bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bortezomib and Thalidomide, a Steroid Free Regimen in Newly Diagnosed Patients with Multiple Myeloma.
Authors: Ghosh Nilanjan , Ferguson Anna , Ye Xiaobu , Huff Carol A. , Borrello Ivan M. 
Published: October 2019

Abstract
Abstract 2867
Poster Board II-843
Corticosteroids have historically been the backbone of most myeloma targeted therapies. However, they are often the major cause of toxicities, especially in elderly patients. In recent years, novel agents such as bortezomib and thalidomide have demonstrated significant anti-myeloma activity with increased overall response rates. We thus designed a study combining these two agents in a steroid-free regimen. Bortezomib (B) and thalidomide (T) were examined as first line treatment in 27 patients with symptomatic multiple myeloma between September 2004 and September 2006. Patients received B 1.3 mg/m2 on days 1, 4, 8 and 11 every 21 days and T 150 mg daily for a maximum of 8 cycles. The overall response rate was 81.5%, with a near CR or greater of 25.8% and a CR (immunofixation negative) of 11%. A major response identified by greater than 90% reduction in the paraprotein was seen in 33% of the patients. Responses were rapid: median time to first response was 36.5 days (range, 14-101 days) and median time to best response was 61 days (range, 16-171 days). The most common grade 3 toxicities were peripheral neuropathy (22%), pneumonia (15%) and fatigue (7%). The only grade 3 hematologic toxicity was anemia (7%). No grade 4 toxicities were seen. 3 patients had mild peripheral neuropathy (PN) at baseline. PN was the most common reason for dose reduction with an average B dose of 1.1mg/m2 and T of 110mg daily. The major cause of discontinuation of treatment was PN. The PN completely resolved in 80% of the patients upon completion of therapy. No venous thromboembolic events (VTE) were observed even in the absence of prophylactic anticoagulation. It should be noted that upon completion of the study all patients received either B or T maintenance and no patients proceeded onto stem cell transplant immediately. The median progression free survival (PFS) was 16.8 months (95% CI 8.7-21.6 months). Median overall survival has not yet been reached at a median follow up of 39 months. The 3 year overall survival is 74%. This study demonstrates: 1) the excellent efficacy of a steroid-free regimen; 2) good PFS in the absence of stem cell transplantation; and 3) that most treatment-related PN resolves.

Disclosures:
Huff: Celgene: Consultancy. Borrello:Celgene: Speakers Bureau; Mellenium: Consultancy.
Host Dendritic Cell Vaccinations Combined with Donor Lymphocyte Infusions Induce Host and KLH Specific Immunity in Multiple Myeloma Patients.
Authors: Kneppers Evelien , Minnema Monique C. , Aarts Tineke , Emmelot Maarten E. , Slaper-Cortenbach Ineke , Westinga Kasper , Mutis Tuna , Lokhorst Henk M. 
Published: October 2019

Abstract
Abstract 2875
Poster Board II-851
Allogeneic stem cell transplantation followed by donor lymphocyte infusions (DLI) induces a clinical significant graft versus myeloma (GvM) effect in 30-50% of multiple myeloma (MM) patients. Since this effect can be dependent on the presence of host dendritic cells (DC) at the time of DLI, combining DLI with infusion of host DCs may improve GvM effect. To evaluate this we conducted a phase I/II trial in which DLI- non responding MM patients received host monocyte derived DC vaccinations in combination with a second DLI. Patients received 3 DC vaccinations both i.v. and i.d. with two-week intervals. The first vaccination was combined with DLI. Half of the i.d. DCs was loaded with KLH for immunomonitoring purposes. Specific anti-host and anti-KLH T cell responses were monitored using IFN-gamma release and proliferation assays. To date six patients completed all 3 DC vaccinations, one patient received only one vaccination. Exacerbation of mild pre-existing graft versus host disease occurred in two patients after the first and second vaccination respectively; no other adverse events were seen. Starting from the second vaccination patients developed positive skin reactions against KLH-DCs (n=5/6) and against DCs (n=2/5). The delayed type hypersensivity (DTH) skin tests performed after the last vaccination showed positive indurations against host DCs (n=5/5) and against KLH (n=4/5). All patients (n=4/4) developed significant but variable proliferative and IFN-gamma responses against KLH and host DCs. While 5 patients developed no clinical GvM effect, in one patient disease was stabilized for 29 weeks and the cellular responses against host DCs and KLH were still present 20 weeks after the first vaccination. Another patient, who entered the study with minimal residual disease, is clinically stable for 18 weeks now, however he has not yet been evaluated further. We conclude that administration of host DCs combined with DLI is safe and feasible, and that the vaccinations result in enhanced T cell responses. However, clinical GvM effects are limited. This GvM effect may be increased after vaccination with DCs loaded with hematopoietic restricted minor H antigens.

