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After analyzing treatment patterns in chronic lymphocytic leukemia (CLL) (objective 1), we investigated the relative effectiveness of ibrutinib versus other commonly used treatments (objective 2) in patients with treatment-naïve and relapsed/refractory CLL, comparing patient-level data from two randomized registration trials with two real-world databases. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated using a multivariate Cox proportional hazards model, adjusted for differences in baseline characteristics. Rituximab-containing regimens were often prescribed in clinical practice. The most frequently prescribed regimens were fludarabine + cyclophosphamide + rituximab (FCR, 29.3%), bendamustine + rituximab (BR, 17.7%), and other rituximab-containing regimens (22.0%) in the treatment-naïve setting (n = 604), other non-FCR/BR rituximab-containing regimens (38.7%) and non-rituximab–containing regimens (28.5%) in the relapsed/refractory setting (n = 945). Adjusted HRs (95% CI) for progression-free survival (PFS) and overall survival (OS), respectively, with ibrutinib versus real-world regimens were 0.23 (0.14–0.37; p < 0.0001) and 0.40 (0.22–0.76; p = 0.0048) in the treatment-naïve setting, and 0.21 (0.16–0.27; p < 0.0001) and 0.29 (0.21–0.41; p < 0.0001) in the relapsed/refractory setting. When comparing real-world use of ibrutinib (n = 53) versus other real-world regimens in relapsed/refractory CLL (objective 3), adjusted HRs (95% CI) were 0.37 (0.22–0.63; p = 0.0003) for PFS and 0.53 (0.27–1.03; p < 0.0624) for OS. This adjusted analysis, based on nonrandomized patient data, suggests ibrutinib to be more effective than other commonly used regimens for CLL.

In the past decade, over 3 dozen studies reported a relationship between self-reported short sleep and disturbed glucose metabolism. A study with insulin sensitivity assessed according to the gold standard hyperinsulinemic-euglycemic clamp is, however, still missing.To evaluate the cross-sectional association of sleep duration with insulin sensitivity and β-cell function in the European group for the study of insulin resistance (EGIR-RISC) study cohort.We used data from the baseline measurements of the European, multicentre EGIR-RISC study that included 1319 clinically healthy participants. Sleep and physical activity were measured using a single-axis accelerometer. Insulin sensitivity and β-cell function were estimated by hyperinsulinemic-euglycemic clamp and from the oral glucose insulin sensitivity index model, using an oral glucose tolerance test. Associations of sleep duration with insulin sensitivity and β-cell function were analyzed by multiple linear regression, stratified by sex.In our current analysis, we included 788 participants (57% women, age 44 ± 8 y), who had an average sleep duration of 7.3 ± 1.5 hours. In men, we observed an inverted U-shaped association between sleep duration categorized per hour and M/I (in μmol/min per kgFFM/nM per hour) (β-estimate [95% confidence intervals] 41 [2, 80]; P = .04 and β(2)-estimate -3 [-6, -0.2], P = .04) as well as a trend for the oral glucose insulin sensitivity index (in mL/min per kgFFM) (β-estimate [95% confidence intervals] 0.8 [-0.4, 2]; P = .17). In women, we observed a U-shaped association between sleep duration and β-cell function (in pmol/min per m(2)/mM per hour) (β-estimate -45 [-86, -3]; P = .04 and β(2)-estimate 3 [0.2, 6]; P = .04).Sleep duration is associated with insulin sensitivity and β-cell function in a sex-specific manner in clinically healthy people.

Background: Previously reported incidences for intraoperative hypersensitivity reactions vary more than 15-fold. The goal was to determine the incidence of intraoperative hypersensitivity events at a U.S. surgical center. Methods: With institutional review board (Cleveland, Ohio) approval and waiver of written/informed consent, the anesthesia records of adult patients undergoing noncardiac surgery from 2005 to 2011 at the Cleveland Clinic were queried using a novel electronic search protocol developed to identify potential hypersensitivity reactions: cardiovascular collapse defined as systolic arterial blood pressure less than 50 mmHg; administration of epinephrine; administration of diphenhydramine; physician comments in the anesthesia record suggestive of hypersensitivity reactions; laboratory tests for histamine, tryptase, or immunoglobulin-E within 24 h of surgery; and International Classification of Diseases, Ninth Revision, codes suggestive of hypersensitivity reactions. Each electronically identified candidate chart was evaluated by an adjudication committee. Hypersensitivity reactions were graded on a 5-point severity scale. From these data, the authors determined the proportion of operations having adjudicated hypersensitivity reactions, and calculated the 95% exact binomial CI. Results: Among 178,746 records, 4,008 charts were identified by the search strategies. After adjudication, 264 hypersensitivity cases were identified. The overall incidence of hypersensitivity reactions was 1:677 surgeries, corresponding to 15 (95% CI, 13 to 17) cases per 10,000 operations. The incidence of severe hypersensitivity reactions (grades 3 to 5) was 1:4,583, corresponding to 2 (95% CI, 2 to 3) cases per 10,000 operations. Conclusions: The incidence of severe hypersensitivity reactions was similar to previous reports. However, the overall incidence of hypersensitivity reactions was much greater than reported elsewhere, possibly because of a comprehensive search strategy.

