Citations

Abstract Abstract 3404 Background: Appropriate periprocedural management of the chronically-anticoagulated patient with an inherited or acquired thrombophilia is uncertain. Objective: To estimate the 3-month cumulative incidence of thromboembolism (TE) and major bleeding and test thrombophilia as a potential predictor of these outcomes among chronically-anticoagulated patients undergoing a procedure. Methods: 2182 consecutive patients referred to the Mayo Thrombophilia Center for standardized peri-procedural anticoagulation management were followed for TE, major bleeding and survival. The three-month cumulative incidence rates for TE, major bleeding and death were estimated by Kaplan-Meier analyses. For each chronic anticoagulation indication, we tested “strong” thrombophilia (antithrombin, protein C or protein S deficiency, homozygous or combined heterozygous Factor V Leiden or prothrombin G20210A), ”weak” thrombophilia (heterozygous Factor V Leiden or prothrombin G20210A), lupus anticoagulant/antiphospholipid antibodies and bridging heparin as potential predictors of TE and major bleeding using Cox proportional hazards modeling. Results: Patients with thrombophilia tended to be younger with a slight female predominance. Compared to no thrombophilia, thrombophilia patients (n=202; 143 bridged with heparin) had similar rates of venous (0% vs. 0.5%; p=0.34) and arterial (0.5% vs. 0.5%; p=0.94) thromboembolism, major bleeding (2.0% vs. 2.0%; p=0.97) and mortality (1.5% vs. 2.2%; p=0.52). Among thrombophilia patients, the TE and major bleeding rates were similar for strong (n=29) or weak thrombophilia (n=99), or lupus anticoagulant/antiphospholipid antibodies (n=74). Similarly, among thrombophilia patients, bridging heparin did not affect the rates of major bleeding (2.1% vs. 1.7%; p=0.85) or TE (0.7% vs. 0%, p=0.52). Conclusions: Inherited or acquired thrombophilia does not appear to impact the rates of TE, major bleeding or mortality after temporary interruption of chronic anticoagulation for an invasive procedure. Disclosures: No relevant conflicts of interest to declare.

Background The incidence of VTE in African-Americans (AAs) is similar to or higher than in Americans of European ancestry. However, the carrier frequencies of inherited thrombophilias common in whites (i.e., Factor V Leiden, Prothrombin G20210A) are very low in AAs, suggesting that other inherited thrombophilias may be associated with VTE in AAs. Objective To identify potentially novel non-hypothesis-driven single nucleotide polymorphisms (SNPs) associated with VTE in AAs. Methods We used the resources of the eMERGE Network to perform a GWAS of VTE in AAs. The eMERGE Network (funded by NHGRI) is comprised of nine sites each with DNA biobanks linked to electronic health records (EHRs). Approximately 39,206 unique DNA samples have been genotyped using either Affymetrix or Illumina genome-wide SNP arrays. Led by the Coordinating Center and eMERGE genomics workgroup, an imputation pipeline was developed for merging genomic data across the different SNP arrays used by the eMERGE sites, to maximize sample size and the power to detect associations. The imputation was performed using the 1000 Genomes Cosmopolitan reference panel which includes 1092 individuals and over 36 million SNPs. From our previously-identified cohort of Olmsted County, MN residents with incident or recurrent VTE, 1996-2005, we derived and validated an EHR-driven phenotype extraction algorithm that leveraged structured data based on ICD-9-CM codes and unstructured data from clinical notes via natural language processing to identify VTE cases and controls with 100% and 94% positive and negative predictive values, respectively. We tested for an association between each SNP and VTE among AAs using unconditional logistic regression, adjusting for age, sex and eMERGE site. Results Among 294 AA VTE cases and 3,661 AA controls (total n=3,955; females, n=2,512), the Factor V Leiden (F5 rs6025) was not analyzed due to a very low minor allele frequency (MAF=0.0036). The prothrombin G20210A (F2 rs1799963) and ABO blood type O (ABO rs8176719) SNPs were not genotyped