Majority Of Serious Adverse Events Research Articles

Outcome of adult patients with JIA treated with the biosimilar Benepali®: results of the biologic register JuMBO

BackgroundTo analyze therapy adherence, safety, and outcome in adult patients with juvenile idiopathic arthritis (JIA) treated with the etanercept biosimilar Benepali® (Biogen Inc, Cambridge, USA).MethodsData from the prospective registry, JuMBO (Juvenile arthritis MTX/Biologics long-term Observation), were used for the analysis. JuMBO is a long-term observational cohort study. It follows adult patients with JIA who were formerly included in the national JIA biologic register (BiKeR Registry). Both registries provide individual trajectories of clinical data and outcomes from childhood to adulthood in JIA patients treated with disease-modifying anti-rheumatic drugs (DMARDs).ResultsEighty-three patients from the German JuMBO registry were treated with Benepali®. Of these, 74% had switched from Enbrel® (Pfizer Inc., NYC, USA) the originator of etanercept to Benepali® for cost reasons. Therapy survival of patients treated with Benepali® in comparison to Enbrel® in patients matched by significant parameters was comparable. Adverse events (AE) were reported in 25.3% and serious adverse events (SAE) in 9.6% of patients. Physicians rated no SAE causative related to Benepali®. The majority of SAEs were surgical/medical procedures and there was only one infection. All efficacy parameters (cJADAS-10, Physician Global Assessment, number of joints with active arthritis, patients’ overall well-being, pain, and HAQ) demonstrated improvement over 24 months (p-values were not significant). 9.6% of patients permanently discontinued Benepali® because of an AE.ConclusionsTolerability and effectiveness of the biosimilar Benepali® were satisfactory and therapy survival was comparable to the originator. Further data on therapy with biologics and biosimilars such as Benepali® must be collected by registries such as BiKeR and JuMBO in order to optimize therapy and patient outcomes and to reduce costs in the health system in the long term.

Repurposing Ophthalmologic Timolol for Dermatologic Use: Caveats and Historical Review of Adverse Events.

Ophthalmic timolol solution is increasingly being repurposed as a topical therapeutic for a variety of dermatologic diseases, including pyogenic granulomas, infantile hemangiomas, and chronic wounds. There are no published guidelines or protocols for use in these indications in adults, and the dermatologic community may not be familiar with adverse events that have been extensively documented relating to its ophthalmic use. We review the evidence available relating to adverse events to topical timolol use to evaluate its safety in dermatologic applications and to alert clinicians to screening and monitoring that is needed when repurposing this drug for dermatologic use. The majority of serious adverse events associated with ophthalmic timolol were reported in the first 7 years of use, between 1978 and 1985, of which most common were cardiovascular and respiratory events, but also included 32 deaths. The available evidence suggests that ophthalmic timolol safety profiling may have been incomplete prior to widespread use. Recent clinical trials for dermatologic indications have focused on documenting efficacy and have not had rigorous monitoring for potential adverse events. Topical timolol may be safe and effective for the treatment of various dermatologic conditions in patients whose medical histories have been carefully reviewed for evidence of pre-existing cardiac or pulmonary disease and are monitored for potential adverse events. Despite the wide use of timolol in ophthalmologic practice, safe dermatologic repurposing requires recognition of the potential for facilitated systemic absorption though the skin and appreciation of its history of adverse events.

Predictors of Medical Serious Adverse Events in Hip Fracture Patients Treated With Arthroplasty.

Patients with hip fractures are often frail with multiple comorbidities and at risk of medical serious adverse events (SAEs). We investigated the HEALTH trial patient population to ascertain predictors of SAEs. We performed a multivariable Cox regression analysis. Occurrence of SAEs was included as the dependent variable with 31 potential prognostic factors being included as independent variables. One thousand four hundred forty-one patients were included in this analysis. Three hundred seventy (25.6%) patients suffered from an SAE. The most common events were cardiac (38.4%, n = 105), respiratory (20.8%, n = 77), and neurological (14.1%, n = 77). The majority of SAEs (50.8%, n = 188) occurred in the first 90 days after hip fracture with 35.4% occurring in the first 30 days (n = 131). Body mass index (BMI) between 18.5 and 24.9 compared with BMI between 25 and 29.9 [hazard ratio (HR) 1.32, P = 0.03] and receiving a total hip arthroplasty compared with a bipolar hemiarthroplasty (HR 1.36, P = 0.03) were associated with a higher risk of a medical SAE within 24 months of femoral neck fracture. Age (P = 0.09), use of femoral cement (P = 0.59), and use of canal pressurization (P = 0.37) were not associated with a medical SAE. Total hip arthroplasty is associated with more SAEs in the immediate postoperative period, and care should be taken in selecting patients for this treatment compared with a hemiarthroplasty. A higher BMI may be protective in hip fracture patients while age alone does not predict SAEs and neither does the use of femoral cement and/or pressurization. Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

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Ketorolac for postoperative pain in children.