Introduction Ibrutinib, a first-in-class, oral, covalent inhibitor of Bruton's tyrosine kinase, is approved in several countries as monotherapy for adults with WM, based on the high response rate (90.5%) observed in a phase 2, single-arm trial of symptomatic patients who had received ≥ 1 prior therapy (NCT01614821; Treon SP, et al. N Engl J Med. 2015;372:1430-1440). In the phase 3 iNNOVATE trial (NCT02165397; Dimopoulos MA, et al. N Engl J Med. 2018;378:2399-2410), adding rituximab to ibrutinib (IR) led to a statistically significant improvement in progression-free survival (PFS) compared with placebo-rituximab, in both treatment-naïve (TN) patients and those with disease recurrence. This analysis examined the relative treatment effect of IR versus other RW treatment regimens used in daily clinical practice in TN and relapsed/refractory (R/R) WM. An adjusted comparison was conducted using patient-level data from the iNNOVATE trial and the Lyon-Sud RW database in France. Methods The Lyon-Sud database holds medical records for patients with WM diagnosed between 1980 and 2017 from the Centre Hospitalier Lyon-Sud. PFS and overall survival (OS) outcomes were compared between the IR arm of iNNOVATE and RW physicians' choice (PC) treatment in Lyon-Sud (excluding RW ibrutinib). Kaplan-Meier survival curves by patient cohort were generated for both end points. A multivariate Cox proportional hazards model was fitted on the pooled patient-level data from both sources to estimate adjusted hazard ratios (HRs) for effect of IR on PFS and OS versus RW treatment, with age, sex, and treatment line as covariates. The unit of observation for the RW databases was the treatment line (rather than the patient) number, whereby RW patients receiving multiple treatment lines contributed to multiple observations, and baseline was defined as the line-specific treatment start date. Results Overall, 242 treatment lines from patients with WM were identified from the Lyon-Sud database; 224 were analyzed. Baseline characteristics were comparable between the IR arm of iNNOVATE (n = 75) and the RW cohort: 62.7% versus 66.5% ≥ 65 years of age; line of therapy, 45.3% versus 48.7% TN [1L], 25.3% versus 25.0% second-line [2L], and 29.3% versus 26.3% third-line or later [3L+]. Median follow-up was 26.7 months for iNNOVATE and 68.5 months for the RW cohort. Non-ibrutinib PC regimens in the RW cohort included rituximab (n = 51 treatment lines), chemotherapy (n = 66; including chlorambucil, n = 31), rituximab-cyclophosphamide-dexamethasone (n = 35), rituximab-CHOP/CHOP-like (n = 21), rituximab-chlorambucil (n = 15), fludarabine-cyclophosphamide-rituximab (n = 14), bendamustine-rituximab (n = 10), other rituximab-containing chemoimmunotherapy (n = 10), and rituximab-targeted agent (n = 2). Two ibrutinib lines were excluded from the RW cohort analysis. Figures A and B show the observed 1L+ Kaplan-Meier curves for IR versus RW PC therapy for all analyzed patients with WM (unadjusted HRs: 0.32 [95% confidence interval (CI), 0.19-0.55] for PFS and 0.38 [95% CI, 0.13-1.09] for OS). After adjusting for differences in patient characteristics, HRs (1L+ therapy) became 0.28 (95% CI, 0.16-0.48; p < 0.001) for PFS and 0.29 (95% CI, 0.09-0.93; p = 0.037) for OS. Restricting the analysis to 1L treatment only (Lyon-Sud n = 109; iNNOVATE n = 34), the adjusted HRs were 0.25 (95% CI, 0.09-0.70; p < 0.009) for PFS and 0.20 (95% CI, 0.02-2.00; p = 0.170) for OS; respective unadjusted HRs were 0.31 (95% CI, 0.12-0.78) and 0.30 (95% CI, 0.04-2.34). In the 2L+ setting (Lyon-Sud n = 115; iNNOVATE n = 41), the adjusted HRs were 0.28 (95% CI, 0.15-0.56; p < 0.001) for PFS and 0.34 (95% CI, 0.08-1.35; p = 0.126) for OS; respective unadjusted HRs were 0.31 (95% CI, 0.16-0.61) and 0.39 (95% CI, 0.12-1.31). Concl usions In the absence of randomized controlled trial data for ibrutinib versus other treatment regimens for WM, these adjusted comparisons of clinical trial and RW patient-level data suggest that IR significantly improves both PFS and OS versus RW PC regimens as 1L+ therapy. These results help inform physicians on the standard of care for WM in clinical practice. Funding Source: This project was sponsored by Janssen Pharmaceutica NV, and Pharmacyclics LLC, an AbbVie Company. The real-world databases are independently owned. Writing assistance was provided by Emma Fulkes of PAREXEL and funded by Janssen Pharmaceutica NV. Disclosures Karlin: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support. Besson:Janssen Pharmaceutica NV: Employment. Tapprich:Janssen Pharmaceutica NV: Employment. Garside:Janssen Pharmaceutica NV: Employment. Salles:Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; AbbVie: Honoraria; Acerta: Honoraria; Amgen: Honoraria; Novartis: Consultancy, Honoraria; Merck: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Servier: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Epizyme: Honoraria; Morphosys: Honoraria.

Introduction Ibrutinib, a first-in-class, oral, covalent inhibitor of Bruton's tyrosine kinase, is approved in many countries for treatment-naïve (TN) and previously treated CLL, supported by improved response rates, progression-free survival (PFS), and overall survival (OS) vs chlorambucil in RESONATE-2™ (NCT01722487; Burger JA, et al. N Engl J Med. 2015;373:2425-2437) and ofatumumab in RESONATE™ (NCT01578707; Byrd JC, et al. N Engl J Med. 2014;371:213-223). We analyzed survival outcomes for ibrutinib vs RW treatments for TN and relapsed/refractory (R/R) CLL by del11q status, an adverse prognostic factor linked with poor patient outcomes despite conventional chemoimmunotherapy. An adjusted comparison restricted to patients with confirmed del11q status was conducted using patient-level data from RESONATE-2™ and RESONATE™ and RW databases from 2 countries. Methods The Lyon-Sud RW database holds medical records for CLL patients diagnosed between 1980 and 2017 from the Centre Hospitalier Lyon-Sud, France; the Chronic Lymphocytic Leukemia Registry (CLLEAR) RW database holds medical records for CLL patients diagnosed between 1988 and 2017 from 7 academic centers in the Czech Republic. TN CLL database patients were selected using RESONATE-2™ criteria (which excluded those aged < 65 years or del17p positive). For the R/R group, patients ≥ 18 years of age or those with del17p were allowed per RESONATE™ inclusion criteria. PFS and OS outcomes by del11q status were compared between the ibrutinib arms of RESONATE-2™/RESONATE™ and physicians' choice (PC) treatment in the pooled RW databases (excluding ibrutinib). A multivariate Cox proportional hazards model was fitted on pooled RCT/RW data to estimate adjusted hazard ratios (HRs) for effect of ibrutinib vs RW PC treatment using age, sex, and treatment line as covariates. The unit of observation for the RW databases was the treatment line (rather than patient) number; RW patients receiving multiple lines of therapy contributed to multiple observations, and baseline was defined as the line-specific treatment start date. Results For the RW TN cohort, 466 treatment lines were analyzed; 134 (28.8%) patients were del11q positive. In RESONATE-2™, 29/136 (21.3%) TN patients were del11q positive. The table below shows adjusted HRs for PFS and OS for patients with/without del11q. For the del11q-positive subgroup, adjusted HRs for ibrutinib vs RW PC first-line (1L) therapy were 0.02 (95% confidence interval [CI], 0.00-0.17; p = 0.0002) for PFS and not estimable for OS (no deaths on ibrutinib). For the del11q-negative subgroup, adjusted HRs were 0.34 (95% CI, 0.2-0.57; p < 0.0001) for PFS and 0.74 (95% CI, 0.37-1.49; p = 0.3957) for OS. For second-line (2L) PC treatment in the RW R/R cohort, 385 treatment lines were analyzed; 135 (35.1%) were from del11q positive patients. In RESONATE™, 13 (37.1%) 2L patients were del11q positive. For the del11q-positive subgroup, adjusted HRs for ibrutinib vs RW PC of 2L therapy were 0.03 (0.00-0.21; p = 0.0003) for PFS and 0.08 (0.01-0.46; p = 0.0050) for OS. For the del11q-negative subgroup, adjusted HRs were 0.27 (0.14-0.51; p < 0.0001) for PFS and 0.50 (0.24-1.05; p = 0.0670) for OS. For 2L and beyond (2L+) treatment in the RW R/R cohort, 727 treatment lines were analyzed; 291 (40.0%) were from del11q positive patients. In RESONATE™, 63/195 (32.3%) 2L+ patients were del11q positive. For the del11q-positive subgroup, adjusted HRs (95% CIs) for ibrutinib vs RW PC of 2L+ therapy were 0.13 (0.08-0.20; p < 0.0001) for PFS and 0.15 (0.08-0.26; p < 0.0001) for OS. For the del11q-negative subgroup, adjusted HRs were 0.20 (0.14-0.29; p < 0.0001) for PFS and 0.33 (0.21-0.52; p < 0.0001) for OS. Concl usions Adjusted comparisons of the registration trial (RESONATE-2™/RESONATE™) and RW patient-level data suggest that OS and PFS improvements with ibrutinib vs PC therapies are pronounced for patients with CLL harboring del11q compared with those who are del11q negative. The findings inform physicians of the comparative effectiveness of ibrutinib in the RW for patients with this high-risk cytogenetic abnormality. Funding Source: This project was sponsored by Janssen Pharmaceutica NV, and Pharmacyclics LLC, an AbbVie Company. The real-world databases are independently owned. Writing assistance was provided by Emma Fulkes of PAREXEL and funded by Janssen Pharmaceutica NV. Disclosures Salles: Takeda: Honoraria; Acerta: Honoraria; Epizyme: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Gilead: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Servier: Honoraria; Janssen: Honoraria; Merck: Honoraria; Morphosys: Honoraria. Besson:Janssen Pharmaceutica NV: Employment. Doyle:Janssen Pharmaceutica NV: Employment. Garside:Janssen Pharmaceutica NV: Employment. Spacek:Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Doubek:Novartis: Consultancy; AbbVie: Consultancy, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Affimed: Research Funding; Gilead: Consultancy, Honoraria, Research Funding.

