ALBERT

Description: Background: The community-associated methicillin-resistant S. aureus (CA-MRSA) ST93 clone is becoming dominant in Australia and is clinically highly virulent. In addition, sepsis and skin infection models demonstrate that ST93 CA-MRSA is the most virulent global clone of S. aureus tested to date. While the determinants of virulence have been studied in other clones of CA-MRSA, the basis for hypervirulence in ST93 CA-MRSA has not been defined. Results: Here, using a geographically and temporally dispersed collection of ST93 isolates we demonstrate that the ST93 population hyperexpresses key CA-MRSA exotoxins, in particular alpha-hemolysin, in comparison to other global clones. Gene deletion and complementation studies, and virulence comparisons in a murine skin infection model, showed unequivocally that increased expression of alpha-hemolysin is the key staphylococcal virulence determinant for this clone. Genome sequencing and comparative genomics of strains with divergent exotoxin profiles demonstrated that, like other S. aureus clones, the quorum sensing agr system is the master regulator of toxin expression and virulence in ST93 CA-MRSA. However, we also identified a previously uncharacterized AraC/XylS family regulator (AryK) that potentiates toxin expression and virulence in S. aureus. Conclusions: These data demonstrate that hyperexpression of alpha-hemolysin mediates enhanced virulence in ST93 CA-MRSA, and additional control of exotoxin production, in particular alpha-hemolysin, mediated by regulatory systems other than agr have the potential to fine-tune virulence in CA-MRSA.

Description: Stream and rainfall gauging and runoff sampling were used to determine changes in hydrology and export of nutrients and suspended sediment from a June 2004 wildfire that burned 3,010 ha in chaparral coastal watersheds of the Santa Ynez Mountains, California. Precipitation during water year 2005 exceeded average precipitation by 200 to 260%. Burned watersheds had order of magnitude higher peak discharge compared to unburned watersheds but similar annual runoff. Suspended sediment export of 181 metric tons ha -1 from a burned watershed was approximately 10 times greater than from unburned watersheds. Ammonium export from burned watersheds largely occurred during the first 3 storms and was 32 times greater than from unburned watersheds. Nitrate, dissolved organic nitrogen, and phosphate export from burned watersheds increased by 5.5, 2.8, and 2.2 times, respectively, compared to unburned chaparral watersheds. Storm runoff and peak discharge increases in burned compared to unburned sites were greatest during early season storms when enhanced runoff occurred. As the winter progressed, closely spaced storms and above average precipitation reduced the fire-related impacts that resulted in significant increases in annual post-fire runoff and export in other studies in southern California chaparral. Copyright © 2012 John Wiley & Sons, Ltd.

Description: Abstract 3166 Background: In ENESTnd, nilotinib (NI) significantly reduced progression and demonstrated superior molecular response rates vs. imatinib (IM) in patients newly diagnosed with Philadelphia chromosome positive chronic phase chronic myelogenous leukemia (CML-CP). Additionally, fewer NI patients discontinued therapy vs. IM (Table 1). Previously reported 24-month analyses of PROs indicated similar health-related quality of life (HRQoL) and functioning mean scores between the treatment arms, and scores similar to general population norms. Aim: To evaluate the PROs for patients in ENESTnd with minimum follow-up of 36 cycles and to understand cohort-level (per treatment arm) HRQoL outcomes Methods: In ENESTnd, nNewly diagnosed CML-CP patients were randomized to NI 300 mg twice daily (BID), NI 400 mg BID, or IM 400 mg once daily (QD). HRQoL was assessed using the Functional Assessment of Cancer Therapy – Leukemia (FACT-Leu) and the Short Form 36 Health Survey (SF-36). The FACT-Leu has two components: a) the FACT-General (FACT-G) which measures physical, social/family, emotional, and functional well-being and b) a 17-item leukemia specific subscale. The SF-36 assesses eight domains (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health) that enable a mental component score (MCS) and physical component score (PCS). Questionnaires were administered at enrollment and end of cycles 3, 12, 24, and 36. Mixed effects models for longitudinal data were used to compare trends over time between treatment arms. Study discontinuation prevented collection of PROs from patients with inadequate response or intolerance to treatment. Pattern-mixture models were fit to attempt to control for missing PRO data resulting from discontinuation or other reasons. Separately, missing data were imputed consistently across arms for cohort-level analysis of the FACT-Leu subscale so mean cohort scores could be reported (Table 1). Results: In both mixed effects and pattern-mixture models, FACT-Leu subscale, FACT-G, and SF-36 scores (PCS and MCS) were similar across treatment arms over time. Of the patients remaining on study and completing PRO questionnaires, SF-36 PCS and MCS scores at cycle 36 in all arms were comparable to the general US population; FACT-G scores were slightly better (Table 2). In the cohort-level analysis with imputation according to reason, IM FACT-Leu subscale scores began to trend increasingly lower vs. NI arms beginning at day 168 (Figure 1). By day 1008, the IM arm mean score is 10% and 13% lower than the NI 300 mg and NI 400 mg arms, respectively (Figure 1). Higher rates of discontinuation in the IM arm are the main factors that lead to the HRQoL deficit. Conclusions: In ENESTnd, patients who respond to and tolerate treatment have consistent HRQoL that is comparable to the general population. Cohort-level analysis indicates that discontinuation rates due to inadequate response and intolerance must be considered when determining the HRQoL across the entire cohort. These results suggest that in a population of newly diagnosed patients with CML-CP, NI results in higher HRQoL than IM. These findings may have particularly important implications for payers and policy makers when evaluating treatment options. Disclosures: Beaumont: Novartis: Research Funding. Magestro:Novartis: Employment. Coombs:Novartis: Employment. Fan:Novartis Pharmaceuticals Corp: Employment. Kemp:Novartis Pharmaceuticals Corp: Employment. Waltzman:Novartis: Employment.