Children who undergo surgical procedures in ambulatory and inpatient settings are at risk of experiencing acute pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce moderate to severe pain without many of the side effects associated with opioids. However, NSAIDs may cause bleeding, renal and gastrointestinal toxicity, and potentially delay wound and bone healing. Intravenous administration of ketorolac for postoperative pain in children has not been approved in many countries, but is routinely administered in clinical practise. To assess the efficacy and safety of ketorolac for postoperative pain in children. We searched the following databases, without language restrictions, to November 2017: CENTRAL (The Cochrane Library 2017, Issue 10); MEDLINE, Embase, and LILACS. We also checked clinical trials registers and reference lists of reviews, and retrieved articles for additional studies. We included randomised controlled trials that compared the analgesic efficacy of ketorolac (in any dose, administered via any route) with placebo or another active treatment, in treating postoperative pain in participants zero to 18 years of age following any type of surgery. We used standard methodological procedures expected by Cochrane. Two review authors independently considered trials for inclusion in the review, assessed risk of bias, and extracted data. We analyzed trials in two groups; ketorolac versus placebo, and ketorolac versus opioid. However, we performed limited pooled analyses. We assessed the overall quality of the evidence for each outcome using GRADE, and created a 'Summary of findings' table. We included 13 studies, involving 920 randomised participants. There was considerable heterogeneity among study designs, including the comparator arms (placebo, opioid, another NSAID, or a different regimen of ketorolac), dosing regimens (routes and timing of administration, single versus multiple dose), outcome assessment methods, and types of surgery. Mean study population ages ranged from 356 days to 13.9 years. The majority of studies chose a dose of either 0.5 mg/kg (as a single or multiple dose regimen) or 1 mg/kg (single dose with 0.5 mg/kg for any subsequent doses). One study administered interventions intraoperatively; the remainder administered interventions postoperatively, often after the participant reported moderate to severe pain.There were insufficient data to perform meta-analysis for either of our primary outcomes: participants with at least 50% pain relief; or mean postoperative pain intensity. Four studies individually reported statistically significant reductions in pain intensity when comparing ketorolac with placebo, but the studies were small and had various risks of bias, primarily due to incomplete outcome data and small sample sizes.We found limited data available for the secondary outcomes of participants requiring rescue medication and opioid consumption. For the former, we saw no clear difference between ketorolac and placebo; 74 of 135 (55%) participants receiving ketorolac required rescue analgesia in the post-anaesthesia care unit (PACU) versus 81 of 127 (64%) receiving placebo (relative risk (RR) 0.85, 95% confidence interval (CI) 0.71 to 1.00, P = 0.05; 4 studies, 262 participants). For opioid consumption in the PACU, we saw no clear difference between ketorolac and placebo (P = 0.61). For the time period zero to four hours after administration of the interventions, participants receiving ketorolac received 1.58 mg less intravenous morphine equivalents than those receiving placebo (95% CI -2.58 mg to -0.57 mg, P = 0.002; 2 studies, 129 participants). However, we are uncertain whether ketorolac has an important effect on opioid consumption, as the data were sparse and the results were inconsistent. Only one study reported data for opioid consumption when comparing ketorolac with an opioid. There were no clear differences between the ketorolac and opioid group at any time point. There were no data assessing this outcome for the comparison of ketorolac with another NSAID.There were insufficient data to allow us to analyze overall adverse event or serious adverse event rates. Although the majority of serious adverse events reported in those receiving ketorolac involved bleeding, the number of events was too low to conclude that bleeding risk was increased in those receiving ketorolac perioperatively. There was not a statistically significant increase in event rates for any specific adverse event, either in pooled analysis or in single studies, when comparing ketorolac and placebo. When comparing ketorolac with opioids or other NSAIDs, there were too few data to make any conclusions regarding event rates. Lastly, withdrawals due to adverse events were vary rare in all groups, reflecting the acute nature of such studies.We assessed the quality of evidence for all outcomes for each comparison (placebo or active) as very low, due to issues with risk of bias in individual studies, imprecision, heterogeneity between studies, and low overall numbers of participants and events. Due to the lack of data for our primary outcomes, and the very low-quality evidence for secondary outcomes, the efficacy and safety of ketorolac in treating postoperative pain in children were both uncertain. The evidence was insufficient to support or reject its use.

