Citations

Abstract Background: Reactive oxygen species cause DNA damage and altered immunologic responses, and have been linked to the development of NHL. Diets rich in fruits and vegetables are excellent sources of antioxidants, and vitamins C, E, polyphenols, and carotenoids, along with selected micronutrients such as zinc are thought to be responsible for most of the antioxidant activity in foods. We evaluated the hypothesis that vegetables, fruits and nutrients involved in antioxidant activity would protect against developing NHL. In a secondary analysis, we also assessed heterogeneity of this hypothesis for the most common subtypes of NHL: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), follicular lymphoma, and diffuse large B cell lymphoma (DLBCL). Methods: We evaluated dietary antioxidant intake and NHL risk in a clinic-based study of 416 newly diagnosed NHL cases and 926 frequency-matched controls enrolled at the Mayo Clinic from 2002–2007. Usual diet two years before diagnosis/enrollment was assessed using a self-administered, 128-item food frequency questionnaire. Dietary intake of antioxidants was estimated using the Food Processor SQL system, further supplemented with data from US Department of Agriculture nutrient databases. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI), adjusted for age, sex, residence, and total energy. NHL subtypes were centrally reviewed, and subtype-specific risks were estimated using polychotomous logistic regression. Results: The mean age at diagnosis was 60.8 years for cases and 57% were male; for controls, the mean age at enrollment was 60.8 years and 54% were men. NHL risk was inversely associated with intake of total vegetables (OR for highest compared to lowest quartile, 0.46; 95% CI 0.32–0.68; p-trend<0.001), and specifically green leafy (OR=0.54; 95% CI 0.39–0.76; p-trend<0.001) and cruciferous (OR=0.62; 95% CI 0.43–0.88; p-trend=0.02) vegetables, but not legumes or red/yellow/orange vegetables. There was no association with total fruit intake or intake of citrus fruits in particular. When modeled together, the association for green leafy vegetables was unchanged while the association for cruciferous vegetables attenuated (OR=0.75; 95% CI 0.50–1.13; p-trend=0.3). Higher intake of total vitamin A (OR=0.60; 95% CI 0.41–0.88; p-trend<0.001) and vitamin E (OR=0.53; 95% CI 0.34–0.82; p-trend<0.001), but not vitamin C, were associated with lower NHL risk. For vitamin A, there was no association with preformed Vitamin A, but there was an inverse association with beta-carotene (OR=0.56; 95% CI 0.39–0.81; p-trend<0.001); only weak inverse associations were observed for other carotenoids (lutein/zeaxanthin, lycopene, and cryptoxanthin). When modeled together, the inverse association for vitamin E was unchanged while the association for beta-carotene attenuated. For micronutrients, there were inverse associations for manganese (OR=0.60; 95% CI 0.40–0.90; p-trend=0.02), selenium (OR=0.47; 95% CI 0.27–0.80; p-trend=0.01), and zinc (OR=0.46; 95% CI 0.27–0.80; p-trend<0.001) but not copper; when modeled simultaneously, both manganese (p-trend=0.03) and zinc (p-trend=0.02) remained significantly and inversely associated with NHL risk. Further adjustment for education, family history of NHL, smoking, alcohol use, and body mass index did not alter these results. There was no NHL subtype heterogeneity for the associations with total vegetables, green leafy vegetables or vitamin E, while inverse associations were not observed for manganese and follicular lymphoma or zinc and CLL/SLL. Conclusion: Higher intakes of vegetables, particularly green leafy vegetables, vitamin E, manganese, and zinc were associated with lower risk of NHL. These finding extend a growing literature from case-control and cohort studies that support a protective role of foods and nutrients that function in antioxidant related pathways against development of NHL, and therefore may represent one of the few known modifiable risk factors for this cancer.

