Academic literature on the topic 'Directors label'

Return rates were studied for a survey on the perceived professional preparation of therapeutic recreation specialists by directors of college and university recreational therapy programs. Specifically, returns for surveys with self-addressed, stamped return envelopes enclosed were compared to those with self-adhering return address labels. Of the 75 surveys sent with a self-addressed, stamped return envelope, 42 responses (56%) were returned at a cost of $2.58 per respondent. Of the 72 surveys sent with a self-adhering return address label 43 responses (59.7%) were returned at a cost of $1.56 per response. While there was no significant difference in return rates, the self-adhering return address label was more cost effective than the self-addressed, stamped, return envelopes.

Return rates were studied for a survey on the perceived professional preparation of therapeutic recreation specialists by directors of college and university recreational therapy programs. Specifically, returns for surveys with self-addressed, stamped return envelopes enclosed were compared to those with self-adhering return address labels, Of the 75 surveys sent with a self-addressed, stamped return envelope, 42 responses (56%) were returned at a cost of $2.58 per respondent. Of the 72 surveys sent with a self-adhering return address label 43 responses (59.7%) were returned at a cost of $1,56 per response. While there was no significant difference in return rates, the self-adhering return address label was more cost effective than the self-addressed, stamped, return envelopes.

Background: Recombinant FVIIa (rFVIIa) was approved by the Food and Drug Administration (FDA) as a hemostatic agent in 1999 for the treatment of patients with hemophilia and inhibitory antibodies against either factor VIII or IX and subsequently approved for use in patients with congenital factor VII deficiency and Glanzmann Thrombasthenia refractory to platelet transfusions in 2005 and 2014 respectively. These are rare disorders and the use of rFVIIa in these conditions has been found to be effective and safe. Despite this very narrow indication for usage, rFVIIa is being used for a diverse range of off-label indications. Along with uncertainty regarding clinical efficacy, available data suggests that the risk of thromboembolic events is increased when rFVIIa is used in off-label settings. Studies on the off-label use of rFVIIa in children are limited to a few large case series. In a retrospective multicenter cohort study utilizing the Pediatric Health Information System (PHIS) administrative database, Witmer et al demonstrated a 10-fold increase in the annual rate of off-label admissions from 2000 to 2007. The mortality rate in the off-label group was 34% and thrombotic events occurred in 11% of the off-label admissions. We conducted a follow up study to characterize the evolution of the off-label use of rFVIIa in children. Objective: To describe current trends of off-label utilization and adverse effects of rFVIIa in children. Study design: A retrospective multicenter cohort study utilizing the PHIS administrative database was conducted. The PHIS dataset includes 51 children's hospitals in the United States and is representative of tertiary care centers in the nation. In patients, 18 years of age or younger who received rFVIIa between 2012-2018 were included. A label admission was defined as an admission with an International Classification of Diseases (ICD-9 and ICD-10) diagnostic code for hemophilia, Factor VII deficiency or Glanzmann thrombaesthenia; admissions without these codes were classified as off-label. Data were analyzed descriptively. Results: There were 7,738 number of admissions, representing 6,493 unique individual subjects. A total of 78.3 % of the admissions were off-label. The rate of off-label use was stable at approximately 80% of the admissions from 2012-18. The most frequent admitting services for the off-label admissions included cardiology (29.8%), cardiovascular/thoracic surgery (15.7%), critical care (15.0%), neonatal-perinatal medicine (8.7%), and hematology/oncology (6.1%). Over half (54.6%) of off-label administration occurred in children younger than 1 year old. Among the off-label admissions 57 % were male and the median days of use of rFVIIa was 1 day. The mortality rate in the off-label group was 22.3 %. Thrombotic events occurred in 11.4% of the off-label admissions. Among the off-label admissions with thrombotic events, the most common admitting services were cardiology (35.0%) and critical care (21.2%). Conclusion: We have demonstrated that on a per admission basis the predominant use of rFVIIa is off-label. Thrombotic events are common. Although the mortality rate in the pediatric patients who received off-label rFVIIa is high; its lower when compared with the previous review. This may likely reflect, in part, the severity of illness in this patient group. In the absence of clearly supportive data demonstrating safety and efficacy, restraint should be exercised with careful consideration of risk versus benefit for use of rFVIIa in off-label settings. Disclosures Gupta: Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; Takeda-Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. O'Brien:Pfizer: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Recombinant FVIIa (rFVIIa) was approved by the Food and Drug Administration (FDA) as a hemostatic agent in 1999 for the treatment of patients with hemophilia and inhibitory antibodies against either factor VIII or IX and subsequently approved for use in patients with congenital factor VII deficiency and Glanzmann Thrombasthenia refractory to platelet transfusions in 2005 and 2014 respectively. These are rare disorders and the use of rFVIIa in these conditions has been found to be effective and safe. Despite this very narrow indication for usage, rFVIIa is being used for a diverse range of off-label indications.

