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2039 Background: Vorinostat (V) is an oral inhibitor of histone deacetylase. In preclinical studies it inhibits growth of glioblastoma (GBM) cell lines and has supra-additive activity when combined with TMZ. Methods: The North American Brain Tumor Consortium (NABTC) is conducting a phase I study of V in combination with TMZ in patients with malignant gliomas (MG). Eligibility criteria are histologically proven GBM and anaplastic gliomas (AG) who have received radiotherapy and have not progressed on temozolomide, > 18 yrs old, life expectancy > 8 weeks, KPS > 60, adequate bone marrow reserve and organ function. There was no limitation to the type of antiepileptic drugs that could be used. All patients received TMZ at a dose of 150 mg/m2/day on days 1–5 days every 28 days. Variable doses of V were administered with food on days 1–14 every 28 days. Dose-limiting toxicities (DLT), determined during the first 4 weeks of therapy, were defined as any grade 4 hematologic toxicity except for grade 3 thrombocytopenia, and any grade 3 non-hematologic toxicities. Escalation was performed in standard groups of 3. The maximum tolerated dose (MTD) was defined as the dose at which DLTs occurred in no more than 1/6 patients. PKs were determined on cycle 1 for TMZ, V and its metabolites. Results: To date, 19 eligible patients have been enrolled (15 GBM; 4 AG). Patients’ characteristics are 11 male, 8 female; median age 54 yrs (36–78); median KPS 90 (70–100). DLTs were encountered at 300 mg bid of vorinostat (1 grade 3 thrombocytopenia; 1 grade 3 fatigue in 3 patients), 200 mg tid (1 grade 3 nausea, 1 grade 4 thrombocytopenia in 3 patients) and 200 mg twice daily (grade 3 fatigue in 2/6 patients). No DLTs were encountered in 6 patients receiving 300 mg daily. TMZ PKs included [n=16: Cmax 5.2 (± 1.55) μg/ml; AUC 20.1 (±4.66) μg x hr/ml; t1/2 1.9 (±0.32)/hr]. Vorinostat PKs (300mg dose level) were [n=4; Cmax 267 (±174) ng/ml; AUC0–8 603 (±197) ng x hr/ml]. The t1/2 for V and its glucuronide metabolite were identical (1.6 hrs) vs. 5.6 hrs for the acid metabolite. Conclusions: The MTD of vorinostat in combination with TMZ is 300 mg daily on days 1–14 every 28 days. Final PK results, and toxicities from an additional 10 patients enrolled at the MTD will be presented. [Table: see text]

Abstract Purpose: To determine if the degree of estrogen suppression with aromatase inhibitors (AI: anastrozole, exemestane, letrozole) is associated with efficacy in early-stage breast cancer, and to examine for differences in the mechanism of action between the three AIs. Experimental Design: Matched case–control studies [247 matched sets from MA.27 (anastrozole vs. exemestane) and PreFace (letrozole) trials] were undertaken to assess whether estrone (E1) or estradiol (E2) concentrations after 6 months of adjuvant therapy were associated with risk of an early breast cancer event (EBCE). Preclinical laboratory studies included luciferase activity, cell proliferation, radio-labeled ligand estrogen receptor binding, surface plasmon resonance ligand receptor binding, and nuclear magnetic resonance assays. Results: Women with E1 ≥1.3 pg/mL and E2 ≥0.5 pg/mL after 6 months of AI treatment had a 2.2-fold increase in risk (P = 0.0005) of an EBCE, and in the anastrozole subgroup, the increase in risk of an EBCE was 3.0-fold (P = 0.001). Preclinical laboratory studies examined mechanisms of action in addition to aromatase inhibition and showed that only anastrozole could directly bind to estrogen receptor α (ERα), activate estrogen response element-dependent transcription, and stimulate growth of an aromatase-deficient CYP19A1−/− T47D breast cancer cell line. Conclusions: This matched case–control clinical study revealed that levels of estrone and estradiol above identified thresholds after 6 months of adjuvant anastrozole treatment were associated with increased risk of an EBCE. Preclinical laboratory studies revealed that anastrozole, but not exemestane or letrozole, is a ligand for ERα. These findings represent potential steps towards individualized anastrozole therapy.