in any of the arrays and could not be imputed. Among SNPs with an imputation score >0.8, the most significant SNPs associated with VTE were ITPR3 (inositol 1,4,5-triphosphate receptor type 3) rs2229637 (OR=1.65; p=3.61E-07; MAF=0.19) and CLEC7A (C-type lectin domain family 7, member A) rs59819090 (OR=2.16; p=1.06E-06; MAF=0.056). ITPR3 SNPs have been associated with coronary artery aneurysm in Kawasaki disease, type 1 diabetes mellitus and other autoimmune disorders. CLEC7A rs59819090 encodes for a serine82 to leucine nonsynonymous amino acid change in dectin-1. Dectin-1 is a transmembrane innate immune pattern recognition receptor on myeloid cells that upon binding it’s agonist, β-glucans, stimulates cytokine production and the respiratory burst, a prerequisite for formation of neutrophil extracelluar traps (NETs). NETs have been associated with VTE (van Montfoort, et al. Ateriosclero Thromb Vasc Biol 2013;33:147-51). Dectin-1 serine82 is not evolutionarily conserved and the serine82 to leucine amino acid change is predicted to be tolerated, with a moderate effect on protein function. Conclusions ITPR3 rs2229637 and CLAC7A rs59819090 may be associated with VTE in African-Americans. These observations require replication and functional studies toward understanding how they may lie on the causal pathway to VTE. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 491 Introduction: Chronically-anticoagulated patients with active cancer (Ca) often require temporary interruption of warfarin for an invasive diagnostic or therapeutic procedure. While such patients may be at increased risk for periprocedural thromboembolism and bleeding, there are virtually no estimates of these outcomes among Ca patients or the most appropriate periprocedural anticoagulation management. The aims of this study were to estimate rates of these outcomes among Ca patients and to test active cancer and “bridging” low molecular weight heparin (LMWH) as potential predictors of these outcomes. Patients and Methods: In a retrospective cohort study, all chronically-anticoagulated patients referred to the Mayo Clinic Thrombophilia Center for periprocedural anticoagulation management over the 11-year period, 1997-2007, were followed forward in time for the outcomes of venous and arterial thromboembolism (VTE; ATE), major bleeding and vital status within 3 months of consultation. Warfarin was stopped 4-5 days prior to the procedure and patients received bridging LMWH according to the estimated risk of thromboembolism and bleeding. All outcome events were centrally adjudicated using pre specified criteria. Results: The total cohort (n=2517) included 500 patients with Ca. Chronic anticoagulation indications included prior VTE (n=1033), mechanical heart valve (n=669), atrial fibrillation (n=530) and other (mainly vascular bypass; n=285). 65% and 64% of patients with and without Ca received bridging LMWH, respectively. Prior VTE was more common among Ca patients compared to those without CA, both in the bridged (56% vs 37%; p<0.001) and the non-bridged (48% vs 39%; p<0.05) groups. The 3 month rate for the composite of VTE, ATE or bleeding was higher among Ca patients compared to patients without Ca (5% vs 2%; p=0.004) due to higher post procedure rates of VTE (1% vs 0.2%; p<0.001) and major bleeding (4% vs 1.7%; p=0.009); the post procedure ATE rates were low in both groups (0.40% vs 0.45%). For the entire cohort, patients receiving bridging LMWH had a significantly higher rate of post procedure bleeding (5% vs 1%; p<0.05). Finally, there were significantly more deaths in Ca patients compared to non-Ca patients (5% vs. 1%; p<0.001). Conclusions: The three-month rates of VTE, major bleeding and death among patients with Ca in whom anticoagulation is temporarily interrupted for an invasive procedure is significantly higher than in patients without Ca, especially the major bleeding rate. Use of heparin increases this rate even farther, suggesting that bridging should be used with caution in patients with active cancer. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 259 Despite recent progress, our understanding of the genomic basis of diffuse large B cell lymphoma (DLBCL) is incomplete. We have performed massively parallel whole exome sequencing with deep coverage of 57 primary tumor samples from patients with DLBCL and compared them to matched normal tissue to gain insight into the genetic defects leading to DLBCL. We define genes that are significantly enriched for somatic mutations, and thus, may be drivers of the disease. In addition to identifying genes that are well established to be functionally relevant in DLBCL, such as MyD88, CARD11, EZH2, and BCL2, we also discovered new genes that are significantly mutated that have not been described to play a role in DLBCL previously, such as MLL2, 3 and4 genes and PCLO. One of the challenges for the understanding of DLBCL biology is to determine the relative contribution of different genes with somatic mutations to the pathogenesis of the disease in an individual patient. Identification of functionally relevant mutated genes that only occur in a small number of patients based on prevalence alone may require thousands of patient samples. We therefore devise several strategies to discover genes with a high likelihood of functionally relevant mutations independent of their prevalence. Genes that do not co-occur with other mutated genes in the same patients, i.e. are mutually exclusive, are more likely to represent strong drivers, and to occur early in the development of DLBCL. We determined that TP53, BCL2, PIM1, and CD79B fall into this group. We apply pathway-focused analysis to identify mutated genes with low prevalence that are highly likely to have a functional impact. For instance, we identified G13D mutations in KRAS in two patients, and mutations in BRAF, NOTCH1, SOCS1, and PTEN in other patients that were previously described in other malignancies. These mutated genes are identified as part of significantly enriched gene sets, including the B cell receptor signaling/NFkB pathway, JAK/STAT, and antigen processing gene sets. In addition to these pathways that are important for physiological B cell activation, we find that many histone methyltransferases are enriched as a geneset in addition to MLL2. We identified a number of hotspots that are subject to somatic mutation. Our data imply that many of these hotspots may be targets of activation-induced cytidine deaminase (AID), which is usually involved in somatic hypermutation, suggesting a possible mechanism of how somatic mutation in DLBCL is mediated. In summary, our data define novel genetic defects in DLBCL by whole exome sequencing of 57 patients. Our data suggest that driver mutations may not be randomly distributed across the genome, but may occur in a directed fashion. We identified new genes not previously implicated in DLBCL, and have developed strategies to prioritize mutations that are most likely to be drivers of the disease. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Lenalidomide with dexamethasone (Rd) is a standard of care for patients with previously untreated multiple myeloma. SWOG S0777, a randomized phase III trial, has compared Rd with bortezomib, lenalidomide and dexamethasone (VRd). The primary end point is progression-free survival (PFS) using a pre-specified one-sided stratified log rank test at a significance level of 0.02. The stratification factors are International Staging System (ISS) stage (I, II or III) and intent to transplant (yes or no), a total of 6 strata. Overall response rate (ORR), overall survival (OS) and safety are secondary end points. Methods: This analysis includes 474 patients evaluable for survival endpoints: 232 patients were randomized to Rd and 242 patients to VRd. Rd patients received lenalidomide 25 mg/day on days 1-21 and dexamethasone 40 mg/day on days 1, 8, 15 and 22 of a 28-day cycle. VRd patients received lenalidomide 25 mg/day on days 1-14 and dexamethasone 20/mg/day on days 1, 2, 4, 5, 8, 9, 11 and 12 plus bortezomib 1.3 mg/m2 IV push on days 1, 4, 8 and 11 of a 21-day cycle. All patients received aspirin 325 mg/day and VRd patients received HSV prophylaxis per institutional standard. Induction was six 28-day cycles of Rd and eight 21-day cycles of VRd followed by