Disclosures:
Off Label Use: Rituximab, a monoclonal anti-CD20 antibody, is used to deplete B cells in the treatment of chronic GVHD.
IPSS-Independent Cytogenetic Risk Categorization in Primary Myelofibrosis.
Authors: Hussein Kebede , Pardanani Animesh D. , van Dyke Daniel , Hanson Curtis A. , Tefferi Ayalew 
Published: October 2019

Abstract
Abstract 2909
Poster Board II-885

Background:
Previous studies have identified sole abnormalities of del(20q) and del(13q) as prognostically favorable cytogenetic markers in primary myelofibrosis (PMF) (Tefferi et al. BJH 2001;113:763). A more recent study (Tam et al. Blood 2009;113:4171) confirmed these findings and suggested additional cytogenetic markers of prognosis. In the current study with larger numbers of informative patients studied at time of diagnosis, we wanted to validate these observations and examine the prognostic interaction between cytogenetic risk categorization and the International Prognostic Scoring System (IPSS).

Methods:
Patients with cytogenetic information at diagnosis were selected from the Mayo Clinic database of WHO-defined PMF. Specific cytogenetic categories were considered only in the presence of at least 5 informative patients; otherwise, they were included in the category of “other cytogenetic abnormalities”. Follow-up information was updated in July, 2009. Survival curves were prepared by the Kaplan-Meier method and compared by the log-rank test. Cox regression model was used for multivariable analysis.

Results:
200 patients were studied (median age, 62 years; 63% males). The IPSS risk distributions were low in 66 patients, intermediate (int)-1 in 64, int-2 in 44 and high in 26. Cytogenetic findings at diagnosis were abnormal in 83 (42%) patients and included sole del(20q) in 21, complex (i.e. 3 or more abnormalities) in 13, sole del(13q) in 8, sole +8 in 7, sole +9 in 6, and other abnormalities in 28 patients. Median survivals in low, int-1, int-2 and high IPSS risk groups were 188, 71, 47 and 26 months, respectively (p < 0.0001). Median survival in patients with sole +9 was not reached and in those with sole del(13q), sole del(20q), normal karyotype, complex abnormalities and sole +8 was 112, 108, 80, 37 and 27 months, respectively, while it was 46 months for patients with other cytogenetic abnormalities (p = 0.01). Accordingly, sole abnormalities of +9, del(20q) and del(13q) were categorized as being favorable (n = 35) and complex abnormalities and sole +8 as unfavorable (n = 20); the respective median survivals were 112 and 34 months (p=0.002; Figure). Multivariable analysis confirmed the IPSS-independent prognostic value of cytogenetic risk categorization and the intra-IPSS risk prognostic distinction was most apparent in the int-1 group: median survival was 35 and 81 months in the presence of unfavorable or favorable cytogenetic markers, respectively (p=0.0009; Figure).

Conclusion:
The current study identifies sole +9, along with del(13q) and del(20q), as favorable and sole +8, along with complex abnormalities, as unfavorable cytogenetic markers of prognosis in PMF. Cytogenetic risk categorization in PMF has an IPSS-independent prognostic value that is important in patient selection for specific therapy.

Disclosures:
No relevant conflicts of interest to declare.
Clinical and Biological Implications of Hepatitis C Virus Positivity in Waldenstrom's Macroglobulinemia Patients.
Authors: Tedeschi Alessandra , Vismara Eleonora , Varettoni Marzia , Greco Antonino , Ricci Francesca , Basilico Claudia Maria , Ravelli Erika , Rusconi Chiara , Nichelatti Michele , Montillo Marco , Lazzarino Mario , Morra Enrica 
Published: October 2019

Abstract
Abstract 2934
Poster Board II-910

Background:
hepatitis C virus (HCV) infection has been associated with increased risk of developing B-cell lymphoprolipherative disorders through chronic immune stimulation. Discordant data have been reported about the prevalence of HCV infection in patients with Waldenström's Macroglobulinemia (WM) and the putative role of HCV in lymphomagenesis of this non-Hodgkin Lymphoma subtype remains controversial.

