To see the other types of publications on this topic, follow the link: T Advisor.
Journal articles on the topic 'T Advisor'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'T Advisor.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Walti, Carla S., Joyce Maalouf, Jim Boonyaratanakornkit, et al. "196. Antibodies to Vaccine-preventable Infections After CAR-T Cell Immunotherapy for B Cell Malignancies." Open Forum Infectious Diseases 7, Supplement_1 (2020): S226—S227. http://dx.doi.org/10.1093/ofid/ofaa439.506.
Full textAbstract:
Abstract Background Chimeric antigen receptor-modified T (CAR-T) cell immunotherapy for B cell hematologic malignancies results in prolonged B cell depletion. Little is known about the effects of CAR-T cell therapy on pre-existing pathogen-specific humoral immunity. Methods We conducted a prospective, cross-sectional study of children and adults treated with CD19- or BCMA-CAR-T cell therapy. Eligible patients were ≥ 6 months post-CAR-T cell infusion and in remission without subsequent chemoimmunotherapy. We measured total immunoglobulin G (IgG), pathogen-specific IgG levels for 12 vaccine-preventable infections, and B cell subsets from blood. Seroprotective antibody titers were based on standard thresholds. We described the proportion of patients with seroprotective titers and tested for associations between clinical factors and seroprotection using generalized estimating equations. Results We enrolled 65 patients who received CD19- (n=54) or BCMA- (n=11) CAR-T cell therapy. Seven patients were < 18 years old. Samples were collected a median of 20 months (range, 7–68) after CAR T cell infusion. Seroprotection to vaccine-preventable pathogens was generally comparable to the U.S. population (Fig 1) even though blood CD19+ B cell counts were low (< 20 cells/mm3) in 60% of patients. Among 30 patients without IgG replacement in the prior 16 weeks (4 half-lives of IgG), 27 (90%) had hypogammaglobulinemia. Despite this, these individuals had seroprotection to a median of 67% (IQR, 59%-73%) of tested pathogens (Fig 2A). The proportion of patients with seroprotection was lowest for mumps, hepatitis A and B, H. influenzae type B (Hib), S. pneumoniae, and B. pertussis. Patients receiving BCMA-CAR-T cells had seroprotection to fewer pathogens than those receiving CD19-CAR-T cells (Fig 2B), but the difference did not reach statistical significance (Fig 3). There were no significant differences by other variables. Figure 1. Proportion of CAR-T cell recipients with seroprotection to vaccine-preventable infections compared to the U.S. population, stratified by receipt of IgG replacement in the previous 16 weeks. Figure 2 A-B. Percentage of pathogens with seroprotective antibody titers among patients without IgG replacement in the previous 16 weeks. Figure 3. Association of clinical factors with seroprotection to vaccine-preventable infections among patients without IgG replacement in the previous 16 weeks (n=30) Conclusion Seroprotection for vaccine-preventable infections after CD19-CAR-T cell therapy was comparable to the general population. BCMA-CAR-T cell recipients may benefit most from replacement IgG. Vaccinations after CAR-T cell therapy should be considered and prioritized for S. pneumoniae, Hib, hepatitis viruses, and B. pertussis. Disclosures Justin J. Taylor, PhD, Vir Biotechnology (Grant/Research Support) Damian J. Green, MD, Cellectar Biosciences (Grant/Research Support)GSK (Advisor or Review Panel member)Juno Therapeutics (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Royalities)Seattle Genetics (Grant/Research Support, Advisor or Review Panel member) Michael Boeckh, MD PhD, AlloVir (Consultant)EvrysBio (Advisor or Review Panel member, Other Financial or Material Support, share options)Gilead (Consultant, Grant/Research Support)GSK (Consultant)Helocyte (Advisor or Review Panel member, Shareholder)Lophius (Grant/Research Support)Merck (Consultant, Grant/Research Support)SymBio (Consultant)VirBio (Consultant, Grant/Research Support) David G. Maloney, MD, PhD, A2 Biotherapeutics (Consultant, Other Financial or Material Support, Stock Options)Bioline Rx (Consultant)Celgene (Consultant, Grant/Research Support)Gilead (Consultant)Juno Therapeutics (Consultant, Research Grant or Support, Other Financial or Material Support, four pending patents, not issued, licensed, no royalities, no licensees)Kite Pharma (Consultant, Grant/Research Support)Novartis (Consultant)Pharmacyclics (Consultant) Cameron J. Turtle, MBBS, PhD, Allogene (Other Financial or Material Support, Ad hoc advisory board (last 12 months))ArsenalBio (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)AstraZeneca (Grant/Research Support, Other Financial or Material Support, Ad hoc advisory board (last 12 months))Caribou Biosciences (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)Century Therapeutics (Advisor or Review Panel member)Eureka Therapeutics (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)Juno Therapeutics (Grant/Research Support, Other Financial or Material Support, Patent: Licensed to Juno Therapeutics)Myeloid Therapeutics (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)Nektar Therapeutics (Grant/Research Support, Other Financial or Material Support, Ad hoc advisory board (last 12 months))PACT Pharma (Other Financial or Material Support, Ad hoc advisory board (last 12 months))Precision Biosciences (Advisor or Review Panel member, Other Financial or Material Support, Stock/options)TCR2 Therapeutics (Grant/Research Support)T-CURX (Advisor or Review Panel member) Joshua A. Hill, MD, Allogene (Consultant)Allovir (Consultant)Gilead (Consultant)Karius (Grant/Research Support, Scientific Research Study Investigator)Takeda (Grant/Research Support, Scientific Research Study Investigator)
2
Mokhtari, Sepideh, Justin M. Asquith, Christina A. Bachmeier, et al. "The Use of Intravenous Immunoglobulin (IVIG) during Severe Neurotoxicity Among the Recipients of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy." Blood 134, Supplement_1 (2019): 5627. http://dx.doi.org/10.1182/blood-2019-122343.
Full textAbstract:
INTRODUCTION: Severe neurotoxicity occurs in ~30% of Diffuse Large B Cell Lymphoma (DLBCL) patients treated with CAR-T cell therapy. The current treatment for severe neurotoxicity is glucocorticoids +/- tocilizumab (an IL-6 antagonist) depending on concurrent cytokine release syndrome. Even with these treatments, neurotoxicity can have a complicated course. It is therefore essential to find the optimal treatment to reverse neurotoxicity timely. METHOD:This is a retrospective cohort study of neurologic and oncologic outcomes among patients with grade ≥ 3 neurotoxicity treated with glucocorticoids and IVIG compared to glucocorticoids only. Severe neurotoxicity was defined as grade 3 and graded by CRES/CARTOX score. Time to resolution of severe neurotoxicity (TTR) was defined as improvement of severe neurotoxicity to grade ≤ 2. RESULTS: We identified a total of 20 patients who received CAR-T therapy and developed severe neurotoxicity. Ten patients received glucocorticoids and IVIG (group A) and ten patients received glucocorticoids alone (group B). The median age was 62 (range: 52-74) for group A vs 64 years (range: 48-75) for group B. Both groups had similar ECOG performance status (p=0.17), IPI scores (p=0.34), and onset of severe neurotoxicity (median=6 days in both groups). Median TTR was 3 days (range, 1-7) for group A and 4.5 days (range, 2-22) for group B. There was no significant difference in TTR of severe neurotoxicity among both groups (Log-rank p=0.18, Figure). The median time to administration of IVIG after initiation of glucocorticoids was 2 days (range, 0.5-8). The median TTR following initiation of IVIG was 0.5 day (0.5-4). The objective response rate at 30 days was 80% in both groups. None of the patients who received IVIG developed thromboembolism, renal failure, autoimmune hemolytic anemia or acute lung injury. CONCLUSIONS: Although the use of IVIG during severe neurotoxicity after CAR-T therapy appeared to be safe, this pilot retrospective analysis demonstrated no significant difference in resolution of severe neurotoxicity with addition of IVIG to glucocorticoids. Further controlled studies limiting selection bias inherent in this retrospective analysis will help to determine the efficacy of IVIG in severe neurotoxicity in the context of CAR-T cell therapy. Disclosures Mokhtari: KITE PHARMA: Other: Clinical Advisor; NOVARTIS: Other: Clinical Advisor. Bachmeier:Kite/Gilead: Speakers Bureau. Jain:Kite/Gilead: Consultancy. Forsyth:Department of Defense: Research Funding; Pfizer: Research Funding; State of Florida Bankhead Coley: Research Funding; Moffitt Center of Excellence Celgene Project: Research Funding; Florida Academic Cancer Center Alliance: Research Funding; NIH/NCI 1R21 Grant: Research Funding; NIT DT Study Section Grant Review: Membership on an entity's Board of Directors or advisory committees; AbbVie Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ziopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tocagen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BTG: Consultancy, Membership on an entity's Board of Directors or advisory committees; Inovio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novocure: Consultancy, Membership on an entity's Board of Directors or advisory committees. Locke:Novartis: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy; Kite: Other: Scientific Advisor. Lazaryan:Kadmon: Consultancy.
3
Kambhampati, Swetha, Bita Fakhri, Ying Sheng, et al. "Infectious Complications of BCMA-Targeted and CD19-Targeted Chimeric Antigen Receptor T-Cell Immunotherapy." Blood 136, Supplement 1 (2020): 4–5. http://dx.doi.org/10.1182/blood-2020-138940.
Full textAbstract:
Background: Chimeric antigen receptor T-cell (CAR T) immunotherapy is an evolving treatment for relapsed/ refractory non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). There is a growing need to elucidate the infectious complications of BCMA- and CD19-directed CAR T therapy. We performed a single-center retrospective analysis of infection outcomes up to 1-year post BCMA and CD19-directed CAR T treatment. Methods: All patients treated at our institution with a BCMA-directed CAR T therapy for MM or with a CD19-directed CAR T for NHL from 2018-2020 were analyzed for risk factors for infection and infectious complications. Bacterial, viral and fungal infections were recorded if there was a microbiologic or histopathologic diagnosis or if clinical suspicion for infection required empiric treatment. Infection severity was classified as mild, moderate, severe, life-threatening, or fatal as previously described (Young et al. 2016, van Burnik et al. 2007). Infections were identified from the day of the first CAR T-cell infusion up to 1 year after infusion. Observation of infections was terminated at the time of disease progression, initiation of next therapy, or death, whichever occurred first. Fisher's exact test and Wilcoxon rank-sum test were used to compare between cohorts. Poisson mixed effects model with a subject-specific random intercept and an offset to account for the duration at risk was used to identify risk factors for infections. Results: Of the 104 subjects in this study, 55 patients (53%) had MM treated with BCMA CAR T and 49 patients (47%) had NHL treated with CD19 CAR T. Median number of prior therapies was 6 (4 - 9) in the BCMA cohort and 3 (2-4) in the CD19 cohort (Table 1). Prior to starting lymphodepleting (LD) chemotherapy, most patients did not have IgG< 400, ALC< 200, or ANC< 500. Almost all the patients were on antibacterial (99%), antiviral (99%) and antifungal (92%) prophylaxis (ppx), with 18%, 90% and 9% of patients starting this before LD chemotherapy, respectively. Median follow-up time was 5.8 months (95% CI: 4.2-6.4). In total, there were 87 infection events (48 bacterial, 33 viral, and 6 fungal) observed in 56 patients (54%), with 47 infections in 29 (53%) patients in the BCMA CAR T cohort and 40 infections in 27 (55%) patients in the CD19 CAR T cohort (p =0.9). The BCMA cohort had 19 bacterial (40%) vs 29 bacterial (73%) in CD19 cohort (p=0.005), while BCMA cohort had 25 viral (53%) vs 8 viral (20%) in CD19 cohort (p=0.002). Fungal infection rates were comparable between BCMA and CD19 cohorts, 3 (6%) vs 3 (8%) respectively (p=1). Among the infections that occurred, 20 (23%) were high severity occurring in 16 patients (15%) of the overall cohort. Four high severity infections (5%) occurred in 3 patients (5%) in the BCMA cohort while 16 high severity infections (18%) occurred in 13 patients (27%) in the CD19 cohort (p < 0.001) (Figure 1). The BCMA cohort had higher rates of respiratory infections (68% vs 50%, p=0.1), while the CD19 cohort had higher rates of bloodstream infections (15% vs 2%, p=0.05) and gastrointestinal infections (10% vs 0%, p=0.04). The rates of grade (Gr) 3-4 neutropenia and IgG < 300 in both the cohorts at various time points post CAR T were comparable. At 9-12 months, Gr 3-4 neutropenia was 7% vs 8% (p=1) and IgG < 300 was 7% vs 33% (p=0.1) for the BCMA and CD19 cohorts respectively. Adjusting for time periods, risk factors for development of infections were use of steroids (incidence rate ratio [IRR] 1.6, 95% CI: 1.1-2.5, p=0.03) and post CAR T hypogammaglobulinemia (IgG < 600) (IRR =2.1, 95% CI: 1.2-3.9, p=0.02). Conclusions: This retrospective study is one of the largest studies to date comparing the post CAR T infections rates between BCMA and CD19 directed CAR T treated patients. While the incidence of infection, use of antimicrobial ppx, and rates of Gr 3-4 neutropenia and hypogammaglobulinemia were comparable between BCMA and CD19 CAR T cohorts, viral infections were more common post BCMA CAR T while bacterial infections were more frequent post CD19 CAR T. Use of steroids as well as post CAR T hypogammaglobulinemia are possible risk factors for development of infections. Further studies are needed to examine the infectious complications post-CAR T treatment, characterize the underlying risk factors, and to establish appropriate prophylactic approaches in patients undergoing CD19- and BCMA-directed CAR T therapy. Disclosures Fakhri: University of California San Francisco: Current Employment. Ai:Nurix Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics, Kymera: Membership on an entity's Board of Directors or advisory committees. Martin:Seattle Genetics: Research Funding; GSK: Consultancy; Sanofi: Research Funding; AMGEN: Research Funding; Janssen: Research Funding. Wolf:Adaptive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Shah:BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy. Andreadis:Genentech: Other: Spouse Employee (salary and stock); Novartis: Research Funding; Celgene/Juno: Research Funding; Amgen: Research Funding; Merck: Research Funding; Gilead/Kite: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Astellas: Other: Advisor; Seattle Genetics: Other: Advisor; Karyopharm: Other: Advisor; Incyte: Other. Wong:GSK: Research Funding; Amgen: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Roche: Research Funding; Janssen: Research Funding; Fortis: Research Funding.
4
Hosry, Jeff, Felipe Samaniego, Francesco Turturro, Minas P. Economides, and Harrys A. Torres. "Effect of Lenalidomide on Hepatitis C Viremia in Cancer Patients: A Case Series." Blood 128, no. 22 (2016): 5691. http://dx.doi.org/10.1182/blood.v128.22.5691.5691.