Rd maintenance for all patients until progression, unacceptable toxicity or withdrawal of consent. Initial analyses utilized the pre-specified one-sided stratified log rank test. Results: Data are presented for VRd followed by Rd throughout. Between 2008 and 2012, 525 patients from 48 institutions were randomized. Fifty-one patients, 29 randomized to Rd and 22 randomized to RVd, were ineligible for the following reasons: missing, insufficient or early or late baseline labs (40); not meeting requirements of measurable disease (6); inadequate marrow function (1); inadequate creatinine clearance (1); prior malignancy (1); prior therapy (1); and more than 2 weeks of prior steroid therapy (1). The pre-specified significance level of 0.02 was reached in the log rank testing. The stratified hazard ratio (HR) was 0.742 (96% Wald confidence interval: 0.579, 0.951), and the one-sided stratified log rank p-value for PFS (VRd vs. Rd) was 0.0066. The OS was improved for VRd vs. Rd with HR = 0.666; two-sided log-rank p-value = 0.0114. The PFS and OS survival charts are displayed below. Median PFS was 43 months (VRd) versus 31 months (Rd). Median OS was not reached (VRd) versus 63 months (Rd). Patient characteristics were well-matched between VRd and Rd with the exception of fewer women (37% vs. 47%: P = 0.033) and fewer older patients (≥ 65 years 38% vs. 48%: P = 0.042) receiving VRd. With univariate Cox regression analysis correlates of better PFS/OS were: use of VRd (HR 0.72/0.65; P = 0.006); hemogoblin ≥10 g/dl (HR 1.17/1.43; P = 0.2/0.026) and lower ISS disease stage (HR 1.35/1.98; P = 0.014/< 0.001). The ORR for VRd was 71.07% versus 63.79% for Rd. The adverse events by CTC category and toxicity category were fairly well balanced. The most common hematologic adverse events (≥ Grade 3 and at least possibly attributable to therapy) were low hemoglobin (RVd=13%; Rd=16%), leukopenia (RVd=14%; Rd=16%), lymphopenia (RVd=23%; Rd=18%), neutropenia (RVd=19%; Rd=21%), and thrombocytopenia (RVd=18%; Rd=14%). The most common non-hematologic adverse events (≥ Grade 3 and at least possibly attributable to therapy) were: fatigue (RVd=16%; Rd=14%), sensory neuropathy (RVd=23%; Rd=3%), hyperglycemia (RVd=7%; Rd=11%), thrombosis/embolism (RVd=8%; Rd=9%), hypokalemia (RVd=9%; Rd=6%), muscle weakness (RVd=7%; Rd=4%), diarrhea (RVd=8%; Rd=2%), and dehydration (RVd=8%; Rd=2%). As expected ≥ Grade 3 neuropathy was more frequent with VRd (24% vs. 5%: P < 0.0001). Sixteen patients experienced a second primary malignancy, 7 (3%) on VRd and 9 (4%) on Rd. Conclusion: The addition of bortezomib to lenalidomide dexamethasone for induction therapy in previously untreated myeloma results in a statistically significant and clinically meaningful improvement in PFS as well as better OS. VRd had an acceptable safety and tolerability profile despite increased neurotoxicity and represents a potential new standard of care. Support: NIH/NCI/NCTN grants CA180888, CA180819, CA180821, CA180820; and in part by Millennium Pharmaceuticals, Inc., The Takeda Oncology Company, for provision of study drug. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Durie: Johnson & Johnson: Consultancy; Takeda: Consultancy; Onyx: Consultancy; Celgene: Consultancy. Abidi:Millennium: Research Funding. Epstein:University of Arkansas for Medical Sciences: Employment. Reu:Takeda/Millennium: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Orlowski:BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Acetylon: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Forma Therapeutics: Consultancy; Array BioPharma: Consultancy, Research Funding. Barlogie:Dana Farber Cancer Institute: Other: Travel Stipend; International Workshop on Waldenström's Macroglobulinemia: Other: Travel Stipend; ComtecMed- World Congress on Controversies in Hematology: Other: Travel Stipend; European School of Haematology- International Conference on Multiple Myeloma: Other: Travel Stipend; Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Myeloma Health, LLC: Patents & Royalties: Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC; Multiple Myeloma Research Foundation: Other: Travel Stipend.