Aim:
the current retrospective study was conducted to assess the impact of this infection itself in the clinical and biological features and outcome among WM patients as compared with those with HCV negative WM.

Patients and methods:
we analyzed 140 WM patients with tested anti-HCV antibody (HCV-Ab). HCV-Ab positivity was detected in 21 cases (15%).
Clinical characteristics of patients at diagnosis of WM are reported in the table below.

Results:
HCV positivity was correlated to lower counts of platelets, neutrophil granulocytes, haemoglobin and with presence of cryoglobulins or autoantibodies and splenomegaly. Interestingly we even found a strong link between the presence of HCV and serum parameters of tumor burden such as beta-2 microglobulin (B2-M) and lactate dehydrogenase (LDH).
Furthermore we did not reveal any outcome implications in terms of disease progression needing treatment, time from diagnosis to first therapy, overall survival between HCV- and HCV+ patients.
Overall, 88 patients (63%) received treatment for disease progression with schedules including Rituximab in 46 cases (52% of treated patients). Rituximab was administered even in HCV-RNA positive patients associated to Cyclophosphamide and Fludarabine and this did not translate in hepatitis development. HCV-RNA was strictly monitored during immunotherapy and we did not observe any significant flair.

Conclusions:
in our series of patients HCV infection does not seem to affect clinical outcome of disease. Moreover, in our experience patients with documented infection can receive the same schedule of treatment including intensive chemotherapy even with monoclonal antibodies without development of further toxicity.

Disclosures:
No relevant conflicts of interest to declare.
P-ERK1/2 Is a Predictive Factor of Response to ESA Treatment in Myelodysplastic Syndromes.
Authors: Frisan Emilie , Pawlikowska Patrycja , Pierre-Eugène Cécile , Bardet Valérie , Gibault Laure , Viallon Vivian , Kosmider Olivier , Verdier Frederique , Park Sophie , Kuhnowsky Frédérique , Guesnu Martine , Lacombe Catherine , Mayeux Patrick , Dreyfus Francois , Porteu Francoise , Fontenay Michaela 
Published: October 2019

Abstract
Abstract 294
Endogenous serum erythropoietin (sEPO) less than 500UI/L and a transfusion requirement lower than 2 units per month are the best predictive factors for response to treatment by erythropoiesis-stimulating agents (ESA) in low/int-1 myelodysplastic syndromes (MDS). However, the highest response rate hardly reaches 60% suggesting that other factors may influence the response. To investigate the biological signature of response to ESA, we enrolled 100 low/int-1 MDS patients in a prospective study of erythropoiesis at diagnosis before they were treated with ESA. According to the IWG 2006 criteria, 43 patients were non-responders. These patients had significantly higher serum EPO level, higher number of transfusion per month, and lower number of bone marrow-deriving BFU-E and CFU-E than responders. Analysis of CD34+-deriving erythroid progenitors by in vitro liquid culture, demonstrated that all MDS patients (n=54) had an increased apoptosis and a delayed expression of erythroid marker, glycophorin A (GPA). A collapse of EPO-induced DNA synthesis was observed in non-responders, while EPO-dependent erythroid cell differentiation and survival to Fas-induced apoptosis was equivalent in the two groups. Thus, non-responders exhibited an early and isolated default in EPO-induced cell proliferation, suggesting a defect in EPO-R signaling. Immunofluorescence to p-ERK1/2 before and after EPO-R stimulation in immature erythroblasts was negative in 6/8 non-responders, and positive in all 11 responders. Immunohistochemistry to p-ERK1/2 on bone marrow biopsies in 5 non-responders was negative and positive in immature cells in 4 responders. By flow cytometry, p-ERK1/2 expression in the CD71+/GPA− bone marrow cell fraction corresponding to immature erythroblasts (n=30) was significantly lower in non-responders (n=16) than in responders (n=14; Wilcoxon-test: p<0.0001). Receiver operator curve (ROC) analysis of the flow cytometry test demonstrated a good predictive value for the response to ESA with a 0.96 area under the curve (AUC) [95%CI: 0.89 – 1.00]. ROC were also constructed for BFU-E number, serum EPO level, and number of transfusion per month and the AUC were computed. p-ERK1/2 was equivalent to BFU-E and superior to serum EPO level or number of transfusion in predicting the response to ESA. Although requiring validation in a larger cohort, these results suggest that p-ERK1/2 is a ready tool available for the prediction of response to ESA in MDS patients.