Analyzing the Safety Profiles of IBD Biologics

BACKGROUND: There are four routinely prescribed classes of medications to treat inflammatory bowel disease (IBD): aminosalicylates (balsalazide, mesalamine, olsalazine, sulfasalazine), corticosteroids (budesonide, methylprednisolone, prednisone, prednisolone), immunomodulators (6-mercaptopurine, azathioprine, cyclosporine, methotrexate), and biologics (TNF-alpha antagonists [adalimumab, certolizumab, golimumab, and infliximab] and integrin receptor antagonists [natalizumab and vedolizumab]). Many patients worry about the safety of these medications as all classes except aminosalicylates carry warnings for serious adverse events on the Food & Drug Administration (FDA) labels. The biologic medications are of special concern due to media attention related to fatal cancers associated with use, particularly in boys and young men. We aimed to compare serious adverse events for biologics and other IBD medications with all other FDA-approved medications using adverse events reported to the FDA Adverse Event Reporting System (FAERS). We limited our primary analyses to medications associated with an IBD indication. METHODS: We queried FAERS for serious adverse events (SAE) using Empirica Signal (Oracle Corp., Redwood Shores, CA) based on reports made to the FDA between January 1998 and March 2017. We customized our disproportionality analysis to calculate and compare the cumulative EB05 values for serious adverse events of all IBD medications since their dates of approval. An EB05 value of 2 indicates that a medication-event frequency is double that of other medication-event pairs in the FAERS database (the EB05 is the lower confidence limit of a Bayesian disproportionality measure). We examined the SAE that are most common and carry the highest EB05 signals for each biologic. Lastly, we compared safety signals of IBD biologics indicated for a gastrointestinal indication versus all other indications. Gastrointestinal indications were selected by using Medical Dictionary for Regulatory Activities (MedDRA), a standardized dictionary of adverse events. RESULTS: From our analysis comparing cumulative EB05 values of SAE associated with a biologic with the indication of IBD to all other serious adverse events reported to FAERS, infliximab had the highest EB05 signal of 1.53. Adalimumab had the lowest cumulative EB05 value of 0.58. The cumulative EB05 values of corticosteroids, immunomodulators, and aminosalicylates were 1.0, 1.19, and 0.92, respectively. The majority of SAE were gastrointestinal and were present for biologics and other treatment classes. Relaxing the inclusion criteria to include a gastrointestinal indication, instead of an IBD indication, and allowing all indications (including rheumatoid arthritis) resulted in higher EB05 values. The highest cumulative EB05 values were observed for infliximab, vedolizumab, and immunomodulators. The highest safety signal associated with any IBD biologic treatment that was not a known complication of IBD or already listed on the label was listeria meningitis (EB05 38.05) which was only elevated for infliximab. Clostridium difficile (EB05 26.67) was the second highest safety signal and was seen with golimumab. CONCLUSION(S): Medications to treat IBD, including biologics, are as safe as all other FDA-approved drugs. There was no safety signal associated with any biologic to treat IBD associated with serious adverse events in general. We identified new serious adverse events that were not previously listed on the safety labels of biologics.

Long-Term Safety Experience with Arsenic Trioxide in Patients with Acute Promyelocytic Leukemia

Introduction: Therapeutic agents approved by the FDA are required to undergo postmarketing safety surveillance to meet regulatory and contractual requirements. Arsenic trioxide (Trisenox®) is approved for the treatment of patients with acute promyelocytic leukemia (APL) in the second-line setting, but is also commonly used in first-line regimens in combination with all-trans retinoic acid. Here, we summarize the accumulated safety data from global postmarketing surveillance of arsenic trioxide since its initial approval in 2000 to better understand its long-term safety in patients with APL.Methods: Cumulative data were collected from patients with APL since initial approval in 2000 from spontaneous reports submitted by healthcare professionals and consumers. The data collected were housed in the Teva Pharmaceuticals safety database. Adverse events (AEs) were coded according to MedDRA terms and classified by seriousness and expectedness (unexpected AEs are those not included in the product label at the time of the report or those that occurred at a higher incidence than previously reported).Results: As of July 7, 2016, a total of 2197 AE reports were received in association with arsenic trioxide use in patients with APL. There were 1735 reports classified as serious and 462 classified as nonserious. The most frequently reported (≥ 30 reports) serious AEs and serious AEs of interest are summarized in the table. Serious QT prolongation was the most commonly reported event, but the majority of events were expected, including four cases of torsades de pointes that may be associated with prolonged QT. Serious hematologic toxicities, including neutropenia and leukocytosis, were also common and expected, as was liver toxicity. The most common serious and unexpected events reported included white blood cell decrease, pancytopenia, increased gamma-glutamyltransferase level, and cardiac disorders (primarily ventricular tachycardia, ventricular extrasystoles) that may be associated with prolonged QT in some patients.Conclusions: The overall safety profile of arsenic trioxide is consistent with known toxicities; the majority of serious AEs are associated with QT prolongation. The clinical significance of the reported QT events is unclear, and reporting rates may change in the future because of evolving criteria for QT assessments (Roboz GJ, et al. J Clin Oncol 2014;32(33):3723). This overview was limited by voluntary reporting. However, the long-term, real-world experience with arsenic trioxide administration as a single agent or in combination provides a broader understanding of its safety profile.Sponsor: Teva Branded Pharmaceutical Products R&D [Display omitted] DisclosuresLo-Coco:Teva, Novartis, Baxalta, Pfizer: Consultancy; Teva, Lundbeck: Honoraria, Speakers Bureau. Pathak:Teva Pharmaceuticals: Employment, Equity Ownership.

Serious adverse events reported for antiobesity medicines: postmarketing experiences from the EU adverse event reporting system EudraVigilance.