Abstract Introduction Over the last 15 years gene expression profiling (GEP) has been used to define myeloma molecular subgroups and to determine clinical prognosis. Two major molecular subgroup classifications have been used: the UAMS which determines 7 subgroups and the TC classification based on the presence of IgH translocations and expression of D group cyclins. For prognosis, although a number of different GEP signatures have been defined, the widely used GEP70 identifies 15% of patients with high risk (HR) disease who have a median PFS and OS of 1.75 and 2.83 years. An ideal classification system would identify clinically relevant subgroups with distinct etiology and biology using standardized techniques. We have examined a large group of patients characterized at multiple genetic levels to optimize the diagnostic approach of newly diagnosed patients going forward. Materials and methods Study subjects included 1349 cases enrolled in Total Therapy trials (median follow up 7.5 years). Gene expression profiling was used to determine GEP70 risk status, molecular subgroup by UAMS and TC classifications, and to devise a new and extended TC classification (TC10). Interphase FISH associated with IgH translocations and 1q+ and 17p- were used to build GEP proxies. Data from mutational analysis generated by the FoundationOne targeted sequence panel was also incorporated. Results were validated on the UK MRC MyelomaIX and Hovon65/GMMG-4 studies. Results An initial agnostic analysis of GEP data using sparse k-means clustering verified the existence of TC based groups. Six groups were identified that corresponded overwhelmingly with known TC subgroups; CCND1-t(11;14), D1-HRD, D2-HRD, MMSET, MAF/CCND2, and CCND3. Further comparisons between the molecular subgroup and TC classifier revealed that the UAMS 7 subgroups clustered strongly within one predominant TC group: CD-1 and CD-2 to t(11;14), HY to D1, LB and PR to D2, MF to t(14;16) or t(14;20), and MS to t(4;14). As the UAMS molecular subgroups are largely contained within the TC framework, we aimed to extend the TC by developing the TC10. To extend the known TC subgroups, unsupervised clustering was applied to the 3 largest subgroups [t(11;14), D1, and D2] to determine the strongest single divisor within each respective subgroup. The dominant feature within the t(11;14) cases was CD20 expression, while the D1 and D2 subgroups both split according to RRAS2. CD20 is associated with PAX5 and VPREB3 expression, and RRAS2 is associated with decreased PTP4A3 and increased TNFAIP3 and BIRC3 expression. RRAS2 activation within D1 subgroup and CD20 activation within t(11;14) cases corresponds to an increased time to response to induction therapy suggesting they constitute important biological subgroups. The TC10 combines the known etiologic subgroups of the TC with functionally relevant subdivisions to create 10 novel subgroups: t(11;14) CD20+/-, D1: RRAS2+/-, D2: RRAS2+/-, t(4;14), t(14;16), t(14;20), and t(6;14). Analysis of mutational data revealed that RRAS2 and CD20 activation within the D1, D2, and t(11;14) subgroups reduced the number of mutations in the MAPK pathway. Further mutational analysis revealed that median mutational load was highest in t(14;16) and lowest in D2: RRAS2+ subgroups. The GEP70 score identifies 15% of patients with HR disease and is specific for this purpose. In an analysis of risk assessment methods, we compared GEP detected adverse lesions [t(4;14), t(14;16), t(14;20), 17p- and 1q+] with the GEP70 and revealed that GEP70 HR identified samples have lower OS rates than cases with more than one adverse lesion (validated in external sets). GEP70 HR segregates non-uniformly across molecular subgroups as over 40% of all HR cases are found in the TC10 t(4;14), t(14;16), and t(14;20) subgroups. GEP70 HR cases also have a higher mutational load than low risk cases. Furthermore, GEP70 HR is uniquely associated with 1q+ and 17p- as cases with at least one of these adverse lesions are 4.9 times as likely to be GEP70 HR as cases with neither. Conclusion GEP profiling has a central role in simplifying and standardizing the molecular subgroup designation and risk stratifying of MM patients. The GEP70 risk score reliably identifies HR cases and outperforms FISH in risk assessment, even in validation data sets. The TC10 provides a classification system that improves upon previous methods by defining both etiological and functionally meaningful subgroups. Disclosures Stein: University of Arkansas for Medical Sciences: Employment. Davies:University of Arkansas for Medical Sciences: Employment; Celgene: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Onyx: Consultancy. Heuck:University of Arkansas for Medical Sciences: Employment; Celgene: Consultancy; Janssen: Other: Advisory Board; Millenium: Other: Advisory Board; Foundation Medicine: Honoraria. Weinhold:University of Arkansas for Medical Sciences: Employment; Janssen Cilag: Other: Advisory Board. Chavan:University of Arkansas for Medical Sciences: Employment. Thanendrarajan:University of Arkansas for Medical Sciences: Employment. Epstein:University of Arkansas for Medical Sciences: Employment. Yaccoby:University of Arkansas for Medical Sciences: Employment. Zangari:University of Arkansas for Medical Sciences: Employment; Novartis: Research Funding; Onyx: Research Funding; Millennium: Research Funding. van Rhee:University of Arkansa for Medical Sciences: Employment. Kaiser:Janssen: Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; BristolMyerSquibb: Consultancy; Chugai: Consultancy. Sonneveld:Janssen-Cilag, Celgene, Onyx, Karyopharm: Honoraria, Research Funding; novartis: Honoraria. Goldschmidt:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Barlogie:University of Arkansas for Medical Sciences: Employment. Morgan:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; MMRF: Honoraria; CancerNet: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; University of Arkansas for Medical Sciences: Employment; Weismann Institute: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Purpose: Deep vein thrombosis (DVT) is increasingly recognized as a major complication of thalidomide (T; Thal) and lenalidomide (R; Rev) based therapy for multiple myeloma. Estimated incidence varies widely in the literature. There is no consensus on specific risk factors, indications for thromboprophylaxis or the agent of choice for DVT prophylaxis. The purpose of this study was to develop a consensus among members of the IMWG. Patients and Methods: A survey was electronically mailed to 67 IMWG members on July 21, 2006 and consisted of 24 multiple-choice questions. Results: Twenty-three IMWG members (34%) sent in their responses by the cut-off date. All (100%) felt that DVT was an important question, but most (95%) did not avoid Thal/Rev based therapy because of the DVT risk. Overall results are summarized in the Table below. A majority of physicians felt that concomitant therapy with high dose dexamethasone (90% of physicians), alkylators (55%), doxorubicin/liposomal doxorubicin (90%), and erythropoietin (75%) increase the risk of DVT associated with Thal or Rev based therapy. Aspirin (81 mg or 325 mg per day) was the preferred choice of prophylaxis when necessary. However, 65% of respondents preferred warfarin to a therapeutic INR or LMW heparin if either doxorubicin or liposomal doxorubicin was added to the regimens. Most (95–100%) felt that DVT prophylaxis was not indicated for: VAD, MP, bortezomib +/− dexamethasone regimens. Seventy-five percent felt it to be safe to resume therapy with Thal/Rev after therapeutic anticoagulation. Most (95%) believed randomized trials were needed. Conclusion: DVT is recognized as a major clinical problem associated with Thal/Rev containing regimens. Most respondents felt that the DVT risk did not warrant any prophylaxis when either Thal or Rev were used as single agents. Aspirin was the preferred form of DVT prophylaxis for most Thal/Rev containing regimens, except when doxorubicin/liposomal doxorubicin or melphalan were added. Additional responses will be analyzed both electronically and by conference call prior to the meeting. Therapy Estimated incidence of DVT (% respondents) Choice of thromboprophylaxis (% respondents) Single agent thal <5% (61%) None (65%) Single agent Rev <5% (80%) None (65%) Thal-Dex 10–20% (52%) Aspirin (60%) Rev-Dex 10–20% (48%) Aspirin (60%) MPT 10–20% (65%) Aspirin (40%) R-MP 5–10% (57%) Aspirin (70%)

AbstractBackgroundThe extent to which obesity and genetics determine postoperative complications is incompletely understood.MethodsWe performed a retrospective study using two population cohorts with electronic health record (EHR) data. The first included 736,726 adults with body mass index (BMI) recorded between 1990 and 2017 at Vanderbilt University Medical Center. The second cohort consisted of 65,174 individuals from 12 institutions contributing EHR and genome‐wide genotyping data to the Electronic Medical Records and Genomics (eMERGE) Network. Pairwise logistic regression analyses were used to measure the association of BMI categories with postoperative complications derived from International Classification of Disease‐9 codes, including postoperative infection, incisional hernia, and intestinal obstruction. A genetic risk score was constructed from 97 obesity‐risk single‐nucleotide polymorphisms for a Mendelian randomization study to determine the association of genetic risk of obesity on postoperative complications. Logistic regression analyses were adjusted for sex, age, site, and race/principal components.ResultsIndividuals with overweight or obese BMI (≥25 kg/m2) had increased risk of incisional hernia (odds ratio [OR] 1.7–5.5, p < 3.1 × 10−20), and people with obesity (BMI ≥ 30 kg/m2) had increased risk of postoperative infection (OR 1.2–2.3, p < 2.5 × 10−5). In the eMERGE cohort, genetically predicted BMI was associated with incisional hernia (OR 2.1 [95% CI 1.8–2.5], p = 1.4 × 10−6) and postoperative infection (OR 1.6 [95% CI 1.4–1.9], p = 3.1 × 10−6). Association findings were similar after limitation of the cohorts to those who underwent abdominal procedures.ConclusionsClinical and Mendelian randomization studies suggest that obesity, as measured by BMI, is associated with the development of postoperative incisional hernia and infection.

