Citations

Objective This study was designed to evaluate the roles of microRNAs (miRNAs) in slow transit constipation (STC). Design All human tissue samples were from the muscularis externa of the colon. Expression of 372 miRNAs was examined in a discovery cohort of four patients with STC versus three age/sex-matched controls by a quantitative PCR array. Upregulated miRNAs were examined by quantitative reverse transcription qPCR (RT-qPCR) in a validation cohort of seven patients with STC and age/sex-matched controls. The effect of a highly differentially expressed miRNA on a custom human smooth muscle cell line was examined in vitro by RT-qPCR, electrophysiology, traction force microscopy, and ex vivo by lentiviral transduction in rat muscularis externa organotypic cultures. Results The expression of 13 miRNAs was increased in STC samples. Of those miRNAs, four were predicted to target SCN5A , the gene that encodes the Na + channel Na V 1.5. The expression of SCN5A mRNA was decreased in STC samples. Let-7f significantly decreased Na + current density in vitro in human smooth muscle cells. In rat muscularis externa organotypic cultures, overexpression of let-7f resulted in reduced frequency and amplitude of contraction. Conclusions A small group of miRNAs is upregulated in STC, and many of these miRNAs target the SCN5A-encoded Na + channel Na V 1.5. Within this set, a novel Na V 1.5 regulator, let-7f, resulted in decreased Na V 1.5 expression, current density and reduced motility of GI smooth muscle. These results suggest Na V 1.5 and miRNAs as novel diagnostic and potential therapeutic targets in STC.

Introduction: Selinexor is a novel, oral selective inhibitor of nuclear export (SINE) which forces nuclear retention and activation of tumor suppressor proteins. Selinexor plus low dose dexamethasone (Sel-dex) was recently approved in the United States based on data from the STORM study wherein, Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. The presence of high-risk cytogenetic abnormalities is known to have a poor prognosis in multiple myeloma, with transient responses. We performed post-hoc analyses to determine the outcomes in patients with relapsed/refractory myeloma treated with Sel-dex based on the baseline cytogenetic abnormalities. Methods: STORM was a phase 2b, open-label study which enrolled patients with relapsed and refractory myeloma. Selinexor 80 mg in combination with dexamethasone 20 mg was administered orally, twice weekly. The primary endpoint was ORR. For this analysis, we pooled 78 patients (48 quad-refractory and 30 penta-refractory) from STORM, part 1 and 122 patients (penta-exposed and triple class refractory) from STORM, part 2 to compare outcomes between high-risk and standard risk cytogenetics groups. High-risk cytogenetics was defined as having at least 1 of the following abnormalities by fluorescence in-situ hybridization (FISH) at baseline: del(17p), t(4;14), t(14;16), and gain(1q) in >5% of screened plasma cells. The FISH analyses were performed at a central laboratory and used to assess cytogenetic risk status. Results: Of the 200 patients, 122 (61%) had high-risk disease (del(17p): 36%, t(4;14): 18%, t(14;16): 5%, and gain(1q): 36%). The ORR in high-risk patients was 20.5% (very good partial response [VGPR)]: 5.7% and partial response [PR]: 14.8%) and the ORR was 29.5 % (complete response [CR]: 2.6%, VGPR: 3.8%, and PR: 23.1%) in standard-risk patients. The clinical benefit rate (CBR) was 35.2% in high-risk patients compared with 38.5% in standard-risk patients. Median duration of clinical benefit (DOCB) was 4.4 and 6.2 months in the high-risk and standard-risk patients respectively. Median progression-free survival (PFS) was 3.8 and 4.2 months and overall survival (OS) was 8.6 and 9.4 months in the high-risk and standard-risk patients, respectively. Efficacy by specific cytogenetic abnormality is presented in Table 1 below (Due to the small sample size (n=11), data for the t(14;16) subgroup are not presented separately). Conclusions: Sel-dex demonstrated a similar CBR in patients with high risk and standard risk disease and preserved clinical benefit in heavily pre-treated patients who had rapidly proliferative disease and high-risk cytogenetics at baseline. The benefit was maintained across cytogenetic risk subgroups with a higher ORR in the t(4;14) and gain(1q) subgroups. The DOR and OS was similar across all the subgroups. These analyses support the use of Sel-dex in patients with high-risk cytogenetics and warrant further evaluation of selinexor in combination with other anti-myeloma therapies in high-risk disease. Disclosures Nooka: GSK: Honoraria, Other: advisory board participation; Amgen: Honoraria, Other: advisory board participation; BMS: Honoraria, Other: advisory board participation; Janssen: Honoraria, Other: advisory board