Use of antiobesity medicines has been linked with serious cardiac and psychiatric adverse events (AEs). Spontaneous reports can provide information about serious, rare and unknown AEs occurring after the time of marketing. In Europe, information about AEs reported for antiobesity medicines can be accessed in the EudraVigilance (EV) database. Therefore, we aimed to identify and characterise AEs associated with the use of antiobesity medicines in Europe. AE reports submitted for antiobesity medicines (Anatomical Therapeutic Chemical (ATC) group A08A) from 2007 to 2014 and located in the EV database were analysed. AE data were categorised with respect to time, age and sex of patient/consumer, type of reporter, category and seriousness of reported AEs and medicines. Consumer AE reports were compared with reports from other types of reporters with respect to age and sex of consumer, seriousness, system organ class and medicine. The unit of analysis was one AE and one AE report, respectively. We located 4941 AE reports corresponding to 13 957 AEs for antiobesity medicines in the EV database. More than 90% of all AE cases were serious, including 159 deaths. The majority of AE cases were reported for female adults. The majority of serious AEs was reported for orlistat (37%) and rimonabant (22%). The largest share of serious AEs was of the type 'cardiac disorders' (19%) and 'psychiatric disorders' (18%). Consumer AEs reporting differed from other sources with respect to share and seriousness of AEs, type of AEs (system organ class) and medicines (ATC level 5). Many serious AEs were found for antiobesity medicines in EV, and consumers contributed with a relatively high share of reports. Although several products have been withdrawn from the market and new medicines are being marketed, the utilisation of antiobesity medicines is widespread, and therefore systematic monitoring of the safety of these medicines is necessary.

Molecular Profiling and Relationship with Clinical Response in Patients with IDH1 Mutation-Positive Hematologic Malignancies Receiving AG-120, a First-in-Class Potent Inhibitor of Mutant IDH1, in Addition to Data from the Completed Dose Escalation Portion of the Phase 1 Study

INTRODUCTION: Somatic mutations in the metabolic enzymes isocitrate dehydrogenase 1 and 2 (IDH1/2) confer gain-of-function activity in cancer cells, resulting in accumulation of the oncometabolite D-2-hydroxyglutarate (2-HG). High levels of 2-HG result in epigenetic changes and impaired cellular differentiation. IDH mutations have been identified in a spectrum of solid tumors and hematologic malignancies, with mutations in DNMT3A and NPM1 co-occurring with IDH1 most frequently (Molenaar et al. Leukemia 2015). AG-120 is a first-in-class, oral, potent, reversible, selective inhibitor of the IDH1 mutant enzyme being evaluated in an ongoing, first-in-human, phase 1, open-label study (NCT02074839). We report data, including clinical activity and safety, based on patients from the completed dose escalation phase. Molecular profiling, including observations of co-occurring genomic alterations at baseline, and relationship with clinical activity is also presented. METHODS: Patients with advanced IDH1 mutation-positive hematologic malignancies, diagnosed by local evaluation, receive AG-120 as a single agent orally once daily (QD) or twice daily (BID) continuously, in 28-day cycles. Bone marrow is examined on Days 15, 29, 57, and every 56 days thereafter. Primary objectives are safety, determination of maximum tolerated dose (MTD) and selection of a dose schedule for expansion cohorts and future phase 2 studies. Secondary objectives include clinical activity assessed by investigators using modified 2003 International Working Group Criteria in AML (Cheson et al). Molecular profiling was performed with the FoundationOne Heme next-generation sequencing (NGS) test on bone marrow and/or peripheral blood from all patients at pre-defined time points throughout the study. RESULTS: As of July 1, 2015, 66 patients were treated in the dose escalation phase, of whom 25 remain on treatment. Therapy has been well tolerated and the MTD was not reached. Dosing in the first cohort was 100 mg BID. The long half-life of AG-120 supported QD dosing subsequently, and 1200 mg QD was the highest dose evaluated. Dose escalation is now closed. The majority of adverse events (AEs) were grade 1 and 2, the most common being diarrhea (23%), fatigue (22%), and pyrexia (22%); the most common Grade ≥3 AE was febrile neutropenia (11%). The majority of serious AEs were disease-related. Of the 66 patients, 61 are response evaluable (patients with a Day 28 or later response assessment or who discontinued earlier than Day 28 for any reason). In all response evaluable patients, an estimated 55% had treatment durations of at least 3 months. Objective responses have been observed in 22 subjects (11 complete remissions [CR], 1 CR with incomplete platelet recovery, 4 partial responses and 6 marrow CRs), with a CR rate of 18% and an overall response rate (ORR) of 36% (22/61). Responses are durable, with a median duration of response among responders of 5.6 months [1.9, NE], including responses ≥11 months. Molecular profiling data from screening bone marrow was available in 38 patients. Among these 38, the most common co-mutations associated with IDH1 mutation were DNMT3A (67%) and NPM1 (24%). Incidence of additional co-mutations was CONCLUSION: AG-120, a potent, selective, oral inhibitor of mutant IDH1, is well tolerated in patients with advanced hematologic malignancies, and induces objective durable responses, with an ORR of 36%, including complete remissions. Molecular profiling may provide insights into the mechanisms of response and resistance. The data support the efficacy of AG-120 and provide continued validation of mutant IDH1 as a therapeutic cancer target. Disclosures DiNardo:Novartis: Research Funding. de Botton:Agios pharmaceuticals: Research Funding. Pollyea:Glycomimetics: Other: Member of data safety monitoring board; Pfizer: Consultancy; Karyopharm: Consultancy; Agios Pharmaceuticals: Consultancy; Celgene: Consultancy, Research Funding; Ariad: Consultancy. Stein:Seattle Genetics, Inc.: Membership on an entity9s Board of Directors or advisory committees; Agios: Membership on an entity9s Board of Directors or advisory committees. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Other: Advisory Board participation, Research Funding; Merck: Other: Advisory Board participation. Flinn:Cephalon, Inc; Teva Pharmaceutical Industries Ltd; Genentech, inc; Gilead: Research Funding. Altman:Astellas: Membership on an entity9s Board of Directors or advisory committees; BMS: Membership on an entity9s Board of Directors or advisory committees; Novartis: Membership on an entity9s Board of Directors or advisory committees; Spectrum: Membership on an entity9s Board of Directors or advisory committees; Ariad: Membership on an entity9s Board of Directors or advisory committees; Seattle Genetics: Membership on an entity9s Board of Directors or advisory committees. Derti:Agios Pharmaceuticals: Employment, Equity Ownership. Goldwasser:Agios Pharmaceuticals: Employment, Equity Ownership. Prahl:Agios Pharmaceuticals: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Agresta:Agios Pharmaceuticals: Employment, Equity Ownership. Stone:Agios: Consultancy; Novartis: Research Funding; AROG: Consultancy; Merck: Consultancy; Celator: Consultancy; Roche/Genetech: Consultancy; Karyopharm: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Abbvie: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Juno: Consultancy.