Disclosures:
No relevant conflicts of interest to declare.
Genomic and Transcriptomic Analyses Revealed Differences and Similarities Between T-Lbl and T-ALL .
Authors: Mussolin Lara , Basso Katia , Lettieri Antonella , Brahmachary Manisha , Cazzaniga Giovanni , Califano Andrea , Lim Wei-Keat , Basso Giuseppe , Biondi Andrea , Rosolen Angelo 
Published: October 2019

Abstract
Abstract 2943
Poster Board II-919

Introduction:
T-cell acute lymphoblastic leukemia (T-ALL) and lymphoma (T-LBL) share common morphologic and immunophenotypic features and are treated with similar therapeutic approaches. Nonetheless, they show distinct clinical presentations suggesting that they may represent two different biological entities. In order to gain insights into the biological characteristics of these T-cell malignancies we applied genomic and transcriptomic approaches on residual diagnostic specimens from pediatric patients affected by T-ALL or T-LBL.

Patients and methods:
Genome-wide gene expression profiling (HG-U133Plus2.0, Affymetrix) was performed for 20 patients affected by T-LBL and 10 patients affected by T-ALL. In order to control for normal cells contamination present in the nodal biopsies (T-LBL) and bone marrow aspirates (T-ALL), we used gene expression profiles of B-cell lymphoblastic lymphoma and common (CD10+) lymphoblastic leukemia, respectively.

Results:
Genes differentially expressed in nodal versus bone marrow-derived samples were subtracted from the T-LBL versus T-ALL signature allowing the identification of a subset of genes able to discriminate the two T-cell malignancies regardless of their localization. This gene signature includes genes involved in chemotactic response, cell adhesion and angiogenesis which may play a role in the different tumor cell localization. Indeed, genes involved in promoting angiogenesis, invasion and nodal localization were up-regulated in T-LBL. Copy number analysis was performed using single nucleotide polymorphism (SNP) arrays (Human Mapping 100K arrays, Affymetrix) on a subset of the samples (9 T-ALL and 9 T-LBL) analyzed by gene expression profiling. This analysis detected approximately 200 genetic loci recurrently affected by copy number alterations in T-ALL and/or T-LBL. The most common aberration was the 9p21.3 deletion which includes CDKN2A/B. Consistent with previous reports amplifications involving MYB were identified in two cases of T-ALL. Although most aberrations were commonly found in both entities several were recurrently detected in T-LBL but not in T-ALL and vice versa.

Conclusion:
Taken together these results suggest that T-LBL and T-ALL share a large fraction of their biological features; nevertheless each malignancy displays also a unique pattern of genetic lesions and specific gene expression signatures, which may contribute to the understanding of the distinct evolution of these T-cell malignancies.

Disclosures:
No relevant conflicts of interest to declare.
Differential Expression of Mirna* Species in Cancer and the Contribution of MiR-223* to the Development of Acute Myeloid Leukemia.
Authors: Kuchenbauer Florian , Mah Sarah M , McPherson Andrew , Heuser Michael , Argiropolous Bob , Morin Ryan , Berg Tobias , Lai David , Muranyi Andrew L , Hogge Donna E. , Ruschmann Jens , Starczynowski Daniel T. , Karsan Aly , O'Connor Michael , Eaves Connie J. , Watahiki Akira , Wang Yuzhuo , Aparicio Samuel , Ganser Arnold , Krauter Juergen , Johnnidis Jonathan , Marra Marco , Carmago Fernando , Humphries R. Keith 
Published: October 2019

