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Abstract Abstract 487FN2 Background: Given the life-threatening nature of severe VOD (sVOD) and multi-organ failure (MOF), DF was made available in the US through a prospective treatment IND protocol (T-IND) to gather additional safety and response data from SCT patients (pts) with sVOD who were not eligible for a pivotal Phase 3 trial. Following completion of this Phase 3 trial, the T-IND protocol has continued and been amended to include pts who would have met eligibility criteria for the completed phase 3 trial, as well as pts with non-severe VOD and non-SCT pts who develop VOD after chemotherapy (chemo). This is the largest prospective evaluation of DF for the treatment of sVOD/MOF post SCT and non-SCT pts to date. Methods: Pts were initially required 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) that followed SCT. Following treatment of 104 pts, an amendment expanded eligibility criteria to include pts with VOD after chemo and pts with non-severe VOD (defined as no MOF). Key exclusion criteria included clinically significant bleeding or >1 pressor to maintain BP. CR was defined as bilirubin < 2 mg/dL + resolution of MOF (if applicable). Mortality was assessed at Day +100 (D+100) in all pts. DF was given at 6.25 mg/kg IV q6h (25 mg/kg/d) with treatment duration recommended for at least 21d. Results: This interim analysis is based on 269 pts enrolled between December 2007 and March 2011 at 67 centers. Nearly all pts (n=251) had undergone SCT (with allogeneic SCT in 225, 90%); 18 developed VOD after chemo alone. Of the 269 cases of VOD, 200 were severe at study entry, with 25% (66/269) of all pts dialysis dependent and 31% (83/269) ventilator dependent. Median age was 16 years (range 0.1 – 70); 55% were male. In the SCT pts, the most common diagnosis was leukemia (29% AML; 22% ALL; CML 3%; 4% other), with conditioning of CY (71%), BU (46%) and TBI (38%) respectively; 18% had undergone multiple SCTs (>1 SCT). Median onset of VOD was 15 d post-SCT. When presenting after chemo alone (n=18), median onset of VOD was 16 d after the first dose, most frequently after CY (61%), cytarabine (44%) and vincristine (39%), and for treatment of leukemia (AML 33%, ALL 33%, other 6%). Overall mean number of days of DF administration in all pts was 22 (range 1–88).Of 269 pts, 32% (85/269) achieved a CR and 50% [ by Kaplan-Meier estimate] survived to D+100. In the subgroup of SCT pts, 31% (78/251) achieved CR and 50% survived to D+100; 134 pts met entry criteria for the original Phase 3 trial and comparison to the Phase 3 historical control showed a statistically improved outcome in CR (30% vs 9%, p=0.0006) and D+100 survival (46% vs 25%; p=0.006). Of 200 pts with sVOD, CR was 28% and D+100 survival was 44%. In the 18 chemo only pts, CR was 39% and D+100 survival was 50%. CR rate and D+100 survival for the 69 pts with non-severe VOD were 42% and 62%, respectively. Delay of >2 d (vs < 2 d) in the start of DF after VOD diagnosis resulted in reduced CR (23% vs 35%, p=0.0339) and survival (37% vs 56%, p=0.01). Children as compared to adults had higher rates in CR (35% vs 29%) and survival (55% vs 43%). Toxicity proved generally manageable: 22% of pts experienced a total of 81 related AEs, primarily consisting of hemorrhage (19%) and hypotension (4%). Hemorrhage included pulmonary bleeding (6%), GI hemorrhage (3%), epistaxis (3%) and hematuria (3%). Similar to the observation of decreased GvHD in other studies, the incidence of all grade GvHD in the allogeneic SCT pts was 8%. Conclusions: In 269 pts with mainly sVOD/MOF, DF therapy achieved significantly improved outcome compared to an untreated historical control. Importantly, CR and survival were improved in pts who were treated within 2d of VOD diagnosis (vs. later) and in pts who had not yet progressed to sVOD. As with prior studies, there was a low incidence of DF-associated toxicities. Interestingly, the incidence of GvHD in allo-SCT pts was low, consistent with the reduction of GvHD seen in the large randomized EBMT pediatric prevention study. These results confirm the findings of previous trials and strongly support early intervention with DF once the diagnosis of VOD is made after SCT, as well as its use in pts who have not progressed to advanced MOF. The use of DF for VOD following intensive chemotherapy without SCT also appears promising, but more research in this patient population is needed. Enrollment to the T-IND study continues. Disclosures: Richardson: Gentium: Membership on an entity's Board of Directors or advisory committees. Arai:Gentium: Research Funding. Symons:Otsuka Pharmaceuticals: Research Funding. Martin:Gentium: Research Funding. Massaro:Gentium: Consultancy. D'Agostino:Gentium: Membership on an entity's Board of Directors or advisory committees. Hannah:Gentium: Consultancy. Tudone:Gentium: Employment. Hume:Gentium: Employment. Iacobelli:Gentium SpA: Employment. Soiffer:Gentium: Honoraria.