Introduction: For patients with newly diagnosed multiple myeloma (NDMM) who are transplant-eligible, bortezomib/thalidomide/dexamethasone (VTd) is a standard of care (SoC) for induction and consolidation therapy. Clinical practice has evolved to use a modified VTd dose (VTd-mod; 100 mg thalidomide daily), which is reflected in recent treatment guidelines. As VTd-mod has become a real-world SoC, a matching-adjusted indirect comparison (MAIC) of the VTd-mod dose from recent clinical trials versus the dose included in the label (VTd-label; ramp up to 200 mg thalidomide daily) was performed to understand the effect on efficacy of modified VTd dosing for patients with NDMM who are transplant-eligible. Methods: For each outcome (overall survival [OS], progression-free survival [PFS], overall response rates [ORR] post-induction and post-transplant, and rate of peripheral neuropathy), a naïve comparison and a MAIC were performed. Data for VTd-label were obtained from the phase 3 PETHEMA/GEM study (Rosiñol L, et al. Blood. 2012;120[8]:1589-1596). Data for VTd-mod were pooled from the phase 3 CASSIOPEIA study (Moreau P, et al. Lancet. 2019;394[10192]:29-38) and the phase 2 NCT00531453 study (Ludwig H, et al. J Clin Oncol. 2013;31[2]:247-255). Patient-level data for PETHEMA/GEM and CASSIOPEIA were used to generate outcomes of interest and were validated against their respective clinical study reports; aggregate data for NCT00531453 were extracted from the primary publication. Matched baseline characteristics were age, sex, ECOG performance status, myeloma type, International Staging System (ISS) stage, baseline creatinine clearance, hemoglobin level, and platelet count. Results: Patients received VTd-mod (n = 591) or VTd-label (n = 130). After matching, baseline characteristics were similar across groups. For OS, the naïve comparison and the MAIC showed that VTd-mod was non-inferior to VTd-label (MAIC HR, 0.640 [95% CI: 0.363-1.129], P = 0.121; Figure 1A). VTd-mod significantly improved PFS versus VTd-label in the naïve comparison and MAIC (MAIC HR, 0.672 [95% CI: 0.467-0.966], P = 0.031; Figure 1B). Post-induction ORR was non-inferior for VTd-mod versus VTd-label (MAIC odds ratio, 1.781 [95% CI: 1.004-3.16], P = 0.065). Post-transplant, VTd-mod demonstrated superior ORR in both the naïve comparison and MAIC (MAIC odds ratio, 2.661 [95% CI: 1.579-4.484], P = 0.001). For rates of grade 3 or 4 peripheral neuropathy, the naïve comparison and MAIC both demonstrated that VTd-mod was non-inferior to VTd-label (MAIC rate difference, 2.4 [⁻1.7-6.49], P = 0.409). Conclusions: As naïve, indirect comparisons are prone to bias due to patient heterogeneity between studies, a MAIC can provide useful insights for clinicians and reimbursement decision-makers regarding the relative efficacy and safety of different treatments. In this MAIC, non-inferiority of VTd-mod versus VTd-label was demonstrated for OS, post-induction ORR, and peripheral neuropathy. This analysis also showed that VTd-mod significantly improved PFS and ORR post-transplant compared with VTd-label for patients with NDMM who are transplant-eligible. A limitation of this analysis is that unreported or unobserved confounding factors could not be adjusted for. Disclosures Sonneveld: Takeda: Honoraria, Research Funding; SkylineDx: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding. Mateos:Janssen, Celgene, Takeda, Amgen, Adaptive: Honoraria; AbbVie Inc, Amgen Inc, Celgene Corporation, Genentech, GlaxoSmithKline, Janssen Biotech Inc, Mundipharma EDO, PharmaMar, Roche Laboratories Inc, Takeda Oncology: Other: Advisory Committee; Janssen, Celgene, Takeda, Amgen, GSK, Abbvie, EDO, Pharmar: Membership on an entity's Board of Directors or advisory committees; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Takeda Oncology.: Speakers Bureau; Amgen Inc, Janssen Biotech Inc: Other: Data and Monitoring Committee. Alegre:Celgene, Amgen, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees. Facon:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hulin:celgene: Consultancy, Honoraria; Janssen, AbbVie, Celgene, Amgen: Honoraria. Hashim:Ingress-Health: Employment. Vincken:Janssen: Employment, Equity Ownership. Kampfenkel:Janssen: Employment, Equity Ownership. Cote:Janssen: Employment, Equity Ownership. Moreau:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

Abstract Background: Children with ITP for ≥6 months who completed a romiplostim phase 1/2 or phase 3 parent study could enroll in an open-label long-term extension study, data from which is presented here. Methods: Patients enrolled at 28 sites in the US, Canada, Spain, and Australia. All patients received SC romiplostim once weekly. The initial dose was the final dose from the parent study or 1 µg/kg for patients previously receiving placebo, adjusted from 1−10 µg/kg to target platelet counts of 50−200×109/L. Incidence of adverse events (AEs) was the primary endpoint. Results: As of 24 Feb 2016, 66 patients entered the extension study; 65 received romiplostim for up to 6.2 years. At baseline, median (min-max) age was 11 (3-18) years; 56% were female; 61% were white, 14% African American, 14% Hispanic/Latino, 9% Asian, and 3% other; 9.1% had prior splenectomy. Median (min-max) baseline platelet count was 27.5 (2-458)×109/L. Median (min-max) treatment duration was 100 (5-321) weeks. Median (min-max) average weekly romiplostim dose was 4.8 (0.1-10.0) µg/kg, which included escalation to a stable dose; 19 patients started on 1 μg/kg. After ~week 200 (n ≤8 patients), the median dose was observed to fluctuate. All 65 patients received their doses per protocol >90% of the time; 18 patients missed ≥1 dose due to noncompliance for a total of 41 times. Reasons for discontinuing treatment (n = 22, 33%) included consent withdrawn (n = 8), required other therapy (n = 4), noncompliance (n = 3), administrative decision (n = 3), treatment no longer needed (n = 1), per protocol (n = 1), and AE (n = 2) (asthenia, headache, dehydration, and vomiting in one patient and anxiety in the other, per investigator, none of the AEs were treatment-related); 43 (65%) patients continued in the study. Fifty-two serious AEs occurred in 17 patients, 3 deemed treatment-related (anemia, epistaxis, and thrombocytopenia). Bleeding AEs occurred in 56 patients; 5 deemed treatment-related (gingival bleeding, petechiae, injection site bruising, injection site hematoma, and epistaxis). Bleeding AEs occurring in ≥10 patients included contusion (n = 30), epistaxis (n = 29), petechiae (n = 19), and gingival bleeding (n = 12). No thrombotic events were reported. There were no peripheral blood abnormalities to warrant a bone marrow examination. After sporadic platelet responses and negative antibody (Ab) results in the parent study, a patient left the extension due to a need for other therapies and was then identified to have anti-romiplostim neutralizing Ab which were not present on retesting 3 and 6 months later. No patients had anti-TPO neutralizing Ab. From week 2 on, median platelet counts remained >50×109/L; platelet counts were >100×109/L at most timepoints, despite an observed decrease in the median dose from 4-5 μg/kg to 2-3 μg/kg around week 160 (Figure). For 15 patients (23%), the first study week was the first week receiving romiplostim (previously these patients received placebo). Nearly all (94%, 61/65) patients had a platelet response (median platelet counts for a month ≥50×109/L); the mean (SD) % of months with a platelet response was 77% (33%). Most (72%, 47/65) patients had a platelet response ≥75% of the time and over half (58%, 38/65) of patients had a platelet response ≥90% of the time. Nine (14%) patients entered remission (Table), defined here as platelet counts ≥50×109/L for 24 weeks with no ITP treatments; these patients, 5 boys and 4 girls, none with prior splenectomy, had ITP for a median (min-max) of 5 (2-10) years and had received romiplostim for a median (min-max) of 1.6 (0.7-6.2) years. Fifty-eight (89%) patients (or caregivers) self-administered romiplostim. Twenty-three (35%) patients received rescue medications. Conclusion: Over 6 years of data from this ongoing open-label extension study of romiplostim in children with ITP show that >90% of children achieved a platelet response with romiplostim, most responding ≥75% of the time. The safety profile was overall tolerable, similar to that in past studies. Some children (9/66) with longstanding ITP entered remission after receiving romiplostim. Table Table. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Bussel: Symphogen: Membership on an entity's Board of Directors or advisory committees; Physicians Education Resource: Speakers Bureau; Immunomedics: Research Funding; Cangene: Research Funding; UpToDate: Patents & Royalties; Boehringer Ingelheim: Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Sysmex: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; BiologicTx: Research Funding; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tarantino:Biogen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Blanchette:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Data safety monitoring boards , Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Other: Data safety monitoring boards . Wang:Amgen Inc.: Employment, Equity Ownership. Mehta:Amgen Inc.: Employment, Equity Ownership. Eisen:Amgen Inc.: Employment, Equity Ownership.