Full textAbstract:
Abstract Background: T cells play an important role in controlling hepatitis C virus (HCV) infection. Immunomodulatory drugs affecting T cells such as thalidomide and lenalidomide are used in the treatment of some hematologic cancers (mainly multiple myeloma). Lenalidomide is up to 1000 times more potent than thalidomide in stimulating T cell proliferation, interferon-γ and interleukin-2 production. HCV reactivation (increase of HCV-RNA by at least 1 log10IU/mL) with hepatitis flare after thalidomide therapy was recently reported (Mahale et al., Open Forum Infect Dis. 2015); however, the effect of lenalidomide on HCV-viremia has not been studied yet. Methods: HCV-infected cancer patients treated with lenalidomide at MD Anderson Cancer Center (11/2012-3/2016) were studied. HCV-RNA levels were measured before and after lenalidomide use. Since chronically infected patients have stable HCV-RNA levels that only varies ∼0.5 log10 IU/m, a significant change in HCV viremia was defined as a change of HCV-RNA ≥ 1 log10IU/ml from baseline. Hepatitis flare was defined by an increase of ALT level to ≥ 3 times upper limit of normal (or >170 IU/ml). Results: Five HCV-infected cancer patients treated with lenalidomide were studied. All the patients were males with a median age of 56 years. They had multiple myeloma (n=4) or large B-cell lymphoma (n=1). Four patients had HCV genotype 1 (80%) and 1 had genotype 2 (20%). Two patients (40%) were cirrhotics. The 5 patients studied received 6 different lenalidomide-containing regimens: 2 with lenalidomide monotherapy, 2 lenalidomide + rituximab and 2 lenalidomide + steroids. HCV-RNA levels were measured between week 4 (1, 17%) and week 12 (5, 83%) on lenalidomide treatment. A decrease of HCV-RNA was seen with all the 6 regimens (100%) (Figs 1A, 1B and 1C). Nonetheless, a significant decrease (>1 log10IU/ml) was noted in 4 out of the 6 regimens: two on lenalidomide monotherapy (1.21 and 1.49 log10IU/ml) and two on lenalidomide + rituximab (1.15 and 1.3 log10IU/ml). Hepatitis flare was only seen in one patient treated with lenalidomide + rituximab but he did not have concomitant HCV-RNA changes. Conclusion: Unlike thalidomide,lenalidomide does not cause HCV reactivation. On the contrary, this agent seems to inhibit HCV replication. Figure 1 Figure 1. Disclosures Samaniego: Karus Therapeutics: Research Funding. Torres:Pfizer: Other: Scientific advisor; Theravance Biopharma: Other: Scientific advisor; Astellas Pharma: Other: Scientific advisor; Novartis: Other: Scientific advisor; Genentech: Other: Scientific advisor; Janssen Pharmaceuticals: Other: Scientific advisor; Vertex Pharmaceuticals: Other: Scientific advisor, Research Funding; Merck & Co.: Other: Scientific advisor, Research Funding; Gilead Sciences: Other: Scientific advisor, Research Funding.
5
Nai, Wei, Lanfei Ma, and Yidan Xing. "Teaching Effect and Reform Strategies on Graduation Design for Undergraduates in Information Related Majors in Independent College Based on Psychological Identity." International Journal of Information and Education Technology 11, no. 1 (2021): 35–40. http://dx.doi.org/10.18178/ijiet.2021.11.1.1486.
Full textAbstract:
The annual graduation design in universities is the final cultivation process of the comprehensive professional competencies for undergraduates before they end their college career, and is also an important component in the tasks of undergraduate education. Teaching effect of graduation design on one hand depends on the foundation and application ability of professional knowledge of each student, and also depends on the psychological identity on advisor and the topic chosen from the student point of view on the other hand. In this paper, undergraduates who have all finished their graduation design in Department of Electronic and Information Engineering in Independent College T from the year 2017 to 2019 have been set as study objects, by deeply investigating students’ attitudes toward advisors and topics chosen from questionnaire survey, and by analyzing the grade point averages (GPA) of students, the relationship between psychological identity on advisor as well as topic chosen and the teaching effect of graduation design for each student has been found out, and related reform strategies on teaching methods has been discussed.
6
Soriano, Alex, Laura A. Puzniak, Matteo Bassetti, et al. "1612. Evaluation of the Use of Ceftolozane/Tazobactam for the Treatment of ESBL-producing Enterobacterales Infections Using International Data from SPECTRA (Study of Prescribing Patterns and Effectiveness of Ceftolozane/Tazobactam Real World Analysis)." Open Forum Infectious Diseases 7, Supplement_1 (2020): S800. http://dx.doi.org/10.1093/ofid/ofaa439.1792.
Full textAbstract:
Abstract Background There is a paucity of data on outcomes of patients with severe ESBL-producing Enterobacterales infections treated with empiric or directed ceftolozane/tazobactam (C/T). This study looked at the treatment patterns and outcomes associated with C/T use in the treatment of ESBL-producing Enterobacterales. Methods Data were collected from an international cohort of 32 hospitals in 6 countries as part of SPECTRA, a retrospective multicenter database of C/T use globally, from 2016 – 2019. All adult patients with an ESBL positive Enterobacterales sterile site culture and treated with ≥ 48 hours of C/T were eligible. Outcomes assessed were clinical success, 30-day mortality from index event and readmission. Results There were 59 patients with 121 ESBL positive isolates. Blood and urine were the most common sites of infection at 19.8% each, followed by respiratory (18.2%). E. coli (50%) and K. pneumoniae (30%) were the most common pathogens. On average patients had 2 positive ESBL isolates; median 1; range 1-15. Most patients had the same infection site and ESBL pathogen, however 13 had multi-site ESBL pathogens identified and only 2 had polymicrobial ESBL pathogens. Septic shock was observed in 14 (24%) patients; 29 (49%) were in the ICU at the onset of infection. The most common comorbid conditions were immunocompromised hosts (37%) and cardiac disease (32%). 29% of patients were transplant recipients, and 28% had a CrCl < 50 ml/min. In most patients (71%), C/T was given as directed therapy (i.e., once culture results were available). C/T was given prior to culture results (i.e., as empiric therapy) in 17 (29%) patients, of which 77% had clinical success. C/T dose was 1.5 g in 49%. Only 2 of 10 patients with a respiratory source received the currently licensed 3 g dose. Overall, clinical success was observed in 36 (61%) patients. 30-day mortality was 12%. Readmissions occurred in 5%, of which 2 were infection related. Conclusion The role of newer non-carbapenem antibiotics in the treatment of severe ESBL infections is currently undefined. In a multinational patient database, C/T was found to be effective in severe infections caused by ESBL-producing Enterobacterales. Prospective studies are needed to further define the role of C/T in the setting of frequent drug-resistant Gram-negative pathogens. Disclosures Laura A. Puzniak, PhD, Merck (Employee) Matteo Bassetti, MD, Shionogi Inc. (Advisor or Review Panel member) Pamela Moise, PharmD, Merck & Co., Inc. (Employee, Shareholder) David Paterson, Accelerate (Speaker’s Bureau)BioMerieux (Speaker’s Bureau)BioMerieux (Advisor or Review Panel member)Entasis (Advisor or Review Panel member)Merck (Advisor or Review Panel member)Merck (Grant/Research Support)Merck (Speaker’s Bureau)Pfizer (Speaker’s Bureau)Shionogi & Co., Ltd. (Grant/Research Support)VenatoRx (Advisor or Review Panel member)
7
Huang, Wei-chieh, Sung-Hsi Huang, and Chien-Ching Hung. "1020. Higher efavirenz mid-dose plasma concentration is associated with less weight gain among virologically suppressed people living with HIV." Open Forum Infectious Diseases 7, Supplement_1 (2020): S539—S540. http://dx.doi.org/10.1093/ofid/ofaa439.1206.
Full textAbstract:
Abstract Background Recently, an association between CYP2B6 516 G > T polymorphism and weight change was observed among African people living with HIV (PLWH) who were started on efavirenz(EFV)-based antiretroviral therapy (ART). We aimed to investigate the effect of EFV mid-dose plasma concentration on weight change among Taiwanese PLWH. Methods The medical records of adult PLWH who were taking EFV-containing ART and had been enrolled in a EFV therapeutic drug monitoring study between Oct 2009 and May 2014 were accessed. EFV mid-dose plasma concentration (C12) was determined in the previous study and those with serial weight measurements within 48 weeks around the time of EFV C12 measurement were included in the present study. The weight change in the 48 weeks and its associations with mid-dose EFV concentrations and CYP2B6 516 G > T polymorphism were examined by general estimating equations (GEE) after adjusting for age, baseline HIV viremia, baseline weight, and the companion backbone antiretroviral agents. Results One-hundred and fifteen predominantly male (94.8%) PLWH were included in this study (Table 1). The mean CD4 lymphocyte count was 542 cells/μL at the beginning of the observation and 94.8% achieved HIV viral suppression. Forty-four (38.3%) patients had non-wildtype CYP2B6 516 G > T polymorphism. On average, the included PLWH gained 0.8 kilogram at 48 weeks and the weight change did not differ among those with wildtype and non-wildtype CYP2B6 516 G > T(Figure 1). In the GEE models, CYP2B6 516 G > T polymorphism was not associated with weight change (p=0.81), instead, higher EFV C12 was found to be independently associated with less weight gain (p=0.045). Table 1. Baseline characteristics. Figure 1. The absolute weight (A) and weight change from baseline (B) among patients with wildtype and non-wildtype CYP2B6 516G>T polymorphism. Conclusion Our findings support that increased EFV exposure may have a negative effect on weight gain. Disclosures Chien-Ching Hung, MD,PHD, Abbvie (Advisor or Review Panel member, Speaker’s Bureau)Bristol-Myers Squibb (Speaker’s Bureau)Gilead Sciences (Advisor or Review Panel member, Speaker’s Bureau)Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support)ViiV (Grant/Research Support, Advisor or Review Panel member, Speaker’s Bureau)
8
Schuchert, A., and W. Brunekreeft. "775 T-STAR interim results: therapy Advisor for optimising the pacemaker AF therapy." EP Europace 7, Supplement_1 (2005): 176. http://dx.doi.org/10.1016/eupace/7.supplement_1.176-a.
Full text
9
Thomas, Toney K., and Diya Jose. "Adapting to Political Activism in Destination." Tourism 69, no. 3 (2021): 367–80. http://dx.doi.org/10.37741/t.69.3.3.
Full textAbstract:
The way of protest through hartal (general strike) has sparked heated debates about its impact on the tourism industry in Kerala. This paper is aimed in the viewpoint that political activism has adverse consequences on tourism in the state of Kerala which is seamlessly propagated through the Media. Through a thematic analysis of online texts published on trip advisor, this paper explores tourists’ perceptions and opinions of the implication of hartal on tourism in Kerala. Overall, our analysis reveals that hartal would not discourage tourists to visit Kerala, although many regarded that certain level of challenges at the destination will enhance the visitor experience. Importantly, our study also contends that the narratives about the ‘hartal’ produced and propagated online were often representative of political structures of power, which linked tourism to hartal irrespective of the real impact on tourism.
10
Rolston, Kenneth V. I., Bahgat Gerges, Issam Raad, Samuel L. Aitken, Ruth Reitzel, and Randall Prince. "1375. In vitro Activity of Cefiderocol and Comparator Agents against Gram-Negative Isolates from Cancer Patients." Open Forum Infectious Diseases 5, suppl_1 (2018): S421—S422. http://dx.doi.org/10.1093/ofid/ofy210.1206.
Full textAbstract:
Abstract Background Gram-negative bacilli (GNB) are now the predominant cause of bacterial infection in cancer patients (CP). Many GNB are problematic because they have become resistant to commonly used antibiotics. Cefiderocol (CFDC), a novel siderophore cephalosporin, is active against a wide spectrum of GNB. We evaluated its in vitro activity and that of eleven comparator agents against GNB isolated from CP. Methods A total of 341 recent GNB blood isolates from CP were tested using CLSI approved methods for MIC determination by broth microdilution. Comparator agents were amikacin (A), aztreonam (AZ), ceftazidime (CZ), ceftazidime/avibactam (CAV), cefepime (CEF), ciprofloxacin (CIP), colistin (CL), meropenem (MR), ceftolozane/tazobactam (C/T), tigecycline (TG), and trimethoprim/sulfamethoxazole (T/S). Results CFDC MIC90s as mg/L were: S. maltophilia [50 isolates] 0.25, E. coli (ESBL−) [50 isolates] 0.5, E. coli (ESBL+) [51 isolates] 2.0, K. pneumoniae (ESBL− and +) [60 isolates] 0.5; K. pneumoniae (CRE) [22 isolates] 2.0; P. aeruginosa (MDR) [32 isolates] 1.0; E. cloacae [27 isolates] 4.0; Achromobacter spp. [15 isolates] 0.12. CFDC inhibited P. agglomerans, Burkholderia spp., Sphingomonas spp., Ochrobactrum spp. at ≤1 mg/L [23 total isolates] and Elizabethkingia spp. and R. radiobacter at ≤8 mg/L [11 total isolates]. Among comparator agents, only T/S had consistent activity against S. maltophilia. For E. coli (ESBL− and +) MR, TG, CAV, CL were most active. For K. pneumoniae (ESBL–and +) MR, CAV were most active. For K. pneumoniae (CRE) and P. aeruginosa (MDR), none of the comparators had significant activity. For E. cloacae, MR, A, CAV, TG were most active. Among the uncommon organisms, MR and TG had the greatest activity. Conclusion Although susceptibility breakpoints have yet to be determined, CFDC has significant activity (≤4 mg/L) against most problematic Gram-negative organisms causing infections in CP based on available pharmacokinetic/pharmacodynamic data. In particular, its activity against S. maltophilia was superior to the comparators. Also, it was the most active agent against P. aeruginosa (MDR) and K. pneumoniae (CRE). Based on our results, CFDC warrants clinical evaluation for the treatment of blood stream infections caused by GNB in CP. Disclosures K. V. I. Rolston, Merck: Investigator, Research grant; JMI Laboratories: Investigator, Research grant; Shionogi (Japan): Investigator, Research grant. B. Gerges, Shionogi: Collaborator, Research support. S. L. Aitken, Shionogi: Scientific Advisor, Consulting fee; Merck: Scientific Advisor, Consulting fee; Medicines Co: Scientific Advisor, Consulting fee; Achaogen: Scientific Advisor, Consulting fee; Zavante: Scientific Advisor, Consulting fee; R. Prince, Shionogi: Investigator, Research support. Merck: Investigator, Research support.