Background: Treatment outcomes and risk factors for neurological deficits in pediatric patients with an os odontoideum are unclear. Methods: We reviewed the data for 102 children with os odontoideum who were managed at 11 centers between 2000 and 2016 and had a minimum duration of follow-up of 2 years. Thirty-one children had nonoperative treatment, and 71 underwent instrumented posterior cervical spinal arthrodesis for the treatment of C1-C2 instability. Nonoperative treatment consisted of observation (n = 29) or immobilization with a cervical collar (n = 1) or halo body jacket (n = 1). Surgical treatment consisted of atlantoaxial (n = 50) or occipitocervical (n = 21) arthrodesis. One patient also underwent transoral odontoidectomy. Results: Thirty children (29%) presented with neurological deficits, 28 of whom had radiographic atlantoaxial instability (atlantoaxial distance >5 mm) or limited space (≤13 mm) available for the spinal cord (risk ratio, 7.8 [95% confidence interval, 2.0 to 31] compared with children with no radiographic risk factors). The 27 children without neurological deficits or atlantoaxial instability at presentation underwent nonoperative treatment and remained asymptomatic. Of the initial nonoperative cohort, one child developed atlantoaxial instability, and another had a persistent neurological deficit; both children underwent spinal arthrodesis during the study period. One child with cervical instability declined surgery and remained asymptomatic. Spinal fusion occurred in 68 patients in the surgical group by the end of the study period (mean, 3.7 years; range, 2.0 to 11.8 years). Surgical complications occurred in 21 children, including nonunion in 12, new neurological deficits in 4, cerebrospinal fluid leak in 2, symptomatic instrumentation requiring removal 2, and vertebral artery injury in 1. Nine children underwent revision surgery. In the surgical group, Japanese Orthopaedic Association neurological function scores improved significantly from preoperatively to the latest follow-up for the upper extremities (p = 0.026) and lower extremities (p = 0.007). Conclusions: The risk of developing a neurological deficit was strongly associated with atlantoaxial instability and limited space available for the spinal cord in children with os odontoideum. Nonoperative treatment was safe for asymptomatic patients without atlantoaxial instability. Spinal arthrodesis resolved the neurological deficits of children with symptomatic os odontoideum. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Abstract Background: Pev (TAK-924/MLN4924), a novel investigational NAE inhibitor, enhances the anti-leukemic effects of aza in AML cell lines and murine xenografts (Smith et al, Blood 2011). Single-agent pev activity was confirmed in relapsed/refractory AML pts (Swords et al, Br J Haematol 2015). This open-label, multi-center, dose-escalation study (NCT01814826) investigated pev + aza in treatment-naïve older AML pts. Dose-limiting toxicities (DLTs)includedG2 hyperbilirubinemia and G4 AST elevation (n=1 each) at pev 30 mg/m2. The maximum tolerated dose (MTD) for the combination was pev 20 mg/m2 + aza 75 mg/m2 (Swords et al, ASH 2014).We present updated safety/efficacy results for the MTD cohort (fully enrolled). Methods: Primary objectives included safety and tolerability assessments of pev + aza in addition to defining the MTD. Secondary objectives included pharmacokinetics (PK) and disease response assessments. Treatment-naïve pts ≥60 yrs unlikely to benefit from standard induction therapy (defined by ≥1 of: antecedent hematologic disease; known adverse cytogenetic risk; ECOG PS 2; ≥75 yrs), received pev 20 or 30 mg/m2 IV on d 1, 3 and 5, + fixed-dose aza (75 mg/m2 IV/SC) on d 1-5, 8 and 9, every 28 d until disease progression or unacceptable toxicity. Adverse events (AEs) were assessed per NCI-CTCAE v4.03; response per IWG criteria for AML. Bone marrow samples were collected at screening to assess cytogenetic risk (CALGB) and mutation profile; serial samples for PK analysis were drawn in cycle 1. Results: Demographics:As of May 17 2016, 61 pts (median age 75 yrs [range 61-89]; 54% male; 77% ECOG PS 0/1, 23% ECOG PS 2; 57% de novo, 43% secondary AML; median marrow blasts 36% [range 5-92]) had received pev 20 mg/m2, of whom 48% had intermediate-, 