Television viewing (TV), a highly prevalent behaviour, is associated with higher cardiovascular risk independently of physical activity. The relationship with mortality, however, is relatively unknown.We examined the prospective relationship between TV time and all-cause, cardiovascular and cancer mortality in a population-based cohort [The European Prospective Investigation into Cancer and Nutrition (EPIC), Norfolk] of 13 197 men and women {age [SD (standard deviation)]: 61.5 ± 9.0 years}. Participants were free from stroke, myocardial infarction and cancer at baseline in 1998-2000 and were followed up for death ascertainment until 2009 (9.5 ± 1.6 years). TV time, total physical activity energy expenditure (PAEE), education level, smoking status, alcohol consumption, anti-hypertensive and lipid-lowering medication use, participant and family history of disease and total energy intake were self-reported; height and weight were measured by standardized procedures. Hazard ratios (HRs) [95% confidence interval (CI)] for mortality were estimated per 1-h/day increase in TV.Each 1-h/day increase in TV time was associated with increased hazard of all-cause (HR = 1.04, 95% CI = 1.01-1.09; 1270 deaths) and cardiovascular (HR = 1.07, 95% CI = 1.01-1.15; 373 deaths), but not cancer mortality (HR = 1.04, 95% CI = 0.98-1.10; 570 deaths). This was independent of gender, age, education, smoking, alcohol, medication, diabetes history, family history of cardiovascular disease and cancer, body mass index (BMI) and PAEE. They were similar when stratified by gender, age, education, BMI and PAEE. The population-attributable fraction for all-cause mortality comparing the highest TV tertile (3.6 h/day) with the lowest (2.5 h/day) was 5.4%.These findings suggest that public health recommendations should consider advising a reduction in TV time, a predominant leisure activity in modern society, in addition to advocating physical activity.

5058Background: AQUARiUS is an ongoing study of PROs and medical resource use in chemotherapy-naive pts with mCRPC newly initiated on AAP or ENZ in a real-world setting. Initial 3-month (mo) subset...

AIMS/HYPOTHESIS: We sought to determine the effect of an aerobic exercise intervention on clustered metabolic risk and related outcomes in healthy older adults in a single-centre, explanatory randomised controlled trial. METHODS: Participants from the Hertfordshire Cohort Study (born 1931-1939) were randomly assigned to 36 supervised 1 h sessions on a cycle ergometer over 12 weeks or to a non-intervention control group. Randomisation and group allocation were conducted by the study co-ordinator, using a software programme. Those with prevalent diabetes, unstable ischaemic heart disease or poor mobility were excluded. All data were collected at our clinical research facility in Cambridge. Components of the metabolic syndrome were used to derive a standardised composite metabolic risk score (zMS) as the primary outcome. Trial status: closed to follow-up. RESULTS: We randomised 100 participants (50 to the intervention, 50 to the control group). Mean age was 71.4 (range 67.4-76.3) years. Overall, 96% of participants attended for follow-up measures. There were no serious adverse events. Using an intention-to-treat analysis, we saw a non-significant reduction in zMS in the exercise group compared with controls (0.07 [95% CI -0.03, 0.17], p = 0.19). However, the exercise group had significantly decreased weight, waist circumference and intrahepatic lipid, with increased aerobic fitness and a 68% reduction in prevalence of abnormal glucose metabolism (OR 0.32 [95% CI 0.11-0.92], p = 0.035) compared with controls. Results were similar in per-protocol analyses. CONCLUSIONS/INTERPRETATION: Enrolment in a supervised aerobic exercise intervention led to weight loss, increased fitness and improvements in some but not all metabolic outcomes. In appropriately screened older individuals, such interventions appear to be safe. TRIAL REGISTRATION: Controlled-trials.com ISRCTN60986572 FUNDING: Medical Research Council.

Purpose: The purpose of this study was to describe the association of the overall and domain-specific physical activity on all-cause and cardiovascular mortality. A large body of epidemiological evidence suggests a strong and consistent inverse association between physical activity and mortality risk. However, it is unclear how this association varies according to the domain of life in which the activity takes place. Methods: In an English population-based cohort of 14,903 participants (mean age = 63 yr), total and domain-specific physical activity was assessed using a validated questionnaire (EPAQ2). After a median follow-up of 7 yr, there were 1128 deaths, with 370 from cardiovascular disease. Results: The relative risks (95% confidence interval) for all-cause mortality due to physical activity undertaken at home, during exercise, at work, for transport, and in total were 0.81 (0.66-0.99), 0.66 (0.54-0.80), 0.84 (0.55-1.30), 0.82 (0.67-1.00), and 0.77 (0.61-0.98), respectively, after adjustment for baseline age, sex, social class, alcohol consumption, smoking status, history of diabetes, history of cancer, and history of cardiovascular disease and stroke. Cardiovascular mortality was inversely associated with physical activity undertaken at home (P for trend = 0.03), during exercise (P for trend = 0.001), and in total (P for trend = 0.007). The results were unchanged after excluding individuals with a history of heart disease, stroke, and cancer at baseline and those who died within the first 2 yr of follow-up. Conclusions: In this study, physical activities at home and during exercise are associated with lower risk of mortality, whereas occupational and transportation-related activities are not. Promoting the potential benefits of physical activity undertaken at home and during exercise may be an important public health message for aging populations