Abstract Abstract 3933 Poster Board III-869 Background Non-Hodgkin Lymphoma (NHL) is a malignancy of lymphocytes with few known risk factors identified to date. Members of the BCL2 and caspase gene families are known regulators of programmed cell death in these cells, and the t(14;18)(q32;q21) is the most commonly observed chromosomal translocation in NHL, a somatic event which results in constitutive BCL2 expression and inhibition of apoptosis. Further, recent pooled analyses of three case-control studies reported gene level associations for both BCL2L11 (Cancer Epidemiol Biomarkers Prev 2009;18:1259) and CASP9 (Blood 2009;114:264) with NHL risk. We therefore evaluated the hypothesis that germline variation in genes from the apoptosis pathway is associated with risk of developing NHL. Methods We genotyped 226 single nucleotide polymorphisms (SNPs) within 36 candidate BCL2-family and capsase-family member genes within the apoptosis pathway in a clinic-based study of 441 newly diagnosed NHL cases (within 9 months of first NHL diagnosis) and 475 frequency matched controls from Minnesota, Iowa, and Wisconsin who were seen at the Mayo Clinic from 2002-2005. Tagging SNPs were selected from HapMap for the following candidate genes: BCL2; BCLAF1; BCL2LA1; BCL2L1, 2, 10, 11, 12, 13, 14; BAD; BAX; BAG1, 3, 4, 5; BAK1; BID; BIK; BNIP2, 3; HRK; CASP1 – CASP10; APAF1; BIRC3; AIF1; and DFFB. Genotyping was completed using the ParAllele (now Affymetrix) Immune and Inflammation SNP panel, supplemented with 9 SNPs from a custom Illumina OPA. SNP call rate and per person call rate were >95% for all SNPs evaluated. The most prevalent homozygous genotype was used as the reference group, and each SNP was modeled individually as having a log-additive effect in a logistic regression model adjusted for age, sex, and residence. We used principal components analysis to assess the association with NHL risk at the gene level. Genes at p<0.05 were declared statistically significant, as were SNPs at p<0.05 from significant genes. Results The mean age at diagnosis for cases was 60.1 years, and 58% were male; among controls, the mean age at enrollment into the study was 61.7 years, and 55% were male. The most common NHL subtypes were chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL, 29%), follicular lymphoma (FL, 27%), and diffuse large B-cell lymphoma (DLBCL, 16%). In gene level analyses, BCL2L11 (also know as BIM) (p=0.0019), BLCAF1 (p=0.0097), BAG5 (p=0.026), and CASP9 (p=0.0022) were statistically significant at p<0.05. For BCL2L11, 2 of the 5 tagSNPs (both intronic) were significant at p<0.05 (rs6746608 and rs12613243). Both genotyped BCLAF1 tagSNPs (rs797558 and rs703193, both intronic) were significant, as was the single genotyped BAG5 tagSNP (rs7042474) from the non-coding region interval of an mRNA transcript. Three of the 7 genotyped CASP9 tagSNPs were significant (rs6685648, rs2020902, rs2042370, all intronic). Similar associations (as assessed by ordinal odds ratios) were observed for significant SNPs from BCLAF1, BAG5, BCL2L11 and CASP9 within the subtypes of CLL/SLL, FL, and DLBCL; however, caution is warranted in interpreting the subtype results due to small sample sizes. Conclusions Three genes from the BCL2 family (BCL2L11, BCLAF1, and BAG5) and one gene from the caspase family (CASP9) were associated with risk of NHL. This confirms gene level results for BCL2L11 and CASP9 in NHL overall and suggests a role for additional BCL2 family members in NHL etiology. In addition to extending these results to other populations, investigation of the functional significance of these genes and consideration of their upstream regulators and downstream targets should assist in clarifying the role of this pathway in lymphomagenesis. Furthermore, in the era of targeted therapeutics, identification of genetic variation in the apoptotic pathway may also assist in predicting prognosis as therapies targeting this pathway are developed. Disclosures: No relevant conflicts of interest to declare.