participation; Spectrum pharmaceuticals: Honoraria, Other: advisory board participation; Adaptive technologies: Honoraria, Other: advisory board participation; Celgene: Honoraria, Other: advisory board participation; Takeda: Honoraria, Other: advisory board participation. Yee:Adaptive: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Huff:Karyopharm, Sanofi, MiDiagnostics: Consultancy; Member of Safety Monitoring Board for Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees. Vogl:Karyopharm Therapeutics: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Active Biotech: Consultancy. Chari:Novartis Pharmaceuticals: Research Funding; GlaxoSmithKline: Research Funding; Array Biopharma: Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Oncoceutics: Research Funding. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; alexion: Consultancy; Janssen: Consultancy. Lonial:Genentech: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy; BMS: Consultancy; Janssen: Consultancy, Research Funding; GSK: Consultancy; Celgene Corporation: Consultancy, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding. Vij:Takeda: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Janssen: Honoraria; Genentech: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Tuchman:Karyopharm: Honoraria; Celgene: Honoraria, Research Funding, Speakers Bureau; Amgen: Research Funding; Merck: Research Funding; Prothena: Research Funding; Roche: Research Funding; Sanofi: Research Funding; Alnylam: Honoraria, Research Funding. Biran:Bristol Meyers Squibb: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Siegel:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Richardson:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Liu:Karyopharm Therapeutics: Employment, Equity Ownership. Joshi:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jagannath:Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Merck: Consultancy.

Introduction: Short telomere syndromes (STS) are accelerated aging syndromes affecting hematopoietic, pulmonary, hepatobiliary and/or immunological systems. Clinical assessment of age-appropriate telomere length (TL) is performed using flow cytometry & fluorescence in-situ hybridization (flowFISH). Screening for germline variants in STS-related genes is guided by flowFISH-determined centile categories of TL, with screening recommended for TL <1st centile or 1-10th centile in lymphocytes (L) or granulocytes (G). However, the utility of genetic testing for patients with TL >10th centile and integration of clinical phenotype with flowFISH data in predictive algorithms is currently unclear. Methods: FlowFISH testing was done at reference laboratories in Vancouver (Repeat Diagnostics; Canada) & Johns Hopkins University (JHU, USA). Salient clinical features were pre-determined as, personal history of premature hair greying (onset at age < 30 years), idiopathic pulmonary fibrosis (IPF) or IPF/emphysema overlap (in smokers), cryptogenic cirrhosis or NRH, unexplained cytopenias &/or immunodeficiency, & family history of the above (in >1 1st or 2nd degree relatives). Clinical likelihood score (CLS) was assigned as low (1), intermediate (int, 2) or high (>2), based on the number of aforementioned clinical features present prior to flowFISH testing. Genetic testing was performed using either an in-house or commercial bone marrow failure-specific next generation sequencing (NGS) panel or whole exome sequencing (WES), and data for known variants affecting telomerase or telomeric function (TERT, TERC, DKC1, TINF2, NHP2, NOP10, TCAB1, NAF1, & RTEL1) was recorded. Results: One hundred forty-nine patients at our institution underwent TL assessment at Repeat diagnostics (n=38) and JHU (n=111) laboratories, respectively. Median age was 56 (range: 7-79) years; 88 (59%) being males. Significant family history was present in 40 (27%) patients, while premature greying of hair was present in 13 (9%) patients. Organ-specific clinical features included unexplained cytopenias (n=89, 60%) IPF (n=71, 48%), cryptogenic cirrhosis or NRH (n=21, 14%), & unexplained immunodeficiency (n=14, 9%). CLS stratification included low (n=74, 50%), int (n=54, 36%), & high (n=21, 14%), with higher CLS significantly correlating with lower delta TL for L (p=0.0005) but not G (p=0.3). Genetic testing was performed in 51 (35%) patients (NGS-51, WES-1) among which 13 (26%) patients had a telomere-associated variant; 5 (10%) pathogenic (pv, all TERT). CLS alone was unable to predict likelihood of finding a telomere-associated variant (p=0.4). Based on age-appropriate centile categorization of L & G TL (information for both available in 134 patients), patients were stratified into six groups (table 1). TL <1st centile in L: This group was further divided into two groups; TL<1st centile in both L & G [A1, n=7, CLS low-3 (43%), int-2 (29%), & high-2 (29%)] and TL <1st centile in L and 1-50th centile in G (A2, n=2, CLS low & high) patients. Among the 4 (57%) patients who underwent genetic (NGS-3, WES-1) testing, 3 (75%) had TERTpv in A1 subgroup and 1 A2 subgroup patient had a VUS in TERT.TL <1st centile in G, 1-10th centile in L (n=18): This group included 9 (50%) low, 8 (44%) int and 1 (6) high CLS patients, of which only 1 of 8 NGS-tested patients had TERTpv.TL 1-10th centile in L or G: This group was divided into; 1-10th centile in both L & G [C1, n=28, CLS low-3 (11%), int-14 (50%), high-11(39%)] of whom 8 (22%) underwent NGS with no pathogenic variants but 3 VUS in RTEL1, NAF1 & PARN genes, and 1-10th centile in L, >1-90th centile in G [C2, n=36, CLS low-19 (53%), 16 (44%), 1 (3%)] of whom 8 (22%) underwent NGS with 1 TERTpv and 2 VUS in TINF2TL >10th centile in L & 1-90th centile in G (n=43, 32%): CLS stratification in this group included 27 (63%) low, 12 (28%) int, 4 (9%) high. NGS testing was done in 13 (30%) patients [CLS low-9(69%), int 2(15%), high 2 (15%)], of whom only 2 (15%) had VUS in TINF2 and TERT gene, but no pathogenic variants (figure 1). Conclusion: Our study demonstrates the importance of using a flowFISH assay based predictive algorithm to screen patients with suspected STS for telomere-related genetic alternations, in comparison to a clinical likelihood score. We also demonstrate a limited role for genetic testing in patients with lymphocyte TL >10th centile, regardless of the clinical likelihood score. Disclosures Patnaik: Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Myelofibrosis (MF) is a myeloproliferative neoplasm associated with splenomegaly, debilitating symptoms, progressive bone marrow fibrosis and shortened survival. Inflammatory cytokines are associated with the disease and monitoring cytokine levels provides information about response to therapy. Momelotinib (MMB) is a JAK1/2 inhibitor under investigation for the treatment of MF that has been shown to be safe and efficacious while providing an anemia benefit to MF patients in the phase I/II studies: CCL09101 (ASH 2013) and YM387-II (EHA 2014). AIMS: To perform an exploratory analysis of the association between cytokines and anemia-related laboratories, 8 week transfusion response, spleen response by MRI at 24 weeks and total symptom score (TSS) reduction (≥50% decrease at week 24) and JAK2 mutation status, in the phase I/II, open-label YM387II trial. METHODS: 61 patients were enrolled and received MMB treatment. Whole blood samples were collected at baseline, 6 and 24 hours post-dose on day 1, and weeks 8 and 20. Plasma levels of 25 cytokines were analyzed by ELISA or MSD. Comparison of post-treatment data with baseline was carried out using Wilcoxon signed rank tests. Significant change from baseline was declared when ≥ 20% change from baseline was observed with Bonferroni adjusted p < 0.05. As this was an exploratory evaluation, comparison between treatment responders and non-responders was carried out using Wilcoxon rank sum test with no multiple testing corrections. Correlations between the cytokines and main biological parameters were investigated using Spearman correlation coefficients. RESULTS: JAK2V617F allele burden. The prevalence of JAK2V617F-positive patients was 68%. A statistically significant decline in JAK2V617F allele burden from baseline in this subgroup was observed at week 12 (median decrease 16.6%; p = 0.0063; n=21) and week 24 (median decrease 21.1%; p = 0.0019; n=18). Higher baseline IGFBP1 was associated with JAK2V617 mutation (48.2% higher in JAK2 mutated patients than in wildtype patients; p = 0.027). Cytokines and iron metabolism markers at baseline At baseline, hepcidin and IL-8 were anti-correlated with anemia-related markers such as transferrin and hemoglobin (Hb) (Spearman correlation coefficients < -0.5). IL-6, CRP and IL-10 showed strong, positive correlation (Spearman correlation coefficients > 0.5). Lower baseline IL-6 was associated with 24 week spleen response (42.3% lower in responders, p = 0.005); higher baseline thrombopoeitin (TPO) was associated with transfusion response at 8 week (3-fold higher in responders, p = 0.002). Baseline ferritin was 63.7% lower in TSS responders compared to non-responders (p = 0.015). On-treatment changes of cytokines and iron markers A significant decrease was observed in CRP, EPO, IL-6, IL-10, IL-12, TNFRII and TNFα following MMB treatment. IL-6 was reduced 30.3% as early as 6 hrs after first dose of MMB and CRP levels were reduced 27.3% after 24 hrs after treatment and continued to decline to 75% by week 4. A peak of IGFBP1 at 24h and increased TPO were observed. Decreased IL-12 and increased IL-8 at week 8 was significantly associated with 24 week spleen response (p < 0.05). Decline of CRP at week 8 was associated with TSS response (p = 0.045). Hb stayed at or above