Abstract Introduction: Invasive fungal infections (IFIs) are important causes of morbidity and mortality among patients (pts) with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), and consensus guidelines recommend the use of mold-active antifungal prophylaxis (ppx), e.g., voriconazole (vori) or posaconazole (posa). Isavuconazole (ISAV), the most recently introduced triazole antifungal, is currently approved for the treatment of invasive aspergillosis and invasive mucormycosis. ISAV is an appealing option for ppx against IFIs in neutropenic pts with AML/MDS because of its extended spectrum, superior tolerability (over vori), fewer drug-drug interactions (than posa), absence of need for therapeutic drug monitoring (TDM) and lack of prolongation of the QT interval (enabling easier administration in pts receiving certain anti-leukemic targeted therapies, 5-HT3 antagonists, quinolones, etc). NCT03019939 is an investigator-initiated, phase 2, single-arm, open-label trial of primary antifungal ppx with ISAV in pts with AML/MDS. Methods: Previously untreated adult pts with AML or MDS who are or are anticipated to become neutropenic as a result of their first therapy for AML/MDS are eligible to participate in this ongoing trial. Accrual of 100 pts is planned. Stopping rules exist for both futility and toxicity, assuming equivalence between ISAV and the current standard of care, posa, in preventing breakthrough IFIs (expected rate, 5%). In pts who have begun definitive anti-leukemic treatment, ISAV must be initiated within 4 days. Use of systemic antifungal therapy for >72 hours during the week prior to ISAV initiation is not allowed. ISAV is administered orally as the pro-drug, isavuconazonium sulfate, and dosed per the US label. ISAV ppx is administered until recovery from neutropenia (absolute neutrophil count (ANC) ≥0.5 x 109/L and attainment of complete remission (CR), with or without complete count recovery, occurrence of a proven or probable IFI (per 2008 EORTC/MSG criteria), development of unacceptable toxicity, pt withdrawal or death, or for a maximum of 12 weeks. The primary endpoint is the incidence of proven/probable IFI during the study period (up to 30 days from the last dose of ISAV). ISAV plasma concentrations are determined immediately pre-dose on days 8 and 15 using a validated assay. Results: A total of 50 pts were enrolled between April 28, 2017 and July 10, 2018. Four pts did not begin ppx with ISAV (1 each could not complete caspofungin washout and screening tests in time, 2 insurance denials). Of the remaining 46 pts (Table 1), 2 remain on study. Reasons for going off study (n = 44) included achievement of CR with neutrophil recovery (n = 26), completion of 12 weeks of therapy (n = 7), possible IFI (n = 5), investigator decision (n = 2), death (n = 2, 1 disease progression, 1 cardiac arrest), probable IFI (n = 1) and transaminitis (n = 1). In these 44 pts, the median duration of ISAV ppx was 30 (10-86) days. Only 1 case of proven breakthrough IFI occurred: a gluteal abscess that later grew Candida glabrata in a pt who had come off study upon achievement of CR. One case of probable IFI (focal mass-like opacity with ground-glass halo on CT; elevated Aspergillus antigen in broncho-alveolar lavage (BAL) fluid) occurred. All 5 cases of possible IFI were based on pulmonary radiologic findings alone: lower respiratory fungal cultures remained negative at 4 weeks in all 5 pts, and galactomannan was not detected in serum or BAL fluid in any pt. Tolerability of ISAV was excellent, with mild transaminitis attributed to ISAV reported in 1 pt (2%). No pt experienced QTc prolongation while on ISAV. Plasma ISAV levels were measured in 62 blood samples from 34 individual pts, including 28 paired samples. Median (range) ISAV concentrations were 3.74 (2.03-7.65) and 4.1 (2.17-9.25) mcg/ml on days 8 and 15, respectively. There was no correlation between plasma ISAV concentrations (available in 4 of the 7 pts) and the occurrence of confirmed, probable or possible IFI. Conclusions: These results demonstrate ISAV to be a safe and effective alternative for antifungal ppx in treatment-naïve pts with AML/MDS undergoing induction therapy with a variety of different regimens. ISAV's weak inhibition of P-glycoprotein and lack of risk of QT prolongation may make ISAV particularly attractive for antifungal ppx in the era of recently approved or emerging AML therapies such as enasidenib, ivosidenib, midostaurin and quizartinib. Disclosures Bose: CTI BioPharma: Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines Corporation: Research Funding; Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding. Wiederhold:Astellas Pharmaceuticals: Research Funding. Kadia:Celgene: Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; BMS: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Research Funding; Takeda: Consultancy; Jazz: Consultancy, Research Funding. Ravandi:Abbvie: Research Funding; Xencor: Research Funding; Xencor: Research Funding; Jazz: Honoraria; Orsenix: Honoraria; Jazz: Honoraria; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria. Thompson:Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pemmaraju:celgene: Consultancy, Honoraria; abbvie: Research Funding; SagerStrong Foundation: Research Funding; cellectis: Research Funding; samus: Research Funding; stemline: Consultancy, Honoraria, Research Funding; daiichi sankyo: Research Funding; novartis: Research Funding; plexxikon: Research Funding; Affymetrix: Research Funding. Daver:Sunesis: Consultancy; Otsuka: Consultancy; Incyte: Research Funding; BMS: Research Funding; Karyopharm: Research Funding; Daiichi-Sankyo: Research Funding; Kiromic: Research Funding; ARIAD: Research Funding; Incyte: Consultancy; Karyopharm: Consultancy; Pfizer: Research Funding; Sunesis: Research Funding; ImmunoGen: Consultancy; Novartis: Consultancy; Alexion: Consultancy; Novartis: Research Funding; Pfizer: Consultancy. Cortes:Arog: Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees. Konopleva:Stemline Therapeutics: Research Funding. Jain:Verastem: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Celgene: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Genentech: Research Funding; Seattle Genetics: Research Funding; Adaptive Biotechnologioes: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Astra Zeneca: Research Funding; Genentech: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Cellectis: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Incyte: Research Funding; Infinity: Research Funding; Pfizer: Research Funding; ADC Therapeutics: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Adaptive Biotechnologioes: Research Funding; Infinity: Research Funding; BMS: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: 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; Cellectis: Research Funding; Abbvie: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: 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. DiNardo:Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Sasaki:Otsuka Pharmaceutical: Honoraria. Kontoyiannis:Astellas Pharmaceuticals: Research Funding.