Abstract Introduction: CMML is a clinically heterogeneous myeloid neoplasm hallmarked by the coexistence of dysplastic and proliferative patho-clinical features, which can include cytopenias, constitutional symptoms, splenomegaly, and leukocytosis. However, according to the FAB classification schema, CMML may be differentiated in dysplastic and proliferative subgroups only by the presence of leukocytosis in the latter (WBC ≥13 x 109/L). We hypothesize that incorporation of other clinically discriminating features may yield a more informative CMML stratification system. To address this, we propose three distinct CMML categories and explore their clinical relevance leveraging our existing international CMML database (Padron E et al. Blood Cancer J. 20151). Method: 1622 WHO-defined CMML cases diagnosed between 1973 and 2014 were collected from eight large cancer centres that include up to 80 discrete data elements as previously described1. Cases were placed into three clinically distinct groups and the Pearson Chi-Square test and the Kruskal-Wallis test were applied respectively to compare categorical and continuous characteristics. The Kaplan-Meier (KM) method was used to estimate median OS and the log rank test was used to compare survival curves.Cox models whereapplied to obtain univariate and adjusted hazard ratios. Identification of optimal cut-off values for continuous variable was supported by graphical inspection of martingale residuals from the null Cox model. Statistical analyses were done in SPSS v23 and R v.3.3.0. Results: We propose three categories to delineate clinically distinct CMML subtypes: (1) Myelodysplastic (MD)-CMML: WBC≤10 x 109/L, PB-immature myeloid cells (IMC) = 0%, no splenomegaly (2) MD/MP-CMML: WBC 10-20 x 109/L or WBC ≤10 x 109/L but PB-IMC>0% and/or splenomegaly (3) Myeloproliferative (MP)-CMML: WBC >20 x 109/L. A recursive partitioning approach was used to identify the WBC cut points, with splenomegaly and IMC added to more accurately depict the MPN aspect of CMML. Numbers of patients included in the MD-, MD/MP-, and MP-CMML subcategories were 319 (19.7%), 789 (48.6%) and 514 (31.7%), respectively (Table 1). According to the FAB criteria, the MD/MP group included 521 (66%) MD- (WBC ≤13 x 109/L) and 268 (34%) MP-CMML (WBC>13 x 109/L) patients suggesting that the proposed classification clinically reclassifies FAB-defined CMML. Within the MD/MP group, 344 patients (21.2%) had a WBC <10 x 109/L but with IMC>0% and/or splenomegaly. Comparison of overall survival (OS) among proposed groups demonstrated that this classification schema was capable of discriminating the CMML natural history (Figure 1). In comparison to MD/MP-CMML, the unadjusted OS Hazard Ratio (HR) was 0.60 (95% CI 0.49-0.73) for MD-CMML and 1.57 (95% CI 1.36-1.81) for MP-CMML (p<0.001 for both). This difference was retained after adjusting for BM-Blasts (< vs ≥5%), IPSS or CPSS cytogenetics (High-risk vsInterm/low-risk), and elevated levels of LDH (HR was 0.73 with 95% CI 0.57-0.93, p=0.011 for MD-CMML, and 1.33 with 95% CI 1.12-1.58, p=0.001 for MP-CMML, respectively). We next explored whether each proposed group may have distinct variables that uniquely govern its prognosis. Peripheral blood blasts >5%, RBC- and PLT-transfusion-dependence predicted poor OS only in the MD and MD/MP-subcategories (p<0.005), but had no impact in the MP-CMML. Male gender and elevated LDH were only significantly associated with prognosis in the MD/MP group (p<0.05 and p<0.005, respectively) while absolute lymphocyte count >2.5 x 109/L and absolute monocyte count >10 x109/L were uniquely predictive for shorter survival in the MP-CMML subcategory (p<0.005). Notably, we additionally identified gene mutations that uniquely predicted prognosis in each proposed group (Table 2). Conclusions: We demonstrate that our proposed 3-group clinical classification schema is capable of independently stratifying prognosis. Further, our analysis identified clinical and genetic variables that uniquely govern each group's prognosis, suggesting independent clinical behaviour. Further investigations are warranted to validate these groups. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Kantarjian:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau.

