to the other group (p=0.027). No significant correlation between NT-proBNP and VEGF levels was found. We know that proBNP levels are significantly increased in patients with systemic amyloidosis and cardiac involvement. On the other hand, VEGF serum levels resulted to be increased in systemic disease. Nevertheless, on the basis of our results, we found absence of a significant correlation between NT-proBNP and VEGF increases. In our opinion, such finding could suggest that VEGF based neoangiogenesis is not significantly involved in AL amyloidosis heart dysfunction.

Disclosures:
No relevant conflicts of interest to declare.
Mir-223 Is Dispensable for the Onset of Acute Myeloid Leukemia
Authors: Kuchenbauer Florian , Berg Tobias , Mah Sarah M , mirkovic-Hosle Milijana , Salmi Anisa , Ruschmann Jens , Muranyi Andrew , Agiropoulos Bob , Rouhi Arefeh , Starczynowski Daniel T , Heuser Michael , Hogge Donna E. , Camargo Fernando D. , Dohner Hartmut , Buske Christian , Humphries R. Keith 
Published: October 2019

Abstract
Abstract 501
The functional roles of microRNAs in the development of acute myeloid leukemia (AML) are not yet clear. Due to its myeloid-specific expression, miR-223 has been one of the most-investigated miRNAs in normal and malignant hematopoiesis. However, the role of miR-223 in myeloid differentiation is not completely understood, as contradicting data exists. Genetic depletion of miR-223 led to a significant increase of myeloid progenitor cells as well as circulating hyperreactive neutrophils. Here, we investigate the role of miR-223 in the development of AML in vivo, using retroviral overexpression models of Hoxa9 with Meis1 or MN1 as two potent models of leukemic transformation in a miR-223+/+ or miR-223−/− background. In contrast to the observed high level expression of miR-223 in human CD34- bulk AML cells (p=0.0106), we could show that miR-223 was dispensable for the development of AML and did not impact on either the leukemic stem cell frequency nor the AML cell phenotype in Hoxa9-Meis1 AML cells. While these findings reveal that miR-223 is not necessary for leukemic transformation in highly aggressive AML models, we became interested if miR-223 functions rather as modulator of disease progression, especially at the early development of AML. Therefore, we investigated the role of miR-223 with regards to differentiation and self-renewal in two preleukemic model systems by retrovirally infecting miR-223−/− and miR-223+/+ BM cells with AML1-ETO and Hoxa9 respectively. Characterization of these models demonstrated that miR-223 expression is a determinant of differentiation, as miR-223−/− preleukemic cells exhibit a significant lower Mac-1 expression (p=0.0003). However, in contrast to normal miR-223−/− BM cells, which show a significantly higher colony forming capacity in methylcellulose compared to miR-233+/+ BM cells, the colony forming capacity of miR-223−/− or miR-223+/+ preleukemic cells did not significantly change.
These findings demonstrate that miRNA miR-223 is hierarchically expressed in AML cells, and functionally link miR-223 to impaired differentiation rather than increased self-renewal in the initiation of AML. This indicates that miR-223 is more likely a fine tuner of leukemic development than a potent tumor suppressor or oncogenes as suggested in the literature. However, it still remains to be shown if the presence of miR-223 influences the susceptibility of preleukemic cells to convert into leukemia initiating cells.

Disclosures:
No relevant conflicts of interest to declare.
Membrane Associated TGF-β1 on Leukemia Blast-Derived Microvesicles In Sera of Acute Myeloid Leukemia Patients Suppresses NK Cell Function
Authors: Boyiadzis Michael , Szczepanski Miroslaw , Whiteside Theresa 
Published: October 2019

Abstract
Abstract 502
Natural killer (NK) cell cytotoxicity in patients with acute myeloid leukemia (AML) is significantly decreased relative to that in normal controls (NC). TGF-β1 is a potent inhibitor of NK cell cytotoxicity. We considered the possibility that suppression of NK cell activity in AML patients is mediated by leukemia blast-derived microvesicles (MV) via TGF-β1. Sera of 19 patients newly diagnosed with AML prior to any treatment were used to isolate MV by ultracentrifugation. MV from AML patients were positive for the blast-associated markers (CD33, CD34, CD117) by flow cytometry and for membrane-associated TGFb-1 in Western blots, whereas neither these markers nor TGFb-1 were detected in MV from NC. The protein content of blast-derived MV was higher (p<0.001) than that of MV isolated from sera of 25 NC (75μ g±12/mL vs 1.2μ g±0.4/mL). To evaluate MV-mediated NK cell suppression, NK cells obtained from NC were co-incubated with MV isolated from patients' sera. A significant decrease (p<0.002) in NK cell cytotoxicity (2412 LU pre- vs 1640 LU post co-incubation) was accompanied by a concomitant decrease (p<0.004) in the NK-cell activating receptor, NKG2DR, expression levels. To determine whether MV-associated TGF-β1 was responsible for these adverse effects of MV on NK cells, neutralizing anti-TGF-β1 mAb was added to the co-cultures. This mAb significantly abrogated MV-mediated inhibition of NK cell cytotoxicity and down-regulation of the NKG2DR expression level. We next measured the plasma concentrations of TGF-β1 in AML patients and NC. The mean ± SD plasma concentration of TGF-β1 was 2,600 pg/mL ± 2,500 in patients vs. 101 pg/mL ± 55 in NC (p<0.0001). The use of urea, which disassociated membrane-bound TGF-β1 in MV, resulted in a significant increase of the measured TGF-β1 levels (mean 13,700 pg/mL ± 9,800) only in the sera of AML patients but not in the sera of NC. To determine whether the SMAD pathway used by the TGF-β family members is involved in the MV-NK cell interactions, we co-incubated NK cells with MV isolated from sera of AML patients. These MV induced SMAD phosphorylation in NK cells. The addition of anti-TGF-β1 mAbs to the co-culture inhibited SMAD phosphorylation but did not alter expression of the SMAD protein itself. These data provide evidence for a novel mechanism responsible for down-regulation of NK cell activity and NKG2DR expression levels by TGF-β1 associated with leukemia blast-derived MV in AML patients.

Disclosures:
No relevant conflicts of interest to declare.