Abstract Background Chronic pediatric ITP is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production, resulting in low platelet counts. Romiplostim is a peptibody that stimulates platelet production via activation of the thrombopoietin (TPO) receptor. Romiplostim increased and maintained platelet counts in thrombocytopenic children with ITP in a phase 1/2 trial. Patients who completed this study or an ongoing phase 3 trial were given the option of rolling over into an open-label long-term extension study. Objectives To evaluate the safety and efficacy of long-term use of romiplostim in pediatric ITP. Methods Patients received weekly subcutaneous injections of romiplostim; the starting dose was the last dose in the prior study. Patients who had received placebo started at 1 μg/kg. Dose adjustments targeted platelet counts in the range of 50–200 x 109/L. The maximum allowed romiplostim dose was 10 µg/kg. Assessments of adverse events, concomitant medications, and local platelet counts were performed weekly. The primary endpoint was incidence of adverse events. The protocol did not require bone marrow biopsies to be performed, but when performed, specimens were submitted to a central lab for analysis. Patients who were on a stable dose had the option to receive romiplostim at home; patients and their caregivers then recorded dosing date, time, volume administered, and any dosing errors. Patients who turned 18 years of age during this study were permitted to remain on study. Results Twenty-two patients (N = 12 from the phase 1/2 study and N = 10 from the phase 3 study) were treated with romiplostim for up to 172 weeks (3.3 years). Baseline demographics included a median age of 12.0 years (range 3–16), 50% male, and 18.2% with prior splenectomy. Median romiplostim treatment duration was 89.0 weeks (range 3–172); median total number of doses was 64 (range 3–171); median average weekly romiplostim dose was 4.0 µg/kg (range 1–10), including ramp up to stable dose; and median maximum dose was 8.0 µg/kg (range 1–10). Of the 4 patients who discontinued the study, 3 withdrew consent and 1 was noncompliant; no patients withdrew due to safety issues and 18 continued on study. After the first week of this extension study, which for some patients was the first week of romiplostim, median platelet counts remained above 50 x 109/L throughout the study, and were in the target range of 50–200 x 109/L for all visits but weeks 76 and 156 (Figure). The median romiplostim dose (Q1, Q3) was 6.0 (2.0, 8.0) µg/kg at week 1 and 3.5 (0.0, 7.0) µg/kg at week 168 (Figure). Four patients discontinued romiplostim. Eight patients received rescue medications (defined as medications used for platelet counts < 10 x 109/L, bleeding/wet purpura, or investigator decision) which included immunoglobulins (3 patients), tranexamic acid (3 patients), platelet transfusion (1 patient), aminocaproic acid (1 patient), and prednisone (1 patient). Four patients had serious adverse events (asthma, hemangioma, hypotension, infection, thrombocytopenia, and transfusion reaction) and 1 had life-threatening adverse events (infection and thrombocytopenia). None of the serious adverse events were deemed treatment-related by the investigators. There were no fatal adverse events. Twelve patients had bleeding adverse events; 2 of which were deemed treatment-related (gingival bleeding and petechiae). Bleeding adverse events included epistaxis (4 patients); petechiae (3 patients); gingival bleeding (2 patients); hemorrhage (2 patients); and bleeding from the anus, injection site, lip, and mouth (1 patient each). No bone marrow biopsies were performed as part of this study. Conclusion In this open-label extension study, long term treatment with romiplostim maintained platelet counts in pediatric patients with chronic ITP without significant toxicity. Future results from this ongoing study will provide additional safety and efficacy data regarding long-term use of romiplostim in children with ITP. Disclosures: Tarantino: Pfizer: Membership on an entity’s Board of Directors or advisory committees; Octapharma: Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; BPL: Membership on an entity’s Board of Directors or advisory committees; Baxter: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees. Off Label Use: Romiplostim is approved for the treatment of adults with chronic ITP. Romiplostim is not approved for the treatment of pediatric patients with chronic ITP. Bussel:Amgen: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees. Nie:Amgen: Employment, Equity Ownership. Eisen:Amgen: Employment, Equity Ownership.