We analysed the effects of tobacco and alcohol in the aetiology of Hodgkin's lymphoma (HL), based on 340 cases and 2465 controls enrolled in Spain, France, Italy, Germany, Ireland and Czech Republic, between 1998 and 2004. Current smokers showed a significantly increased odds ratio (OR) of HL of 1.39 (95% confidence interval (CI)=1.04-1.87). Analyses were also conducted separately for subjects younger than 35 years (179 cases) and for older subjects (161 cases). For subjects below age 35, no association was observed between tobacco and HL, whereas for older subjects, ever-smokers experienced a doubled risk of HL as compared to never smokers and the OR of HL for current smoking was 2.35 (95% CI=1.52-3.61), with suggestion of a dose-response relationship. A protective effect of alcohol was observed in both age groups. The OR for ever-regular drinking was 0.58 (95% CI=0.38-0.89) for younger subjects and 0.50 (95% CI=0.34-0.74) for older subjects. There was no evidence of interaction between tobacco and alcohol. Our results are consistent with previous studies, suggesting a protective effect of alcohol on HL. An effect of tobacco was suggested for HL occurring in middle and late age, although this finding might have occurred by chance. © 2006 Cancer Research.

To study the role of tobacco smoking and alcohol drinking in the etiology of non-Hodgkin's lymphoma (NHL), we conducted a multicenter case-control study in Spain, France, Germany, Italy, Ireland and Czech Republic between 1998 and 2004, which included 1,742 cases of NHL and 2,465 controls matched on age, sex and recruitment area. Tobacco smoking was not associated with the risk of NHL overall or with risk of specific histological subtypes. Similarly, there was no association between alcohol drinking and the risk of NHL overall or across histological subtypes. However, a protective effect of alcohol drinking was observed among men (OR = 0.76, 95% CI = 0.62-0.93) and in non-Mediterranean countries (OR = 0.73, 95% CI = 0.61-0.86). There was no evidence of interaction between alcohol drinking and tobacco smoking in NHL etiology. The results of this large-scale European study did not support an association between tobacco and NHL and suggested a protective effect of alcohol on development of NHL for men and in non-Mediterranean countries. © 2006 Wiley-Liss, Inc.

Objective: To study the relation between smoking and non-Hodgkin/s lymphoma (NHL), in the Rhone-Alpes region of France. Methods: We conducted a hospital-based case–control study that included 180 cases of NHL and 360 age-, gender-matched hospital controls. Matched univariable and multivariable logistic regression models were used for analysis. Results: For the whole study population as well as for men, smoking does not elevate the risk of NHL. However, the risk of NHL is higher for women who currently smoke compared to women who have never smoked (odds ratio [OR] = 2.40, 95% confidence interval [95% CI] = 1.19–4.84). Among ever smokers, the OR of NHL is 5.04 (95% CI = 1.40–18.12) for women who have smoked for more than 30 years compared with those who have never smoked. Similarly, women who started to smoke before the age of 20 years compared with women who have never smoked are at greater risk of developing NHL (OR = 2.40, 95% CI = 0.99–5.85). In the total population (women and men), smoking may be associated with one histologic subtype, follicular NHL with an adjusted OR for the current smokers compared to subjects having never smoked of 3.20, 95% CI = 0.79–12.97. Conclusions: In spite of the small number of subjects in the subgroups, a relation is observed between smoking and NHL among women, but not men, and in the total population a relation is suggested between smoking and follicular NHL.

INTRODUCTION: The benefits of ibrutinib (ibr) have been demonstrated by the phase 3 RESONATE and RESONATE-2 trials for patients (pts) with R/R and TN (≥ 65 years) CLL, respectively. In these studies, ibr showed significantly improved progression-free survival (PFS) and overall survival (OS) vs approved comparators (ofatumumab [ofa] in RESONATE and chlorambucil [clb] in RESONATE-2). However, a number of other treatment regimens are widely used in clinical practice for CLL based on individual patient and disease characteristics; it is currently unknown if ibr results in better survival outcomes when compared directly with each of these other treatments. AIM: In the absence of a head-to-head comparison, we investigated the relative efficacy of ibr vs physician's choice (PC) in pts with R/R or TN CLL by comparing pt-level data from RESONATE and RESONATE-2 with data from pts in a real-world setting (the Lyon-Sud database). This database holds electronic medical records for 390 pts with CLL from the academic Lyon-Sud Hospital in France; nearly all patients were diagnosed between 1990 and 2014. This is the first analysis of ibr vs PC in a real-world setting for pts with TN CLL. METHODS: Pt-level data from RESONATE (ibr, n = 195; ofa, n = 196) were compared with data on pts with CLL from Lyon-Sud who received 2nd(n = 107) or later-line treatment (3rd [n = 62], 4th [n = 43], and subsequent [n = 51] lines). Similarly, RESONATE-2 (ibr, n = 136; clb, n = 133) pt-level data were compared with those of pts aged ≥ 65 years who received 1st-line treatment (n = 131). In order to account for non-comparability due to lack of randomization, a multivariate Cox proportional hazards model was used to compare PFS and OS between treatments, including line of therapy, age, sex, disease stage (based on Binet/Rai), and deletion 17p or 11q mutations as covariates. For the definition of PFS, missing data for date of disease progression for pts in Lyon-Sud who initiated subsequent therapy were replaced by the conservative proxy of date of initiation of next treatment. Predicted PFS and OS curves for the Lyon-Sud cohort were derived from the multivariate model. RESULTS: For R/R pts in Lyon-Sud, across all treatment lines the most frequent regimens used were rituximab (R) + chemotherapy (n = 46), bendamustine + R (BR; n = 28), fludarabine + cyclophosphamide + R (FCR) (n = 27), clb + R (n = 19), R monotherapy (n = 21), and R-CHOP-based (n = 19); the remaining percentages comprised various other therapies, each used in < 5% of pts. Median age at treatment initiation for Lyon-Sud and RESONATE was 69 and 67 years, respectively; median number of prior therapies was 2 and 3, and median follow-up was 30.0 and 21.9 months. More lines of prior therapy, older age, male sex, advanced disease stage (Binet C/Rai III/IV), and presence of deletion 17p/11q were independent risk factors for worse PFS and OS outcome. After adjustment for differences in baseline characteristics, PFS and OS hazard ratios (HRs) for ibr vs PC were 0.18 (95% confidence interval [CI], 0.13-0.26) and 0.28 (0.17-0.46), respectively. Adjusted HRs for ibr vs the most frequent treatments ranged from 0.09 (R monotherapy) to 0.38 (FCR) for PFS and 0.21 (R monotherapy) to 0.33 (FCR) for OS; all were statistically significant. For TN pts in Lyon-Sud, the most frequent treatment regimens used were FCR (n = 40), clb + R (n = 21), clb monotherapy (n = 17), R-(mini)CHOP (n = 11), and BR (n = 11). Median age at treatment initiation was 73 years for both Lyon-Sud and RESONATE-2; median follow-up was 36.9 and 28.1 months, respectively. Older age, male sex, and advanced disease stage were independent risk factors for worse PFS and OS outcome. After adjustment for baseline differences, the PFS and OS HRs for ibr vs PC were 0.25 (0.14-0.47) and 0.41 (0.17-0.99). Predicted PFS and OS curves for both R/R and TN patients are presented in Figure 1. CONCLUSIONS: Investigation of survival outcomes suggests that ibr administered to pts in RESONATE and RESONATE-2 was more effective than PC used in a real-world cohort of French pts with R/R or TN CLL, suggesting a 4.8-fold improvement in PFS and a 3.4-fold improvement in OS in R/R pts and 4-fold and 2.4-fold improvements in TN pts, respectively. These results further support the growing evidence that ibr significantly improves both PFS and OS vs commonly used regimens in the R/R and TN settings, and could have important implications for improving treatment of CLL in clinical practice. Disclosures Salles: Janssen: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Mundipharma: Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding. Sarkozy:Sandoz: Research Funding; Janssen Research & Development: Honoraria; Gilead: Honoraria; Takeda: Research Funding. Ghesquieres:Mundipharma: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche France: Research Funding. Diels:Johnson & Johnson: Employment, Equity Ownership. Besson:Janssen: Employment. MacDougall:Janssen Research & Development: Research Funding; IMS Health: Employment. Hermans:Janssen Research & Development: Research Funding; IMS Health: Employment. Healy:Janssen Research & Development: Employment. Garside:Janssen Research & Development: Employment. Iraqi:Janssen Research & Development: Employment.