11
Sax, Paul, Keri N. Althoff, Keri N. Althoff, et al. "LB-7. Weight Change in Suppressed People with HIV (PWH) Switched from Either Tenofovir Disoproxil Fumarate (TDF) or Abacavir (ABC) to Tenofovir Alafenamide (TAF)." Open Forum Infectious Diseases 7, Supplement_1 (2020): S846—S847. http://dx.doi.org/10.1093/ofid/ofaa515.1904.
Full textAbstract:
Abstract Background Weight gain in PWH occurred in both naïve and switch studies and is linked to use of integrase inhibitors (INSTIs) with varying associations with nucleoside reverse transcriptase inhibitors (NRTIs). One hypothesis is that gain associated with TAF when switching from TDF is a result of cessation of TDF-induced weight suppression. Methods The study evaluated weight change in suppressed PWH on INSTI+NRTIs switched from ABC or TDF to TAF. Eligible pts had HIV, were ≥ 18 yrs at index (date of switch), treatment-experienced with known prior regimen, suppressed at index (-12 to +1 mo) and 1 yr, ≥ 6 mo pre-index history, with weight measures at index and 1 yr, no current or pre-index use of protease inhibitor or non-nucleoside reverse transcriptase inhibitor. Univariate comparisons were performed using Χ2 for categorical and t-test for continuous variables; negative binomial model with log link function evaluated risk of gain ≥ 3% of body weight between groups accounting for age, gender, race, body mass index (BMI), CD4. Linear mixed effects model was used to estimate mean weight at index and 1 yr post switch. Results Of 970 pts, 828 (85%) switched from TDF to TAF and 142 (15%) from ABC to TAF. Groups were balanced by race, gender, index BMI [Table 1]. Figures 1a-b describe pre- and post-switch INSTI use. At 1 yr, mean unadjusted weight change was 1.4 kg in TDF and 0.2 in ABC group p=0.039. TDF to TAF had higher proportion of PWH with gain ≥ 3% vs ABC to TAF (40% vs 27% p=0.003); differences in gain ≥ 5% and ≥ 10% were not statistically significant (26% vs 22% p=0.323 and 10% vs 6% p=0.220). Pts who gained ≥ 3% were younger, with greater proportion of females, non-obese, with 1 prior regimen, and prior elvitegravir (EVG) use. In adjusted analysis TDF to TAF had higher risk of gain ≥ 3% vs ABC to TAF [Figure 2]. In sensitivity analysis accounting for EVG or dolutegravir (DTG) use, TDF to TAF also had higher risk of ≥ 3% gain vs ABC to TAF: adjusted risk ratio (aRR)= 1.38 [1.01–1.89] and aRR= 1.42 [1.02–1.97]. Table 1. Baseline (index) characteristics. Figures 1a-b. Distribution of pre switch and post switch INSTI use. Figure 2. Risk of weight gain ≥ 3% of body weight at 1 year post switch accounting for age, gender, race, index BMI, and CD4. Conclusion Switching from TDF to TAF in INSTI-based regimens had a greater risk of weight gain vs ABC to TAF. This difference persisted when accounting for impact of the INSTI agent in the current regimen. These data suggest that differences in weight gain between TAF and TDF are driven by removal of TDF-associated weight suppression. Disclosures Paul Sax, MD, Gilead (Consultant, Research Grant or Support)Janssen (Consultant)Merck (Consultant, Research Grant or Support)ViiV Healthcare (Consultant, Research Grant or Support) Keri N. Althoff, PhD, MPH, Gilead (Advisor or Review Panel member) Keri N. Althoff, PhD, MPH, All of Us Study (NIH) (Individual(s) Involved: Self): Consultant; MedIQ (Individual(s) Involved: Self): Consultant; TrioHealth (Individual(s) Involved: Self): Advisor or Review Panel member Todd T. Brown, MD, PhD, Gilead (Consultant)Merck (Consultant)Theratechnologies (Consultant)ViiV Healthcare (Consultant) Janna Radtchenko, MBA, Trio Health (Employee) Helena Diaz Cuervo, PhD, Gilead Sciences (Employee) Steven Santiago, MD, Gilead (Advisor or Review Panel member, Speaker's Bureau)Janssen (Speaker's Bureau) Graeme Moyle, MD, Theratechnologies (Consultant) Karam Mounzer, MD, Epividian (Advisor or Review Panel member)Gilead (Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau)Janssen (Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau)Merck (Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau)ViiV Healthcare (Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau) Richard Elion, MD, Gilead (Advisor or Review Panel member, Research Grant or Support, Speaker's Bureau)Janssen (Speaker's Bureau)Proteus (Research Grant or Support)ViiV Healthcare (Advisor or Review Panel member, Research Grant or Support)
12
Mahmoud, K., A. Zayat, M. Y. MD Yusof, et al. "FRI0599 USEFUL II: DERIVATION OF THE LUPUS ARTHRITIS AND MUSCULOSKELETAL DISEASE ACTIVITY SCORE (LAMDA) USING DATA FROM A MULTICENTRE LONGITUDINAL STUDY." Annals of the Rheumatic Diseases 79, Suppl 1 (2020): 905.2–906. http://dx.doi.org/10.1136/annrheumdis-2020-eular.2810.
Full textAbstract:
Background:Musculoskeletal (MSK) disease is the commonest manifestation of SLE. We showed that the MSK components of the BILAG index and SLEDAI have limited sensitivity, specificity and responsiveness compared to ultrasound (US) synovitis. The USEFUL study evaluated response to glucocorticoids in SLE patients with inflammatory pain.Objectives:To develop a disease activity tool for lupus MSK manifestations that is continuous, responsive, sensitive, and correlates with US-synovitisMethods:133 patients who received depomedrone 120mg IM were assessed at 0, 2 and 6 weeks for 66/68 swollen and tender joint counts, BILAG2004 index, SLEDAI-2K, physician global and MSK-VAS, inflammatory markers, patient pain and disease activity-VAS. Total US score (OMERACT-EULAR) in the hands and wrists was calculated blinded to patient and clinical assessor. Patients reported overall response using a Likert scale.The LAMDA was developed by modelling a core set of clinical variables against total US score using penalized (Lasso) regression. Responsiveness was compared between LAMDA and other variables at week 6 using effect sizes. Minimum clinically important difference (MCID) was explored using the SEM and minimal disease activity threshold using ROC.Results:The variables selected for the LAMDA score were swollen joint count, patient MSK pain VAS, physician MSK disease activity VAS and ESR. A continuous score was derived. This had a theoretical range from 0 to 26.5 based on maximum ESR of 100. The highest value observed in USEFUL was 15. LAMDA was significantly higher in patients with active US (mean (SD) 5.71 (2.67), n=78) compared to patients with normal US (3.27 (1.77), n=55; difference (95% CI) -2.45 (-3.26, -1.63), t=-5.93, p<0.001). This difference remained significant in patients with no swollen joints (difference (95% CI) -0.71 (-1.40, -0.02), t=-2.06, p=0.044).Effect size was greater for the LAMDA (0.37) than the BILAG-MSK (0.31), SLEDAI-MSK (0.27) and total US score (0.33). In patients with active US at baseline, LAMDA’s effect size was 0.42.The MCID was 0.71 and correlated with patient-reported change in pain. A threshold for minimal disease activity of 3.23 optimized sensitivity (0.77 (0.65, 0.89)) and specificity (0.80 (0.68, 0.92)) against US score >0.Conclusion:The LAMDA score is a novel continuous disease activity instrument for MSK manifestations of SLE derived from variables familiar to rheumatologists. The LAMDA score is sensitive to imaging detected synovitis without swelling and more responsive than other instruments. . LAMDA may improve the ability of clinicians to accurately determine therapeutic efficacy in clinical trials and practice. Future work will validate the LAMDA score in independent cohorts and randomized trials.Acknowledgements:This project was funded by Lupus UKDisclosure of Interests:Khaled Mahmoud: None declared, Ahmed Zayat: None declared, Md Yuzaiful Md Yusof: None declared, Coziana Ciurtin Grant/research support from: Pfizer, Consultant of: Roche, Modern Biosciences, Chee-Seng Yee: None declared, David Isenberg Consultant of: Study Investigator and Consultant to Genentech, Lee-Suan Teh: None declared, Katherine Dutton: None declared, David d’cruz Grant/research support from: GlaxoSmithKline, Nora Ng: None declared, Philip G Conaghan Consultant of: AbbVie, BMS, Eli Lilly, EMD Serono, Flexion Therapeutics, Galapagos, GSK, Novartis, Pfizer, Speakers bureau: AbbVie, Eli Lilly, Novartis, Pfizer, Paul Emery Grant/research support from: AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche (all paid to employer), Consultant of: AbbVie (consultant, clinical trials, advisor), Bristol-Myers Squibb (consultant, clinical trials, advisor), Lilly (clinical trials, advisor), Merck Sharp & Dohme (consultant, clinical trials, advisor), Novartis (consultant, clinical trials, advisor), Pfizer (consultant, clinical trials, advisor), Roche (consultant, clinical trials, advisor), Samsung (clinical trials, advisor), Sandoz (clinical trials, advisor), UCB (consultant, clinical trials, advisor), Christopher Edwards Grant/research support from: Abbvie, Biogen, Roche, Consultant of: Abbvie, Samsung, Speakers bureau: Abbvie, BMS, Biogen, Celgene, Fresenius, Gilead, Janssen, Lilly, Mundipharma, Pfizer, MSD, Novartis, Roche, Samsung, Sanofi, UCB, Elizabeth Hensor: None declared, Edward Vital Grant/research support from: AstraZeneca, Roche/Genentech, and Sandoz, Consultant of: AstraZeneca, GSK, Roche/Genentech, and Sandoz, Speakers bureau: Becton Dickinson and GSK
13
Dubash, S., O. Alabas, X. Michelena, et al. "SAT0401 SWOLLEN JOINTS ARE ASSOCIATED WITH ULTRASOUND POWER DOPPLER SYNOVITIS, WHEREAS TENDER JOINTS IN THE ABSENCE OF SWELLING ARE NOT: AN ANALYSIS OF AGREEMENT AND CORRELATION IN VERY EARLY DMARD NAÏVE PSORIATIC ARTHRITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (2020): 1152.1–1152. http://dx.doi.org/10.1136/annrheumdis-2020-eular.781.
Full textAbstract:
Background:Ultrasound (US) is an imaging adjunct to clinical joint examination adding sensitivity and objectivity to the assessment of inflammation. Previous studies in PsA have shown disparity between ultrasound and clinical findings with significant subclinical joint inflammation. A clinical challenge in PsA is to interpret tender joints (TJ) that are not swollen (SJ). As US is not widely used, alignment of clinical with US assessment is needed to determine its future role.Objectives:To determine how joint clinical examination relates to US findings in very early DMARD naïve PsA.Methods:Newly diagnosed DMARD naïve PsA patients, fulfilling CASPAR criteria, were recruited into the Leeds Spondyloarthropathy Register for Research and Observation (SpARRO), a prospective observational cohort study. US examination of 48 joints per patient was conducted by trained ultra-sonographers, blinded to clinical details with semi-quantitative scoring (0-3) for gray scale (GS) and power Doppler (PD). TJ and SJ counts were independently recorded. Cross-sectional baseline analysis was performed. The prevalence-adjusted and bias-adjusted kappa (PABAK) was calculated to determine agreements between clinical and US parameters. Spearman’s rank correlation coefficient was calculated to identify permutations of TJ/SJ correlating with GS ≥2, PD≥1 or both.Results:A total 5927 joints were scanned in 155 PsA patients. The mean age was 44.4 years, (SD 12.8), median disease duration 5.1 weeks (0.4-13.1); median TJC=7 (3-14) and SJC=2 (1-7). Oligoarthritis was present in 63.9% (99/155). US GS≥2 was frequently detected in the feet at MTPs1-4 (37.4- 53.6 %) and wrists (26.5- 33.6%). PD was most prevalent at wrists (17.5%) and MTP1 (12.6%) but observed less in other joints. Erosions were less frequent, the commonest site being MTP5 (17/310, 5.4%).Overall, SJ demonstrated high agreement (p<0.001) with US synovitis (GS ≥2 and/or PD ≥1). High agreement was equivalent between combined GS ≥2 and PD ≥1 compared with PD ≥1 alone (p<0.001) indicating it was predominantly driven by PD. Agreement with TJ and US was consistently lower yet still significant (p<0.001). Combinations of TJ/SJ were explored with US synovitis (table 1). Correlation was significant for T+ S+ and PD≥1 at wrists, MCP1-5, PIP2-5, MCP3-4 (p<0.001); DIP2 (p<0.05), knees and ankles (p<0.01) but weaker correlation in MTP3,4. In contrast, poor correlation was observed in the T+ S- group for most joints.Table 1.Agreement between TJ or SJ with GS≥2 & PD ≥1 and correlations for tender with/ without swollen combinations for right sided hand/feet joints.TenderSwollenT+ S-T+ S+Joint (Right)A (%)PABAKA (%)PABAKrrWrist75.50.51*89.10.78*-0.090.35*MCP184.10.68*87.50.75*0.090.44*MCP277.70.55*83.10.66*0.080.35*MCP379.10.58*84.50.69*0.0050.50*MCP478.40.57*86.40.72*0.070.22†MCP587.80.76*95.60.91*-0.030.49*MTP169.80.40*83.90.68*-0.03-MTP279.10.58*90.50.81*0.060.11MTP377.00.54*88.50.77*0.050.22‡MTP477.70.55*87.20.74*-0.0020.23‡MTP579.90.60*89.90.80*0.150.09T+= tender, S+ =swollen, S- = not swollen, A=agreement (%), r =coefficient, † p<0.05, ‡ p<0.01, *p<0.001.Conclusion:Swollen joints demonstrate higher agreement with US synovitis (PD≥1 alone or GS ≥2 & PD ≥1 combined) than tender joints in early PsA. In addition, joints that are tender but not swollen have poor correlation with US synovitis at the individual joint level indicating that swelling is a better clinical discriminator of active synovitis, and factors other than synovial inflammation may drive tenderness in very early, DMARD naïve PsA. These results suggest re-appraisal of clinical joint counts is needed to refine treatment decision making in early PsA.Disclosure of Interests:Sayam Dubash: None declared, Oras Alabas: None declared, Xabier Michelena: None declared, Leticia Garcia-Montoya: None declared, Gabriele De Marco: None declared, Mira Merashli: None declared, Richard Wakefield Speakers bureau: Novartis, Janssen, GE, Philip Helliwell: None declared, Dennis McGonagle Grant/research support from: Janssen Research & Development, LLC, Ai Lyn Tan: None declared, Paul Emery Grant/research support from: AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche (all paid to employer), Consultant of: AbbVie (consultant, clinical trials, advisor), Bristol-Myers Squibb (consultant, clinical trials, advisor), Lilly (clinical trials, advisor), Merck Sharp & Dohme (consultant, clinical trials, advisor), Novartis (consultant, clinical trials, advisor), Pfizer (consultant, clinical trials, advisor), Roche (consultant, clinical trials, advisor), Samsung (clinical trials, advisor), Sandoz (clinical trials, advisor), UCB (consultant, clinical trials, advisor), Helena Marzo-Ortega Grant/research support from: Janssen, Novartis, Consultant of: Abbvie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, UCB, Speakers bureau: Abbvie, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Takeda, UCB
14
Mayfield-Johnson, Susan, Danielle Fastring, Daniel Le, and Jane Nguyen. "Addressing the Social Vulnerability of Mississippi Gulf Coast Vietnamese Community through the Development of Community Health Advisors." Sustainability 12, no. 9 (2020): 3892. http://dx.doi.org/10.3390/su12093892.