Abstract Introduction Emicizumab is a therapeutic bispecific antibody being studied for the the prevention of bleeding in people with hemophilia A. HAVEN 1 and HAVEN 2 are multicenter, open-label phase 3 studies of subcutaneous administration of emicizumab in patients with hemophilia A with inhibitors; HAVEN 1 in adults and adolescents, and HAVEN 2 in children. Patients with planned surgeries, with the exception of minor procedures, were excluded from both studies. However, unplanned emergency surgeries, in addition to minor procedures, were performed in patients receiving emicizumab. Perioperative management was at the discretion of the investigators based on individual clinical assessment, without specific guidance (per protocol) on surgical management provided by the sponsor. Methods We describe the combined surgical experiences from HAVEN 1 and an interim analysis of HAVEN 2, specifically, the frequency of peri-operative bypassing agent (BPA) use and post-operative bleeding events in patients who were treated with emicizumab. Additionally, the type and frequency of surgical procedures and the numbers of surgical procedures associated with and without use of prophylactic BPAs are summarized. Frequency of post-operative bleeding, which were reported in the data as bleeding events resulting from a surgery or procedure, as well as the doses of peri-operative BPAs are also described. Bleeding events were defined as in HAVEN 1 (Oldenburg et al. NEJM 2017; July 10: epub). Results In HAVEN 1 and in the interim analysis of HAVEN 2, there were 22 patients who underwent a total of 29 surgical procedures (24 surgical procedures in 17 patients in HAVEN 1, and 5 surgical procedures in 5 patients in HAVEN 2). Twenty of these procedures (69%) were managed without prophylactic BPAs. Nine procedures (31%) were managed with prophylactic BPAs. Among the 29 surgeries, 6 were tooth extractions and 9 were central venous access device (CVAD)-related procedures (insertion/replacement/removal). Of the remaining 14 surgical procedures, 12 were minor and 2 were major: (1) right knee arthroscopy, synovectomy, debridement of arthrofibrosis, and chondroplasty in HAVEN 1, and (2) a laparoscopic appendectomy in HAVEN 2. Among the 20 surgeries that were not managed with surgical prophylactic BPAs, 14 (70%) did not result in post-operative bleed(s), and 6 (30%) resulted in post-operative bleeds (2 treated with BPAs and 4 not treated with BPAs). The 2 treated post-operative bleeding events occurred with a tooth extraction and with a right knee arthroscopy, synovectomy, debridement of arthrofibrosis, and chondroplasty. Among the 9 surgeries that were managed with surgical prophylactic BPA, 8 were managed with rFVIIa with mean dose (range): 152.81 µg/kg (86.54-254.72 µg/kg) and median number of injections of 1; 1 surgery used prophylactic aPCC (single dose of 49.78 U/kg). Eight (89%) of these surgeries did not result in post-operative bleeding, and 1 (11%) was a tooth extraction that resulted in a single treated post-operative bleeding event. Anti-fibrinolytics were used in 4 of 29 surgical procedures, 3 of which were tooth extractions and 1 of which was a CVAD removal. Among the 7 surgeries that resulted in post-operative bleeding, 3 surgeries were managed with rFVIIa and no surgery was managed with aPCC. BPA doses administered post-operatively in these surgeries are shown in Table 2. Conclusions In HAVEN 1 and an interim analysis of HAVEN 2,management of perioperative BPA use was at the discretion of the investigator. In the two studies combined, the majority (20/29; 69%) of surgeries performed were not managed with prophylactic BPAs, with no post-operative bleeding reported in the majority (14/20; 70%) of these surgeries. Among the 4 tooth extractions that were not managed with prophylactic BPAs, 3 resulted in post-operative bleeding, only 1 of which was treated with BPAs. Among the 5 CVAD-related procedures that were not managed with prophylactic BPAs, only 1 resulted in a post-operative bleed that was not treated with BPAs. In this analysis of patients with hemophilia A with inhibitors who underwent mostly minor surgical procedures while receiving emicizumab prophylaxis, the majority of patients did not receive pre-operative treatment with BPAs. Post-operative bleeding requiring additional BPA treatment seldom occurred. Disclosures Kruse-Jarres: Roche/Genentech: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Grifols: Consultancy, Honoraria; Baxalta: Honoraria. Callaghan: CSL Behring: Membership on an entity's Board of Directors or advisory committees; Bayer HealthCare; Pfizer Inc.; Roche; Shire: Consultancy; Biogen: Membership on an entity's Board of Directors or advisory committees; Roche; Shire: Speakers Bureau; Global Blood Therapeutics: Other: Site PI; Grifols: Membership on an entity's Board of Directors or advisory committees; Alnylam Pharmaceuticals, Inc: Other: Owns stock, stock options, or bonds ; Novo Nordisk: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Site PI, Speakers Bureau; Sancillio: Other: Site PI; Octapharma: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Site PI, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees. Croteau: Aptevo, Baxalta/Shire, Bayer, CSL Behring, Genentech, Novo Nordisk, Octapharma, Pfizer: Consultancy; ATHN/Hemophilia of Georgia: Research Funding; Octapharma: Honoraria; Baxalta, Dimension Therapeutics, Genentech, Pfizer: Research Funding. Jimenez-Yuste: Novo Nordisk: Consultancy, Honoraria, Research Funding; Roche: Consultancy. Khoo: Novo Nordisk: Honoraria; Biogen: Honoraria; Baxalta/Shire: Honoraria. Liesner: Bio Products Laboratory: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; SOBI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; SOBI/Bioverativ: Research Funding, Speakers Bureau. Matsushita: Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Recht: Biogen: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding. Young: Novo Nordisk: Consultancy; CSL Behring: Honoraria. Chang: Genentech: Employment, Equity Ownership. Dhalluin: F. Hoffmann-La Roche Ltd: Employment. Mu: Genentech, Inc.: Employment. Xu: Genentech: Employment. Devenport: Genentech, Inc.: Employment. Ko: Genentech, Inc.: Employment. Solari: Genentech, Inc.: Employment. Oldenburg: Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Investigator Clinical Studies and Research Funding, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies and Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Chronic ITP in children is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production. Pediatric patients with chronic ITP that completed a romiplostim phase 1/2 or phase 3 study could enroll in this open-label long-term extension; 5.2 years of data are reported. Methods: All patients received SC romiplostim once weekly. The initial dose was the final dose from the parent study or 1 µg/kg (for patients previously receiving placebo or who had not received romiplostim for >24 weeks), adjusted from 1-10 µg/kg to target platelet counts of 50-200×109/L. The incidence of adverse events (AEs) was the 1° endpoint. If approved by investigators, patients who maintained platelet counts ≥50×109/L for ≥4 consecutive weeks at a stable dose could subsequently administer doses by self or caregiver. Patients who turned 18 years of age could remain on study. Results: A total of 66 patients (phase 1/2, n=12; phase 3, n=54) entered the extension; 65 received romiplostim for ≤269 weeks (5.2 years); 1 patient withdrew consent before treatment. At baseline, median (range) age was 11 (3-18) years; 56% were female; 61% were white, 14% African American, and 14% Hispanic/Latino; 9.1% had prior splenectomy. Median (range) treatment duration was 57.9 (1-269) weeks; median number of doses was 53.0 (1-268). Median (range) average weekly romiplostim dose was 5.5 (0.1-10.0) µg/kg, including escalation to stable dose, median maximum dose was 8.0 (1.0-10.0) µg/kg, and median most frequent dose was 6.0 (0-10) µg/kg. The median dose fell from 6 to 1 µg/kg; after ~week 140 (n≤9), the median dose fluctuated (Fig 1). Thirteen patients discontinued treatment: consent withdrawn (n=6), noncompliance (2), administrative decision (2), nonresponse (2), and per protocol (1). Fifty-two (79%) patients continued in the study; none withdrew due to AEs. After the first study week median platelet counts remained >50×109/L (Fig 2); for 15 patients (23%), the first study week was the first week receiving romiplostim (ie, previously received placebo). Fifty-six (86%) patients (or caregivers) self-administered romiplostim. Twenty-one (32%) patients received rescue medications on 63 occasions (for low platelet counts [n=35], bleeding/bruising [17], pre- or post-procedure [9], and other [2]), including IVIG (n=10), prednisone (9), aminocaproic acid (3), tranexamic acid (2), methylprednisolone (2), and platelet transfusion (1). Patients required rescue treatment during the first 3 months (27/63 instances), >3-6 months (9), >6-9 months (6), >9-12 months (7), and after 1 year (14) in the extension. Five previous placebo recipients received rescue medication, mostly during the first 3 months (10/14 instances). Three patients achieved remission (platelet counts ≥50×109/L for 24 weeks with no ITP treatments): 1) 9-year-old boy with ITP for 9 years, after 4.3 years of romiplostim, entered remission for the last 2.1 years as of this datacut; 2) 13-year-old boy with ITP for 8.5 years, after 3.3 years of romiplostim, entered remission for the last 1.1 years; and 3) 17-year-old girl with ITP for 8.2 years, after 5.9 years of romiplostim, entered remission for the last 44 weeks. Thirty-four serious AEs occurred in 14 patients, including pyrexia (n=3), epistaxis (2), and thrombocytopenia (2); 3 were deemed treatment-related (anemia, epistaxis, and thrombocytopenia), and none led to discontinuation of romiplostim. Five patients had life-threatening AEs, including thrombocytopenia (n=2) and infection, decreased platelet counts, and subcutaneous abscess (1 each); none were fatal or deemed treatment-related. Bleeding AEs occurred in 47 patients; 3 were deemed treatment-related by the investigator (gingival bleeding, petechiae, and epistaxis). Bleeding AEs occurring in ≥4 patients included contusion (n=25), epistaxis (21), petechiae (16), gingival bleeding (9), mouth hemorrhage (6), ecchymosis (5), and hemorrhage, injection-site bruising, and purpura (4 each). No thrombotic events were reported. There were no peripheral blood abnormalities suggestive of malignancy to warrant a bone marrow examination in any patient. There was no development of anti-TPO or anti-romiplostim antibodies. Conclusion: In this ongoing open-label extension of children with chronic ITP, romiplostim for ≤5.2 years maintained platelet counts with a safety profile similar to that seen in past studies. Disclosures Tarantino: BPL: Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen, Inc: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Cangene: Research Funding; UptoDate, Inc.: Patents & Royalties: royalties. Off Label Use: Romiplostim is indicated for use in adults with chronic immune thrombocytopenia who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. The use of romiplostim in children with ITP is investigational.. Bussel:Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Immunomedics: Membership on an entity's Board of Directors or advisory committees, Research Funding; IgG of America: Research Funding; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Blanchette:Baxter Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Board, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Other: Data Safety Monitoring Board; Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Morales:CSL Behring: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees. Nie:Amgen Inc.: Employment, Other: Stockholder. Eisen:Amgen Inc: Employment, Other: stock ownership.