Abstract Introduction: Despite recent advances in available treatments, chronic lymphocytic leukemia (CLL) remains an incurable disease, and the vast majority of patients (pts) will relapse and require additional lines of therapy. Thus, prolonging remission is a key treatment goal in CLL. This multicenter, randomized, double-blinded phase 3 trial (NCT00774345) was designed to evaluate the efficacy and safety of lenalidomide (LEN) vs placebo (PBO) as maintenance therapy in previously treated CLL pts. Methods: Eligible CLL pts must have had at least a partial response (PR) to second-line therapy. Pts were randomized 1:1 to receive either LEN 2.5 mg once daily on days 1-28 of the first 28-day cycle, or matching PBO. If LEN was well tolerated, escalation to 5 mg/day was permitted from cycle 2, and further escalation to 10 mg/day at cycle 7 and thereafter. Pts were stratified by their response at the end of second-line therapy (PR, nodular PR, complete response [CR], or CR with incomplete bone marrow recovery; vs minimal residual disease [MRD]-negative CR by flow cytometry); age (≤ 70 vs > 70 years); and presence of at least one of the following poor prognostic factors: del(11q), del(17p), unmutated IGHV, or b2M > 0.4 mg/L (Yes vs No vs Unknown). Co-primary endpoints were progression-free survival (PFS; IRAC assessed) and overall survival (OS). Secondary endpoints included: safety, tumor response, duration of response, second PFS (PFS2, time from randomization to second disease progression or death), and health-related quality of life (HRQoL). Results: Overall, 314 pts were enrolled (LEN, n = 160; PBO, n = 154). Baseline characteristics were balanced between the treatment arms: median age was 63 years (range 37-82) and 63 years (range 37-84), 71.9% and 72.1% were male, 9.4% and 11.7% had MRD-negative CR to second-line treatment, and 47.5% and 47.4% had at least one poor prognostic factor, in the LEN and PBO arms, respectively. On review of the primary analysis, 30 Sept 2015 data cutoff, the required number of progression events to complete the co-primary analysis had occurred, and the data monitoring committee recommended that the study be unblinded. Median follow-up time was 31.5 months, and the median PFS was significantly longer for LEN vs PBO: 33.9 vs 9.2 months, respectively (HR 0.40 [95% CI 0.29, 0.55]; P < 0.001). At the time of the analysis there were 86 deaths and there was no significant difference in the OS (HR 0.96 [95% CI 0.63, 1.48]; P = 0.856). Subsequent CLL therapy was received by 35.7% of pts in the LEN arm and 58.4% of pts in the PBO arm, of these pts 16% in the LEN arm and 20% in the PBO arm were treated with a BTK or PI3K inhibitor. Median PFS2 was significantly longer for LEN vs PBO: 57.5 vs 32.7 months, respectively (HR 0.46 [95% CI 0.29, 0.70]; P <0.001). Median number of treatment cycles received was 18 vs 9 cycles, for LEN vs PBO, respectively; a higher proportion of pts in the LEN arm started ≥25 cycles vs the PBO arm (38.9% vs 24.0%, respectively). Median dose intensity in the LEN arm was 4.2 mg/day. The most common adverse events (AEs) of all grades were neutropenia (66.2% vs 30.5%) and diarrhea (40.8% vs 16.2%) in the LEN vs PBO arm, respectively. Febrile neutropenia occurred in 1.9% vs 0%, deep vein thrombosis in 1.9% vs 0%, and pulmonary embolism in 2.5% vs 0.6% of pts in the LEN vs PBO arm, respectively. Most common grade 3/4 AEs were neutropenia (59.9% vs 22.7%), thrombocytopenia (16.6% vs 6.5%), and diarrhea (8.3% vs 0.6%) in the LEN vs PBO arm, respectively; all other grade 3/4 AEs occurred in <5% of pts in either arm. While there was a significant difference in the incidence of neutropenia, the rate of grade 3/4 infections was 16.6% for LEN vs 10.4% for PBO-treated pts. There were 13 (8.3%) vs 14 (9.1%) pts with at least one invasive second primary malignancy (SPM) in the LEN vs PBO arm, respectively. Hematologic invasive SPMs occurred in 7 vs 2 pts, and solid tumor invasive