283 Background: Cancers of the esophagus, stomach, pancreas, gallbladder, liver, bile duct, colon and rectum will account for 17% of incident cancer diagnoses and 26% of cancer-related deaths in the US in 2019. We developed a methylation-based cfDNA early multi-cancer detection test that also can predict the tissue of origin (TOO) of these and other cancers types; performance of this test for gastrointestinal (GI) tract cancers is reported here. Methods: The Circulating Cell-free Genome Atlas (CCGA; NCT02889978) study is a prospective, multi-center, observational, case-control study with longitudinal follow-up, enrolling individuals with cancer ( > 20 cancers, all stages, newly diagnosed) and without cancer. Plasma cfDNA was subjected to a cross-validated targeted methylation (TM) sequencing assay. Methylation fragments were combined across targeted genomic regions and assigned a probability of cancer and a predicted TOO. GI cancer classes were upper GI (esophagus/stomach, n = 67), pancreas/gallbladder/extrahepatic bile duct (n = 95), liver/intrahepatic bile duct (n = 29), and colon/rectum (n = 121). Results: Detection across all GI cancers was 82% (95% CI 77-86) at a > 99% pre-set specificity. Overall predicted TOO accuracy was 92% (88-95) among the samples for which TOO was predicted (6/255 had indeterminate predicted TOO). The table shows performance by GI cancer type. Conclusions: Simultaneous detection at high specificity ( > 99%) of multiple cancer types, including GI cancers across stages at high sensitivity (82%), was shown using TM analysis of cfDNA. Accurate (92%) localization of cancers to specific regions of the GI tract was also achieved. Detection of multiple GI cancers from a single noninvasive blood test could be a practical method for detecting GI and other cancers, and may facilitate diagnostic work-ups. Clinical trial information: NCT02889978. [Table: see text]

Abstract Background Nurse leaders who are mothers are at significant risk for experiencing stress, burnout, and occupational fatigue. Authentic Connections (AC) Groups is an intervention shown to be effective for fostering resilience among at‐risk moms, including physicians; however, it has not previously been tested with nurse leaders. Aims Our aims were to test the feasibility and acceptability of the AC Groups intervention with nurse leader mothers and examine its effects on participant resilience, as measured by increased self‐compassion and decreased distress, depression, perceived stress, and burnout. Methods A randomized controlled trial design was employed for this pilot study, with 36 nurse leaders at Mayo Clinic. AC participants attended group sessions for an hour per week for 12 weeks. Control group members were provided 1 hr per week of free time over 12 weeks. Multiple self‐report psychological measures were completed at baseline, post‐intervention, and 3‐month follow‐up. Results The AC Groups intervention was feasible and well‐received by nurse leaders. Session attendance rates averaged 92%. Despite the small n ’s, repeated measures of Analysis of Variance showed significantly greater improvements ( p < .05) for participants in the AC Groups than control condition for depression, self‐compassion, and perceived stress, with large effect sizes ( 0.18–0.22). In addition, effect sizes for anxiety and feeling loved approximated the moderate range ( 0.05 and .07). Linking Evidence to Action The AC intervention shows promise as a feasible intervention for mitigating nurse leader mothers’ stress by positively impacting indices of well‐being, including depression, self‐compassion, and perceived stress. Given, the prevalence of stress and burnout among nurse leaders, the effectiveness of the AC intervention in fostering resilience in this population has significant implications for research and practice. Further research is warranted with larger numbers from multiple sites, longer follow‐up periods, and biomarker measures of stress.