Novel method to collect medication adverse events in juvenile arthritis: results from the childhood arthritis and rheumatology research alliance enhanced drug safety surveillance project.

Few data are available regarding the rates of serious adverse events (SAEs) and important medical events (IMEs) outside of product-based registries and clinical trials for juvenile idiopathic arthritis (JIA). The Enhanced Drug Safety Surveillance Project (EDSSP) was developed to pilot a novel system to collect SAEs/IMEs in children with JIA. This analysis reports the results from this 4-year (2008-2012) EDSSP. Participating physicians were surveyed monthly to ascertain whether their JIA patients experienced an SAE or IME. Sites were surveyed every 6 months to determine the number of unique JIA patients seen at each site during that 6-month period. Reporting rates were calculated per 100 person-years and 95% confidence intervals (95% CIs) were calculated based on a Poisson distribution. Thirty-seven Childhood Arthritis and Rheumatology Research Alliance sites with 115 physicians participated. The mean response rate to the monthly surveys was 65%. There were 147 total SAEs and 145 total IMEs. The largest proportion of SAEs and IMEs occurred in children with polyarticular JIA (39% and 37%, respectively). The majority of SAEs and IMEs were reported for patients receiving therapy with biologic agents (76% and 69%, respectively). The total event rate for SAEs and IMEs combined was 1.07 events per 100 person-years (95% CI 0.95-1.19). The rates for SAEs and IMEs were 0.54 per 100 person-years (95% CI 0.45-0.63) and 0.53 per 100 person-years (95% CI 0.49-0.62), respectively. The EDSSP provided a simple tool for SAE/IME reporting within an established research network and resulted in a similar range of reported events as captured by a traditional product-based registry.

Updated Results from a Large, Ongoing, Treatment IND Study Using Defibrotide for Patients with Hepatic Veno-Occlusive Disease

