bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decitabine Is Effective In Patients with Myelodysplastic Syndromes Who Failed Prior Intensive Regimen: No Negative Impact of Prior Therapy
Authors: Jabbour Elias , Kantarjian Hagop , Kadia Tapan , Borthakur Gautam , Cortes Jorge E. , Cornelison A. Megan , Ravandi Farhad , Garcia-Manero Guillermo 
Published: October 2019

Abstract
Abstract 2936

Background:
Decitabine is a hypomethylating agent (HMA) with demonstrated activity and an acceptable safety profile for the treatment of all FAB subtypes of myelodysplastic syndromes (MDS). A retrospective analysis was conducted to determine the effect of prior MDS treatment on overall response rate (ORR), duration of response, time to response, and overall survival (OS).

Methods:
Of 188 patients, 54 had prior MDS treatment consisting of cytotoxic chemotherapy (n=31), immunomodulators (n=21), stem cell transplant (n=4), monoclonal antibodies (n=2), oblimersen (n=1), or HMAs (n=1) were identified from two clinical trials with decitabine (Phase III, 3-day and Phase II, 5-day dosing studies). Patients were stratified on the basis of those who had received prior treatment (PT, n=54) for MDS and those who had not (NPT, n=134). Descriptive statistics were used to quantify the differences between the two groups for baseline characteristics, response rates (based on IWG 2006 criteria), safety and survival data.

Results:
Baseline characteristics showed the PT group had a longer time from diagnosis; the NPT group had a greater percentage of patients with High risk and Int-2 IPSS scores. There were differences noted in the baseline NPT group (5-day dosing only), with more patients with FAB classification of RAEB and RAEB-t (n=45), whereas the baseline PT group had a greater number of CMML patients (n=8). Objective response rate (ORR), overall improvement rate (OIR) and median survival were greater in NPT patients with no significant difference observed between the groups (Table 1). Patients with PT had a shorter duration of improvement (median 208 days) vs. the NPT group (median 296 days, p=NS) for the 5-day dosing study.

Conclusions:
Decitabine is active in patients with MDS with low rate of side effects. Prior therapy with intensive regimens have no impact on response to decitabine and such patients should be considered for hypomethylating therapy.

Disclosures:
Jabbour: Eisai Inc.: Editorial and statistical support, Honoraria. Kantarjian:Novartis: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy. Borthakur:Eisai Inc.: Research Funding. Cortes:Novartis: Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding. Ravandi:Eisai Inc.: Research Funding; Eisai Inc.: Honoraria.
Incidence of Plasma Cell Myeloma In Ethnic Chinese In British Columbia, a 30-Year Survey From 1975–2004
Authors: Chan Vicky W. , Song Kevin , Mang Oscar , Ip Dennis , Au Wing Y 
Published: October 2019

Abstract
Abstract 2956

Introduction:
The incidence of plasma cell myeloma (PCM) in East Asian population is known to be 3–4 times lower than that in Caucasians. This may be due to genetic or environmental factors. Migrant studies may separate these factors to some extent by determining whether the disease incidence follows the parent or destination prevalence. British Columbia (BC) has a large population of Chinese migrants and therefore, it is an ideal population for migrant studies. Hong Kong (HK) is chosen as the comparison population because it has meticulous census data and a population-based cancer registry.

Methods:
Computerized records of all PCM cases diagnosed from 1975 to 2004 were retrieved from the British Columbia Cancer Agency (BCCA) and the Hong Kong Cancer Registry (HKCR). Cases with Chinese ethnicity in BC were identified by surname using a previously validated methodology and verified from electronic charts. Age distribution of HK, BC and BC Chinese populations for consecutive 5-secular year (yr.) periods were obtained from census departments from the respective governments. The crude incidence rates of PCM were calculated and 95% CI were determined using normal approximation of Poisson distribution. Projected PCM incidence rates in BC Chinese using HK and BC models were calculated and standard incidence ratios (SIR) estimated.

Results:
There was a steady increase in PCM from 1975 to 2004: from 42 to 159 cases/yr. in HK and from 86 to 207 cases/yr. in BC. This is likely due to population growth and aging. The proportion of population with age >65 grew from 5.4% to 11.2% in HK and from 9.7% to 13.2% in BC. From 1975–2004, a total of 106 cases of BC Chinese PCM were identified, increasing from 0.4 to 8 cases/yr. The BC Chinese population grew from 0.07 to 0.37 million, while the elderly subgroup (age >65) grew from 7.9% to 12.9%. Age specific mean 30-year crude incidence/100,000 person-years and 95% CI in the 3 cohorts were determined (Table 1). The standardized incidence ratio (SIR) of PCM in BC Chinese from 1975–2004 was 0.83 (95% CI 0.68–1.00) when compared to HK and 0.44 (0.36-0.53) when compared to the BC population. Cumulative SIRs of PCM in BC Chinese when compared to BC population remained low for incremental 5-year from 1975–2004 (Table 2).