SPMs occurred in 7 vs 12 pts, in the LEN vs PBO arm, respectively. Overall, 44 pts in the LEN arm and 41 pts in the PBO arm died; 1 pt died on treatment in the LEN arm, and 2 pts in the PBO arm. There was no clinically meaningful difference in HRQoL for LEN vs PBO, as measured by FACT-Leu and EQ-5D, during maintenance treatment. Conclusions: LEN maintenance therapy significantly improved PFS from 9.2 to 33.9 months following second-line treatment in pts with CLL. The incidence of invasive SPMs was similar in both arms, and LEN maintenance treatment had an expected and acceptable safety profile. Disclosures Foà: Roche: Consultancy, Speakers Bureau; Janssen: Speakers Bureau; Gilead,: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau; Pfizer, Ariad: Speakers Bureau; Genentech, Janssen, BMS: Consultancy. Schuh:Gilead: Consultancy, Honoraria, Research Funding; Roche, Janssen, Novartis, Celgene, Abbvie: Consultancy, Honoraria. Zaritskey:Novartis: Consultancy; Janssen: Consultancy. Semochkin:Celgene, Sandoz, Novartis, Astellas, Janssen Pharmaceuticals, Bristol-Myers Squibb: Speakers Bureau; Celgene, Bayer Healthcare, Astellas Pharma Inc.: Research Funding; City Clinical Hospital 52, Moscow, Russia: Consultancy. Simpson:Amgen Pharmaceuticals: Research Funding; Celgene, Roche, Janssen: Honoraria. Vokurka:Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Zhang:Celgene Corporation: Employment, Equity Ownership. Purse:Celgene Corporation: Employment, Equity Ownership.

INTRODUCTION: Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease for which there is an unmet clinical need for new therapies. The safety and efficacy of budesonide oral suspension (BOS) for the treatment of EoE has been demonstrated in a previous phase 2 study. The current phase 3 study evaluated the efficacy and safety of BOS in a large cohort of patients with EoE. METHODS: This randomized, double-blind, placebo-controlled trial (SHP621-301; NCT02605837) investigated the safety and efficacy of BOS in patients (11–55 years) with EoE and dysphagia. Patients were randomized 2:1 to 2.0 mg BOS or placebo twice daily (b.i.d.) for 12 weeks (Figure 1). Co-primary endpoints were histologic (peak eosinophil count ≤6 eosinophils/high-powered field [eos/hpf]) and dysphagia symptom (≥30% decrease in symptoms as measured by the Dysphagia Symptom Questionnaire [DSQ]) responses after 12 weeks of therapy. Secondary endpoints included change in DSQ score and change in EoE Endoscopic Reference Score (EREFS) from baseline to final treatment period. Safety was also assessed. RESULTS: A total of 322 patients were randomized (BOS, n = 215; placebo, n = 107), of whom 318 patients received at least one dose of double-blind therapy (BOS, n = 213; placebo, n = 105) (Table 1). The primary outcomes were achieved, with significantly more histologic and symptom responders in the BOS-treated than the placebo-treated group (53.1% vs 1.0%, P < 0.001; 52.6% vs 39.1%, P = 0.024, respectively; Figure 2). Improvements in mean DSQ score from baseline to week 12 were significantly greater in the BOS group (n = 197) than the placebo group (n = 89) (−13.0 vs −9.1; P = 0.015). Similarly, improvements in mean EREFS scores were significantly greater with BOS (n = 202) than placebo (n = 93) (−4.0 vs −2.2; P < 0.001). In total, 61.0% of patients reported a treatment-emergent adverse event (TEAE) (BOS, 61.0%; placebo, 61.0%). Only 2.5% of patients experienced a TEAE leading to dose discontinuation (BOS, 1.4%; placebo, 4.8%). Few patients had severe or serious TEAEs on BOS or placebo. No life-threatening TEAEs were reported. CONCLUSION: This phase 3 trial demonstrated the efficacy of BOS as induction therapy for EoE. BOS resulted in significant improvements in histologic, symptomatic and endoscopic endpoints compared with placebo. The majority of TEAEs were mild to moderate and comparable between placebo and BOS. A double-blind, placebo-controlled maintenance study (SHP621-302) is ongoing.