Abstract Introduction: Current therapies for patients with r/r ALL who have had prior allogeneic hematopoietic stem cell transplantation (alloHSCT) have very poor outcomes. Improvements in the therapeutic options available for adult r/r ALL are required. Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct that redirects cytotoxic T cells to lyse CD19-positive B cells. The aim of the present analysis was to characterize a subset of patients with r/r ALL and prior alloHSCT before treatment with blinatumomab from a large confirmatory open-label, single-arm, multicenter phase 2 study (Topp MS et al Lancet Oncol 2015;16(1):57-66). Methods: Eligible patients (≥18 years) had Philadelphia chromosome-negative r/r ALL with 1 of the following negative prognostic factors: primary refractory, first relapse within 12 months of first remission, relapse within 12 months of alloHSCT, or second or greater salvage. Patients with active acute or chronic graft-versus-host disease (GvHD) were excluded. Patients were required to stop all immunosuppressive GvHD therapy within 2 weeks before starting blinatumomab. A total of 189 patients were enrolled and received blinatumomab by continuous intravenous infusion (4 weeks on/2 weeks off) for up to 5 cycles. The primary endpoint was complete remission or complete remission with partial hematologic recovery (CR/CRh) within the first 2 cycles. Secondary endpoints included overall survival (OS), relapse-free survival (RFS), and adverse events (AEs). Results: 64 (34%) patients had received alloHSCT before study enrollment; 10 patients had 2 prior alloHSCTs. Donor types primarily included 29 (45%) matched sibling and 31 (48%) unrelated, with 34 (59%) patients receiving myeloablative conditioning regimens (donor chimerism data were unavailable). Among those with prior alloHSCT, median age (range) was 32 (19-74) years. At baseline, 23 (36%) patients had 1 prior relapse, 24 (38%) had 2 prior relapses, and 17 (27%) had ≥3 prior relapses; 28 (44%) patients had relapsed post-alloHSCT. Of the 55 patients who had received previous salvage therapy, 38 (69%) had received salvage therapy after last alloHSCT and prior to blinatumomab. Median time (range) between the last alloHSCT and subsequent relapse was 6 (1-33) months. Median time from last prior alloHSCT to first dose of blinatumomab was 10 (3-40) months. Nineteen (30%) patients had a history of GvHD, and 42 (66%) had ≥50% bone marrow blasts at start of treatment as assessed by a central laboratory. Patients received blinatumomab for a median of 2 (1-5) cycles. Efficacy data are presented in Table 1. Overall, 45% (29/64; 95% confidence interval [CI], 33-58) of patients achieved CR/CRh within the first 2 cycles, with similar rates of remission also observed in the alloHSCT-naïve (42%; 52/125) group. With a median follow-up of 8.8 months, median (95% CI) OS was 8.4 (4.2-9.4) months for the 64 patients with prior alloHSCT treated with blinatumomab. Of the 29 responders (CR, n=18 and CRh, n=11), 22 (76%) had a minimal residual disease (MRD) response and 19 (66%) achieved a complete MRD response. Median RFS (95% CI) was 6.1 (5.0-7.7) months. 9/29 (31%) responders subsequently underwent another alloHSCT. In total, 56 (88%) patients had grade ≥3 treatment-emergent AEs, with the most frequent including neutropenia (22%), febrile neutropenia (20%), anemia (17%), and thrombocytopenia (14%). Six patients reported treatment-emergent GvHD (two grade ≥ 3) during blinatumomab treatment, 3 of whom had GvHD in skin. Eight patients had fatal treatment-emergent AEs, which included 1 due to gastrointestinal hemorrhage, 1 due to respiratory failure, and 6 due to infection/infestation; 1 of these (candida infection) was considered to be possibly related to treatment by the investigator. Of the subjects who had treatment-emergent fatal AEs, none were in remission at the time of death. Summary: In this heavily pretreated group of patients with r/r ALL and prior alloHSCT, single-agent blinatumomab was able to induce a CR/CRh rate of 45%, with an AE profile consistent with that previously reported. Post-alloHSCT patients who had relapsed performed equally as well as those without prior alloHSCT. To prolong remission in this poor outcome patient group, the addition of other immunotherapies to the treatment regimen may be considered for future investigations. Disclosures Stein: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Research Funding. Topp:Astra: Consultancy; Regeneron: Consultancy; Affimed: Consultancy, Research Funding; Roche: Consultancy, Other: Travel Support; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria, Other: Travel Support. Goekbuget:Erytech: Consultancy; Gilead Sciences: Consultancy; Kite: Consultancy; Mundipharma: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bayer: Equity Ownership; Sanofi: Equity Ownership; GlaxoSmithKline: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Eusapharma/Jazz: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; SigmaTau: Consultancy, Honoraria, Research Funding. Bargou:Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Patents & Royalties: Patent for blinatumomab; University of Wuerzburg, Germany: Employment; GEMoaB GmbH: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Rambaldi:Roche: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Celgene: Research Funding; Pierre Fabre: Honoraria. Zhang:Amgen: Employment, Equity Ownership. Zimmerman:Amgen: Employment, Equity Ownership. Forman:Mustang: Research Funding; Amgen: Consultancy.