Full textAbstract:
Background: Resiliency is the ability to prepare for, recover from, and adapt to stressors from adverse events. Social vulnerabilities (limited access to resources, political power, and representation; lack of social capital; aspects of the built environment; health inequities; and being in certain demographic categories) can impact resiliency. The Vietnamese population living along the Mississippi Gulf Coast is a community that has unique social vulnerabilities that impact their ability to be resilient to adverse events. Objectives: The purpose of this project was to address social vulnerability by implementing and evaluating a volunteer Community Health Advisor (CHA) project to enhance community resiliency in this community. Methods: A program implemented over eight three-hour sessions was adapted from the Community Health Advisor Network curriculum that focused on healthy eating, preventing chronic conditions (hyperlipidemia, diabetes, hypertension, cancer, and poor mental health). Topics also included leadership and capacity development skills. Results: Participants (n = 22) ranged from 35 to 84 years of age. Most were female (63.6%), married (45.5%), unemployed (63.6%), had annual incomes of <$10,000, and had high school diplomas (68.2%). Community concerns were crime (50.0%), volunteerism (40.0%), language barriers (35.0%), and food insecurity (30.0%). Approximately 75% had experienced war trauma and/or refugee camps, and 10% had experienced domestic violence. Scores on the Community Health Advisor Core Competency Assessment increased from pre-test to post-test (t = −5.962, df = 11, p < 0.0001), as did SF-8 scores (t = 5.759, df = 17, p < 0.0001). Conclusions: Strategies to reduce vulnerabilities in the Vietnamese community should include developing interventions that address health risks and strengths and focus on root causes of vulnerability.
15
Guiñazú, Javier Ruiz, Jelena Tica, Charles P. Andrews, et al. "121. A Respiratory Syncytial Virus Prefusion F Protein (RSVPreF3) Candidate Vaccine Administered in Older Adults in a Phase I/II Randomized Clinical Trial Is Immunogenic." Open Forum Infectious Diseases 7, Supplement_1 (2020): S188—S189. http://dx.doi.org/10.1093/ofid/ofaa439.431.
Full textAbstract:
Abstract Background RSV causes significant disease burden in older adults, since reinfections are common and may lead to severe disease presentations while only supportive treatment is available. We present immunogenicity of different formulations of an investigational vaccine (RSVPreF3) in young and older adults. Methods This is a phase I/II, placebo-controlled, multi-country trial (NCT03814590). Healthy adults aged 18–40 years were randomized 1:1:1:1 to receive 2 doses of either Low-, Medium- or High-dose of RSVPreF3 non-adjuvanted vaccine or placebo, 2 months apart. Following favorable safety outcomes, adults aged 60–80 years were randomized 1:1:1:1:1:1:1:1:1:1 in a 2-step staggered manner to receive 1 of the 9 RSV vaccine formulations containing Low-, Medium- or High-dose of RSVPreF3, non-adjuvanted or adjuvanted with AS01E or AS01B, or placebo (same schedule). Humoral and cellular-mediated immune responses are assessed before and after each dose; results up to 1 month post-dose 1 are shown here. Results Of 48 adults aged 18–40 years and 1005 aged 60–80 years included in the exposed set, 42 and 933, respectively, were part of per-protocol set at 1 month post-dose 1. RSVPreF3 IgG geometric mean antibody concentrations were 8.4–13.5 and 7.2–12.8 fold-higher at 1 month post-dose 1 vs baseline in the 18–40- and 60–80-year-old vaccinees, respectively (Fig 1A). RSV-A neutralization activity significantly increased in all RSV vaccinees, geometric mean antibody titers being 7.5–13.7 and 5.6–9.9 fold-higher in 18–40- and 60–80-year-olds, respectively, at 1 month post-dose 1 vs baseline (Fig 1B). Geometric mean ratios of the fold increase between RSVPreF3 IgG antibody concentrations and RSV-A neutralizing antibody titers ranged between 0.9–1.1 in 18–40-year-old and 1.3–1.5 in 60–80-year-old vaccinees. A robust RSVPreF3-specific CD4+ T-cell response was elicited at 1 month post-dose 1 vs baseline in both 18–40- and 60–80-year-olds (Fig 2). Figure 1. RSVPreF3 IgG geometric mean antibody concentrations (GMCs, enzyme-linked immunosorbent assay, panel A), RSV-A neutralizing geometric mean antibody titers (GMTs, neutralization assay, panel B) Figure 2. RSVPreF3-specific CD4+ T-cells identified as expressing ≥2 markers among IL2, CD40L, TNF-□, IFN-□ (intracellular cytokine staining assay) Conclusion One dose of RSVPreF3 candidate vaccine boosted humoral and cellular immune responses in all vaccinees. In older adults, higher humoral response, mostly neutralizing, was observed with increased RSVPreF3 antigen dosage and a tendency of higher cellular response was observed after adjuvanted formulations. Funding GlaxoSmithKline Biologicals SA Disclosures Javier Ruiz Guiñazú, MD MSc, GSK group of companies (Employee, Shareholder) Jelena Tica, PhD, GSK group of companies (Employee, Shareholder) Charles P. Andrews, MD, GSK group of companies (Scientific Research Study Investigator) Charles Fogarty, MD, GSK group of companies (Grant/Research Support) Edward Kerwin, MD, Amphastar (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)AstraZeneca (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Boehringer Ingelheim (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Chiesi (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Cipla (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)GSK group of companies (Employee, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Mylan (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Novartis (Employee, Advisor or Review Panel member, Research Grant or Support, Speaker’s Bureau)other around 40 pharmaceutical companies (Other Financial or Material Support, conducted multicenter clinical research trials)Pearl (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Sunovion (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau)Theravance (Consultant, Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau) Isabel Leroux-Roels, MD PhD, GSK group of companies (Scientific Research Study Investigator) Corinne Vandermeulen, MD PhD, GSK group of companies (Other Financial or Material Support, My university only received Grant/Research Support) Marie-Pierre David, MSc, GSK group of companies (Employee, Shareholder) Nancy Dezutter, PhD, PharmD, RPh, GSK group of companies (Employee, Shareholder) Nathalie De Schrevel, PhD, GSK group of companies (Employee) Laurence Fissette, MSc, GSK group of companies (Employee) Narcisa Mesaros, MD, MSc, GSK group of companies (Employee)
16
Garcia-Montoya, L., Z. Wigston, A. Burska, K. Mankia, E. Vital, and P. Emery. "THU0015 TYPE I INTERFERON SIGNATURE PREDICTS PROGRESSION TO INFLAMMATORY ARTHRITIS IN ACPA+ AT-RISK INDIVIDUALS WITHOUT CLINICAL SYNOVITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (2020): 220.2–221. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4981.
Full textAbstract:
Background:Interferon (IFN) is known to play a role in the pathogenesis of many autoimmune diseases, among them, rheumatoid arthritis (RA). A study showed that two interferon-stimulated gene expression scores (IFN-Score-A and IFN-Score-B) can be used to predict progression to connective tissue disease (CTD) in at-risk individuals, positive for anti-nuclear antibodies (ANA+) [1]. This validated score could potentially be applied to individuals at-risk of RA.Objectives:To investigate the role of type I IFN in patients at-risk of RA and assess its potential role as a biomarker to predict progression to inflammatory arthritis (IA).Methods:PBMC samples were taken from 36 at-risk individuals positive for anti-citrullinated protein antibodies (ACPA+), with a non-specific musculoskeletal complaint but no clinical synovitis and a normal ultrasound scan at baseline (BL). 17 of them developed IA later on, and had a second sample taken at the moment of progression. The other 19 did not progress and had a second sample taken after 1 year. Expression of IFN stimulated genes was assessed using TaqMan. T-test was used to compare the expression of the genes at the two time points of each individual. Binary logistic regression was used to assess BL predictors of progression. Multivariable analysis was adjusted for confounders such as C-reactive protein (CRP) rheumatoid factor (RF) and ACPA titre.Results:Table 1 shows the list of tested genes. There were no differences in the gene expression of progressors at BL and at the moment of IA diagnosis. Similarly, no differences were found between the non-progressors at BL and after 1 year. Comparing BL samples from progressors and non-progressors, there was a trend to higher expression of IFN-score-B in the progressors (Mann Whitney p=0.055), whereas IFN-score-A was similarly expressed in both groups. This is similar to the results found in a cohort of ANA+ individuals at risk of progressing to CTD [1]. Multivariable analysis showed that IFN-score-B and RF titre were predictive for IA progression with an odds ratio (OR) of 2.18 (p=0.048) and OR 1.01 (p=0.035).Table 1.Interferon stimulated genes and scores A and BGENEIFN scoreGENEIFN scoreCCL8BST2CEACAM1IFI16CXCL10IFIH1GBP1LAMP3IFI27NT5C3BIFI44PHF11IFI44LASERPING1BIFIT1SOCS1IRF7SP100ISG15STAT1RSAD2TAP1XAF1TRIM38UBE2L6UNC93B1Table 2.Baseline characteristics and predictors of progressionConclusion:These exploratory results suggest that IFN changes in IA progressors precede subclinical inflammation on ultrasound. A preliminary risk model shows that IFN-score-B could be useful to predict progression to IA in at-risk of RA individuals; however, these results require validation in a larger at-risk cohort.References:[1]Md Yusof MY. Ann. Rheum. Dis. 2018;77(10):1432-9.Disclosure of Interests:Leticia Garcia-Montoya: None declared, Zoe Wigston: None declared, Agata Burska: None declared, Kulveer Mankia: None declared, Edward Vital Grant/research support from: AstraZeneca, Roche/Genentech, and Sandoz, Consultant of: AstraZeneca, GSK, Roche/Genentech, and Sandoz, Speakers bureau: Becton Dickinson and GSK, Paul Emery Grant/research support from: AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche (all paid to employer), Consultant of: AbbVie (consultant, clinical trials, advisor), Bristol-Myers Squibb (consultant, clinical trials, advisor), Lilly (clinical trials, advisor), Merck Sharp & Dohme (consultant, clinical trials, advisor), Novartis (consultant, clinical trials, advisor), Pfizer (consultant, clinical trials, advisor), Roche (consultant, clinical trials, advisor), Samsung (clinical trials, advisor), Sandoz (clinical trials, advisor), UCB (consultant, clinical trials, advisor)
17
Hashmi, Hamza, Alicia Darwin, Christina A. Bachmeier, et al. "Fever Characteristics Associated with Toxicity and Outcome after Anti-CD19 CAR T-Cell Therapy for Aggressive Lymphoma." Blood 134, Supplement_1 (2019): 1612. http://dx.doi.org/10.1182/blood-2019-126148.
Full textAbstract:
Background: Fever is a cardinal symptom of cytokine release syndrome (CRS) after CAR T-cell therapy with 84% of patients experiencing fever on the ZUMA-1 trial of axicabtagene ciloleucel (axi-cel). Knowledge of the patterns of fever and associated symptoms may inform the clinical management of these patients. Methods: We performed a single center retrospective study in 78 patients receiving axi-cel for large B cell lymphoma (LBCL) as of 12/31/2018. We evaluated all the patients who developed fever during lymphodepleting chemotherapy with fludarabine (Flu) and cyclophosphamide (Cy), after CAR T-cell infusion, and after administration of tocilizumab (toci); and analyzed the association of fever with toxicity rates (grade 3+ CRS and neurotoxicity) and efficacy [overall response rates (ORR) and complete response (CR) rate 6 months post CAR T-cell infusion]. Fever was defined per the Lee criteria [equal to or greater than 38 °C], CRS used the modified Lee criteria and neurotoxicity used the CARTOX grading system. Results: Fever occurred in 71/78 (91%) of patients. Rates of grade 3+ CRS and neurotoxicity were 9% (7/78) and 26% (20/78) respectively. The CR rate at 6 months was 41% (32/78). Toxicities and outcomes in patients with the described fever characteristics are shown in the Table. During lymphodepletion with Flu/Cy, fever was observed in 11% (9/78) of patients. Fever occurred within 24 hours of axi-cel infusion in 47% (37/78) and within 72 hours of axi-cel infusion in 71% (55/78) of the patients. In total, 41% (32/78) of patients were treated with anti-IL6R therapy (tocilizumab; toci) for CAR T toxicity. After the first dose of toci, fever recurred in 69% of patients (22/32), of which 34% (11/32) experienced fever recurrence within 24 hours of toci infusion. Conclusions: This is the first study to our knowledge that describes in detail the characteristics of fever after CAR T-cell therapy with axi-cel. Fever was common and occurred in 71% of the patients within 72 hours of axi-cel infusion. When toci was used, fever recurred in a majority of patients (69%) and in 1/3 of patients the fever recurred within 24 hours of toci infusion. These descriptive data may be used by clinicians to inform their expectations of fever occurring after treatment with axi-cel and/or toci. Table Disclosures Bachmeier: Kite/Gilead: Speakers Bureau. Chavez:Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals, Inc.: Speakers Bureau. Shah:AstraZeneca: Honoraria; Novartis: Honoraria; Spectrum/Astrotech: Honoraria; Adaptive Biotechnologies: Honoraria; Pharmacyclics: Honoraria; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria. Pinilla Ibarz:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Sanofi: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding. Lazaryan:Kadmon: Consultancy. Davila:Bellicum: Consultancy; Anixa: Consultancy; GlaxoSmithKline: Consultancy; Precision Biosciences: Consultancy; Novartis: Research Funding; Adaptive: Consultancy; Celgene: Research Funding; Atara: Research Funding. Locke:Cellular BioMedicine Group Inc.: Consultancy; Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor. Jain:Kite/Gilead: Consultancy.
18
Palomba, Maria Lia, Leo I. Gordon, Tanya Siddiqi, et al. "Safety and Preliminary Efficacy in Patients with Relapsed/Refractory Mantle Cell Lymphoma Receiving Lisocabtagene Maraleucel in Transcend NHL 001." Blood 136, Supplement 1 (2020): 10–11. http://dx.doi.org/10.1182/blood-2020-136158.