Conclusion:
The incidence of PCM in ethnic Chinese in British Columbia is lower compared to the Caucasian counterparts, but similar to the incidence seen in HK. The trend is apparent in all age groups over 45 years old. This observation suggests a strong genetic predisposition in the development of PCM.

Disclosures:
No relevant conflicts of interest to declare.
High Resolution Genome-Wide Analyses Revealed That Bortezomib Selects a Prediagnosis Clone In Relapsed Patients with Multiple Myeloma
Authors: Magrangeas Florence , Avet-Loiseau Hervé , Decaux Olivier , Gouraud Wilfried , Harousseau jean Luc , Anderson Kenneth C. , Moreau Philippe , Munshi Nikhil C. , Minvielle Stephane 
Published: October 2019

Abstract
Abstract 2960
Despite advances and significant improvement in survival, multiple myeloma (MM) remains incurable and nearly all patients relapse after treatment. In order to gain insights into the genomic lesions associated with acquisition of drug resistance and progression of disease, we performed high resolution genome-wide single nucleotide polymorphism and copy number analyses on matched diagnostic and relapse samples from 24 MM patients either treated with proteasome inhibitor (bortezomib)-based induction regimen (n=12) or conventional chemotherapeutic agents (n= 12). All relapse samples have a clear relationship to the diagnosis clone. The vast majority of patients (92%) acquired additional copy number abnormalities (CNAs) or uniparental disomy (UPD) at relapse or exhibited change in the pattern of lesions present at diagnosis. Of these, 45% acquired new lesions and 41% both acquired new lesions and lost lesions present at diagnosis. Remarkably, loss of lesions at relapse was significantly associated with initial bortezomib treatment (8 out of 12 versus 1 out of 12; P = 0.009). Moreover, in 75% of the bortezomib-treated MM, the lesions lost at relapse included either UPD or deletion providing direct evidences that the relapse clone arose from a common prediagnosis clone present as a minor population at diagnosis that acquired additional abnormalities before emerging as the relapse clone. These results suggest that resistance to novel therapeutic agent known to target MM cells in the bone marrow milieu preferentially goes through with selection of minor prediagnosis clone while escape to conventional chemotherapeutic agents is almost exclusively associated with clonal evolution from diagnosis clone. These data support the proposal to combine several anti-myeloma drug upfront in order to obtain long-term remissions.

Disclosures:
Anderson: Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Munshi:Millennium Pharmaceuticals: Honoraria, Speakers Bureau.
Improved Myeloma Targeting by Combination of the Human Anti-CD38 Antibody Daratumumab with Lenalidomide and Bortezomib
Authors: van der Veer Michael S. , de Weers Michel , van Kessel Berris , Bakker Joost M , Wittebol Shulamiet , Parren Paul W.H.I. , Lokhorst Henk M , Mutis Tuna 
Published: October 2019

Abstract
Abstract 3030
Although multiple myeloma (MM) is considered an incurable malignancy of antibody-producing clonal plasma cells, over the past decade significant progress has been made in MM treatment by the availability of novel immunomodulating agents such as lenalidomide (LEN) and bortezomib (BORT). We are currently exploring the possibility to further improve MM therapy by combining LEN and BORT with novel agents, such as daratumumab (DARA), a human antibody directed against CD38 which mediates MM cell lysis via ADCC (antibody dependent cellular cytotoxicity), CDC (complement dependent cytotoxicity) and apoptosis. Our initial in vitro work show significantly improved MM cell killing by combined DARA with LEN treatment. We now investigated whether further improvement of this combination therapy is possible by addition of BORT. In ex vivo assays, which allow us to address killing directly in BM-MNC isolated from MM patients, we demonstrate that the DARA+LEN+BORT combination significantly exceeds the effectiveness of LEN+BORT treatment (P<0.001). Remarkably, triple therapy was also very effective, even when there was little or no response against LEN+BORT (P=0.0001). In other assays we further mimicked the in vivo conditions by incubating BM-MNC not only with LEN, BORT and DARA for 48 hours but also by adding complement. Addition of complement resulted in substantial enhancement of DARA-mediated MM tumor cell killing. This killing could not be further improved by addition of LEN and BORT. In conclusion, we demonstrate that addition of DARA to a LEN+BORT treatment regime increases overall clearance of MM cells ex vivo, suggesting that patients, even when not responding to LEN+BORT treatment, might benefit from a DARA+LEN+BORT combination therapy.

