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Background:Lenalidomide plus rituximab (R2) has established efficacy and a tolerable safety profile in patients with previously untreated and relapsed/refractory (R/R) indolent NHL. This includes patients with marginal zone lymphoma (MZL) who are generally treated in a similar manner to follicular lymphoma (FL).Aims:Primary results for the AUGMENT study in R/R FL grade 1–3a and MZL showed significantly improved progression‐free survival (PFS) for R2 over R/placebo in the overall population and in the subgroup analyses, with the exception of the MZL subgroup. Given the small sample size for MZL patients, post hoc analyses of baseline characteristics and univariate/multivariate analyses of PFS were conducted to examine possible explanations for these results.Methods:The phase III AUGMENT study randomized patients 1:1 to R2 (lenalidomide PO 20 mg/day (d), d1–21/28 X12 cycles plus rituximab IV 375 mg/m2 weekly in cycle 1 and d1 of cycles 2–5) or rituximab‐placebo (R/placebo; same dosing schedule). PFS by 2007 IWG (without PET) was the primary endpoint. Post hoc Cox regression models were used for univariate analysis of one risk factor and multivariate analyses including treatment arm and significant risk factors (P < 0.05) from the univariate analyses.Results:A total of 63/358 (18%) MZL patients were part of the overall study population, including n = 14/16 MALT, n = 9/6 splenic, and n = 8/10 nodal MZL subtypes for respective R2 and R/placebo arms. Numerical differences between treatment arms for baseline demographics and disease characteristics for MZL patients favoring the R/placebo arm were: fewer R2 patients had an ECOG score of 0 (55% R2 vs 72% R/placebo), and more R2 (vs R/placebo) patients were older (≥65 y: 68% vs 59%; ≥70 y: 42% vs 38%), were refractory to the last prior regimen (13% vs 3%), had Ann Arbor stage IV disease at enrollment (65% vs 41%), high‐risk MALT‐IPI score (50% vs 19%), elevated LDH (29% vs 19%), B symptoms (13% vs 3%), and high tumor burden per GELF criteria (65% vs 56%). The most common grade 3/4 AEs for MZL patients receiving R2 vs R/placebo, respectively, were neutropenia (47% vs 16%), pneumonia (3% vs 13%), and leukopenia (10% vs 0). A total of 5 deaths occurred in the R2 arm (most associated with progression of disease; 2 deaths occurred early at 3 and 13 days after randomization [one prior to receiving R2 and one 2 days after treatment initiation]) and 2 in the R/placebo arm. Despite worse prognostic features, best response was improved with R2 (vs R/placebo) with ORR = 65% vs 44% (P = 0.13) and CR = 29% vs 13% (P = 0.13), although neither were statistically significant. Improved response rates did not translate into a survival advantage for R2. Median PFS for MZL patients was 20.2 mo R2 vs 25.2 mo R/placebo (HR = 1.00; 95% CI, 0.47–2.13; P = 1.0). Univariate analyses showed that several baseline factors were prognostic for MZL patients (P < 0.05): Ann Arbor stage IV, elevated LDH, and unfit for chemotherapy (Table). Multivariate analyses adjusting for the imbalance in these 3 significant prognostic factors showed an adjusted PFS HR of 0.51 (95% CI, 0.20–1.28) favoring the R2 arm, similar to the PFS HR in the overall population (HR = 0.46; 95% CI, 0.34–0.63). The univariate and multivariate analyses suggested that the imbalance in baseline prognostic factors impacted PFS results for MZL patients.Summary/Conclusion:Overall, these findings suggest that the PFS results in MZL patients were negatively impacted by the imbalance in baseline prognostic factors and more aggressive disease in the R2 over the R/placebo arm.image