Introduction: Acalabrutinib (acala), a Bruton's Tyrosine Kinase inhibitor (BTKi), received accelerated FDA approval for treatment of mantle cell lymphoma (MCL) in 2017. Since approval, there has been limited "real world" data, especially in the setting of off-label utilization. We performed an analysis of the safety and efficacy of acala in non-Hodgkin lymphoma (NHL) at our institution for both on- and off-label indications. Methods: We performed a retrospective analysis of all patients (pts) who had received acala for NHL at the University of Pennsylvania between 1/2017 and 5/2019. We examined best response to therapy, duration of response, and progression free survival. Response assessments were determined by treating physician using standard, disease-specific criteria. We collected clinical and demographic data such as genetic risk factors, staging, previous and concomitant therapies. We analyzed adverse events (AEs) and toxicities associated with acala. Survival analyses were completed as described by Kaplan and Meier; all other analyses were descriptive in nature. Results: We identified 23 pts treated with acala at our institution. The cohort consisted of 83% males (n=19). Diagnoses were chronic lymphocytic leukemia (CLL) (n=10; 44%), MCL (n=9; 39%), and diffuse large B-cell lymphoma (DLBCL) (n=4; 17%). One DLBCL was GCB subtype and three were ABC subtype; two of four DLBCL pts were transformed from marginal zone lymphoma and two were de novo. The median age at diagnosis was 61 years, median age at acala start was 69 years. Sixteen (70%) of the pts were Ann Arbor or Rai stage III or IV at diagnosis. The median number of therapies prior to acala was 3 (range 0-12). Of note, the GCB-DLBCL patient had previously undergone both allogeneic (alloSCT) and autologous (autoSCT) stem cell transplants and four of the MCL patients (44%) also had prior allo and/or autoSCTs. The majority (65%) of pts received acala 100 mg twice daily, with the rest of the patients receiving 100 mg once daily. The median time to best response was 2 months (mos). All CLL pts (n=10; 100%) had at least a partial response (PR), including 1 complete response (CR) by iwCLL criteria. In the MCL cohort of 9 pts, 8 (88%) had at least a PR (including 1 CR), and one patient (11%) had stable disease (SD). One MCL pt achieved a CR and moved to alloSCT. One (25%) of the DLBCL pts had a PR (pt was ABC subtype), and three (75%) had SD (one GCB and two ABC-DLBCL pts.) At the time of last follow up, two DLBCL pts had SD and remain on acala, one progressed after 10 months on acala and was switched to obinutuzumab, and one died due to disease progression. The 12 mo progression free survival (PFS) was 89% for CLL and 83% for MCL; 12 mo overall survival (OS) was 89% for CLL and 100% for MCL respectively. (Figure 1). Of note, 16 pts (70%) had been on ibrutinib previously and all pts discontinued (d/c) ibrutinib due to intolerance. Acala related toxicities included: 26% (n=6) arthralgias/myalgias, 13% (n=3) infection, 13% (n=3) bruising/ bleeding, 9% (n=2) rashes, and 4% (n=1) diarrhea. Two pts required dose adjustment of acala and one patient had to d/c acala due to fatigue and bleeding/bruising. Ten (43%) of pts tolerated acala without any side effects. Of note, there were 6 pts with a history of atrial fibrillation (afib) or an afib-related toxicity of ibrutinib, and none of our pts experienced new afib while on acala. In total, six pts d/c acala: 1 patient moved to alloSCT, 3 had disease progression, 1 d/c due to toxicity, and 2 pts died. One death was unrelated to lymphoma progression (renal cancer). Conclusion: Our "real world" experience with acala demonstrates its efficacy and tolerability in the setting of NHL, supporting previously published literature (ACE-LY-004 and ACE-CL-001 trials). In our analysis of 23 patients, the response rates in our CLL and MCL cohorts were 100% and 88% respectively and only one patient discontinued acala for intolerance. There is limited information on the off-label utilization of acala in the relapsed/refractory DLBCL setting. However, the response in our cohort may warrant further evaluation of acala as a possible therapeutic agent in this aggressive/refractory patient population. Acala continues to demonstrate a favorable toxicity profile, especially in pts who were unable to tolerate ibrutinib. Our experience with acala supports pilot data showing efficacy and thus further research in other B-cell malignancies, especially DLBCL, is warranted. Figure 1 Disclosures Hughes: Genzyme: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta Pharna/HOPA: Research Funding. Landsburg:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding. Schuster:Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Chong:Merck: Research Funding; Novartis: Consultancy; Tessa: Consultancy. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Barta:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Merck: Research Funding; Mundipharma: Honoraria; Bayer: Consultancy, Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria. Dwivedy Nasta:Rafael: Research Funding; Millenium/Takeda: Research Funding; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Roche: Research Funding; 47 (Forty Seven): Research Funding; Debiopharm: Research Funding. OffLabel Disclosure: FDA label indication for acalabrutinib is only for patients with CLL. Utilization in DLBCL and CLL populations is beyond the specified indication.