Disclosures:
Veer: GenMab, Utrecht, NL: Research Funding. Weers:Genmab: Employment. Bakker:GenMab, Utrecht, Netherlands: Employment. Parren:Genmab: Employment. Lokhorst:GenMab, Utrecht,NL: Research Funding. Mutis:GenMab, Utrecht, NL: Research Funding.
Microenvironment-Mediated Bim Down-Regulation through Induction of Microrna-181a Protects Cells From Apoptosis In Mantle-Cell and Other Non-Hodgkin B-Cell Lymphomas
Authors: Lwin Tint , Lin Jian-Hong , Choi Yong Sung , Zhang Xinwei , Moscinski Lynn , Wright Kenneth , Sotomayor Eduardo M. , Dalton William , Tao Jianguo 
Published: October 2019

Abstract
Abstract 3118
Follicular dendritic cells (FDCs), essential components of the lymph node microenvironment, regulate and support B lymphocyte differentiation, survival, and lymphoma progression. Here, we demonstrated that adhesion of mantle cell and other non-Hodgkin lymphoma cells to FDCs reduced cell apoptosis, associated with decreased levels of Bim, a pro-apoptotic protein. Bim down-regulation was epigenetically regulated via up-regulation of microRNA-181a (miR-181a). miR-181a overexpression decreased, whereas miR-181a inhibition increased Bim levels by directly targeting Bim. Furthermore, we found that cell adhesion-up-regulated miR-181a contributes to FDC-mediated cell survival through Bim down-regulation, implicating miR-181a as an upstream effector of the Bim-apoptosis signaling pathway. miR-181a inhibition and Bim up-regulation significantly suppressed FDC-mediated protection against apoptosis in lymphoma cell lines and primary lymphoma cells. Thus, FDCs protect B-cell lymphoma cells against apoptosis, in part through activation of a miR-181a-dependent mechanism involving down-regulation of Bim expression. We demonstrate, for the first time, that cell-cell contact controls tumor cell survival and apoptosis via microRNA in mantle cell and other non-Hodgkin lymphomas. Regulation of microRNAs by B-cell-FDC interaction may support B-cell survival, representing a novel molecular mechanism for cell-adhesion mediated drug resistance (CAM-DR) and a potential therapeutic target in B-cell lymphomas.

Disclosures:
No relevant conflicts of interest to declare.
Systemic Relapses In Primary CNS Lymphoma (PCNSL) - Unexpected Clonal Diversity
Authors: Fischer Lars , Hummel Michael , Korfel Agnieszka , Lenze Dido , Jahnke Kristoph , Kiewe Philipp , Weller Michael , Thiel Eckhard 
Published: October 2019

Abstract
Abstract 3125

Background:
PCNSL is a rare form of extranodal diffuse large B-cell lymphoma (DLBCL). Relapses after initial therapy are usually within the CNS. Systemic relapses (SR) have been reported only occasionally. We conducted a systemic analysis of immunocompetent patients with PCNSL und SR using both clinical data and tumor samples at first diagnosis and SR to determine clonal relatedness.

Methods:
Records of patients included in a multicenter therapy trial (n=411) and all PCNSL patients treated at our institution outside the trial after 1993 (n=39) were reviewed for SR. PCR analysis of the rearranged Ig heavy-chain (IgH) and light-chain (IgL) genes was performed according to the BIOMED-2 protocol.

Result:
All patients had received high-dose methotrexate based chemotherapy with our without adjuvant whole brain irradiation as first line therapy. Of 450 patients 26 (5.8%) were identified with SR. Median time from PCNSL diagnosis to SR was 14.5 months (range 2–61). SR was extranodal in 22 (85%) patients: testicular n=3, gastric n=3, mamma n=3, liver n=2, bone/bone marrow n=3, intestinal n=1, [sub-]cutaneous/muscular n=5, pancreatic n=1, pulmonary n=1. Four patients had concomitant CNS relapse. Median overall survival from diagnosis was 38 months, from SR 9.8 months. Causes of death were SR in 13, CNS relapse in 3, toxicity of chemotherapy in 3 and unknown in 1 patients; 6 patients were alive at last follow up. All 26 patients initially had DLBCL. SR was biopsied in 20 patients: 19 had DLBCL, 1 a Burkitt-like DLBCL. DNA of 7 patients was sufficient for PCR analysis. The same clone was found in the CNS and SR in 4 patients, in 3 patients the clones were different. Clonally related SR occurred after 4, 8, 14 and 25 months; the unrelated SR after 30, 35 and 36 moths.PCR products in 2 of 4 clonally related samples were suitable for sequencing. One case exhibited 6 identical somatic mutations in both biopsies. The second case harbored 35 mutations in the CNS sample and 45 in the SR sample. Here 26 mutations were identical in both samples, 3 involved different nucleosides, 16 were only present in SR, and 6 mutations exclusively present in the CNS sample.