Abstract Introduction: CMML is a heterogeneous malignancy characterized by peripheral monocytosis and a propensity for AML transformation. Given the low incidence of CMML and its broad range complexity, a large disease-specific data set is necessary to discern independent co-variates predictive of disease behavior. Several prognostic models derived from smaller data sets have been developed to stratify CMML patients into distinct groups that are predictive for OS. However, the validity of these models in a large international data set has never been investigated. Here, we present the largest International CMML data base established to date and report key baseline characteristics predictive for disease outcome. We externally validate and perform a detailed statistical comparison between the International Prognostic Scoring System (IPSS), Revised (R)-IPSS, Global MD Anderson Scoring System (MDASC), MD Anderson Prognostic Score (MDAPS), Dusseldorf Score (DS), Mayo, and Spanish Scoring Systems (CPSS). Methods: Data were abstracted by each contributing institution and deposited for central data review at the Moffitt Cancer Center. Manual review of cases was performed to ensure data quality prior to analysis. Only WHO defined CMML was included. The primary objective of this study was to establish an international CMML data set and validate the above models calculated at the time of presentation to each center. All prognostic models were calculated as previously described. The Kaplan–Meier (KM) method was used to estimate median OS and the log rank test was used to compare KM survival estimates with SPSS version 21.0. Random Forest Survival (RSF) and ROC analysis was done with R. Results: Between July 1981 and June 2014, 1832 CMML patients were captured in the International CMML database. Median age at diagnosis was 70 (16-93) years with a male (67%) predominance. By the WHO classification, the majority of patients had CMML-1 (79.9% vs. 20.1%) and most patients were evenly subcategorized as MPN-CMML (49.8%) versus MDS-CMML (50.2%) by FAB criteria. Splenomegaly was demonstrable in 25%. Most patients had favorable cytogenetics by both IPSS (70%) and CPSS (67.6%) classification schemas. Mean BM blast % was 5.6 and mean monocyte count was 4.85x103/dL. Median OS of the entire data set was 31.6 months. All tested prognostic models were valid and able to predict OS (p<0.0001). To compare relative model performance, 1013 complete cases with sufficient data to calculate all risk models were compared using time dependent receiver operator characteristic (ROC) curves and their area under the curves (AUC). ROC curves were calculated for OS at 36 months. The R-IPSS model had the highest AUC (0.694) while the DS model had the lowest (0.635). The difference in AUC between the R-IPSS and DS models was statistically significant (p = 0.003) whereas there was no significant difference from other models tested. To determine which models were most vulnerable to reclassification from low-risk to higher risk, we calculated a vulnerability score defined by the number of models able to up-stage low-risk disease in more than 15% of cases. Using this metric, the Mayo and MDASC scores were least vulnerable to up-staging by other models. Lastly, we used an orthogonal method for determination of variable importance (RSF for OS at 36 months). RSF is an ensemble method of classification and regression tree methodology. Ranking of variables by their weighted importance determined by this procedure identified the top five variables were hemoglobin, circulating blasts, platelet count, number of cytopenias, and karyotype. A new risk model was developed using the results of the RSF with an AUC of 0.720, which was comparable but not significantly different than other modern scoring systems. Conclusions: This represents the largest international CMML-specific data set derived from eight unique centers of excellence. All modern prognostic models were valid and performed comparably. Despite novel strategies for variable importance discovery, an improved model could not be constructed. This data suggest that the power of clinical variables has reached an asymptote and highlights the need for incorporation of molecular and other novel biological features. This data set is currently being populated with molecular data and is being leveraged to test published CMML molecular prognostic models which will be disclosed at the time of presentation. Disclosures Garcia-Manero: Epizyme, Inc: Research Funding. Fenaux:Celgene, Janssenm, Novartis: Research Funding. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Corp: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim Corp: Membership on an entity's Board of Directors or advisory committees.