AbstractOmega-3 polyunsaturated fatty acids (n3-PUFA) are well recognized for their potent triglyceride-lowering effects, but the potential influence of these bioactive lipids on other biological processes, particularly in the context of healthy aging, remains unknown. With the goal of gaining new insight into some less well-characterized biological effects of n3-PUFAs in healthy older adults, we performed metabolomics of fasting peripheral blood plasma collected from 12 young adults and 12 older adults before and after an open-label intervention of n3-PUFA (3.9 g/day, 2.7 g eicosapentaenoic [EPA], 1.2 g docosahexaenoic [DHA]). Proton nuclear magnetic resonance (1H-NMR) based lipoprotein subclass analysis revealed the expected reduction in total triglyceride (TG), but also demonstrated that n3-PUFA supplementation reduced very low-density lipoprotein (VLDL) particle number, modestly increased high-density lipoprotein (HDL) cholesterol, and shifted the composition of HDL subclasses. Further metabolite profiling by 1H-NMR and mass spectrometry revealed pronounced changes in phospholipids, cholesterol esters, diglycerides, and triglycerides following n3-PUFA supplementation. Furthermore, significant changes in hydroxyproline, kynurenine, and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF) following n3-PUFA supplementation provide further insight into some less well-recognized biological effects of n3-PUFA supplementation, including possible effects on protein metabolism, the kynurenine pathway, and glucose metabolism.

TPS3155 Background: Genomic signatures are revolutionizing the definition, identification, and treatment of breast cancer. To precisely stratify breast cancers into actionable subgroups, full genome expression data and matching clinical data must be aggregated into a large data set. Such a data set will accelerate research and discovery, especially for smaller patient subsets who are not as widely represented within the current body of literature. Methods: FLEX is a multicenter, prospective, population-based, observational trial for patients with Stage I, II, and III breast cancer. All patients with stage I to III breast cancer who receive MammaPrint, with or without BluePrint on a primary breast tumor are eligible for enrollment. The study’s primary aim is to create a large scale, population-based registry of full genome expression data matched with clinical data to investigate new gene associations with prognostic and/or predictive value. Secondary objectives include utilizing the shared study infrastructure to examine and generate hypotheses for targeted subset analyses and/or trials based on full genome expression data. The design of FLEX allows targeted sub-studies and sub-analyses to be added as appendices after the initial baseline study is opened. Patients enrolled in the initial study are also eligible for inclusion in sub-studies where they meet all criteria and additional consent is not required. Additional clinical data will be collected as specified in the appendix protocols. The FLEX collaborative platform allows participating investigators the opportunity to author their own sub-study protocols, as approved by the FLEX Steering Committee of their peers. 13 sub-studies have already been identified and are under development. Eligibility: The study will enroll a minimum of 10000 patients aged ≥18 years with histologically proven invasive stage I-III breast cancer who signed informed consent. Enrollment began April 2017 and 1506 patients have been enrolled. Clinical trial information: NCT03053193.

TPS2075 Background: IDH mutant astrocytomas express high levels of 2-hydroxyglutarate (2-HG), an oncogenic metabolite which drives gliomagenesis. Excess 2-HG inhibits branched chain amino acid transaminase, which catalyzes glutamate synthesis from branched chain amino acids. This defect causes these tumors to become more reliant on glutaminase for glutamate biosynthesis from glutamine. CB-839 (telaglenastat) is a novel glutaminase inhibitor which is well tolerated in humans. McBrayer et al have recently demonstrated that CB-839 further depletes intracellular glutamate and glutathione in IDH mutant glioma cells, and enhances RT (radiation therapy) efficacy in an orthotopic glioma model. Methods: NCI #10218 is a CTEP supported phase I clinical trial investigating the safety and tolerability of CB-839 when combined with RT/TMZ (temozolomide) in patients with previously untreated IDH mutant grade II/III astrocytoma. Patients with grade II and III astrocytomas will be treated with 50.4 and 59.4 Gy of RT, respectively, with standard doses of concurrent TMZ. CB-839 will also be administered orally concurrently with RT, with doses escalated in cohorts based on a standard 3+3 design. After defining the maximum tolerated dose (MTD) of CB-839, an expansion cohort will evaluate the pre- and post-CB-839 therapy metabolome of patients with IDH mutant astrocytoma. Enrollment to this cohort will require measurable disease and patients will additionally be treated with a 7 day run-in of CB-839 at MTD prior to RT. The effect of CB-839 on the metabolome will be studied in both plasma (LC/MS/MS) and tumor (magnetic resonance spectroscopy), along with PK to confirm adequacy of systemic exposure. Preliminary data on neurocognitive endpoints will also be acquired. NCI #10218 is currently activated for enrollment to cohort 1. Clinical trial information: NCT03528642.