▪Background: Severe hepatic veno-occlusive disease (VOD, also referred to as sinusoidal obstruction syndrome) with associated multi-organ failure (MOF) is a life-threatening complication of hematopoietic stem cell transplant (HSCT) and has an associated mortality rate >80%. Defibrotide has been shown to have a protective effect on injured endothelium and to restore the thrombo-fibrinolytic balance. In severe VOD, defibrotide has improved complete response (CR) rates and survival at Day +100 post HSCT compared with historical controls, and has also been shown to have a favorable safety profile. In the EU, defibrotide is now approved for the treatment of severe hepatic VOD in HSCT therapy. It is indicated in adults, adolescents, children, and infants >1 month of age. In the USA, there are currently no approved therapies for this complication; however, defibrotide has been made available since 2007 through an expanded access protocol directed treatment IND (T-IND). The aim of the T-IND is to gather additional data on safety and efficacy of defibrotide in a broader patient population, including those with severe VOD/MOF post HSCT, non-severe VOD post HSCT, and VOD following chemotherapy in the non-HSCT setting. This is the largest prospective evaluation of defibrotide for the treatment of VOD. Here we provide an update on the safety of defibrotide from this ongoing study.Methods: The original T-IND protocol required patients to have a diagnosis of VOD by Baltimore criteria (total bilirubin ≥2.0 mg/dL with ≥2 of the following: hepatomegaly, ascites, or 5% weight gain) with MOF (either renal and/or pulmonary failure) following HSCT; the study was amended to allow inclusion of patients with non-severe VOD (defined as no MOF) occurring either post-HSCT or post-chemotherapy. Key exclusion criteria include clinically significant bleeding or the need for >1 vasopressor. Defibrotide was given as a 2-hour infusion at 6.25 mg/kg IV every 6 hours (25 mg/kg/d) with a recommended minimum treatment duration of 21 days.Results: The current interim safety analysis is based on 612 patients enrolled between December 2007 and December 2013 (including 99 in 2013) for whom safety data is available and who received ≥1 dose of defibrotide. Across the USA, over the course of the study approximately 86 centers were active to enroll patients. Median patient age was 12 years (range <0.1–69), with 24.2% aged <1 month to 2 years, 39.4% aged >2 to 18 years, 34.9% aged >18 to 65 years, and 1.2% aged >65 years. Patients were primarily male (55.8%) and predominantly white (65.6%).Overall, 454 patients (74.2%) reported ≥1 treatment emergent adverse events (AEs). Of these, 138 patients (22.5%) had AEs that investigators assessed as related (possibly, probably, or definitely) to study medication. Related AEs in >2.0% were pulmonary hemorrhage (4.7%), gastrointestinal hemorrhage (3.6%), epistaxis (3.1%), and hypotension (2.8%). Serious AEs (SAEs) were reported by 368 patients (60.1%). The majority of SAEs were assessed as not related to study treatment; 82 patients (13.4%) had an SAE at least possibly related to study treatment, most commonly pulmonary hemorrhage (3.9%) and gastrointestinal hemorrhage (2.9%). AEs leading to death occurred in 254 patients (41.5%); these AEs were deemed by the investigators to be possibly related to study medication in only 17 patients (2.8%).Previously reported efficacy data at D +100 in 425 patients evaluable for outcome have shown survival of 55% (by Kaplan-Meier estimate) for patients following HSCT, and survival of 62% (by Kaplan-Meier estimate) in 45 patients following chemotherapy (without HSCT), respectively.Conclusions: Defibrotide therapy in patients with VOD was generally well tolerated in this population, with manageable toxicity, and promising results seen in terms of response and survival. Safety results from prior studies, which have also been associated with a low incidence of defibrotide-associated toxicities, have proven very consistent with the favorable tolerability profile seen in this largest experience to date. Enrollment to the T-IND study continues; updated results will be presented at the meeting.Support:Jazz PharmaceuticalsOff-Label UseDefibrotide is an investigational treatment for hepatic veno-occlusive disease in the United States. DisclosuresRichardson:Gentium S.p.A.: Membership on an entity’s Board of Directors or advisory committees; Jazz Pharmaceuticals Inc.: Research Funding. Off Label Use: Defibrotide is an investigational treatment for veno-occlusive disease in the United States.. Antin:Dana-Farber Cancer Institute: Employment; Tempera: Consultancy; Enlivex: Consultancy. Lehmann:Dana Farber/Boston Children’s Hospital: Employment. Bandiera:Gentium S.p.A.: Employment. Hume:Jazz Pharmaceuticals Inc.: Employment. Hannah:Jazz Pharmaceuticals: Consultancy. Nejadnik:Jazz Pharmaceuticals: Employment. Study Group:Gentium S.p.A.: Employment.

P-0153 - Imatinib Mesylate in Treatment of Advanced GIST – Single Institution Experience

Introduction: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract, representing 1-2% of all gastrointestinal malignancies. Imatinib mesylate is an inhibitor of the tyrosine kinase receptor and standard of care for treatment of metastatic or unresectable GIST. Due to reimbursement limits of our National Health System, currently imatinib used in a dose 400 mg/day is our only treatment option for advanced GIST. Our aim was to assess the efficacy and tolerability of imatinib in our daily practice. Methods: We have retrospectively analyzed data of patients with unresectable or metastatic GIST, treated from 2004 to 2013, with Imatinib mesylate 400 mg/day. The treatment outcomes as well as safety profile were evaluated. Adverse events were assessed in accordance with the National Cancer Institute Common Toxicity Criteria. Response Evaluation in Solid Tumors (RECIST) Criteria was used for estimating the tumor response rate. Results: A total of 51 patients with unresectable or metastatic GIST were identified, of which 45% were males and 55% females. 23 patients are still under treatment and 28 patients have died. Median age 62 (range 17-84). Treatment outcomes included complete response in 2(3,92%) patients, partial response in 14(27,45%), stable disease in 30(58,82%), and primary resistant in 5(9,8%) patients. The median progression-free survival was 28 months (range, 1-90). The median overall survival (OS) was 32 months (range 1,7-96). Following grade 3 or 4 adverse events were observed: anemia (13,5%), renal dysfunction (5%), hypoglycemia (2%), diarrhea (2%). Conclusion: Imatinib is a drug of great importance in treating GIST patents due to high efficacy, good toxicity profile and convenient usage. Our results have demonstrated good PFS as well as OS. However, a small difference between median PFS and OS, emphasizes need for second line therapy or dose escalation. The therapy was well tolerated and majority of serious adverse events were disease related and not caused by the treatment.

EPA-0405 – Tolerability and safety of as-needed nalmefene in the treatment of alcohol dependence: results from the phase 3 programme

The phase 3 programme investigating nalmefene for reduction of alcohol consumption in alcohol dependent patients comprised two 6-month studies (ESENSE1 and 2) and one 12-month study (SENSE), conducted in 19 European countries. To investigate the tolerability and safety of as-needed use of 18 mg nalmefene. 1997 patients with a diagnosis of alcohol dependence were recruited. Adverse events (AEs) and other safety variables were recorded. 797 patients in the placebo group and 1144 patients in the nalmefene group received study medication; patients took study medication on 62% and 51% of the days, respectively. The incidence of AEs was high in both the placebo and the nalmefene group (62.7% and 74.7%, respectively), and was not dependent on the drinking risk level at baseline. While mostly mild or moderate, these AEs did lead to dropout in some patients: 47 patients (6%) in the placebo group and 149 patients (13%) in the nalmefene group. Patients continuing in the studies seemed to develop tolerance with time for the most frequent AEs. Median time to event and median duration of these AEs were generally shorter for nalmefene than for placebo (many started after 1st dose). 35 patients (4.4%) in the placebo group and 57 patients (5.0%) in the nalmefene group had serious adverse events (SAEs). The majority of SAEs were not related to study medication and no apparent trends with respect to overall incidence or distribution across organ systems were noted. Nalmefene was well-tolerated and no major safety issues were identified.