Background: National Collegiate Athletic Association (NCAA) football players are at a high risk of injuries. Elbow injuries are uncommon, but there are insufficient data specifically on elbow injuries sustained in NCAA football players. Purpose: To define the epidemiology of elbow injuries in NCAA football players during the 2009-2010 to 2013-2014 seasons using data from the NCAA Injury Surveillance Program (NCAA-ISP). Study Design: Descriptive epidemiology study. Methods: Using the NCAA-ISP database, a convenience sample of NCAA football athletes was reviewed to determine the types, rates, and trends in elbow injuries. Several factors were examined, including the diagnosis, injury setting, time lost from sport, surgical necessity, and injury recurrence. Raw injury data were obtained as well as weighted totals from the NCAA-ISP to generate national estimates and adjust for underreporting. Injury rates were calculated by dividing the number of injuries by the total number of athlete-exposures (AEs). The rate ratios of injuries during competition versus practice were compared, as were the rate ratios of preseason, regular-season, and postseason injuries by type. Results: We identified 4874 total elbow injuries from the 2009-2010 to 2013-2014 seasons. The rate of injuries overall was 1.892 per 10,000 AEs. The rate for competition was 9.053 per 10,000 AEs and 1.121 per 10,000 AEs for practice. The rate ratio between competition and practice was 8.08 (95% CI, 6.04-10.80). Injury rates for the preseason, regular season, and postseason were 1.851, 1.936, and 1.406 per 10,000 AEs, respectively. Acute elbow instability was the most common injury type (65.43%). The most common mechanism was a contact injury (86.77%); 96.82% of injuries did not require surgery, and most elbow injuries required less than 24 hours of participation restriction (67.33%). Conclusion: Although elbow injuries in NCAA football players are uncommon, it is important to recognize and treat these injuries appropriately. Dislocations and ulnar collateral ligament injuries caused athletes to miss extended periods of play. Fortunately, a majority of injuries resulted in less than 24 hours of participation restriction. Particular attention should be given to preventing elbow injuries, especially ulnar collateral ligament strains, hyperextension injuries, and acute instability.