Distress is defined in the NCCN Guidelines for Distress Management as a multifactorial, unpleasant experience of a psychologic (ie, cognitive, behavioral, emotional), social, spiritual, and/or physical nature that may interfere with the ability to cope effectively with cancer, its physical symptoms, and its treatment. Early evaluation and screening for distress leads to early and timely management of psychologic distress, which in turn improves medical management. The panel for the Distress Management Guidelines recently added a new principles section including guidance on implementation of standards of psychosocial care for patients with cancer.

Randall’s plaque (RP; subepithelial calcification) appears to be an important precursor of kidney stone disease. However, RP cannot be noninvasively detected. The present study investigated candidate biomarkers associated with extracellular vesicles (EVs) in the urine of calcium stone formers (CSFs) with low (<5% papillary surface area) and high (≥5% papillary surface area) percentages of RP and a group of nonstone formers. RPs were quantitated via videotaping and image processing in consecutive CSFs undergoing percutaneous surgery for stone removal. Urinary EVs derived from cells of different nephron segments of CSFs ( n = 64) and nonstone formers ( n = 40) were quantified in biobanked cell-free urine by standardized and validated digital flow cytometer using fluorophore-conjugated antibodies. Overall, the number of EVs carrying surface monocyte chemoattractant protein (MCP)-1 and neutrophil gelatinase-associated lipocalin (NGAL) were significantly lower in CSFs compared with nonstone former controls ( P < 0.05) but did not differ statistically between CSFs with low and high RPs. The number of EVs associated with osteopontin did not differ between any groups. Thus, EVs carrying MCP-1 and NGAL may directly or indirectly contribute to stone pathogenesis as evidenced by the lower of these populations of EVs in stone formers compared with nonstone formers. Validation of EV-associated MCP-1 and NGAL as noninvasive biomarkers of kidney stone pathogenesis in larger populations is warranted.

The in vitro activities of rifampin, rifabutin, rifapentine, and rifaximin were tested against 200 periprosthetic joint infection (PJI)-associated staphylococci. Seven rifampin-resistant isolates had MICs of ≥4 μg/ml. Three isolates had rifampin MICs of 0.25 to 1 μg/ml and harbored an Asp471Gly RpoB variant, suggesting that the CLSI rifampin-susceptible staphylococcal breakpoint of ≤1 μg/ml may be too high.

Abstract Background US public health strategy for eliminating tuberculosis (TB) prioritizes treatment of latent TB infection (LTBI). Healthcare personnel (HCP) are less willing to accept treatment than other populations. Little is known about factors associated with HCP LTBI therapy acceptance and completion. Methods We conducted a retrospective chart review to identify all employees with LTBI at time of hire at a large academic medical center during a 10-year period. Personal demographics, occupational factors, and clinic visit variables were correlated with LTBI treatment acceptance and completion rates using multivariate logistic regression. Results Of 470 HCP with LTBI for whom treatment was recommended, 193 (41.1%) accepted treatment, while 137 (29.1%) completed treatment. Treatment adherence was better with 4 months of rifampin than 9 months of isoniazid (95% vs 68%, P &lt; .005). Increased age of the healthcare worker was independently associated with lower rates of treatment acceptance (odds ratio [95% confidence interval]: 0.97 [0.94–0.99] per year), as was having an occupation of clinician (0.47 [0.26–0.85]) or researcher (0.34 [0.19–0.64]). Male gender was associated with higher treatment acceptance (1.90 [1.21–2.99]). Treatment completion was associated with being from a low- (9.49 [2.06–43.73]) or medium- (8.51 [3.93–18.44]) TB-burden country. Conclusions Geographic and occupational factors affect acceptance and completion of LTBI therapy. Short-course regimens may improve adherence. Physicians, researchers, and HCP from high-TB-burden countries have lower treatment rates than other HCP. Improving LTBI treatment in HCP will require attending to cultural and occupational differences.