Full textAbstract:
Background: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma (NHL). Most patients with MCL relapse after first-line immunochemotherapy, with poor responses to salvage therapy. Chimeric antigen receptor (CAR) T cell therapy has shown clinical efficacy in patients with relapsed/refractory (R/R) NHL. We report the results of the dose-finding and dose-expansion parts of the ongoing phase 1 TRANSCEND NHL 001 study (NCT02631044) in patients with R/R MCL (MCL cohort) who received lisocabtagene maraleucel (liso-cel), an investigational, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. Methods: Eligible patients had confirmed MCL (cyclin D1 expression, t[11;14]) with R/R disease after ≥1 prior line of therapy. After lymphodepleting chemotherapy, patients received liso-cel infusion at 1 of 2 dose levels (DLs): DL1 (50 × 106 CAR+ T cells) or DL2 (100 × 106 CAR+ T cells). Bridging therapy was allowed between leukapheresis and initiation of lymphodepleting chemotherapy. Primary endpoints were safety and objective response rate (ORR). Secondary endpoints included complete response (CR) rate, duration of response, progression-free survival, overall survival, and pharmacokinetics (PK). Results: At data cutoff, 41 patients had undergone leukapheresis and 32 had received liso-cel (DL1, n = 6; DL2, n = 26). Among the 32 patients who received liso-cel, the median (range) age was 67 (36‒80) years and 27 patients (84%) were male. Twelve patients (37.5%) had blastoid morphology, 23 (72%) had documented Ki67 ≥30%, 7 (22%) had a TP53 mutation, and 11 (34%) had a complex karyotype. Patients had a median (range) sum of the product of perpendicular diameters before lymphodepleting chemotherapy of 28.7 (0-209.6) cm2 and median lactate dehydrogenase of 251.5 (117-811) U/L. Patients had received a median (range) of 3 (1-7) prior systemic therapies, and most (72%) were refractory to their last prior therapy. Of 28 patients (87.5%) who had received a prior Bruton tyrosine kinase inhibitor, 11 (34%) were refractory to the therapy. Seventeen patients (53%) received bridging therapy. Eighteen patients (56%) had serious treatment-emergent adverse events (TEAEs), and 27 (84%) had grade ≥3 TEAEs, primarily neutropenia (41%), anemia (34%), and thrombocytopenia (31%). Grade ≥3 thrombocytopenia was more frequent at DL2 (n = 9/26 [35%]) than at DL1 (n = 1/6 [17%]). Prolonged grade ≥3 cytopenias (present at study Day 29) occurred in 11 patients (34%). Sixteen patients (50%; DL1, n = 2/6 [33%]; DL2, n = 14/26 [54%]) had cytokine release syndrome (CRS), including 1 grade 4 event at DL2. There were no grade 3 or 5 CRS events. Median (range) time to CRS onset and resolution was 6 (2‒10) days and 4 (2‒9) days, respectively. Nine patients (28%) had neurological events (NEs), all at DL2, including 3 grade 3 NEs. No grade 4 or 5 NEs were reported. Median (range) time to NE onset and resolution was 8 (2‒25) days and 3 (1‒51) days, respectively. Ten patients (31%) received tocilizumab and/or corticosteroids for treatment of CRS and/or NEs. Grade 5 TEAEs occurred in 2 patients (at DL2): one patient with high tumor burden had tumor lysis syndrome and 1 patient had cryptococcal meningoencephalitis. DL2 was selected for dose expansion. Of 32 patients, 27 responded to liso-cel (ORR, 84%: DL1, n = 4/6 [67%]; DL2, n = 23/26 [88%]), and 19 (59%) achieved a CR (DL1, n = 2/6 [33%]; DL2, n = 17/26 [65%]). Among the 12 patients with blastoid morphology, 9 patients had a response (ORR, 75%), including 7 (58%) who achieved a CR. Overall, the median (range) time to first CR was 1 (1-6) month. At data cutoff, 20 (74%) of 27 responders were censored with an ongoing response or had completed the study. Median (range) follow-up duration was 10.9 (1.2-24.8) months for DL1 and 3.1 (0.4-23.0) months for DL2. Preliminary PK analysis indicated that median maximum expansion was higher among patients at DL2 than at DL1. Conclusions: In this phase 1 study of patients with R/R MCL, treatment with liso-cel was associated with a low incidence of grade ≥3 CRS and NEs, late onset of CRS/NEs, and promising clinical activity. Dose confirmation is ongoing at DL2 in the MCL cohort. Disclosures Palomba: Pharmacyclics: Honoraria; Juno: Honoraria; Celgene: Honoraria; Merck: Honoraria; Novartis: Honoraria; Regeneron: Research Funding; Juno: Research Funding; Genentech: Research Funding. Gordon:Zylem Biosciences: Patents & Royalties: Patents, No Royalties. Siddiqi:Juno: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BeiGene: Other: DMC member; Juno Therapeutics, Pharmacyclics LLC, an AbbVie Company, AstraZeneca, Celgene, Kite Pharma, and BeiGene: Consultancy; Pharmacyclics LLC, an AbbVie Company, Seattle Genetics, Janssen, and AstraZeneca: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Juno Therapeutics, KITE Pharma, AstraZeneca, TG Therapeutics, Celgene, Oncternal, and BeiGene: Research Funding; AstraZeneca: Other: Travel/accommodations/expenses; Astrazenca: Membership on an entity's Board of Directors or advisory committees; PCYC: Membership on an entity's Board of Directors or advisory committees. Abramson:Celgene: Honoraria, Other: Scientific Advisory Board; Juno Therapeutics: Other: Scientific Advisory Board; AbbVie: Other: Scientific Advisory Board; EMD Serono: Other: Scientific Advisory Board; Genentech/Roche: Other: Scientific Advisory Board; Janssen: Other: Scientific Advisory Board; Karyopharm: Other: Scientific Advisory Board; Gilead: Other: Scientific Advisory Board; Verastem: Other: Scientific Advisory Board; Bayer: Other: Scientific Advisory Board; Merck: Other; KIte Pharma: Other; Novartis: Other; Amgen: Other; Seattle Genetics: Other; Allogene: Other; Morphosys: Other; C4 Therapeutics: Other; BeiGene: Other; AstraZeneca: Honoraria; Incyte: Honoraria. Kamdar:Seattle Genetics: Speakers Bureau; Karyopharm: Consultancy; BMS: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy; Pharmacyclics: Consultancy. Lunning:Acrotech: Consultancy; ADC Therapeutics: Consultancy; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; Curis: Research Funding; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; TG Therapeutics: Research Funding; Verastem: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Legend: Consultancy; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria. Maloney:Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Patents are pending, but not issued, licensed, no royalties, no licensees., Research Funding; Bioline Rx: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Andreadis:Genentech: Other: Spouse Employee (salary and stock); Novartis: Research Funding; Celgene/Juno: Research Funding; Amgen: Research Funding; Merck: Research Funding; Gilead/Kite: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Astellas: Other: Advisor; Seattle Genetics: Other: Advisor; Karyopharm: Other: Advisor; Incyte: Other. Arnason:Regeneron: Consultancy; Juno: Consultancy. Ghosh:Forty Seven Inc: Consultancy, Other: Research Bureau, Research Funding; Genmab: Consultancy, Speakers Bureau; AbbVie: Speakers Bureau; Karyopharm: Consultancy; Juno/Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; Kite/Gilead: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Roche/Genentech: Research Funding; SGN: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Celgene/Bristol-Myers Squibb: Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau. Mehta:Innate Pharmaceuticals: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding; Gelgene/BMS: Research Funding; Oncotartis: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Juno Parmaceuticals/BMS: Research Funding; fortyseven Inc/Gilead: Research Funding; Takeda: Research Funding; Roche-Genentech: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Affimed: Research Funding. Farazi:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Garcia:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb Company: Current equity holder in publicly-traded company. Dehner:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Ogasawara:Bristol-Myers Squibb: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Gao:Bristol-Myers Squibb: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current Employment. Wang:Juno: Consultancy, Research Funding; Acerta Pharma: Research Funding; Loxo Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; InnoCare: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Lu Daopei Medical Group: Honoraria; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Molecular Templates: Research Funding; Verastem: Research Funding; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Pulse Biosciences: Consultancy; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Oncternal: Consultancy, Research Funding; Nobel Insights: Consultancy; OMI: Honoraria, Other: Travel, accommodation, expenses; Targeted Oncology: Honoraria; BioInvent: Research Funding; VelosBio: Research Funding.
19
Jain, Michael D., Rawan Faramand, Verena Staedtke, et al. "The Lymphoma Tumor Microenvironment Influences Toxicity after CD19 CAR T Cell Therapy." Blood 134, Supplement_1 (2019): 4105. http://dx.doi.org/10.1182/blood-2019-127305.
Full textAbstract:
Introduction: Of patients receiving CD19 CAR T cell therapy for large B cell lymphoma (LBCL), approximately 1 in 10 experience severe cytokine release syndrome (CRS) and 1 in 3 experience severe neurotoxicity. While CAR T cells trigger the onset of these toxicities, CRS and neurotoxicity are thought to occur as a consequence of activated myeloid cells amplifying cytokine and catecholamine release, thereby stimulating inflammation both systemically and at the blood-brain barrier. However, patient and tumor-related factors that account for differences in the amount of toxicity remain poorly understood. Methods: Serum cytokine levels were measured on an ELLA point of care device prior to lymphodepleting chemotherapy and throughout inpatient treatment with CD19 CAR T cell therapy (axicabtagene ciloleucel) for LBCL. Catecholamine levels were measured as we have previously reported. Tumor biopsies were taken within 1 month prior to infusion of CAR T cells. RNA expression was measured by RNAseq and/or a Nanostring IO360 panel consisting of 770 genes found in the tumor microenvironment (TME) in cancer. Analysis used nSolver to identify cell types, GSEA and differential gene expression between groups. Mouse CAR T cell studies utilized mouse CD19-targeted CAR T cells derived from C57BL/6 splenocytes and cultured in vitro with myeloid cells and target cells to evaluate cytotoxicity and/or cytokine secretion. Elicited mouse macrophages were collected from peritoneal fluid 4 days after IP injection of 3% Brewer's thioglycollate medium. In vivo studies with mouse CD19-targeted CAR T cells were performed in IL2Ra-/- mice given cyclophosphamide as a pre-conditioning chemotherapy followed by adoptive transfer and analyses for CAR T cell and B cell persistence, as well as cytokines. Results: Of 58 patients undergoing CD19 CAR T cell therapy for LBCL, 8 (14%) had severe (grade 3 or higher) CRS and 16 (28%) had severe (grade 3 or higher) neurotoxicity. At baseline, peripheral blood levels of IL-6, IFN-γ, IL-15 and ferritin were significantly higher in patients who would subsequently experience severe CRS and severe neurotoxicity. Confirming our recent animal model of CRS we determined that peak serum catecholamine levels were higher in patients experiencing severe CRS. To identify if myeloid cells potentiate cytokine release we co-cultured CAR T cells with CD19 target and macrophages obtained from elicited mouse peritoneum. When these macrophages were added, IL-6 release from CAR T cells significantly increased compared to when macrophages were absent. Next, we studied the baseline TME in LBCL CAR T patients. Of 36 patients, 10 (27%) experienced severe neurotoxicity following CAR T cell therapy. By cell type score, the severe neurotoxicity group had a lower expression of genes associated with T cells overall and specifically Tregs. Also significantly lower in the severe neurotoxicity group were T cell genes including multiple subunits of CD3, CD3ζ, FOXP3, ICOS, CD62L and others. Association of increased T cell infiltration in the TME with low neurotoxicity raised the possibility that suppressive T cell subsets play a role in limiting toxicity post-CAR T cell therapy. To test this hypothesis, we injected CD19-targeted CAR T cells into an immune competent mouse model of Treg depletion (IL2Ra-/-) with established CD19+ leukemia. Treg deficient mice experienced a massive cytokine release after CAR T infusion and died prematurely due to CAR T toxicity compared to control mice with Tregs intact. Conclusions: Our observations suggest that the incidence of severe toxicity following CD19 CAR T cell therapy is influenced by baseline characteristics that are present prior to the infusion of CAR T cells. These include systemic inflammation characterized by high cytokine levels and a TME notable for a lack of infiltrating T cells. We posit a model whereby inflammation primes myeloid cells that are further activated upon CAR T cell infusion to release toxic amounts of cytokines and catecholamines. T cell subsets in the TME may modulate CAR T cells at the site of antigen encounter and prevent excessive CAR T activation. Reducing systemic inflammation or encouraging T cell infiltration into tumor prior to CAR T infusion are potential strategies for lowering the toxicity associated with CAR T therapy. Disclosures Jain: Kite/Gilead: Consultancy. Chavez:Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Speakers Bureau; Janssen Pharmaceuticals, Inc.: Speakers Bureau. Shah:Novartis: Honoraria; Spectrum/Astrotech: Honoraria; Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria; AstraZeneca: Honoraria. Bachmeier:Kite/Gilead: Speakers Bureau. Mullinax:Iovance: Research Funding. Locke:Novartis: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy; Kite: Other: Scientific Advisor. Davila:Anixa: Consultancy; Precision Biosciences: Consultancy; Novartis: Research Funding; GlaxoSmithKline: Consultancy; Adaptive: Consultancy; Celgene: Research Funding; Atara: Research Funding; Bellicum: Consultancy.
20
Jain, Michael D., Julio C. Chavez, Bijal D. Shah, et al. "Radiation Therapy As a Bridging Strategy for Refractory Diffuse Large B Cell Lymphoma Patients Awaiting CAR T Manufacturing of Axicabtagene Ciloleucel." Blood 132, Supplement 1 (2018): 4220. http://dx.doi.org/10.1182/blood-2018-99-117133.