AbstractEpidemiologic studies show an increased risk of non‐Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen‐stimulation in one disease leads to another. Here we assess shared genetic risk in genome‐wide‐association‐studies (GWAS).Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B‐cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta‐analysis.Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta‐analysis (combing AD with NHL) implicated genes of apoptosis and telomere length.This GWAS‐based analysis four NHL subtypes and three ADs revealed few weakly‐associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

Abstract MYC dysregulation, the most common genetic aberration in multiple myeloma, is frequently due to the translocation of super-enhancers to the MYC locus. Several drugs target proteins that are enriched at many of these enhancers including BRD4 (BET inhibitors, BETi) and Ikaros (IMiDs), although their mechanism of action remains poorly understood. Here we present a characterization of the responses to these drugs in a collection of over sixty myeloma cell lines having a diversity of MYC rearrangements. We found that the anti-proliferative effects of these drugs significantly correlated with changes in MYC protein levels, consistent with both drugs targeting MYC expression. Despite this common target, there was no statistically significant correlation between the individual BETi and IMiD responses, suggesting that they act through different mechanisms. Of those lines having extremes of sensitivity or resistance, there were two major groups (BETiS/IMiDS and BETiS/IMiDR), a smaller group of four lines resistant to both drugs individually (BETiR/IMiDR) and only one line was BETiR/IMiDS. In the BETiR/IMiDR group, resistance to BETi was mediated by a BRD4-independent mechanism as BRD4 was efficiently released from the MYC-associated enhancers. In all three of BETiR/IMiDR cell lines that we examined, treatment with BETi and IMiD together abolished proliferation and down-regulated MYC, consistent with parallel BRD4- and Ikaros-dependent pathways driving MYC expression. These resistant lines all expressed high levels of the transcription factor ETV4 and knocking out its gene sensitized a line to each drug individually. Thus ETV4 appears to be necessary for the parallel pathways driving MYC expression. There were nine lines in the BETiS/IMiDR group. Sensitivity to BETi in these lines could be explained by either low ETV4 expression or by BETi repressing Ikaros levels (which was only observed in BETiS lines, suggesting that BRD4 drives IKZF1 expression in these lines). Thus, in ETV4-containing lines, BETi sensitivity is due to the simultaneously targeting of the BRD4- and Ikaros-dependent pathways. IMiD resistance likely was due to several reasons. In one cell line, OCIMY5, IMiD had little effect on Ikaros levels, likely due to the previously reported low levels of Cereblon. Seven of the eight remaining lines expressed high levels of either ETV4, or the other potential super-enhancer binding factors IRF4 or RUNX1. In the eight BETiS/IMiDS cell lines, IMiD strongly reduced both Ikaros and Aiolos protein levels, which likely caused IMiD sensitivity. As with the BETiS lines described above, the lines in this group either lacked ETV4 or BETi repressed Ikaros levels. In conclusion, by examining drug response in a collection of genetically annotated myeloma cell lines we have been able to identify factors that contribute the broad range of responses to BETi and IMiDs in myeloma cells. Citation Format: Daniel L. Riggs, Camille Herzog, Victoria M. Garbitt, Niamh Keane, Courtney J. Hillukka, Zachary J. Hammond, Julia E. Wiedmeier, Seth J. Welsh, Shulan Tian, Huihuang Yan, Ranjan Maity, Nizar Bahlis, Paola Neri, W Michael Kuehl, Marta Chesi, P Leif Bergsagel. IMiDs and BET inhibitors target distinct pathways of MYC dysregulation by super-enhancers in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3015.

Abstract Aims Wireless capsule endoscopy (WCE) and magnetic resonance enterography (MRE) are increasingly utilized to evaluate the small bowel (SB) in Crohn’s disease (CD). The primary aims were to compare the ability of WCE and MRE to detect SB inflammation in children with newly diagnosed CD, and in the terminal ileum (TI) to compare them to ileo-colonoscopy. Secondary aims were to compare diagnostic accuracy of WCE and MRE and changes in Paris classification after each study. Methods Patients (10 to 17 years of age) requiring ileo-colonoscopy for suspected CD were invited to participate. Only patients with endoscopic/histologic evidence of CD underwent MRE and WCE. SB inflammation and extent were documented and comparative analyses performed. Results Of 38 initially recruited subjects, 20 completed the study. WCE and MRE were similarly sensitive in identifying active TI inflammation (16 [80%] versus 12 [60%]) and any SB inflammation (17 [85%] versus 16 [80%]). However, WCE detected more extensive SB disease than MRE with active inflammation throughout the SB in 15 [75%] versus 1 [5%] patient (P < 0.001). Moreover, WCE was more likely to detect proximal SB disease (jejunum and ileum) compared to MRE (85% versus 50%, P = 0.04). Overall, the Paris classification changed in 65% and 85% of patients following MRE and WCE, respectively. Conclusions WCE is as sensitive as MRE for identifying active TI inflammation, but appears more sensitive in identifying more proximal SB inflammation. In the absence of concern regarding stricturing or extra-luminal disease WCE can be considered for the evaluation of suspected SB CD.