Abstract BACKGROUND: Chronic lymphocytic leukemia (CLL) is a heterogeneous B cell malignancy with patients being categorized into disease subsets based on several key biologic parameters, e.g., mutation status (mutated, M; or unmutated, UM) of the immunoglobulin heavy chain variable region (IGHV), acquired chromosomal abnormalities, and expression of CD38 and CD49d. Furthermore, about one third of CLL patients express stereotyped B cell receptors and/or may acquire high risk common mutations in genes such as NOTCH1 and SF3B1 suggesting ongoing genetic evolution as drivers of disease development. Critical to this concept, those CLL patients with trisomy 12 (T12) defects have a higher incidence of mutations in NOTCH1 and often have a stereotyped receptor. However, T12 patients may have a variable clinical course that appears to be unrelated to these 2 drivers suggesting an additional, possibly non-coding genetic component that may further impact disease progression in these patients. One potentially relevant genetic factor that could influence T12 clinical course is long non-coding RNAs (lncRNAs). LncRNAs are transcripts longer than 200 nucleotides that can affect a number of cellular processes. Importantly, lncRNAs have been implicated in various cancers including malignant hematopoiesis indicating they could be therapeutic targets and/or clinically useful biomarkers. METHODS: To pursue a role for lncRNAs in T12 we used v3.0 Arraystar Human LncRNA Microarrays to assess the global profile of lncRNA expression in CLL with an emphasis on patients with T12. Two cohorts of 6 patients with T12 were selected for comparison: one defined as progressive with a short time to treatment (TTT) (treatment ≤1 year after diagnosis) and one as indolent (no treatment > 5 years after diagnosis). Each cohort included 3 patients with M and 3 with UM IGHV status. RNA from normal CD5+ and CD5- B cells was included as a control. To compensate for the small sample size in each cohort, a significant difference in lncRNA expression between the groups was defined as a fold change (FC) ≥5.0, p-value ≤0.05 and false discovery rate (FDR) ≤ 0.05. RESULTS: An initial global comparison of CD5+/CD5- normal B cells vs all CLL samples found that 609 lncRNAs were differentially expressed using the criteria listed above with 158 lncRNAs having a FC>10. Notable lncRNAs in this group included: LOC541472 (down in CLL and associated with the IL-6 gene), D63785 (up in CLL and associated with TBC1D3C, an oncoprotein), CTC-459I6.1 (up in CLL and associated with RASGRF2) and AC002480.5 (down in CLL and associated with STEAP1B, shown to be overexpressed in prostate cancer). We next evaluated T12 samples and identified 90 candidate lncRNAs that may discriminate between progressive and indolent T12 cases. Within this group were 11 lncRNAs with a FC > 10, 5 of which have no known associated gene. Of those associated with known genes, 3 were ultra-conserved region encoding lncRNAs down-regulated in progressive T12 patients (TTT ≤1 yr) and linked to hephaestin-like protein 1 precursor, pannexin-1, and tubulin beta-3 chain isoform 1. Of potential high relevance we found that the lncRNA LPP-AS1 was down-regulated in progressive T12 patients (TTT ≤1 yr) and known to be associated with the LIM-containing lipoma preferred partner (LPP) gene (p=0.028; FDR=0.03 and FC=18.3). Looking specifically at IGHV M progressive T12 patients (T12M≤1 yr) vs IGHV M indolent T12 patients (T12M>5 yrs), we again found the LPP-AS1 lncRNA was highly down-regulated in T12M≤1 (p=0.00046; FDR=0.006 and FC=34.5) but it was not found to be differentially expressed in the UM T12≤1 yr vs UM T12>5 yr comparison. The LPP gene has been shown to play a role in cell-cell adhesion, motility and signaling, and is often the fusion partner for the mixed lineage leukemia (MLL) gene in secondary acute leukemia. Furthermore, LLP may play a role in breast cancer cell invasion. LPP-AS1 may be participating in IGHV M T12 progression by affecting LPP and thus influencing migration through the lymph node microenvironment. CONCLUSION: While candidate lncRNAs in T12 CLL need to be validated, the LPP-AS1 lncRNA shows promise as a possible marker and potential treatment target for those patients with T12 and M IGHV that may progress rapidly. Further studies are needed to evaluate the impact of lncRNAs on clinical outcome of T12 CLL patients. Disclosures Shanafelt: Hospiria: Research Funding; Pharmacyclics/Jannsen: Research Funding; Cephalon: Research Funding; Celgene: Research Funding; glaxoSmithKline: Research Funding; Genetech: Research Funding; Polyphenon E Int'l: Research Funding. Kay:Celgene: Research Funding.