Physical inactivity is one of the four leading risk factors for global mortality. Accurate measurement of physical activity (PA) and in particular by physical activity questionnaires (PAQs) remains a challenge. The aim of this paper is to provide an updated systematic review of the reliability and validity characteristics of existing and more recently developed PAQs and to quantitatively compare the performance between existing and newly developed PAQs. A literature search of electronic databases was performed for studies assessing reliability and validity data of PAQs using an objective criterion measurement of PA between January 1997 and December 2011. Articles meeting the inclusion criteria were screened and data were extracted to provide a systematic overview of measurement properties. Due to differences in reported outcomes and criterion methods a quantitative meta-analysis was not possible. In total, 31 studies testing 34 newly developed PAQs, and 65 studies examining 96 existing PAQs were included. Very few PAQs showed good results on both reliability and validity. Median reliability correlation coefficients were 0.62–0.71 for existing, and 0.74–0.76 for new PAQs. Median validity coefficients ranged from 0.30–0.39 for existing, and from 0.25–0.41 for new PAQs. Although the majority of PAQs appear to have acceptable reliability, the validity is moderate at best. Newly developed PAQs do not appear to perform substantially better than existing PAQs in terms of reliability and validity. Future PAQ studies should include measures of absolute validity and the error structure of the instrument.

BACKGROUND: The protective effect of physical activity (PA) on abdominal adiposity is unclear. OBJECTIVE: We examined whether PA independently predicted gains in body weight and abdominal adiposity. DESIGN: In a prospective cohort study [the EPIC (European Prospective Investigation into Cancer and Nutrition)], we followed 84,511 men and 203,987 women for 5.1 y. PA was assessed by a validated questionnaire, and individuals were categorized into 4 groups (inactive, moderately inactive, moderately active, and active). Body weight and waist circumference were measured at baseline and self-reported at follow-up. We used multilevel mixed-effects linear regression models and stratified our analyses by sex with adjustments for age, smoking status, alcohol consumption, educational level, total energy intake, duration of follow-up, baseline body weight, change in body weight, and waist circumference (when applicable). RESULTS: PA significantly predicted a lower waist circumference (in cm) in men (β = -0.045; 95% CI: -0.057, -0.034) and in women (β = -0.035; 95% CI: -0.056, -0.015) independent of baseline body weight, baseline waist circumference, and other confounding factors. The magnitude of associations was materially unchanged after adjustment for change in body weight. PA was not significantly associated with annual weight gain (in kg) in men (β = -0.008; 95% CI: -0.02, 0.003) and women (β = -0.01; 95% CI: -0.02, 0.0006). The odds of becoming obese were reduced by 7% (P < 0.001) and 10% (P < 0.001) for a one-category difference in baseline PA in men and women, respectively. CONCLUSION: Our results suggest that a higher level of PA reduces abdominal adiposity independent of baseline and changes in body weight and is thus a useful strategy for preventing chronic diseases and premature deaths. (Less)

Background: Although television viewing time is detrimentally associated with intermediate cardiovascular risk factors, the relationship with incident total (i.e. combined fatal and non-fatal) cardiovascular disease (CVD), non-fatal CVD and coronary heart disease is largely unknown. This study examined whether television viewing time is associated with these three outcomes, independently of physical activity energy expenditure and other confounding variables. Methodology/Principal Findings: A population-based cohort of 12,608 men and women (aged 61.4 +/- 9.0), free from stroke, myocardial infarction and cancer at baseline in 1998-2000 were followed up until 2007 (6.9 +/- 1.9 years). Participants self-reported education, smoking, alcohol use, antihypertensive, lipid lowering and antidepressant medication, disease history, total energy intake, sleep duration, physical activity and television viewing. BMI, waist circumference, blood pressure, triglycerides, HDL cholesterol and glycated haemoglobin (HbA(1c)) were measured by standardized procedures; a clustered metabolic risk score was constructed. Every one hour/day increase in television viewing was associated with an increased hazard for total (HR = 1.06, 95% CI = 1.03-1.08; 2,620 cases), non-fatal CVD (HR = 1.06, 95% CI = 1.03-1.09; 2,134 cases), and coronary heart disease (HR = 1.08, 95% CI = 1.03-1.13; 940 cases), independent of gender, age, education, smoking, alcohol, medication, diabetes status, CVD family history, sleep duration and physical activity energy expenditure. Energy intake, BMI, waist circumference, blood pressure, triglycerides, HDL cholesterol, HbA(1c) and the clustered metabolic risk score only partially mediated these associations. Conclusions: These results indicate that the most prevalent leisure time (sedentary) behaviour, television viewing, independently contributes to increased CVD risk. Recommendations on reducing television viewing time should be considered.