Full textAbstract:
Abstract Background: CD19-directed chimeric antigen receptor (CAR) T cell therapy is FDA approved for relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL) and variants. Due to active lymphoma, "bridging" therapy may be needed to maintain disease control during the 3 or more weeks required for autologous CAR T manufacturing. Bridging therapy was not allowed in trials of axicabtagene ciloleucel (axi-cel), but could improve outcomes by reducing tumor burden. Bridging chemotherapy is one option, however toxicity and chemo-refractory disease are potential concerns. Here we report a case series of patients receiving bridging radiation therapy (XRT) prior to axi-cel therapy, of which the majority had double hit lymphoma. Patient Characteristics: As of July 31, 2018 eight patients received XRT as part of their bridging therapies. Overall, patients had a median of 3 prior lines of chemotherapy (range 2 to 5). Two were primary refractory to their first two lines of chemotherapy. Six of the 8 patients had double hit lymphoma by FISH. All patients received 3-4 Gy per fraction to a total median dose of 20 Gray (range 9 - 30 Gy). The most commonly used regimen was 30 Gy in 10 fractions (3/7 patients). Four patients received bridging chemotherapy in addition to XRT, mainly oral cytoxan. In 2 patients the XRT was given up until the day of leukapheresis and in 1 of these patients it was continued after leukapheresis. In 6 additional patients the XRT started after leukapheresis. Overall, XRT was completed at a median of 9 days (range 3 - 22 days) prior to starting Flu/Cy conditioning. The median mass diameter receiving XRT was 13.6 cm (range 3 - 30 cm). Outcomes: No significant adverse events were noted at the local site of XRT before or after CAR T infusion. Response assessment within the field of radiation is complicated by a short duration between end of XRT and restaging prior to Flu/Cy conditioning. Nonetheless, only one patient experienced progressive disease in-field after XRT and most had stable disease in-field. Of the 4 cases where the baseline LDH was elevated, only the patient with PD saw their LDH rise after the completion of XRT, while the other 3 of 4 patients had declining LDH at the time of Flu/Cy conditioning. In 7 patients evaluable for toxicity, there was one case of severe cytokine release syndrome (CRS). This event occurred in the patient who progressed through XRT and had rising LDH and declining performance status prior to CAR T infusion (this patient later died of infection). In the other 6 patients the maximum CRS was grade 1 or 2. Three out of the 7 patients had grade 3 or 4 CAR T related encephalopathy syndrome (CRES). For lymphoma outcomes at day 30, 1 patient was in CR, 2 patients PR, 2 patients with SD and 1 patient with PD (Lugano criteria). Two patients are evaluable at day 90 with PR, although one of these patients subsequently relapsed at month 4 (in-field to the prior radiation). Conclusions: Bridging XRT (with or without chemotherapy) can be safely administered and provides disease control in refractory poor risk DLBCL patients prior to axi-cel therapy. All patients were able to receive axi-cel. CAR T-related toxicity occurred, but in this case series was most likely related to disease aggressiveness (6 of 8 patients were double hit) and tumor burden. Further research should focus on the immunologic effects of XRT and its impact on CAR T cell efficacy and toxicity. Table. Table. Disclosures Chavez: Humanigen: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau; Merck: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Davila:Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Locke:Cellular BioMedicine Group Inc.: Consultancy; Kite Pharma: Other: Scientific Advisor; Novartis Pharmaceuticals: Other: Scientific Advisor.
21
Diaz, George, Jose Ramon Arribas, Jose Ramon Arribas, et al. "73. Geographical Disparities in Clinical Outcomes of Severe COVID-19 Patients Treated with Remdesivir." Open Forum Infectious Diseases 7, Supplement_1 (2020): S167. http://dx.doi.org/10.1093/ofid/ofaa439.383.
Full textAbstract:
Abstract Background Remdesivir (RDV), a RNA polymerase inhibitor with potent in vitro activity against SARS-CoV-2, is the only treatment with demonstrated efficacy in shortening the duration of COVID-19. Here we report regional differences in clinical outcomes of severe COVID-19 patients treated with RDV, as part of an open-label, randomized phase-3 trial establishing RDV treatment duration. Methods Hospitalized patients with oxygen saturation ≤94%, a positive SARS-CoV-2 PCR in the past 4 days and radiographic evidence of pneumonia were randomized 1:1 to receive 5d or 10d of intravenous RDV. We compared d14 clinical outcomes of patients from different geographical areas, as measured by mortality rates, change in clinical status from baseline (BL) on a 7-point ordinal scale and change in O2 requirements from BL. Based on previous analyses in compassionate use data showing region as an important predictor of outcome, Italy was examined separately from other regions. Results 397 patients were treated with RDV, of which 229 (58%) were in the US, 77 (19%) Italy, 61 (15% in Spain), 12 (3%) Republic of Korea, 9 (2%) Singapore, 4 (1%) Germany, 4 (1%) Hong Kong and 1 (&lt; 1%) Taiwan. BL clinical status was worse in Italy compared to other regions (72% vs 17% requiring high-flow oxygen delivery or higher), and Italian patients were more likely to be male than patients from other regions (69% vs 63%). Overall results showed 5d RDV was as effective as 10d. Mortality at d14 was higher in Italy (18%) compared to all other countries except Italy (7%). Similarly, clinical improvement at d14, measured as ≥2-point increase in the ordinal scale, was lower in Italian patients (39%) compared to all other countries combined (64%). (Fig.1). Figure 1. Change from Baseline in Clinical Status (measured on a 7-point Ordinal Scale) at d14. Conclusion Overall, our results demonstrate significant geographical differences in the clinical course of severe COVID-19 patients treated with RDV. We observed worse outcomes, such as increased mortality and lower rate of clinical improvement, in patients from Italy compared to other regions. Disclosures George Diaz, MD, NO DISCLOSURE DATA Jose Ramon Arribas, MD, Alexa (Advisor or Review Panel member, Speaker’s Bureau, Other Financial or Material Support, Personal fees)Gilead Sciences Inc. (Scientific Research Study Investigator, Advisor or Review Panel member, Speaker’s Bureau, Other Financial or Material Support, Personal fees)Janssen (Advisor or Review Panel member, Speaker’s Bureau, Other Financial or Material Support, Personal fees)Merck (Advisor or Review Panel member, Speaker’s Bureau, Other Financial or Material Support, Personal fees)Viiv Healthcare (Advisor or Review Panel member, Speaker’s Bureau, Other Financial or Material Support, Personal fees) Jose Ramon Arribas, MD, NO DISCLOSURE DATA Philip A. Robinson, MD, NO DISCLOSURE DATA Anna Maria Cattelan, MD, NO DISCLOSURE DATA Karen T. Tashima, MD, Bristol-Myers Squibb (Research Grant or Support)Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator)GlaxoSmithKline (Research Grant or Support)Merck (Research Grant or Support)Tibotec (Research Grant or Support)Viiv Healthcare (Research Grant or Support) Owen Tak-Yin Tsang, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Owen Tak-Yin Tsang, MD, NO DISCLOSURE DATA Yao-Shen Chen, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Yao-Shen Chen, MD, NO DISCLOSURE DATA Devi SenGupta, MD, Gilead Sciences Inc. (Employee, Shareholder) Elena Vendrame, MD, NO DISCLOSURE DATA Christiana Blair, MS, Gilead Sciences (Employee, Shareholder) Anand Chokkalingam, PhD, Gilead Sciences (Employee) Anu Osinusi, MD, Gilead Sciences (Employee) Diana M. Brainard, MD, Gilead Sciences (Employee) Bum Sik Chin, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Bum Sik Chin, MD, NO DISCLOSURE DATA Christoph Spinner, MD, AbbVie (Advisor or Review Panel member, Other Financial or Material Support, Travel)Bristol-Myers Squibb (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel)Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Other Financial or Material Support, Travel)Janssen (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel)MSD (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel)Viiv Healthcare (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel) Gerard J. Criner, MD, Gilead Sciences Inc. (Scientific Research Study Investigator)Regeneron (Scientific Research Study Investigator) Gerard J. Criner, MD, NO DISCLOSURE DATA Jose Muñoz, MD, NO DISCLOSURE DATA David Chien Boon Lye, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) David Chien Boon Lye, MD, NO DISCLOSURE DATA Robert L. Gottlieb, MD, Gilead Sciences Inc. (Scientific Research Study Investigator)
22
Bogler, Yael, Anat Stern, Yiqi Su, et al. "1291. Safety of Isavuconazole Compared with Voriconazole as Primary Antifungal Prophylaxis in Allogeneic Hematopoietic Cell Transplant Recipients." Open Forum Infectious Diseases 7, Supplement_1 (2020): S660—S661. http://dx.doi.org/10.1093/ofid/ofaa439.1474.
Full textAbstract:
Abstract Background Voriconazole (VCZ) is used as mold active primary antifungal prophylaxis (AFP) after allogenic hematopoietic cell transplant (HCT) but is frequently discontinued due to adverse events (AE), variable pharmacokinetics and drug-drug interactions. Limited data exists on the safety of Isavuconazole (ICZ) as AFP in HCT patients (pts). The study objectives were to compare 1) rates of AFP premature discontinuation (d/c), 2) changes in transaminases values from start to end of treatment (EOT) and 3) rates of invasive fungal infections (IFI) and all-cause mortality by Day (D) +180 post HCT between VCZ and ICZ AFP. Methods This is a matched cohort analysis of 95 pts enrolled in a clinical trial of ICZ AFP from 7/1/2017-10/31/2018 (ICZ-cohort) and 210 pts who received VCZ AFP standard of care between 9/1/2014-12/31/2015 at MSKCC (VCZ-cohort). The cohorts were matched using propensity scores (Table 1). AFP was administered for 75-100 days per institutional guidelines. Premature d/c of AFP was defined as d/c for IFI or AE by D +100 post HCT or interruption of &gt;14 days for any reason. The cumulative incidence function and log rank test were used to compare groups. Mean transaminase values were compared using paired T-tests. Table 1. Baseline characteristics Results The median (Interquartile range) duration of AFP was 94 (87-100) days and 76 (23-94) days in ICZ and VCZ cohorts respectively (p&lt; 0.0001). Premature d/c occurred in 14/95 (14.7%) of ICZ and 92/210 (43.8%) of VCZ cohorts (p&lt; 0.0001) (Figure 1). The most common cause for AFP d/c was hepatotoxicity: ICZ-cohort: 5/95 (5.26%) vs VCZ-cohort: 48/210 (22.8%). Transaminases at EOT and up to 14 days were increased in VCZ but not ICZ cohort (Figure 2). IFI occurred in 3.15% (3/95) in ICZ-cohort and 2.85% (6/210) in VCZ-cohort (p=0.88) (Figure 3). In ICZ-cohort IFI included 3 Candida bloodstream infections (BSI) occurring on ICZ AFP. In VCZ-cohort IFI included one Candida BSI after VCZ d/c, and 5 probable mold infections; 3/5 with serum galactomannan &gt; 0.5 and 2 with beta-D-glucan &gt; 80. IFI occurred on VCZ in 1 pt and after VCZ premature d/c in 5 pts. All-cause mortality was 6.31% (6/95) in ICZ-cohort and 2.85% (6/210) in VCZ-cohort (p=0.089). Figure 1. Cumulative incidence of premature discontinuation of AFP by D+100 Figure 2. Transaminases at baseline,end of treatment (EOT), EOT +7 days and EOT +14 days in ICZ- and VCZ cohorts Figure 3. Cumulative incidence of IFI by day +180 Conclusion There was less premature discontinuation and hepatotoxicity with ICZ AFP, but no increase in IFI or death compared to VCZ AFP in allogeneic HCT pts. Disclosures Yeon Joo Lee, MD, MPH, Ansun BioPharma (Scientific Research Study Investigator)Astellas Pharma (Scientific Research Study Investigator) Sergio Giralt, MD, Amgen (Advisor or Review Panel member, Research Grant or Support, Served an advisory board for Amgen, Actinuum, Celgene, Johnson & Johnson, JAZZ pharmaceutical, Takeda, Novartis, KITE, and Spectrum pharma and has received research support from Amgen, Actinuum, Celgene, Johnson & Johnson, and Miltenyi, Takeda.) Miguel-Angel Perales, MD, Abbvie (Other Financial or Material Support, Honoraria from Abbvie, Bellicum, Celgene, Bristol-Myers Squibb, Incyte, Merck, Novartis, Nektar Therapeutics, Omeros, and Takeda.)ASTCT (Other Financial or Material Support, Volunteer member of the Board of Directors of American Society for Transplantation and Cellular Therapy (ASTCT), Be The Match (National Marrow Donor Program, NMDP), and the CIBMTR Cellular Immunotherapy Data Resource (CIDR) Committee)Cidara Therapeutics (Advisor or Review Panel member, Other Financial or Material Support, Serve on DSMBs for Cidara Therapeutics, Servier and Medigene, and the scientific advisory boards of MolMed and NexImmune.)Kite/Gilead (Research Grant or Support, Other Financial or Material Support, Received research support for clinical trials from Incyte, Kite/Gilead and Miltenyi Biotec.) Dionysios Neofytos, MD, Basilea (Advisor or Review Panel member)Gilead (Advisor or Review Panel member)MSD (Advisor or Review Panel member, Research Grant or Support)Pfizer (Advisor or Review Panel member, Research Grant or Support) Genovefa Papanicolaou, MD, Chimerix (Research Grant or Support)Merck&Co (Research Grant or Support, Investigator and received funding and consulting fees from Merck, Chimerix, Shire and Astellas)
23
Horner, John R. "Steak Knives, Beady Eyes, and Tiny Little Arms (A Portrait of T. rex as a Scavenger)." Paleontological Society Special Publications 7 (1994): 157–64. http://dx.doi.org/10.1017/s2475262200009497.
Full textAbstract:
I'll begin with the obvious question, how many people saw the movie “Jurassic Park”? How many people believed it? In the movie, “Jurassic Park”, there were basically two stars. Tyrannosaurus rex was one of them and the Velociraptors (or Deinonychus, or whatever they happened to be) were the others. What you might also know is that I was an advisor on the movie. All I was able to do was basically tell them when the dinosaurs were walking right and tell Laura Dern how to pronounce her words.Any time the dinosaurs were going to do something, any time Steven Spielberg wanted to have the dinosaurs do something in the movie, he would ask me if I thought they could do that. If I said yes or no, he would take that as an answer. But if I said maybe, he would just do whatever he wanted. That's fiction.
24
Tran, Nikki, Gregory Eschenauer, Gianni Scappaticci, David Frame, Marisa H. Miceli, and Twisha S. Patel. "578. Infections in Patients Treated with Chimeric Antigen Receptor T-cells (CAR-T) therapy." Open Forum Infectious Diseases 7, Supplement_1 (2020): S354. http://dx.doi.org/10.1093/ofid/ofaa439.772.