Abstract Background: Monoclonal B-cell lymphocytosis (MBL) is characterized by the presence of a circulating population of clonal B-cells where the total B-cell count is <5 × 109/L and criteria for the diagnosis of other lymphoproliferative disorders are not present. In most patients the immunophenotype is similar to that of chronic lymphocytic leukemia with co-expression of CD19 and CD5. The natural history of MBL is unclear. We used the Mayo Clinic hematopathology database to identify patients with MBL and abstracted clinical information on natural history and prognostic parameters from clinical and research records. Methods: After IRB review and approval, we reviewed the hematopathology records of 2292 patients seen at Mayo Clinic between August 1998 and May 2006 who had a clonal B-cell population on flow cytometry phenotypically consistent with CLL and fewer than <5 × 109/L B-cells. Clinical records were then reviewed to identify patients who fulfilled the criteria for MBL (no evidence of other lymphoproliferative disorders, no adenopathy on exam). Patient characteristics, prognostic parameters, and clinical outcomes were abstracted from the clinical and research records of these patients. Cox regression analysis was used to evaluate association between prognostic markers and time to treatment. Results: A total of 118 patients meeting the criteria for MBL were identified. Median age at the time of MBL diagnosis was 69.4 years (range 39.0 – 91.4). A slight male preponderance was observed (54% male). CD38 status was available for 106 (90%) patients of whom 20% were CD38 positive using the 30% threshold to classify CD38. Cytogenetic analysis by fluorescent in situ hybridization (FISH) was available in 58 (49%) patients. Using the hierarchical classification system of Dohner and colleagues, 26 (44.8%) were 13q-, 10 (17.2%) were trisomy 12, 2 (3.4%) were 11q-, 1 (1.7%) was 17p-, and 19 were (32.8%) no defect was detected. ZAP-70 status was available for 32 patients of whom 22% were ZAP-70+ positive. IgVH gene mutation status was only available for 15 (12.7%) patients of whom 40% were unmutated. Time from MBL diagnosis to treatment is shown in Figure 1. Survival free of treatment was 92.7% (95%CI: 86.8–99.1%) at 1 year, 90.9% (95%CI: 84.2–98.2%) at 2 years, and 87.5% (95% CI: 78.7–97.4%) at 5 years. While age (p=0.68) and gender (p=0.14) were not found to be associated with time to treatment (TTT), CD38 status showed a strong relationship with TTT (p<0.001, HR: 22.7, 95% CI: 3.4–239.6). Conclusion: The distribution of prognostic parameters (e.g. CD38, FISH) in patients with MBL appears similar to that of patients with early stage CLL. We observed a low rate of progression, with 5 year survival free of treatment greater than 87%. TTT among newly diagnosed MBL patients was associated with the CD38 status of clonal B-cells. Figure Figure

Abstract INTRODUCTION: mTOR inhibitors have been associated with responses in Mantle cell lymphoma and other lymphomas (J Clin Oncol23; 5347, 2005). Phase I and II trials with the oral everolimus (RAD001, Novartis Pharmaceuticals) have demonstrated a favorable side effect profile. This phase II study tested everolimus in patients with relapsed/refractory Waldenstrom Macroglobulinemia (WM). METHODS: Patients who had at least one previous therapy for WM and who had relapsed or refractory disease were eligible. Other eligibility criteria included symptomatic disease, > 2 weeks from last therapeutic agent used, >10% involvement with lymphoplasmacytic cells in the bone marrow, IgM paraprotein > 2x upper limit of normal, absolute neutrophil count >1000/mm3 and platelet count >75,000/mm3, serum creatinine of < 2 x upper limit of normal. NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by criteria established at the second consensus panel for WM. All patients received 10mg RAD001 daily for 28 days per cycle for 6 cycles; response was assessed after 2 cycles. RESULTS: 10pts (8 men and 2 women, median age is 62 years, range 52–71) have been treated to date. The median number of lines of prior treatment was 3 (range 1 – 5). The median IgM at baseline was 3970 mg/dL (range 3120– 7410); median M-spike at baseline was 2.07 gm/dL (range 1.41 – 4.02); and median hemoglobin was 11.3 g/dL (9.4–13.3). The median follow up was 4 months (range 1 – 7 months). Prior therapy included rituximab, nucleoside analogues (fludarabine and 2-CDA), combination chemotherapy (e.g CHOP, CVP), chlorambucil. and bortezomib. Seven patients are currently evaluable for response. The best response to single agent RAD001 after 2 cycles is presented in Table 1. Median duration of response has not been reached. Patients tolerated RAD001 well without significant toxicities. The main toxicities observed were apthous ulcers in 4 patients. One patient required dose reduction due to mucositis. One patient stopped therapy within the first month of treatment and went on to hospice care before succumbing to his disease after one month. Attributable toxicities otherwise proved manageable with appropriate supportive care and RAD001 was generally well tolerated, with no peripheral neuropathy. CONCLUSIONS: Oral RAD001 as monotherapy has been well tolerated and demonstrates exciting activity achieving PR + MR in 57%, and/or stabilization of disease in 43% of evaluable patients with relapsed WM. Accrual of a total of 30 patients is rapidly ongoing. Updated data will be presented at the meeting. Table 1 Response N=7; ORR (CR+PR+MR)= 57% Median time to best response (months) Partial Response 1 (14%) 5 Minimal Response 3 (43%) 4 (3–6) Stable Disease (SD) 3 (43%) NA Progressive Disease 0