Expensive anaesthesia complications

The major, costly, and catastrophic adverse consequences of anaesthesia are reviewed. The American Society of Anesthesiologists’ closed claims registry yields valuable insights. The size and success of claims is determined by the standard of care, and extent of injury. Ongoing assessment of the pattern of claims allows determination of high-risk patients and interventions, as well as the formulation of protocols or practice guidelines to reduce risk. Injuries to previously healthy individuals are inevitably more costly. Respiratory mechanisms still account for the majority of serious adverse events. However, the focus has shifted from intubation problems to extubation and the recovery room. Emerging areas of concern are claims that relate to nerve injury, with or without regional anaesthesia, postoperative visual loss, and monitored anaesthesia care and sedation. An area of particular concern, namely spinal-epidural haematoma associated with central neuraxial blockade, is a typical example of the closed claims registry/taskforce/protocol approach. Specific risk factors, such as use of anticoagulants close to the time of performance of the neuraxial block, traumatic technique, elderly patients, and renal dysfunction, have been identified. Protocols have been devised for risk reduction.

A Multicenter Study Evaluating the Efficacy and Safety of Bendamustine in the Treatment of Mantle Cell Lymphoma

Abstract 4940 Background:Bendamustine has evolved as an increasingly used chemotherapeutic agent for diverse lymphomas in the United States (US) and Europe. It is an alkylating agent that was approved in the US for use as a first line therapy for chronic lymphocytic leukemia and relapsed indolent B-cell non-Hodgkin's Lymphoma (NHL) in 2008. However, the two pivotal studies that established bendamustine for this indication included only few patients with mantle cell lymphoma (MCL). The goal of this retrospective study was to evaluate efficacy of bendamustine in MCL. Patients and Methods:We retrospectively reviewed the records of all MCL patients who were treated with bendamustine at Jackson Memorial Hospital and the Sylvester Comprehensive Cancer Center (both in Miami, FL) and the Stanford Cancer Center (in Stanford, CA). The primary endpoint was overall response rate (ORR) and secondary endpoints were overall survival (OS), time to treatment failure (TTF), and safety. Results:Thirty MCL patients received bendamustine, 28 in combination with rituximab and 2 as monotherapy. Nineteen of these patients were treated at the University of Miami and 11 at Stanford. The median age at diagnosis was 58 years and 77% of the patients were male. The most common extranodal site of involvement at diagnosis was the bone marrow (57%), followed by the GI tract (33%). Most patients presented with advanced disease, with 69% and 28% of the patients having stage IV and III disease at diagnosis, respectively. Seven patients (23%) were diagnosed with the blastic variant of MCL. Five patients received bendamustine as initial therapy and 25 for relapsed disease. Five of these patients had relapsed MCL after an autologous HSCT The most common schedule was bendamustine 100mg/m2 on days one and two and rituximab 375mg/m2 on day one of a 28 day cycle, for a median of six cycles. Of the 30 patients, there were fifteen complete responses (CR) and ten partial responses (PR), for an ORR of 83% (95% confidence interval [CI] 70–97%). With a median follow-up of 8 months (range 0.3–29.5 months), the median overall survival (OS) was not reached; the one-year OS rate was 73%; the two year OS rate was 67%. When OS and time to treatment failure (TTF) were stratified by response (using a 2-month landmark as the starting point for analysis), patients achieving a CR had a significantly longer OS and TTF compared to patients who did not achieve a CR (log rank p < 0.001). The TTF and OS were significantly worse for patients with the blastic variant versus the diffuse variant. In 5 patients with relapse post autologous HSCT, bendamustine induced a CR in three and a PR in one other patient. The majority of serious adverse events associated with bendamustine were hematological. Grade 3 or 4 neutropenia, anemia, and thrombocytopenia occurred in 23%, 3%, and 20%, respectively. Common non-hematologic grade 1 or 2 toxicities were fatigue (27%), edema (20%), erythematous rash (20%), and nausea (13%). Two patients developed neurological sequelae during or after treatment with bendamustine. The first patient developed left sided weakness and dysmetria ten months after completing therapy. A brain biopsy revealed progressive multifocal leukoencephalopathy. A second patient developed ataxia and incontinence while on rituximab plus bendamustine therapy and expired before a definitive diagnosis could be established. Conclusions:Bendamustine appears to have a favorable profile as a second-line agent for patients with relapsed MCL. The response rate is at least comparable to other therapies, especially when examined in light of the toxicity profile seen with other regimens. This study supports the need for continued investigation of bendamustine as a therapy for MCL patients both in the frontline and relapsed settings in prospective clinical trials, some of which are presently ongoing. Disclosures:No relevant conflicts of interest to declare.