Music video is an intriguing genre of television due to the fact that music drives the images and ideas found in numerous and varied examples of the form. Pre-recorded pieces of pop music are visually written upon in a palimpsest manner, resulting in an immediate and entertaining synchronisation of sound and vision. Ever since the popularity of MTV in the early 1980s, music video has been a persistent fixture in academic discussion, most notably in the work of writers like E. Ann Kaplan, Simon Frith and Andrew Goodwin. What has been of major interest to such cultural scholars is the fact that music video was designed as a promotional tool in their inception, supporting album sales and increasing the stardom of the featured recording artists. Authorship in music video studies has been traditionally kept to the representation of music stars, how they incorporate post-modern references and touch upon wider cultural themes (the Marilyn Monroe pastiche for the Madonna video, Material Girl (1985) for instance). What has not been greatly discussed is the contribution of music video directors, and the reason for that is the target audience for music videos are teenagers, who respond more to the presence of the singer or the band than the unknown figure of the director, a view that is also adhered to by music television channels like MTV.

The Hollywood Jim Crow marks Black and racial minority movies culturally and economically inferior using the unbankable label—a presumption that they will not perform sufficiently well at the box office, especially in foreign markets. This chapter highlights how the unbankable label is present in Sony emails between Hollywood insiders. Unbankable becomes a new way to discriminate and explicitly use race to make decisions about moviemaking. Hollywood insiders suggest that Black cast movies will make less money and attract smaller audiences compared to white cast movies. Subsequently Black directors work on films with smaller budgets and targeted advertising and promotion to niche audiences. Hollywood decision makers overlook successful Black films as exceptions and still apply the unbankable label to Black cinema as a whole, limiting opportunities for Black and racial minority directors.

The Hollywood Jim Crow creates a resurgence of the Negro Problem previously articulated by W.E.B. Du Bois in which Blackness becomes a race stigma in need of remedy. Black directors’ perspectives and career trajectories are steered in a direction to overcome Hollywood insiders’ presumption of the unbankable label—that movies with Black casts or lead actors do not make enough money and are risky investments. Directors brand their movies as human and universal, stating they are relatable to all moviegoers and not just a subsection of Black audiences. Some directors are pressured to work with mostly white or multiracial casts if they are to have increasing production budgets. This retreat from Blackness undermines the notion that Black directors in Hollywood would necessarily bring more Black movies to the screen.

This chapter shows how racial minorities are marginalized as Hollywood directors. The unbankable label that assumes movies by or about African Americans have limited profit potential gives studio executives justification to discriminate against Black directors and their movies. This amounts to a racialization of Hollywood directing that places Black directors at the bottom of the hierarchy. Of all races, Black directors have the smallest average production budgets, are vastly underrepresented especially directing movies with major studio distribution, and find greater representation directing movies distributed by studio independents and independent companies. Even white-directed Black cast movies appear to have bigger average production budgets than Black-directed Black cast movies. Latinx and Asian directors are underrepresented relative to their proportion of the U.S. population, though their average production budgets are sizeable due to having directed a number of big budget movies. Black directors face additional barriers in the foreign market where their movies rarely get distribution. Black directors face a racial marginalization that ultimately impedes their career advancement in the film directing occupation.

2Many people who do high school musicals return to theatre as adults, maybe after college or settling into working life, in community theatre. Community theatres started in the United States in the early twentieth century to engage citizens in their towns, promote patriotism, and instill a sense of civic pride through performance. The label now applies to the thousands of amateur groups across the country that are typically run by a few paid staff but mostly operate on volunteer labor, including a twelve-group consortium, the Kelsey Theatre in New Jersey. These well-established companies cast intergenerationally, sometimes with six-year-old children and seventy-year-old adults in the same show. They proudly take on the label “community theatre,” and renew themselves through families and through webs of connections that spread to local high schools, community colleges, summer day camps, and other community theatres in the region. This chapter follows a year in the life of this community theatre, focusing on the activities of the three directors with different working styles. It describes auditions, rehearsals, and performances, and includes many voices of people who elect to spend their time after school and after work making musical theatre, which some have been doing their whole lives. The chapter discusses the themes of community, professionalism versus the amateur, and leisure in the context of community theatre.

This introduction explore the book’s aims of demonstrating the ability of dialogue to engage audiences and bind together the narrative, aesthetic and performative elements of selected independent cinema, from the 1980s until the present day. The chapter justifies the focus on the verbally creative works of Wes Anderson, Noah Baumbach, Hal Hartley, Jim Jarmusch, Richard Linklater and Whit Stillman, while highlighting links between such cinema and that of New Hollywood and the French New Wave. It introduces the concept of ‘cinematic verbalism’ and the related label of ‘cinematic verbalists’, which will be used throughout the book to refer to these writer-directors’ work. Overall, the chapter details how, by focusing on the ways in which dialogue in American independent cinema is designed and executed, we can question the association of dialogue-centred films with the ‘literary’ or ‘un-cinematic’.

The aim of this paper is to review empirical and theoretical academic research about Private Label products (PLs) and to suggest directions for future research. The review focuses on the period of greatest scientific output (2000-2014) and consults all the international publications on marketing ranked by the Academic Journal Quality Guide. This work has yielded a large selection of articles (270) on PL. The paper's summary of PL research permit a better understanding of the nature of PL and suggests themes for future research. Emerging areas of research were found to be: consumer perceptions of PL and their related behaviour; price and price promotion; channel relationships and quality; with innovation, segmentation and shelf space the least frequently studied. Most studies used analysed consumer data to focus on the grocery sector data. Finally, the study identifies gaps (such as the lack of focus on private label services) and suggests directions for future PL research.

This introductory chapter provides an overview of Paul Verhoeven's RoboCop (1987). If one were to compile a canon of great science-fiction films, the inclusion of RoboCop would be problematic simply because of the puerile title. Given the way films are inevitably marketed, made palatable for audiences naturally means film titles are transformed to suit commercial inclinations, often conflicting with the content of a film. In terms of high-concept cinema, the title RoboCop is a moribund simplification of the film's existential core. Yet it is such outward simplicity that fosters a contradiction often lurking in Hollywood-genre films like RoboCop. RoboCop's reputation was an early source of ridicule, such was the fate of many violent films of the 1980s when sanitised by the puritanism of the BBC or ITV. Fortuitously, the critical standing of RoboCop has grown over the years, in no small part aided by the intervention of Criterion, a specialist home video label which was first to re-release the film on Laserdisc and then later on DVD in an unrated directors cut. While the Criterion edition of RoboCop has long been out of print, the film's inclusion in the Criterion library accentuates its merit as a seminal science-fiction film; a key American work of the 1980s, overturning familiar genre trappings while its erudite philosophical address transforms the iconic Frankenstein narrative into an altogether more radical, theological work.