Conclusion:
SR is a rare and frequently fatal complication in PCNSL. The localization of SR is predominantly extranodal. A proportion of SR is not clonally related to the primary tumor and then most likely represent a secondary lymphoma. In clonally related SR the presence of somatic mutations unique to the CNS tumor and the SR might be explained by a common ancestor, whose localization however remains unknown.

Disclosures:
No relevant conflicts of interest to declare.
Growth Factor Independent-1 (Gfi1) Is Critically Required for T-Cell Acute Lymphoblastic Leukemia (T-ALL) Tumor Initiation and Maintenance
Authors: Phelan James D. , Khandanpour Cyrus , Horman Shane , Gaudreau Marie-Claude , Zhu Jinfang , Paul William E , Dührsen Ulrich , Grimes H. Leighton , Moroy Tarik 
Published: October 2019

Abstract
Abstract 3156
T cell acute lymphoblastic leukemia (T-ALL) is one of the most common childhood cancers associated with mutations in NOTCH1. The Growth factor independent-1 (Gfi1) transcriptional repressor gene was originally discovered as a common target of Moloney murine leukemia virus (MMLV) proviral insertion in murine T-ALL. In fact, the Gfi1 locus is the most frequently activated gene in MMLV-induced T cell leukemia. Therefore, we investigated whether the most commonly activated gene in MMLV-induced murine T-ALL, Gfi1, could collaborate with the most commonly activated gene in human T-ALL, NOTCH1. Here, we show that GFI1 expression is associated with Notch signaling in human T-ALL (p'0.0003). Functionally, Gfi1 collaborates with Notch-induced murine T-ALL by accelerating an already rapid disease model (p=0.03) without altering the lymphoblastic nature of the disease. Furthermore, inducible deletion of Gfi1 is counter-selected in both Notch-driven retroviral and transgenic mouse models of T-ALL; whereas, constitutive absence of Gfi1 completely prevents transgenic Notch-induced T-ALL (p≤0.04). However, T-ALL tumors can form in Gfi1-/- animals using either ENU-mutagenesis or MMLV-infection, yet tumor formation is delayed (p≤0.02, p≤0.03 respectively). This suggests that Gfi1 deletion does not prevent the formation of the T-ALL initiating cell and that Gfi1 might be absolutely required for Notch-induced T-ALL. Most striking is that Gfi1 is required for T-ALL maintenance in vitro and in vivo. Using three separate Tal1-initiated murine T-ALL cell lines, the overexpression of the Gfi1 dominant-negative, Gfi1N382S, was quickly and completely counter-selected. As Gfi1 has previously been found to regulate pro-apoptotic genes in T cells, we attempted to rescue the above loss of function phenotype by overexpressing the anti-apoptotic factor Bcl2. Notably, counter-selection of Gfi1N382 is not observed or is significantly delayed in all three cell lines. In vivo, inducible deletion of Gfi1 leads to both mutagen- or Notch-induced tumor regression as measured by ultrasound. In fact, levels of Gfi1 expression directly correlate to tumor regression and disease free survival of T-ALL. Finally, targeting Gfi1 enhances the efficacy of radiation therapy and bone marrow transplantation. Deletion of Gfi1 sensitizes T-ALL tumors and T cells to p53-dependent apoptosis after exposure to DNA-damaging agents such as radiation, Etoposide or Daunorubicin by de-repression of the pro-apoptotic Gfi1 target gene Bax. These data extend the role of Gfi1 to human T-ALL and suggest that T-ALL is dependent upon Gfi1 to repress pro-apoptotic genes for tumor survival, ultimately highlighting a new therapeutic target in the fight against lymphoid malignancies.