Background To examine the association of education with body mass index (BMI) and waist circumference (WC) in the European Prospective Investigation into Cancer and Nutrition (EPIC). Method This study included 141,230 male and 336,637 female EPIC-participants, who were recruited between 1992 and 2000. Education, which was assessed by questionnaire, was classified into four categories; BMI and WC, measured by trained personnel in most participating centers, were modeled as continuous dependent variables. Associations were estimated using multilevel mixed effects linear regression models. Results Compared with the lowest education level, BMI and WC were significantly lower for all three higher education categories, which was consistent for all countries. Women with university degree had a 2.1 kg/m2 lower BMI compared with women with lowest education level. For men, a statistically significant, but less pronounced difference was observed (1.3 kg/m2). The association between WC and education level was also of greater magnitude for women: compared with the lowest education level, average WC of women was lower by 5.2 cm for women in the highest category. For men the difference was 2.9 cm. Conclusion In this European cohort, there is an inverse association between higher BMI as well as higher WC and lower education level. Public Health Programs that aim to reduce overweight and obesity should primarily focus on the lower educated population.

A large body of epidemiological evidence suggests an inverse relationship between physical activity and risk of fractures. However, it is unclear how this association varies according to the domain of life in which the activity is undertaken. In this analysis of the European Prospective Investigation of Cancer-Norfolk study, we assessed total and domain-specific physical activity using a validated questionnaire (EPAQ2) in 14,903 participants (6514 men, mean age 62 year) who also underwent quantitative ultrasound of the heel. After a median follow-up of 7.5 years, there were 504 fractures of which 164 were hip fractures. In multivariable linear regression analysis, broadband ultrasound attenuation (BUA) was positively associated with total and leisure-time activities while showing no association with transportation and work activities. Home activities were associated with a lower BUA among younger participants. In multivariable Cox proportional-hazards models, moderate activities at home and in leisure time were associated with lower hip fracture risk among women (hazard ratios [HR] 0.51 and 0.55, p value 0.02 and 0.03, respectively). Among men, leisure-time activities were associated with lower risk of hip fracture (HR=0.58; p for trend

BACKGROUND Few questionnaires that assess usual physical activity have been reported to be valid for all different subdimensions of physical activity. OBJECTIVE The objective was to assess the validity and reliability of the Recent Physical Activity Questionnaire (RPAQ), which assesses usual physical activity (PA) in 4 domains (work, travel, recreation, and domestic life). DESIGN Total energy expenditure (TEE) was measured for 14 d by using the doubly labeled water technique combined with a measure of resting metabolic rate to yield PA energy expenditure (PAEE) in 25 men and 25 women. Simultaneously, intensity of activity was measured by using combined heart rate and movement sensing for 11 d. Repeatability of the RPAQ was assessed in an independent sample of 71 women and 60 men aged 31-57 y. RESULTS Estimated TEE and PAEE were significantly associated with criterion measures (TEE: r = 0.67; PAEE: r = 0.39) with mean (+/-SD) biases of -3452 +/- 2025 kJ/d and -13 +/- 24 kJ d(-1) kg(-1). The correlation between self-reported and measured time spent was significant for vigorous PA (r = 0.70) and marginally insignificant for sedentary time (r = 0.27, P = 0.06). The mean biases were relatively small for sedentary time and vigorous PA: 0.7 +/- 2.8 h/d and -12 +/- 24 min/d, respectively. The intraclass correlation coefficient for repeatability of total PAEE (kJ/d) was 0.76 (P < 0.0001). CONCLUSION The RPAQ is the first questionnaire with demonstrated validity for ranking individuals according to their time spent at vigorous-intensity activity and overall energy expenditure.

Background: While there are compelling observational data confirming that individuals who exercise are healthier, the efficacy of aerobic exercise interventions to reduce metabolic risk and improve insulin sensitivity in older people has not been fully elucidated. Furthermore, while low birth weight has been shown to predict adverse health outcomes later in life, its influence on the response to aerobic exercise is unknown. Our primary objective is to assess the efficacy of a fully supervised twelve week aerobic exercise intervention in reducing clustered metabolic risk in healthy older adults. A secondary objective is to determine the influence of low birth weight on the response to exercise in this group. Methods/Design: We aim to recruit 100 participants born between 1931–1939, from the Hertfordshire Cohort Study and randomly assign them to no intervention or to 36 fully supervised one hour sessions on a cycle ergometer, over twelve weeks. Each participant will undergo detailed anthropometric and metabolic assessment pre- and post-intervention, including muscle biopsy, magnetic resonance imaging and spectroscopy, objective measurement of physical activity and sub-maximal fitness testing. Discussion: Given the extensive phenotypic characterization, this study will provide valuable insights into the mechanisms underlying the beneficial effects of aerobic exercise as well as the efficacy, feasibility and safety of such interventions in this age group. Trial Registration: Current Controlled Trials: ISRCTN60986572

Objectives: Cross-sectional data suggest a strong association between low levels of physical activity and obesity. The EPIC-PANACEA (European Prospective Investigation into Cancer-Physical Activity, Nutrition, Alcohol, Cessation of Smoking, Eating out of home And obesity) project was designed to investigate the associations between physical activity and body mass index (BMI) and waist circumference based on individual data collected across nine European countries. Methods: In the European Prospective Investigation into Cancer and Nutrition (EPIC), 519 931 volunteers were recruited between 1992 and 2000, of whom 405 819 had data on main variables of interest. Height, body weight and waist circumference were measured using standardized procedures. Physical activity was assessed using a validated four-category index reflecting a self-reported usual activity during work and leisure time. The associations between physical activity and BMI and waist circumference were estimated using multilevel mixed effects linear regression models, adjusted for age, total energy intake, smoking status, alcohol consumption and educational level. Results: A total of 125 629 men and 280 190 women with a mean age of 52.9 (s.d. 9.7) and 51.5 (s.d. 10.0) years, respectively were included. The mean BMI was 26.6 kg/m 2 (s.d. 3.6) in men and 25.0 kg/m 2 (s.d. 4.5) in women. Fifty percent of men and 30% of women were categorized as being active or moderately active. A one-category difference in the physical activity index was inversely associated with a difference of 0.18 kg/m 2 in the mean BMI (95% confidence interval, CI, 0.11, 0.24) and 1.04-cm (95% CI 0.82, 1.26) difference in waist circumference in men. The equivalent figures for women were 0.31 kg/m 2 (95% CI 0.23, 0.38) and 0.90 cm (95% CI 0.71, 1.08), respectively. Conclusions: Physical activity is inversely associated with both BMI and waist circumference across nine European countries. Although we cannot interpret the association causally, our results were observed in a large and diverse cohort independently from many potential confounders. © 2009 Macmillan Publishers Limited. All rights reserved.