This research is part of a larger project which aims at developing a tool to help designers create effective GD&T schemas. The first step towards this goal is to determine the particular directions in which dimensions and tolerances need to be controlled. These directions we label here as “Directions of (Dimensional) Control” or DoC for short. Regardless of whether one uses chain dimensioning, reference dimensioning or geometric tolerancing, all size and basic dimensions of position line up in a finite number of directions or Directions of Control. This paper presents an approach for automatically identifying the directions of control from CAD models of mechanical parts. The only input to the system is the geometry of parts or assemblies in STEP file format. The analysis is done part by part for an assembly. First, planar and cylindrical features are recognized and their normal/axes extracted. The extracted features are then organized into groups of parallel normal or axes directions. Cylindrical features can belong to two or more Directions of Control, while planar features belong can only belong to one. Features in each DoC are then ordered based on perpendicular relative distances. Each ordered feature list forms a linear chain in which nodes represent features and links are attributed with relative distance to the nearest neighbors on each side. DoC chains are related to each other by relative orientation. Therefore, the chains are combined into a unified graph, using the junction nodes to contain the relative orientation between the chains. The extracted Directions of Control can be output in both textual and graphical form. Although the primary motivation for automatic DoC graph generation is computer assisted tolerancing and automatic tolerance analysis, the paper also discusses other applications in manufacturing.

Several images are taken for the same scene with many view directions. Given a pixel in any one image of them, its correspondences may appear in the other images. However, by using existing semantic segmentation methods, we find that the pixel and its correspondences do not always have the same inferred label as expected. Fortunately, from the knowledge of multiple view geometry, if we keep the position of a camera unchanged, and only vary its orientation, there is a homography transformation to describe the relationship of corresponding pixels in such images. Based on this fact, we propose to generate images which are the same as real images of the scene taken in certain novel view directions for training and evaluation. We also introduce gradient guided deformable convolution to alleviate the inconsistency, by learning dynamic proper receptive field from feature gradients. Furthermore, a novel consistency loss is presented to enforce feature consistency. Compared with previous approaches, the proposed method gets significant improvement in both cross-view consistency and semantic segmentation performance on images with abundant view directions, while keeping comparable or better performance on the existing datasets.

Drug-drug interactions (DDIs) are a major cause of preventable hospitalizations and deaths. Recently, researchers in the AI community try to improve DDI prediction in two directions, incorporating multiple drug features to better model the pharmacodynamics and adopting multi-task learning to exploit associations among DDI types. However, these two directions are challenging to reconcile due to the sparse nature of the DDI labels which inflates the risk of overfitting of multi-task learning models when incorporating multiple drug features. In this paper, we propose a multi-task semi-supervised learning framework MLRDA for DDI prediction. MLRDA effectively exploits information that is beneficial for DDI prediction in unlabeled drug data by leveraging a novel unsupervised disentangling loss CuXCov. The CuXCov loss cooperates with the classification loss to disentangle the DDI prediction relevant part from the irrelevant part in a representation learnt by an autoencoder, which helps to ease the difficulty in mining useful information for DDI prediction in both labeled and unlabeled drug data. Moreover, MLRDA adopts a multi-task learning framework to exploit associations among DDI types. Experimental results on real-world datasets demonstrate that MLRDA significantly outperforms state-of-the-art DDI prediction methods by up to 10.3% in AUPR.

Face anti-spoofing (FAS) plays a vital role in securing face recognition systems. Recently, central difference convolution (CDC) has shown its excellent representation capacity for the FAS task via leveraging local gradient features. However, aggregating central difference clues from all neighbors/directions simultaneously makes the CDC redundant and sub-optimized in the training phase. In this paper, we propose two Cross Central Difference Convolutions (C-CDC), which exploit the difference of the center and surround sparse local features from the horizontal/vertical and diagonal directions, respectively. It is interesting to find that, with only five ninth parameters and less computational cost, C-CDC even outperforms the full directional CDC. Based on these two decoupled C-CDC, a powerful Dual-Cross Central Difference Network (DC-CDN) is established with Cross Feature Interaction Modules (CFIM) for mutual relation mining and local detailed representation enhancement. Furthermore, a novel Patch Exchange (PE) augmentation strategy for FAS is proposed via simply exchanging the face patches as well as their dense labels from random samples. Thus, the augmented samples contain richer live/spoof patterns and diverse domain distributions, which benefits the intrinsic and robust feature learning. Comprehensive experiments are performed on four benchmark datasets with three testing protocols to demonstrate our state-of-the-art performance.

In a structured prediction problem, one needs to learn a predictor that, given a structured input, produces a structured object, such as a sequence, tree, or clustering output. Prototypical structured prediction tasks include part-of-speech tagging (predicting POS tag sequence for an input sentence) and semantic segmentation of images (predicting semantic labels for pixels of an input image). Unlike simple classification problems, here there is a need to assign values to multiple output variables accounting for the dependencies between them. Consequently, the prediction step itself (aka ``inference" or ``decoding") is computationally-expensive, and so is the learning process, that typically requires making predictions as part of it. The key learning and inference challenge is due to the exponential size of the structured output space and depend on its complexity. In this paper, we present a unifying perspective of the different frameworks that address structured prediction problems and compare them in terms of their strengths and weaknesses. We also discuss important research directions including integration of deep learning advances into structured prediction, and learning from weakly supervised signals and active querying to overcome the challenges of building structured predictors from small amount of labeled data.

Multi-lead electrocardiogram (ECG) provides clinical information of heartbeats from several fixed viewpoints determined by the lead positioning. However, it is often not satisfactory to visualize ECG signals in these fixed and limited views, as some clinically useful information is represented only from a few specific ECG viewpoints. For the first time, we propose a new concept, Electrocardio Panorama, which allows visualizing ECG signals from any queried viewpoints. To build Electrocardio Panorama, we assume that an underlying electrocardio field exists, representing locations, magnitudes, and directions of ECG signals. We present a Neural electrocardio field Network (Nef-Net), which first predicts the electrocardio field representation by using a sparse set of one or few input ECG views and then synthesizes Electrocardio Panorama based on the predicted representations. Specially, to better disentangle electrocardio field information from viewpoint biases, a new Angular Encoding is proposed to process viewpoint angles. Also, we propose a self-supervised learning approach called Standin Learning, which helps model the electrocardio field without direct supervision. Further, with very few modifications, Nef-Net can synthesize ECG signals from scratch. Experiments verify that our Nef-Net performs well on Electrocardio Panorama synthesis, and outperforms the previous work on the auxiliary tasks (ECG view transformation and ECG synthesis from scratch). The codes and the division labels of cardiac cycles and ECG deflections on Tianchi ECG and PTB datasets are available at https://github.com/WhatAShot/Electrocardio-Panorama.