The 12-month safety profile of dexlansoprazole, a proton pump inhibitor with a dual delayed release formulation, in patients with gastro-oesophageal reflux disease

Dexlansoprazole MR is a Dual Delayed Release formulation of dexlansoprazole, an enantiomer of lansoprazole, designed to extend the duration of acid suppression. To assess the 12-month safety of dexlansoprazole MR in patients with symptomatic gastro-oesophageal reflux disease (GERD). In this randomised open-label study, patients received dexlansoprazole MR 60 or 90 mg once-daily for 12 months. Safety was evaluated at months 1, 3, 6, 9 and 12/final visit through physical examinations, laboratory evaluations, endoscopies, gastric biopsies, fasting serum gastrin values and adverse events (AEs). Of 591 patients receiving dexlansoprazole MR 60 and 90 mg, 71% and 65%, respectively, experienced ≥1 treatment-emergent AE; the most frequent AE was upper respiratory infection (14% and 13% in the 60- and 90-mg groups). Thirty patients experienced ≥1 serious AE; a majority of serious AEs were unrelated to study drug. No clinically meaningful change in any clinical laboratory parameters was noted. As expected, serum gastrin values rose with dexlansoprazole therapy; increases were not dose related. No clinically concerning trends were identified in gastric pathology results; no endocrine cell hyperplasia, adenocarcinoma, or lymphoma were observed. Twelve-month treatment with dexlansoprazole MR 60 and 90 mg was well tolerated by GERD patients in this study (Clinicaltrials.gov identifier NCT00255190).

Phase II Trial of Standard Dose Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP) and Rituximab (R-CHOP) Plus Bevacizumab for Advanced Stage Diffuse Large B-Cell (DLBCL) NHL: Southwest Oncology Group Study S0515

AbstractAbstract 591 Introduction:VEGF and VEGF receptors (VEGFR) are frequently over-expressed in DLBCL. Elevated levels of circulating VEGF have also been associated with a worse prognosis and resistance to chemotherapy. This trial was initiated to determine if the addition of anti-VEGF targeted therapy to standard R-CHOP would improve PFS without adding significant toxicity in previously untreated patients with stage III, IV or bulky stage II DLBCL. Methods:64 eligible patients were treated with standard dose R-CHOP plus bevacizumab administered at 15mg/kg on day1. Patients received therapy every 21 days for a maximum of 8 cycles. Both biologics were administered prior to chemotherapy. Pretreatment tumor biopsies from 40 patients were submitted for construction of tissue microarrays for VEGF/VEGFR immunohistochemical analysis. Two 1 mm tissue cores were assessed for each DLBCL specimen and expression of VEGF and VEGFR scored on a scale of 0 (no expression) to +3 (strong expression) by 2 pathologists. Both lymphoma and endothelial cell (blood vessel) staining was assessed with the higher score being recorded. Results:73 patients were enrolled with 9 patients found ineligible, the majority (n = 7) secondary to incorrect histology. Patient characteristics for the 64 eligible patients included: median age 68 years with 77% of the patients over 60 years (age range: 22–85), 44 males, IPI scores: 3 low, 22 low-intermediate, 29 high-intermediate, and 8 high. Median follow-up is 2.0 years. Based on prior studies, and adjusted for the observed IPI factor frequencies seen in this study, the projected 1 year historical PFS rate in this population would be 71%, while the observed 1 year PFS estimate was 77% (95% CI: 66 – 87%). The PFS estimate at 2-years was 69% (95% CI: 57 – 80%). The 1 and 2 year overall survival estimates were 86% and 79%, respectively. Among all patients (including ineligibles), a total of 30 patients experienced 40 serious adverse events (SAE) while on study. The majority of SAE were hematologic, but also included 2 patients with sudden death, 5 patients with GI perforations (4 occurring after cycle 1), and 5 patients with grade 3 or 4 thrombotic events. Additional adverse events of interest included 7 patients who developed hypertension (4 patients with grade 3), and 13 patients who developed grade 2 or 3 left ventricular dysfunction. VEGF expression was observed in 98% (IHC scoring: +1 in 18%, +2 in 38%, and +3 in 43%) of lymphoma cells and VEGFR was expressed in 95% (IHC scoring:+1 in 28%, +2 in 40%, and +3 in 28%) of blood vessels by immunohistochemistry analysis. Conclusions:Despite high protein expression of VEGF and VEGFR in newly diagnosed DLBCL specimens, the addition of bevacizumab to standard R-CHOP chemotherapy did not significantly improve PFS from expected results with R-CHOP alone. Although the observed 1-year PFS estimate trended higher than the historical estimate, a target PFS of 81% was pre-specified as warranting further investigation. Significant toxicities were associated with the addition of bevacizumab, including an increased incidence of cardiac dysfunction and GI perforation. Our results do not support additional studies of this regimen in this patient population. Disclosures:Stopeck:Genentech: Consultancy, Honoraria, Speakers Bureau. Off Label Use: Bevacizumab therapy in NHL. Fisher:Roche: Consultancy.