30% adverse-, and 3% favorable-risk cytogenetics. Safety/PK: Pts received a median of 4 cycles (range 1-33), and 23/61 pts (38%) received ≥6 cycles of pev + aza. The most common AEs were constipation (46%), nausea (44%), fatigue (43%), and anemia (39%). Fifty pts (82%) experienced ≥G3 AEs; the most frequent (≥15%) were anemia, febrile neutropenia (each 28%), thrombocytopenia (21%), neutropenia (18%), and pneumonia (15%). ≥G3 AST/ALT elevations were reported in 5% of pts. Forty-one pts (67%) experienced serious AEs; the most frequent (≥10%) were febrile neutropenia, neutropenia (each 25%), and pneumonia (11%). Two pts discontinued due to pev related toxicity (G3 febrile neutropenia). There were 11 on-study deaths unrelated to study therapy. In the MTD expansion phase (n=55), 2 pts experienced DLTs of transient G3/4 transaminase elevations, and were successfully re-challenged following dose reduction to remain on study. Pev PK was not altered by the addition of aza. Responses: Overall response rate (ORR) in 52 response-evaluable pts was 60% (18CR, 5CRi, 8PR; Figure 1), with a median duration of remission of 8.3 mos (95% CI: 5.75, 12.06); 19/31 (61%) responses occurred within the first 2 cycles.Of the 23 pts with CR/CRi, 14 had responses lasting ≥4 cycles, 2 went on to have allogeneic stem cell transplant, 9 had intermediate-, 7 adverse-, and 1 favorable-risk cytogenetics. ORR was: 64% (14/22; 7CR, 3CRi, 4PR) vs 57% (17/30; 11CR, 2CRi, 4PR) for pts with low- (<30%) vs high- (≥30%) marrow blasts; 58% (18/31; 11CR, 3CRi, 4PR) vs 62% (13/21; 7CR, 2CRi, 4PR) for de novo vs secondary AML pts; 61% (14/23; 8CR, 1CRi, 5PR) vs 50% (8/16; 5CR, 2CRi, 1PR) for intermediate- vs adverse-risk cytogenetic pts; 83% (19/23; 14CR, 2CRi, 3PR) vs 41% (12/29; 5CR, 3CRi, 4PR) for pts who received ≥6 cycles vs <6 cycles of aza, respectively. Responses were seen in pts with typically refractory disease; 7/11 pts with TP53 mutations achieved either a CR/CRi (n=3) or PR (n=4); 4 stayed on study for >10 cycles. After a median follow-up of 16.4 mos, 6-mo survival was 52%. Median overall survival was: 7.0 mos for the MTD cohort; 8.5 vs 5.2 mos for pts with low- (<30%) vs high- (≥30%) marrow blasts (Figure 2); 5.6 vs 11.2 mos for de novo vs secondary AML pts (Figure 3); and 16.1 vs 5.3 mos for pts aged 65-74 vs ≥75 yrs, respectively. Conclusion: Pev + aza was well tolerated. Response rates and durable remissions were observed with limited additional toxicity beyond what is expected for aza alone. The timing and frequency of responses suggests benefit from the addition of pev compared to aza alone (Dombret et al, Blood 2015). At the time of writing, a randomized phase 2 study in low-blast AML/high-risk myelodysplastic syndromes is ongoing. Disclosures Coutre: Janssen: Consultancy; Pharmacylics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Zeidner:Tolero: Research Funding; Merck: Research Funding; Takeda: Research Funding; Otsuka: Consultancy; Agios: Honoraria. Foran:medscape: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; novartis: Honoraria; pfizer: Honoraria; karyopharm: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Cruz:Millennium Pharmaceuticals, Inc.: Honoraria; Millennium Pharmaceuticals, Inc.: Speakers Bureau. Erba:Novartis: Consultancy, Speakers Bureau; Celator: Research Funding; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Juno: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Pfizer: Consultancy; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Amgen: Consultancy, Research Funding; Agios: Research Funding; Sunesis: Consultancy; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Ariad: Consultancy; Jannsen: Consultancy, Research Funding. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding. Tam:Millennium Pharmaceuticals, Inc.: Consultancy. Vardhanabhuti:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dobler:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Faessel:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dash:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Sedarati:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dezube:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Savona:Takeda: Research Funding; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Sunesis: Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.