baseline for 6 months. An early peak of Hb was observed at Day 15 which was correlated with a significant increase in red blood cells and decrease in reticulocytes. CONCLUSIONS: In this exploratory analysis, a rapid and sustained reduction in inflammatory cytokines was observed with MMB treatment as expected based on the mechanism of action of MMB through JAK1/2 inhibition. Data from this study suggest an association between IGFBP1 and JAK/STAT signaling in myelofibrosis that will need to be explored in future studies with larger sample sets. Individual baseline biomarkers were correlated with MMB response, but no single biomarker was associated with all responses. Changes in IL-12 and IL-8 were significantly correlated with 24 week spleen response. The Day 15 data suggest that MMB treatment facilitates erythrocyte maturation. These observations, as well as a panel of iron metabolism markers and cellular signaling pathways, will be investigated in a planned Phase 2 translational biology study of MMB in transfusion-dependent subjects with MF (Gilead Sci: GS-US-352-1672). Disclosures Gupta: Incyte: Honoraria, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis Pharmaceuticals Corporation: Consultancy; NS Pharma: Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Genentech: Research Funding; Pfizer: Research Funding. Deininger:Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zhang:Gilead Sciences: Employment. Xiao:Gilead Sciences: Employment. Collins:Gilead Science: Employment. Kwei:Gilead Sciences: Employment. Joshi:Gilead Sciences: Employment. Brachmann:Gilead Sciences: Employment.

This review compiles scientific data about the real dangers faced by people with epilepsy (PWE) who drive. Those include risks of motor vehicle accidents (MVA) in PWE as compared with controls (individuals without epilepsy) and as compared with persons with other medical conditions that impact fitness to drive. Data regarding Accident rates as related to seizure free intervals (SFI), single vs. multiple seizure events, and/or antiseizure drug (ASD) taper and reintroduction are discussed. Variation in state, national, and international laws and guidance for non-commercial and commercial drivers is highlighted, along with some related reasons for driving restrictions. The review concludes by emphasizing the importance of physicians educating patients about local driving laws and about risks of ASD non-adherence. The need for a broader, multi-stakeholder re-examination of driving regulations for PWE is noted.

e20600 Background: Immune checkpoint inhibitors (ICIs) have changed the treatment paradigm of advanced NSCLC and SCLC. The populations in clinical trials generally were composed of patients (pts) with excellent performance status (PS), a minimal number of prior lines of therapy, and no history of (h/o) autoimmune disease (AD). The aim of this retrospective study was to investigate the predictors of survival in less fit and more heavily pretreated lung cancer pts at our institution. Methods: Medical records of lung cancer pts who started single-agent ICI from 2015 to 2018 were reviewed for data collection. Progression-free survival (PFS) and overall survival (OS) were compared by age, PS, smoking, PD-L1 expression, brain metastasis, prior lines of systemic therapy, h/o AD, and immune-related adverse events (irAE). Results: We included 150 pts who received at least 1 dose of nivolumab, pembrolizumab, or atezolizumab (median age 66, range 36-92, 56% female, 89% NSCLC, 97% stage 4, 13% never smoker, 34% ECOG ≥ 2, 37% ≥ 2 prior lines of therapy, 29% developed irAE). The overall response rate was 30% and clinical benefit rate 51% (3% CR, 27% PR, 21% SD). The median PFS was 3.7 months (m) overall and 12.3 m for those with ≥ 4 cycles of therapy. The median OS was 12.4 m overall and 26.0 m for those with ≥ 4 cycles. The median PFS and OS were not significantly different by age, PS, smoking, PD-L1, brain metastasis, prior lines of therapy, or h/o AD. The median OS was longer for pts with ECOG 0-1 than those ≥ 2 (14.6 vs 7.5 m, p < .001). The median PFS and OS for pts with irAE were longer compared to those without irAE (12.3 vs 2.6 m, p < .001 for PFS and 28.9 vs 9.1 m, p = .001 for OS). Multiple Cox regression analysis identified ECOG 0-1 (HR 0.54, p = .007) and irAE (HR 0.48, p = .003) to be independently associated with improved OS. 27 pts (18%) required steroids for irAE. There were no treatment-related deaths. Of 11 pts with h/o AD, only 1 experienced disease flare. Conclusions: The clinical benefit of ICIs persists in older or heavily pretreated pts. ECOG 0-1 and incident irAE predicted for improved survival. Survival for pts with ECOG ≥ 2 is very limited, suggesting ICIs should be used judiciously in this group. Therapy was well tolerated, with a low risk for flare of previous autoimmune disease.