Objective. The present study investigates the cross-sectional relationship between tobacco smoking and body fatness. Methods. This cross-sectional study consisted of 469,543 men and women who participated in the European Prospective Investigation into Cancer and Nutrition (EPIC) study between 1992 and 2000 providing anthropometric measurements and information on smoking. Adjusted multilevel mixed-effects linear regression models were used to assess the association between smoking and body fat mass. Results. The analyses showed that BMI and WC were positively associated with smoking intensity in current smokers but negatively associated with time since quitting in former smokers. When compared to never smokers, average current smokers (17 and 13 cig/day for men and women, respectively) showed a lower BMI. When average former smokers (men and women who had stopped smoking for 16 and 15 years, respectively) were compared to never smokers, higher BMI and WC were observed in men, whereas no significant associations were observed in women. Conclusions. This cross-sectional study suggests that smoking may be associated with body fatness and fat distribution. Although our findings cannot establish cause and effect, they suggest that providing information and support to those who want to stop may help in preventing weight gain and therefore weaken a barrier against stopping smoking. (C) 2009 Elsevier Inc. All rights reserved.

Contains fulltext : 79873.pdf (Publisher’s version ) (Closed access) Given the lack of consistent evidence of the relationship between Mediterranean dietary patterns and body fat, we assessed the cross-sectional association between adherence to a modified Mediterranean diet, BMI, and waist circumference (WC). A total of 497,308 individuals (70.7% women) aged 25-70 y from 10 European countries participated in this study. Diet was assessed at baseline using detailed validated country-specific questionnaires, and anthropometrical measurements were collected using standardized procedures. The association between the degree of adherence to the modified-Mediterranean Diet Score (mMDS) (including high consumption of vegetables, legumes, fruits and nuts, cereals, fish and seafood, and unsaturated:saturated fatty acids ratio; moderate alcohol intake; and low consumption of meat and meat products and dairy products) and BMI (kg.m(-2)) or WC (cm) was modeled through mixed-effects linear regression, controlling for potential confounders. Overall, the mMDS was not significantly associated with BMI. Higher adherence to the Mediterranean diet was significantly associated with lower WC, for a given BMI, in both men (-0.09; 95% CI -0.14 to -0.04) and women (-0.06; 95% CI -0.10 to -0.01). The association was stronger in men (-0.20; 95% CI -0.23 to -0.17) and women (-0.17; 95% CI -0.21 to -0.13) from Northern European countries. Despite the observed heterogeneity among regions, results of this study suggest that adherence to a modified Mediterranean diet, high in foods of vegetable origin and unsaturated fatty acids, is associated with lower abdominal adiposity measured by WC in European men and women.

Background: Whether obesity is a cause or a consequence of a sedentary lifestyle has not yet been fully elucidated, which leaves uncertainty about the direction of causality. Objective: We aimed to assess the longitudinal associations between objectively measured time spent being sedentary (sedentary time) and obesity indicators. Design: The study was a prospective, population-based cohort study in 393 middle-aged healthy whites (n = 176 M, 217 F). Sedentary time (% of daytime hours) was measured by individually calibrated monitoring of the heart rate. Body weight (BW), body mass index (BMI), and waist circumference (WC) were assessed by standard clinical procedures. Fat mass (FM) was assessed with bioimpedance. All measurements were collected at baseline and at 5.6-y follow-up. Results: At baseline, sedentary time was significantly correlated with FM (partial r = 0.10, P = 0.043) and WC (partial r = 0.11, P = 0.027) after adjustment for sex and age. At follow-up, sedentary time was significantly correlated with BW (partial r = 0.19, P < 0.0001), BMI (partial r = 0.20, P < 0.0001), WC (partial r = 0.15, P = 0.003), and FM (partial r = 0.19, P < 0.0001). Sedentary time did not predict any of the obesity indicators at follow-up. In contrast, BW (β = 0.33; 95% CI: 0.15, 0.50), BMI (1.10; 0.58, 1.63), FM (0.59; 0.11, 0.40), and WC (0.44; 0.23, 0.66) predicted sedentary time at follow-up after adjustment for sex, baseline age, baseline sedentary time, baseline physical activity energy expenditure, and follow-up time. Conclusion: BMI, FM, and WC may predict sedentary time, but our results do not suggest that sedentary time predicts future obesity.

Udgivelsesdato: 2008-Nov BACKGROUND: The incidences of non-Hodgkin's lymphoma and multiple myeloma are increasing steadily. It has been hypothesized that this may be due, in part, to the parallel rising prevalence of obesity. It is biologically plausible that anthropometric characteristics can infuence the risk of non-Hodgkin's lymphoma and multiple myeloma. DESIGN AND METHODS: In the context of the European Prospective Investigation into Cancer and Nutrition (EPIC), anthropometric characteristics were assessed in 371,983 cancer-free individuals at baseline. During the 8.5 years of follow-up, 1,219 histologically confirmed incident cases of non-Hodgkin's lymphoma and multiple myeloma occurred in 609 men and 610 women. Gender-specific proportional hazards models were used to estimate relative risks and 95% confidence intervals (95% CI) of development of non-Hodgkin's lymphoma and multiple myeloma in relation to the anthropometric characteristics. RESULTS: Height was associated with overall non-Hodgkin's lymphoma and multiple myeloma in women (RR 1.50, 95% CI 1.14-1.98) for highest versus lowest quartile; p-trend < 0.01) but not in men. Neither obesity (weight and body mass index) nor abdominal fat (waist-to-hip ratio, waist or hip circumference) measures were positively associated with overall non-Hodgkin's lymphoma and multiple myeloma. Relative risks for highest versus lowest body mass index quartile were 1.09 (95% CI 0.85-1.38) and 0.92 (95% CI 0.71-1.19) for men and women, respectively. Women in the upper body mass index quartile were at greater risk of diffuse large B-cell lymphoma (RR 2.18, 95% CI 1.05-4.53) and taller women had an elevated risk of follicular lymphoma (RR 1.25, 95% CI 0.59-2.62). Among men, height and body mass index were non-significantly, positively related to follicular lymphoma. Multiple myeloma risk alone was elevated for taller women (RR 2.34, 95% CI 1.29-4.21) and heavier men (RR 1.77, 95% CI 1.02-3.05). CONCLUSIONS: The EPIC analyses support an association between height and overall non-Hodgkin's lymphoma and multiple myeloma among women and suggest heterogeneous subtype associations. This is one of the first prospective studies focusing on central adiposity and non-Hodgkin's lymphoma subtypes.

Objective: The objective of this study was to document cancer mortality among American butchers. Methods: Death certificates collected in 24 American states were used to calculate mortality odds ratios (ORs) and their confidence intervals (CIs) for 18,639 butchers. Results: Butcher's experienced an increased mortality of cancer of the oral cavity (OR, 1.40; 95% CI = 1.09-1.81), esophagus (OR, 1.19; 95% CI = 1.01-1.40), pharynx (OR, 1.22; 95% CI = 0.91-1.64), and larynx (OR, 1.19; 95% CI = 0.92-1.54), as well as a reduced mortality from melanoma (OR, 0.70; 95% CI = 0.52-0.94), non-Hodgkin lymphoma (OR, 0.82; 95% CI = 0.69-0.97), and breast cancer (OR, 0.76; 95% CI = 0.58-0.99). Conclusions: It is likely that occupational exposures experienced by butchers have contributed to the increased risk of cancers of the oral cavity and esophagus. Copyright © by American College of Occupational and Environmental Medicine.