Disclosures:
No relevant conflicts of interest to declare.
Prevalence of Venous Thromboembolism In Patients with Secondary Polycythemia
Authors: Nadeem Omar , Gui Jiang , Ornstein Deborah 
Published: October 2019

Abstract
Abstract 3164

Background:
Polycythemia vera is associated with an increased risk for venous thromboembolism (VTE). Although phlebotomy is employed as an adjunct to treatment with hydroxyurea and/or aspirin for VTE risk reduction, emerging data suggest that hematocrit is less of a determinant of VTE risk than leukocyte count and JAK2 V617F gene mutation allele burden. The role of secondary polycythemia as a risk factor for VTE is unknown, but phlebotomy for thrombosis risk reduction is frequently practiced. Based on the polycythemia vera model, however, we hypothesize that secondary polycythemia does not increase VTE risk. The purpose of this study was to determine the prevalence of VTE in patients with secondary polycythemia and to investigate the factors associated with VTE in this population.

Methods:
We performed a case control study that included patients admitted to Dartmouth-Hitchcock Medical Center with a diagnosis of chronic obstructive pulmonary disease (COPD) and a hematocrit greater than or equal to 50% from August 2004 to July 2009. The controls were matched for age and sex and carried a diagnosis of chronic obstructive pulmonary disease (COPD) without evidence of secondary polycythemia. Data were collected on body mass index (BMI), VTE history, comorbid conditions, thrombophilia and smoking history. Clinical characteristics of patients with and without secondary polycythemia were analyzed using chi square and t-test to evaluate for significant differences in the two populations.

Results:
Eighty-six patients with secondary polycythemia and 86 controls were included in the study. The mean hematocrit was 53.5% in the case group and 43.7% in the control group (p=<0.005). Among cases, a history of VTE was documented in 17/86 (19.8%), 10 of which (58.8%) were judged to be idiopathic. In the control group, VTE was documented in 12/86 (14%), 4 of which (33.3%) were judged to be idiopathic. There was no statistically significant difference in the number of total (OR=1.52, p=0.42) or idiopathic (OR=2.7; p=0.16) VTE between cases and controls, respectively. There were no statistically significant differences noted in age, sex, body mass index, presence of diabetes mellitus, smoking history or the presence of malignancy in the two groups. Patients with VTE in both groups had higher BMI, however, compared to patients without VTE.

Conclusions:
We did not observe an increased prevalence of VTE in patients with secondary polycythemia compared to age- and sex-matched controls. Our findings suggest that the high prevalence of VTE observed in patients with secondary polycythemia is more likely related to known risk factors such as obesity rather than hyperviscosity due to increased cell mass. The role of phlebotomy for VTE risk reduction in patients with secondary polycythemia is therefore questionable.

Disclosures:
No relevant conflicts of interest to declare.
Is Higher Soluble P-Selectin a Risk Factor for Chronic Venous Insufficiency?
Authors: Bryan Locke J , Callas Peter , Criqui Michael , Cushman Mary 
Published: October 2019

Abstract
Abstract 3166

Background:
Chronic venous insufficiency (CVI) represents a spectrum of disease characterized by impaired venous return. Deep venous thrombosis (DVT) when complicated by post thrombotic syndrome (PTS) is a well established etiology for CVI. P-selectin is a cell adhesion molecule involved in thrombus formation; higher levels are related to DVT risk. Thus, P-selectin may play a role in CVI pathophysiology.

Objective:
We evaluated whether higher levels of soluble P-selectin are a risk factor for CVI.

Methods:
Data were collected from the San Diego Population Study, an established cohort of 2,404 men and women, in whom CVI was evaluated by symptoms, physical examination, and duplex venous ultrasound. A case-control study was conducted within the cohort to analyze the association of P-selectin with risk and severity of CVI. 352 controls without venous abnormalities were matched by age, race, and sex to 352 cases. Cases consisted of four groups with increasing severity of CVI based on clinical and imaging characteristics. Soluble P-selectin was measured in cases and controls using a commercial immunoassay. Multivariable models were used to determine associations of P-selectin with CVI, controlling for potential confounders.

Results:
P-selectin levels did not differ by CVI risk factors including age, sex, race, body mass index (BMI), smoking status, diabetes, prior DVT, venous surgery, and history of cancer (not shown). Overall, P-selectin was not associated with risk of CVI. However, comparing the two most severe case groups to controls, the age, sex, and race adjusted odds ratios (ORs) of CVI for P-selectin in the top two versus bottom tertiles were increased at 1.4 and 2.3, respectively (see table), with the top tertile OR being statistically significant. The association of P-selectin in the top tertile with CVI were slightly weakened with adjustment for BMI, as the case groups with higher P-selectin levels had on average a higher BMI. Successive addition of other risk factors to the model, shown in the table, had no impact on the ORs.

Conclusions:
Higher levels of soluble P-selectin are associated with risk of more severe, but not mild, CVI. This suggests that thrombosis potential or platelet function is important in the pathogenesis of this disease.

Disclosures:
No relevant conflicts of interest to declare.