Full textAbstract:
Abstract Background Although chimeric antigen receptor T cells (CAR-T) is a promising novel therapy for the treatment of relapsed or refractory (R/R) B-cell malignancies, data on infectious complications associated with this therapy are limited. Therefore, further assessment of infections after CAR-T therapy is warranted. Methods We retrospectively reviewed and analyzed infectious complications for 6 months following CAR-T therapy infusion (CTI) in 39 adult and pediatric patients with R/R acute lymphoblastic leukemia (ALL) and Non-Hodgkin Lymphoma (NHL) at Michigan Medicine. Results Overall, 20 infections were identified in 16 of 39 patients (41%) following CTI [detailed in Table 1]; 8 (40%) infections occurred in the early period (Day 0–30) and 12 (60%) infections occurred during late period (Day 31–180). The most common infections were viral (n=10, 50%; 80% of viral infections were respiratory viruses), followed by 8 bacterial infections (40%), and 2 fungal infections (10%). More bacterial infections were seen in the early period post-CTI (30% vs. 10%, p = 0.019), whereas viral infections were more common during the late period (40% vs. 10%, p = 0.68). Antimicrobial prophylaxis prior to CTI and following CTI were similar (Table 2). The majority of patients included in the study had NHL (n=32, 82%). Mean age of the cohort was 52 ± 22 years, and 64% were male. 85% of the population developed cytokine release syndrome (CRS) with 67% grade 1–2 and 18% grade 3–5. As shown in Table 2, most baseline characteristics were similar between patients with and without infections post CTI except infected patients were older (63.3 ± 11.3 vs. 44.8 ± 24.2, p = 0.01) and more received steroids for CRS (56% vs 17%, p = 0.02). All-cause mortality within 6 months following CTI was similar in infected and uninfected groups (38% vs 26%, p= 0.50). Table 1 Table 2 Conclusion Infectious complications are common following CAR-T therapy. We found the majority of infections to be caused by various bacteria or respiratory viruses in a cohort of patients with lymphoma as the most common underlying malignancy. Disclosures Marisa H. Miceli, MD, FIDSA, SCYNEXIS, Inc. (Advisor or Review Panel member)
25
Jain, Michael D., Miriam T. Jacobs, Loretta J. Nastoupil, et al. "Characteristics and Outcomes of Patients Receiving Bridging Therapy While Awaiting Manufacture of Standard of Care Axicabtagene Ciloleucel CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma: Results from the US Lymphoma CAR-T Consortium." Blood 134, Supplement_1 (2019): 245. http://dx.doi.org/10.1182/blood-2019-129624.
Full textAbstract:
MDJ and MTJ contributed equally; FLL and AG contributed equally. Introduction Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are autologous anti-CD19 CAR T-cell therapies approved for the treatment of adults with relapsed or refractory large B-cell lymphoma (LBCL) who have failed at least two lines of systemic therapy. In the ZUMA-1 trial that led to axi-cel approval, the median time between apheresis and delivery of CAR T cells to the treating facility was 17 days (Neelapu, Locke et al. NEJM 2018). Bridging therapy, defined as lymphoma therapy given between apheresis and the start of lymphodepleting chemotherapy, was not permitted on ZUMA-1. By contrast, the pivotal JULIET trial for tisa-cel (Schuster et al. NEJM 2019) had a median time from enrollment to infusion of 54 days and 92% of patients received bridging therapy. Whether bridging therapy affects lymphoma CAR T outcomes is unknown. Here we evaluate patients receiving bridging therapy for axi-cel in a large multicenter cohort. Methods and Results The US Lymphoma CAR T Consortium includes seventeen US academic centers that contribute data from lymphoma patients treated with standard of care (SOC) CAR T-cell therapy independently of manufacturers. As of 8/31/2018, 300 patients were apheresed with intent to manufacture SOC axi-cel for LBCL. Of the 23 patients that underwent apheresis for axi-cel and did not receive it, 20 had lymphoma progression or death that precluded CAR T infusion, of which 16 received bridging therapy. In this study, we analyze the modified intent-to-treat (mITT) population of 276 patients receiving CAR T infusion with a median follow up of 9 months. In this group, 146 (53%) patients received bridging therapy while 130 (47%) patients received no bridging therapy. Bridging therapy consisted of steroids alone (n = 35, 24%), chemotherapy (n = 73, 50%), radiation (n = 24, 16%), or targeted therapies (n = 14, 10%). At baseline, a higher proportion of patients in the bridging therapy group had an ECOG score of 2 - 4 vs. 0 - 1 (bridging 24.8%, no bridging 6.1%, p &lt;0.001), IPI score of 3 -5 vs. 0 - 2 (bridging 67.6%, no bridging 34.3%, p &lt;0.001), bulky disease greater than 10 cm (28.2% vs. 13.0%, p = 0.002), immunohistochemical double expression of MYC and BCL2 (42.5% vs. 24.6%, p =0.004) and would not have met all the eligibility criteria for ZUMA-1 for reasons other than bridging therapy (48.6% vs. 30.0%, p = 0.002). After axi-cel infusion, patients in the bridging group had similar rates of severe (grade 3 or higher) cytokine release syndrome (CRS) (8.2% vs. 5.3%, p = 0.34) and ICANS (35.2% vs. 28.2%, p = 0.25). However, the rate of ICU admission was higher in the bridging group (41.4% vs. 22.9%, p = 0.001) as was median length of hospital stay (15 vs. 14 days, p = 0.02). While data on cytopenias was not collected, use of G-CSF after CAR T therapy was higher in the bridging group (48.2% vs. 32.1%, p = 0.006). In terms of outcomes, in multivariate analysis correcting for confounding features, there was no statistically significant difference in overall response rate (p = 0.2), complete response rate (p = 0.19), and progression free survival (p = 0.3) between bridging and no bridging groups; but bridging therapy was associated with significantly poorer overall survival (p = 0.001) and lymphoma specific survival (p = 0.019) (figure 1.). Both death due to lymphoma (33.1% vs. 13.0%) and death due to treatment-related mortality (TRM) (6.9% vs. 1.5%) were higher in the bridging group (p &lt;0.001). Conclusions Lymphoma patients receiving bridging therapy had poorer prognostic factors at baseline and after axi-cel infusion experienced decreased lymphoma-specific and overall survival compared with patients with no bridging. This inferior outcome raises the possibility that bridging therapy may identify a sub-group of lymphoma patients with a different biology, or alternatively, bridging therapy may have an effect on the host or the tumor microenvironment that may impact CAR-T efficacy. With or without bridging, 7% of patients in our series did not receive axi-cel due to lymphoma progression and/or death. In addition, there may have been patients where bridging prevented progression or death prior to axi-cel infusion. Prospective evaluation of different bridging strategies is warranted to determine if any can improve outcomes after axi-cel, and/or if they should be utilized only for patients requiring emergent disease control during the manufacture period. Disclosures Jain: Kite/Gilead: Consultancy. Nastoupil:Bayer: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding; Spectrum: Honoraria. Lin:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; BlueBird Bio: Research Funding; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Sorrento: Membership on an entity's Board of Directors or advisory committees. Lunning:Curis: Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; MiRagen: Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy; Bayer: Consultancy; DAVA: Consultancy; Gilead Sciences, Inc.: Consultancy; Kite: Consultancy; Novartis: Consultancy; OncLive: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy; Spectrum: Consultancy; VANIUM: Consultancy; Verastem: Consultancy. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. McGuirk:Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Astellas: Research Funding; Bellicum Pharmaceuticals: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation. Deol:Novartis: Other: Advisory board; Kite: Other: Advisory board; Agios: Other: Advisory board. Goy:University of Nebraska: Research Funding; Hakensackumc: Research Funding; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hackensack University Medical Center, RCCA: Employment; Genentech: Other: Grants outside of the submitted work, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; Takeda: Other: Grants outside of the submitted work; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company. Hill:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; TG therapeutics: Research Funding; Amgen: Research Funding. Munoz:Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Pfizer: Consultancy; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Portola: Research Funding; Incyte: Research Funding; Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Speakers Bureau. Vose:Acerta Pharma: Honoraria, Other: Grants, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; Kite Pharma: Honoraria, Other: Grants, Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; AbbVie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Legend Pharmaceuticals: Honoraria. Miklos:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; AlloGene: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; Becton Dickinson: Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Neelapu:Cellectis: Research Funding; Allogene: Consultancy; Incyte: Consultancy; BMS: Research Funding; Novartis: Consultancy; Karus: Research Funding; Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Acerta: Research Funding; Poseida: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy; Precision Biosciences: Consultancy; Cell Medica: Consultancy. Bennani:Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board. Andreadis:Pharmacyclics: Research Funding; Novartis: Research Funding; Roche: Equity Ownership; Celgene: Research Funding; Juno: Research Funding; Jazz Pharmaceuticals: Consultancy; Genentech: Consultancy, Employment; Merck: Research Funding; Gilead: Consultancy; Kite: Consultancy. Sehgal:Juno/Celgene: Research Funding; Merck: Research Funding; Kite/Gilead: Research Funding. Locke:Novartis: Other: Scientific Advisor; Kite: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy.
26
Maziarz, Richard T., Stephen J. Schuster, Vadim V. Romanov, et al. "Grading of Neurotoxicity in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (r/r DLBCL) Receiving Tisagenlecleucel Treatment in the JULIET Study." Blood 132, Supplement 1 (2018): 4183. http://dx.doi.org/10.1182/blood-2018-99-118595.
Full textAbstract:
Abstract Introduction: CAR-T cell therapy has demonstrated prompt and durable clinical responses in patients with r/r DLBCL, but is associated with unique toxicities such as cytokine-release syndrome (CRS) and neurotoxicity (NT). NT is the second most common unique toxicity frequently attributed to CAR-T therapy and is present in boxed warnings for all approved CD19 targeted therapies. Similar to other organ toxicities, NT is graded using the Common Terminology Criteria for Adverse Events (CTCAE). However, the CTCAE grading system does not adequately characterize the severity, timing and spectrum of CAR-T related NT. New grading tools are needed for this syndrome-specific AE. The CARTOX working group introduced a novel system for CAR-T Related Encephalopathy Syndrome (CRES), i.e. the CRES grading (Neelapu, Nat Rev Clin Oncol, 2017). To better understand CAR-T related NT and move towards harmonized toxicity reporting, this study retrospectively assessed concordance and variances between the CTCAE and a modified version of the CRES (mCRES) grading system among JULIET patients. Methods: Patient level data from case report forms collected for JULIET, a single-arm, open-label, multicenter, global phase 2 trial of tisagenlecleucel in adult patients with r/r DLBCL (NCT02445248) were used. Four medical experts with experience treating DLBCL patients with different CAR-T therapy products independently reviewed the data and definitions of NT proposed by the FDA using CTCAE and mCRES system. Patients were graded using these two systems; however, only NT attributable to CAR-T therapy were considered. For example, headache without temporal association or evidence of cognitive impairment was graded 0. The CARTOX group's CRES grading criteria were modified in this study since the CARTOX-10 questionnaire, a new tool to assess overall cognitive function, was not prospectively utilized. Hence, mCRES grades 1 and 2, distinguished by CARTOX-10 score, could not be distinctly defined and were assigned based upon investigator report of cognitive or attention dysfunction by CTCAE. Results were discussed and reconciled among all medical experts in a live meeting. As per the research group charter, the highest grading by any of the four experts would determine the final grading for an individual event. Graded results were also compared with those in the FDA label of tisagenlecleucel, in which NT was broadly defined as the occurrence of any CTCAE graded neurological or psychiatric AE (e.g., anxiety, dizziness, headache, peripheral neuropathy, and sleep disorder). Results: Among 111 patients infused with tisagenlecleucel (as of December 2017), 68 who had NT per FDA definition were graded. With the CTCAE grading system, the medical experts identified 50 (45%) patients as having experienced CAR-T related NT, including 34 with grade 1/2, 11 with grade 3, and 5 with grade 4; the mCRES system identified 19 (17%) patients, 5 of whom were grade 1/2, 6 were grade 3, and 8 were grade 4 (Figure 1). Among the subgroup of 64 patients who experienced CRS, the CTCAE and the mCRES systems identified 30 (47%) and 15 (23%) patients with any grade NT, respectively (grade ≥3: CTCAE vs. mCRES: 11 vs. 10). For 47 patients without CRS, the CTCAE and the mCRES systems identified 20 (43%) and 4 (9%) patients with NT, respectively (grade ≥3: 5 vs. 4; Table 1). These grades by medical experts also varied from those reported by FDA: among 106 patients receiving tisagenlecleucel (as of September 2017), 62 (58%) had NT including 19 (18%) with grade ≥3. Conclusions: This exploratory study is the first to retrospectively apply a modified version of the new CARTOX-CRES grading system for CAR-T related NT. Using data from JULIET patients, medical experts were able to achieve consensus NT grading using both the CTCAE and the mCRES grading systems. Using the mCRES system, 19 (17%) patients had any grade NT (5 with grade 1/2, 6 with grade 3, and 8 with grade 4) versus the CTCAE system, which identified 50 (45%) patients as having NT (34 with grade 1/2, 11 with grade 3, and 5 with grade 4). The differences between the two grading systems and the NT grading the FDA reported highlight how the same patient data can be represented variably on different scales and highlight the divergent focus of each system, where encephalopathy is the principal focus of CARTOX-10. These results raise an urgent need for broader consensus on a specific grading scale for CAR-T related NT. Disclosures Maziarz: Athersys, Inc.: Patents & Royalties; Kite Therapeutics: Honoraria; Juno Therapeutics: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schuster:Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Research Funding. Romanov:Novartis Pharmaceuticals Corporation: Employment. Rusch:Novartis Pharmaceuticals Corporation: Employment. Ericson:Novartis Pharmaceuticals Corporation: Employment. Maloney:Janssen Scientific Affairs: Honoraria; Juno Therapeutics: Research Funding; Roche/Genentech: Honoraria; Seattle Genetics: Honoraria; GlaxoSmithKline: Research Funding. Locke:Novartis Pharmaceuticals: Other: Scientific Advisor; Kite Pharma: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy.
27
Bennani, N. Nora, Matthew J. Maurer, Loretta J. Nastoupil, et al. "Experience with Axicabtagene Ciloleucel (Axi-cel) in Patients with Secondary CNS Involvement: Results from the US Lymphoma CAR T Consortium." Blood 134, Supplement_1 (2019): 763. http://dx.doi.org/10.1182/blood-2019-129097.