Abstract
Abstract 2960
Poster Board II-936
Processing of the pre-miRNA through Dicer1 generates a miRNA duplex, consisting of a miRNA and miRNA* strand. While the functional roles of miRNAs are now well established, the potential roles of miRNA* species remain unclear. However, recent evidence suggests that the star strand of some miRNAs can be abundant and enter the RISC complex. Since the abundance of miRNA*s has not been comprehensively assessed in mammals and we took advantage of 10 deep sequencing libraries from a variety of human and murine cells to determine the most abundant complementary strand for non-annotated miRNA*s. We then calculated the ratio of miRNA/miRNA* for each miRNA duplex. In contrast to previous assumptions that one strand is highly dominant, we found that approximately 50% of the investigated miRNA duplexes exhibit high ratios with a dominating strand (ratio >100), 20% have intermediate ratios (ratio between 100-10) and a remarkable 10% show low ratios (ratio <10), indicating comparable expression of both strands. In addition, we found that ∼10% of all miRNA/miRNA* duplexes display inverse ratios (ratio<1), indicating incorrect annotation in miRBase. Comparing miRNA/miRNA* ratios across the miRNA sequence libraries revealed that most ratios remain constant across tissues and species. This could possibly allow for a novel classification of miRNAs into a-duplexes, miRNAs duplexes with a dominant strand and b-duplexes with both strands being abundant. However, certain ratios were highly variable across the libraries examined as exemplified for the ratio of miR-223/miR-223* which ranged from 0.11 (317:2684 read counts) to 19.6 (13006:660 read counts) in murine and human leukemia cell lines. Bioinformatics analysis on predicted miR-223* targets showed an enrichment for cancer associated genes (p<0.05), suggesting a tumor suppressor-like role for miR-223. Consistent with this, an analysis of samples from 94 AML patients with normal karyotype revealed an inverse correlation of miR-223* with CD34 expression (p=0.018), a negative prognostic marker in AML. In addition, in vitro experiments with mutated miR-223 and miR-223* constructs revealed regulatory potential for miR-223* in myeloid progenitor cells.
Taken together, we propose a new classification for miRNA duplexes and provide evidence for a possible role a miRNA* in the development of acute myeloid leukemia.

Disclosures:
No relevant conflicts of interest to declare.
Drug Rediscovery: Glybenclamide Exhibits Thromboxane Receptor-Dependent Antithrombotic Activity.
Authors: Ting Harold J. , Murray Wallace J. , Khasawneh Fadi T. 
Published: October 2019

Abstract
Abstract 2994
Poster Board II-971
While proper platelet function is a vital component of hemostasis, inappropriate activation of platelets contributes to occlusive disorders such as myocardial infarction, and stroke. One pathway for platelet activation involves the synthesis of the lipid mediator thromboxane A2 (TXA2), which acts by binding to its seven-transmembrane receptor (abbreviated as TPR). Although this signaling pathway participates in the genesis of thrombosis, currently, there are no TPR antagonists that are available for clinical use; and aspirin remains the sole agent targeting this pathway. However, since aspirin is associated with multiple adverse effects, there is still considerable interest in developing TPR antagonists. To this end, we took the “drug rediscovery” approach to identify TPR antagonists. Since the sulfonylurea glybenclamide appeared to possess most of the pharmacophores known to exist in the TPR antagonist SQ29,548, we predicted it would interact with TPRs (and exhibit antiplatelet/antithrombotic activity). It was found that glybenclamide: 1) inhibited human platelet aggregation induced by the TPR agonist U46619 (1μM) and the TXA2 precursor arachidonic acid (0.5mM), concentration-dependently (1-10μM); 2) displaced SQ29,548 from its binding sites; 3) lacked any detectable effects on aggregation stimulated by 15μM ADP, or the thrombin receptor activating-peptide 4 (40μM); 4) failed to raise cAMP levels; 5) selectively (at 10mg/kg) blocked mouse TPR-mediated aggregation, under ex vivo settings; 6) prolonged (at 10mg/kg) the tail bleeding time in mice; and 6) prolonged (at 10mg/kg) the time for occlusion in a mouse carotid artery thrombosis model. Taken together, these findings indicate that glybenclamide exerts inhibitory effects on platelet function by interacting with TPR, and exhibits antithrombotic activity. Thus glybenclamide, or a rationally designed derivative, has the potential to be applied in the management of thrombotic disorders.

Disclosures:
No relevant conflicts of interest to declare.