To study the relation between smoking and non-Hodgkin's lymphoma (NHL), in the Rhône-Alpes region of France.We conducted a hospital-based case-control study that included 180 cases of NHL and 360 age-, gender-matched hospital controls. Matched univariable and multivariable logistic regression models were used for analysis.For the whole study population as well as for men, smoking does not elevate the risk of NHL. However, the risk of NHL is higher for women who currently smoke compared to women who have never smoked (odds ratio [OR] = 2.40, 95% confidence interval [95% CI] = 1.19-4.84). Among ever smokers, the OR of NHL is 5.04 (95% CI = 1.40-18.12) for women who have smoked for more than 30 years compared with those who have never smoked. Similarly, women who started to smoke before the age of 20 years compared with women who have never smoked are at greater risk of developing NHL (OR = 2.40, 95% CI = 0.99-5.85). In the total population (women and men), smoking may be associated with one histologic subtype, follicular NHL with an adjusted OR for the current smokers compared to subjects having never smoked of 3.20, 95% CI = 0.79-12.97.In spite of the small number of subjects in the subgroups, a relation is observed between smoking and NHL among women, but not men, and in the total population a relation is suggested between smoking and follicular NHL.

BACKGROUND: The European Commission has granted conditional approval to daratumumab (DARA) as monotherapy in adult patients (pts) with relapsed or refractory multiple myeloma (MM) whose prior therapy included a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) and who have demonstrated disease progression on the last therapy. DARA was approved under an accelerated assessment based on single-arm phase 2 studies. Outcomes in these heavily pretreated pts in a real-world (RW) setting can provide evidence on the relative treatment efficacy of DARA versus physician's choice (PC). AIMS: To perform an adjusted comparison of overall survival (OS) and progression-free survival (PFS) for DARA monotherapy versus PC, as observed in a RW historical cohort of heavily pretreated and highly refractory MM pts from the Czech Republic using pt-level data. METHODS: Using RW longitudinal pt chart data from the Registry of Monoclonal Gammopathies (RMG) of the Czech Myeloma Group, pts with ≥2 prior lines of therapy previously exposed to both a PI and an IMiD were identified. Pt-level data from the RMG were pooled from pivotal DARA monotherapy studies (pts treated with DARA 16 mg/kg). Pts in the RMG could contribute information to the analysis for multiple lines of therapy, with baseline defined as the date of initiation of the actual treatment line. For the definition of PFS, missing data for the date of disease progression for pts in the RMG who initiated subsequent therapy were replaced by the conservative proxy of the date of initiation of the next treatment. OS and PFS were analysed using a Kaplan-Meier analysis. To adjust for confounding variables, a multivariate Cox proportional hazards regression was developed that included age, gender, beta-2 microglobulin levels (β2M : 5.5 g/L), albumin levels ( RESULTS: From the RMG database, we identified 971 treatment lines in 463 pts previously exposed to both a PI and an IMID (n=206 in third line, n=256 in fourth line, n=203 in fifth line, n=307 in ≥sixth line). The dates of treatment initiation for the RMG pts ranged from March 2006 to March 2015. The most frequent treatment regimens were lenalidomide (33.4%), chemotherapy (18.1%), bortezomib (13.6%), thalidomide (8.0%), and bortezomib+thalidomide (5.3%). The number of pts treated with carfilzomib (2.5%) and pomalidomide (2.4%) was limited. DARA-treated pts (N=148) differed from the RMG cohort in median age (64 vs 62 years), median prior lines of therapy (5 vs 4), prior exposure to carfilzomib (41.2% vs 0.3%) and pomalidomide (55.4% vs 0.6%), thrombocytopenia incidence (46.9% vs 18.0%), and ≥triple refractory status (64.2% vs 5.3%). Median observed PFS and OS for DARA versus PC were 4.0 and 5.6 months, respectively, for PFS and 20.1 and 11.9 months, respectively, for OS. Older age, male sex, low albumin levels, high β2M levels, thrombocytopenia incidence, and double/triple/quadruple refractory status were all independent, statistically significant risk factors for mortality. Albumin levels, β2M levels, thrombocytopenia incidence, and refractory status were also predictive of PFS. The adjusted hazard ratio (95% confidence interval) for OS and PFS for DARA versus PC was 0.35 (0.22-0.56) and 0.79 (0.56-1.12), respectively. Figure 1 represents the predicted survival curves for the RMG cohort that were derived from the multivariate model, comparing observed PFS/OS versus predicted with DARA treatment. CONCLUSIONS: This adjusted treatment comparison suggests a significant improvement in OS and a numerical improvement in PFS for DARA compared to RW historical control data in heavily pretreated/highly refractory MM pts. The lower PFS benefit estimate for DARA compared to OS may be partly explained by limitations in the availability and comparability of data regarding progressive disease in the RMG cohort compared to clinical trial data. Adjusted comparisons between trial data and historical cohorts can provide useful insights to clinicians and reimbursement decision makers on relative treatment efficacies in the absence of head-to-head comparison studies for DARA monotherapy. Disclosures Hájek: Amgen: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Spicka:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gatopoulou:Janssen Health Economics & Market Access EMEA: Employment. Vesela:Janssen Cilag s.r.o., Czech Republic: Employment. Diels:Johnson & Johnson: Employment, Equity Ownership. Besson:Janssen: Employment. Ito:Janssen: Employment, Equity Ownership.

Background Lifetime physical activity energy expenditure (PAEE) is an important determinant of risk for many chronic diseases but remains challenging to measure. Previously reported historical physical activity (PA) questionnaires appear to be reliable, but their validity is less well established. Methods We sought to design and validate an historical adulthood PA questionnaire (HAPAQ) against objective PA measurements from the same individuals. We recruited from a population-based cohort in Cambridgeshire, UK, (Medical Research Council Ely Study) in whom PA measurements, using individually calibrated heart rate monitoring, had been obtained in the past, once between 1994 and 1996 and once between 2000 and 2002. 100 individuals from this cohort attended for interview. Historical PA within the domains of home, work, transport, sport and exercise was recalled using the questionnaire by asking closed questions repeated for several discrete time periods from the age of 20 years old to their current age. The average PAEE from the 2 periods of objective measurements was compared to the self-reported data from the corresponding time periods in the questionnaire. Results Significant correlations were observed between HAPAQ-derived and objectively measured total PAEE for both time periods (Spearman r = 0.44; P < 0.001). Similarly, self-reported time spent in vigorous PA was significantly correlated with objective measurements of vigorous PA (Spearman r = 0.40; P < 0.001). Conclusions HAPAQ demonstrates convergent validity for total PAEE and vigorous PA. This instrument will be useful for ranking individuals according to their past PA in studies of chronic disease aetiology, where activity may be an important underlying factor contributing to disease pathogenesis.