Description: Abstract 3826 Background: Imatinib is the current standard of care for chronic myelogenous leukemia (CML). Nilotinib is a highly potent and the most selective inhibitor of BCR-ABL. A Phase III multi-center, open label, randomized study (ENESTnd) was conducted comparing these two therapies in adult patients with newly diagnosed Philadelphia Chromosome positive (Ph+) CML in chronic phase. The primary endpoint analysis at 12 months demonstrated that major molecular response (MMR) was significantly improved with nilotinib 300 mg BID (44%) and nilotinib 400 mg BID (43%) compared to imatinib 400 mg QD (22%; p 〈 0.001). The discontinuation rate due to adverse events was lowest among the nilotinib 300mg BID treatment arm (5%) compared to 7% in the imatinib arm, and nilotinib 400 mg BID (9%). Based on the results of this clinical trial, nilotinib 300 mg BID was approved for initial use for CML-CP in the US. Aim: To evaluate the occurrence and rate of hospitalizations and time away from usual activities in this phase III trial. Methods: A total of 846 patients were randomized to receive nilotinib 300 mg BID (n=282), nilotinib 400 mg BID (n=281) or imatinib 400mg QD (n=283). Hospitalizations, defined as any visit to the hospital requiring an overnight stay, excluding pre-planned or elective surgery, were assessed throughout the study period. Overdispersed Poisson regression models were used to compare the days hospitalized per 1,000 patient-days on study. Patients were asked to report time-off, defined as average number of hours per week taken away from all usual activities due to CML and side effects of CML treatment over the past 4 weeks, at Baseline and at the end of Months 3 and 12. The Wilcoxon rank-sum test was used to compare the time off from usual activities at each assessment; and t-tests were used to evaluate the within-group changes in time off. Results: There were a total of 57 hospitalizations in the imatinib arm versus 48 hospitalizations in the nilotinib 300 mg BID arm, and 74 hospitalizations in the nilotinib 400 mg BID arm (Table). Descriptive statistics for length of stay (LOS) are presented in the Table. The hospitalization rate, expressed as hospital days per 1,000 patient days, was 47% higher in the imatinib arm compared to the nilotinib 300 mg BID arm (p=0.057) and 8% higher compared to the nilotinib 400 mg BID arm (p=0.68). Patients in the nilotinib 300mg BID arm had fewer stays and shorter LOS than the imatinib arm, whereas patients in the nilotinib 400mg BID arm had more stays than the imatinib arm but shorter LOS on average resulting in fewer total hospital days. The majority of hospitalizations (56%) in all three arms occurred within the first 9 months. Time off from usual activities, which began at an average level of 8–10 hours per week at Baseline, decreased in each arm, but the decrease did not significantly differ between arms (Table). Similar results were observed when patients reporting zero hours of time off were excluded from the analysis. There was no association between time off and age. Summary/conclusions: In patients with newly diagnosed CML-CP, nilotinib resulted in less hospital time compared to imatinib, although this difference did not reach statistical significance. Additionally, patients in all three treatment groups reported significant improvements from baseline in time off from usual activities. Disclosure: Beaumont: Novartis: Research Funding. Coombs:Novartis: Employment, Equity Ownership. Bollu:Novartis: Employment, Equity Ownership. Woodman:Novartis Oncology: Employment. Cella:Novartis: Research Funding.

Description: Abstract 4765 Introduction: Patients with FLT3-mutated AML have poor prognoses due to shorter survival, a high incidence of relapse, and a lack of effective treatment options. Limited information is published on the burden of illness (BOI) of AML, especially for patients with FLT3-mutated disease. This study reviewed the epidemiologic, clinical, humanistic, and economic literature and estimated the burden of FLT3-mutated AML in the US. Methods: A systematic literature review was conducted in PubMed to identify clinical and economic publications on AML published in English from 2000 to 2011. Data relevant to the burden of FLT3-mutated AML were abstracted. 607 citations were identified in PubMed. 581 abstracts were screened and 35 articles were abstracted. Epidemiologic data were also sought from the Surveillance, Epidemiology and End Results (SEER) database. Areas where information was limited or not available were identified and discussed with clinicians experienced in treating AML. An Excel model was then developed to estimate the population-level BOI of AML by FLT3 status. Resource utilization estimates were obtained from the literature and expert opinion. Direct costs included procedures, hospitalizations, outpatient/office visits, other resource use (home health care, hospice, skilled nursing facility), and medications (including chemotherapy). Indirect costs included lost productivity but did not include costs associated with premature retirement or premature mortality. Results: In patients age