Full textAbstract:
Introduction: Axicabtagene Ciloleucel (axi-cel), a CD19 chimeric antigen receptor (CAR) T-cell therapy, was approved for the treatment of relapsed/refractory aggressive B-cell non-Hodgkin lymphoma in October, 2017. In the ZUMA-1 trial leading to axi-cel FDA approval, patients (pts) with prior or active secondary central nervous system (CNS) lymphoma involvement were excluded. A recent publication of 8 pts with secondary CNS lymphoma who underwent Tisagenlecleucel CAR T cell therapy was reported (Frigault M.J.2019). Since the two FDA approved CAR T cell products have a different neurotoxicity profile, understanding outcomes of axi-cel in this setting is important. We report here the real-world experience of 17 pts treated with axi-cel who had a history of secondary CNS involvement or had active CNS disease at time of CAR T infusion. Methods: Seventeen academic centers from the US Lymphoma CAR T Consortium contributed data independently from the manufacturer. Data regarding secondary CNS involvement, management, and outcome were obtained in addition to CAR T therapy outcome for pts who were identified as having active, secondary CNS involvement at the time of evaluation for CAR-T therapy. Nine centers reported data on 17 cases with CNS involvement. Follow-up data was missing for one pt in the CNS cohort. Lee criteria or the modified Lee grading scale were used for cytokine release syndrome (CRS). CTCAEv4 or CARTOX grading were used for immune effector cells associated neurotoxicity syndrome (ICANS). All leukapheresed pts were included in the intention to treat (ITT) analysis for response rate and event-free survival (EFS). EFS was defined as date of leukapheresis until progression or death due to any cause. EFS was evaluated using Kaplan Meier curves with log-rank test. Differences in clinical characteristics and response between CNS and non-CNS pts were not formally tested due to small sample size and multiple comparison concerns. Results: With a data cut-off of 4/30/2019, 300 pts underwent leukapheresis with intention to manufacture standard of care axi-cel. By the time of leukapheresis, 17 (6%) had secondary CNS involvement (4 parenchymal disease, 10 leptomeningeal/CSF, 3 data not available). Compared to the non-CNS cohort, baseline demographics were comparable (Panel A). Manufactured axi-cel was within specification for 100% of the CNS cohort. There was a higher rate of bridging therapy use in the CNS cohort 82% (1 steroids only, 2 radiation therapy, 12 systemic therapy) vs 52% in non-CNS cohort; p=0.022. Time from leukapheresis to CAR T infusion was 3.5 days longer in the CNS cohort as opposed to the non-CNS cohort: median time of 29.5 (range 20-76) vs. 26 days (range 5-67), (p=0.029), respectively. The CAR T infusion rate was 88% for the CNS cohort (15/17) compared to 93% (262/283) in the non-CNS cohort. Among the 15 infused pts in the CNS cohort, 10 had resolution of CNS involvement, and 5 had persistent active CNS disease at time of CAR T infusion. After axi-cel infusion, the incidence of CRS and ICANS, of any grade or grade 3 or higher, were comparable between the CNS and non-CNS cohorts. Tocilizumab and steroid use were comparable between the two groups (Panel B). No seizures or cerebral edema were noted in the CNS cohort. With a median follow-up of 10.1 months from leukapheresis (range 7.6-12.6), the ITT best overall response rates (CR+PR) and ongoing responses at month 6 between CNS and non-CNS cohorts were 75% vs. 59%, and 41% vs. 31%, respectively (Panel B). In the 5 pts with active CNS disease at time of CAR T infusion, the response of CNS disease were 2 CR, 1 PR and 2 PD as best response. In the 10 pts with resolved CNS disease at time of CAR T infusion, 2 PD were seen and both occurred systemically. EFS from leukapheresis was not statistically significantly different between CNS and non-CNS cohorts (6 months EFS: CNS cohort, 36%; non-CNS cohort 57%. HR=1.58, 95% CI: 0.83-3.01, p=0.16, Panel C). Six month EFS from the date of infusion for the CNS cohort was 49.9% (Panel D). Conclusions: Pts attempting CAR T therapy with secondary CNS disease in the real world setting had similar rates of CAR T infusion, toxicity, and outcomes when compared to patients without CNS disease. Small sample size and limited follow-up caution the strength of conclusions for application to clinical practice, but these results support further investigation of CAR T in pts with history of or active secondary CNS lymphoma. Figure Disclosures Bennani: Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board. Maurer:Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees. Nastoupil:Bayer: Honoraria; Spectrum: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Jain:Kite/Gilead: Consultancy. Chavez:Novartis: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: 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; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Cashen:Seattle Genetics: Other: Speaker's Bureau; Novartis: Other: Speaker's Bureau; Celgene: Other: Speaker's Bureau. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. McGuirk:Novartis: Research Funding; Fresenius Biotech: Research Funding; Astellas: Research Funding; Bellicum Pharmaceuticals: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Deol:Novartis: Other: Advisory board; Kite: Other: Advisory board; Agios: Other: Advisory board. Sehgal:Juno/Celgene: Research Funding; Merck: Research Funding; Kite/Gilead: Research Funding. Goy:COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Nebraska: Research Funding; Hakensackumc: Research Funding; Takeda: Other: Grants outside of the submitted work; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Genentech: Other: Grants outside of the submitted work, Research Funding; Hackensack University Medical Center, RCCA: Employment; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding. Hill:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Takeda: Research Funding; Amgen: Research Funding. Vu:Celgene: Other: Stock. Andreadis:Genentech: Equity Ownership, Other: Spouse is Employee; Novartis: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Gilead: Consultancy; Jazz Pharmaceuticals: Consultancy; Bayer: Consultancy. Munoz:Incyte: Research Funding; Portola: Research Funding; Celgene: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Fosunkite: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau. Vose:Acerta Pharma: Honoraria, Other: Grants, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; Kite Pharma: Honoraria, Other: Grants, Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; AbbVie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Legend Pharmaceuticals: Honoraria. Miklos:Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; Becton Dickinson: Research Funding; AlloGene: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Locke:Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy. Neelapu:Unum Therapeutics: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy; Incyte: Consultancy; Poseida: Research Funding; Allogene: Consultancy; Merck: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Karus: Research Funding; Precision Biosciences: Consultancy; Cell Medica: Consultancy; Acerta: Research Funding; Cellectis: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy. Lin:Novartis: Membership on an entity's Board of Directors or advisory committees; Juno: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; BlueBird Bio: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sorrento: Membership on an entity's Board of Directors or advisory committees.
28
Nastoupil, Loretta J., Michael D. Jain, Jay Y. Spiegel, et al. "Axicabtagene Ciloleucel (Axi-cel) CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma: Real World Experience." Blood 132, Supplement 1 (2018): 91. http://dx.doi.org/10.1182/blood-2018-99-114152.
Full textAbstract:
Abstract Introduction Axi-cel is an autologous anti-CD19 CAR T-cell therapy approved by the US FDA 10/18/2017, for the treatment of adults with relapsed or refractory (r/r) large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL), transformed lymphoma (tFL), and high-grade B-cell lymphoma (HGBCL) who have failed at least two prior systemic lines of therapy. In the pivotal ZUMA-1 trial, 108 patients (pts) with r/r DLBCL were treated with axi-cel: the best overall response rate (ORR) was 82% and complete response (CR) rate was 58%. At a median follow-up of 15.4 months, 42% of the pts had ongoing remission (Neelapu and Locke et al. NEJM 2017). Grade 3 or higher cytokine release syndrome (CRS) by Lee criteria and neurologic events (NEs) occurred in 13% and 31% of the pts, respectively. Here, we evaluated the real world outcomes of pts treated with standard of care axi-cel under the commercial FDA label. Methods and Results Seventeen US academic centers contributed data to this effort independently of the manufacturer. As of 6/30/2018, 211 pts were leukapheresed with intention to manufacture commercial axi-cel. Of these, 165 (78%) pts completed axi-cel infusion as of 6/30/18 and a further 23 (11%) pts are scheduled for axi-cel infusion in July 2018. Of the 23 remaining pts, 7 (3%) received axi-cel therapy on ZUMA-9 expanded access trial (NCT03153462) due to non-conforming cell therapy product, 15 (7%) pts died before axi-cel infusion (14 from lymphoma progression and 1 from sepsis) and 1 (1%) patient attained CR from bridging therapy and was not infused. Safety was evaluable in 163 pts receiving axi-cel. Grade ³3 CRS and NEs occurred in 7% and 31% of pts. Tocilizumab was administered in 62% of pts and 57% received corticosteroids. Outside of lymphoma progression, 3 deaths occurred post-axi-cel; 1 due to HLH, 1 due to systemic candidiasis, and a third due to septic shock. There were no grade 5 NEs observed. Response assessment was done for pts infused with axi-cel and who were re-staged at day 30 and/or day 100, or were deemed to have clinical progression. Of 112 pts evaluable at day 30, ORR was 79% with 50% CR, 29% PR, 6% SD and 14% with PD. Of 39 pts evaluable at day 100, 59% of pts had ongoing response (CR 49%, PR 10%). At the time of abstract submission, more detailed patient characteristics and treatment course data were available in 134/165 pts infused. Median age was 59 (range 21-82) with 57% male. Performance status (PS) was ECOG 0-1 (81%), ECOG 2 (16%) and ECOG 3 (3%). By histology, 61% of pts had DLBCL including HGBCL, 31% had tFL and 8% PMBCL. Thirty-one percent had a prior autologous stem cell transplant. Bridging therapy between apheresis and infusion was given in 56% of patients, the majority of which consisted of chemotherapy. Sixty-six of 134 (49%) would not have met eligibility criteria for ZUMA-1 at the time of leukapheresis. Common criteria that would have made these patients ineligible for ZUMA-1 included ECOG PS >1 (n = 22), platelets <75k (n = 17), GFR <60 (n =12), active DVT/PE (n = 13), liver enzyme abnormalities (n = 10), a history of CNS lymphoma (n = 8), recent checkpoint inhibitor therapy (n = 7), ejection fraction <50% (n = 4), prior CD19 CAR T therapy (n = 4), and prior allogeneic transplant (n=2). Median time from leukapheresis to start of conditioning chemotherapy was 21 days and median time from leukapheresis to axi-cel infusion was 26 days. Median hospitalization period was 14 days. Conclusions This multicenter retrospective study delineates the real world outcomes of axi-cel CAR T-cell therapy for r/r aggressive B-cell lymphoma when used as a standard of care. Though limited by relatively short follow up, 30 day responses in the real world setting are comparable to the best responses observed on the pivotal ZUMA-1 clinical trial (Table 1). Importantly, safety appears comparable to the ZUMA-1 trial despite nearly half the pts failing to meet ZUMA-1 eligibility criteria. Updated results including PFS and OS will be presented at the meeting. L.J.N. and M.D.J. contributed equally; D.B.M., S.S.N. and F.L.L. contributed equally. Disclosures Nastoupil: Merck: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; TG Therappeutics: Research Funding; Karus: Research Funding; Genentech: Honoraria, Research Funding; Janssen: Research Funding; Gilead: Honoraria; Juno: Honoraria; Novartis: Honoraria; Spectrum: Honoraria. Lunning:Celgene: Consultancy; Spectrum: Consultancy; Portola: Consultancy; Genzyme: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Kite: Consultancy; Juno: Consultancy; AbbVie: Consultancy; Astra-Zeneca: Consultancy; Genentech: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Bayer: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy. Reagan:Seattle Genetics: Research Funding. McGuirk:Gamida Cell: Research Funding; Astellas Pharma: Research Funding; Fresenius Biotech: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Other: speaker, Research Funding; Kite Pharma: Honoraria, Other: travel accommodations, expenses, speaker ; Pluristem Ltd: Research Funding. Deol:Novartis: Consultancy; Kite Pharmaceuticals: Consultancy. Hill:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Novartis: 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; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Andreadis:Gilead: Consultancy; Genentech: Consultancy, Employment; Astellas: Consultancy; Bayer: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy; Juno: Research Funding; Kite: Consultancy; Novartis: Consultancy, Research Funding. Munoz:Pfizer: Consultancy; Bayer: Consultancy, Speakers Bureau; Juno: Consultancy, Honoraria; Janssen: Consultancy; Genentech: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy; Pharmacyclics: Consultancy, Honoraria; Kite: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy; Gilead: Speakers Bureau. Westin:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Celgen: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees. Vose:Kite Pharma: Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding; Novartis: Honoraria, Research Funding; Roche: Honoraria; Seattle Genetics, Inc.: Research Funding; Legend Pharmaceuticals: Honoraria; Merck Sharp & Dohme Corp.: Research Funding; Abbvie: Honoraria; Epizyme: Honoraria; Bristol Myers Squibb: Research Funding; Incyte Corp.: Research Funding. Miklos:Genentech: Research Funding; Kite - Gilead: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pharmacyclics - Abbot: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding. Locke:Kite Pharma: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy; Novartis Pharmaceuticals: Other: Scientific Advisor.
29
Ratnasari, Eka, Wiryawan Permadi, and Dany Hilmanto. "E-MONITORING INTERAKTIF MENINGKATKAN REFLEKSI DIRI, MOTIVASI BELAJAR DAN HASIL BELAJAR MAHASISWA DIII KEBIDANAN." Care : Jurnal Ilmiah Ilmu Kesehatan 7, no. 3 (2019): 97. http://dx.doi.org/10.33366/jc.v7i3.1398.
Full textAbstract:
The proportion of practice in Midwifery education has 60% of capacity, more than the proportion of theories which is only 40%. The biggest proportion of practice makes the Clinical Advisor and Academic Advisor try to provide immediate feedback to students in every skill learned in the practice field. Interactive, effective and corrective feedback can help students to do self-reflection so while in the practice field students expected to be motivated to improve learning outcomes. The purpose of this study was to define the effect of Interactive E-Monitoring implementation on self-reflection, motivation and learning outcomes of the student.A research population of this study is students of midwifery diploma program in thirdh semester of 2018/2019 Akademic year who take part in second Laboratory Learning Practices, which are spread over in 13 of independent midwife practice fields (PMB). Samples were taken in based on inclusion criteria, students who were guided by PK that included in the criteria and in aged 19-20 years were 56 students. Data analyzed, if the data is normally distributed then it uses paired t test and if the data is not normally distributed then it uses the Wilcoxon Test.The results showed that students self-reflection increased from 74.9 to 80.5 (p
30
Frank, Matthew J., Nasheed Hossain, Ali Bukhari, et al. "Detectable Circulating Tumor DNA 28 Days after the CD19 CAR T-Cell Therapy, Axicabtagene Ciloleucel, Is Associated with Poor Outcomes in Patients with Diffuse Large B-Cell Lymphoma." Blood 134, Supplement_1 (2019): 884. http://dx.doi.org/10.1182/blood-2019-132057.
Full textAbstract:
Introduction: The autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, axicabtagene ciloleucel (Axi-cel) improved long-term survival of patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). Long-term analysis of the pivotal ZUMA-1 trial indicates a 2-year PFS of ~40% (Locke, Lancet Oncology 2018). Early identification of patients with increased relapse risk may allow for early intervention and improved outcomes. In a pilot study of 6 ZUMA-1 patients, minimal residual disease (MRD) evaluation via a next-generation sequencing MRD assay (Adaptive Biotechnologies, Seattle, WA) to assess for circulating tumor (ct)DNA, mirrored clinical outcome as assessed by PET-CT (Hossain et. al. Leukemia & Lymphoma 2019). Based on these promising results, a multi-institutional prospective study utilizing cell-free MRD assessments to predict outcomes in r/r DLBCL patients after Axi-cel therapy was initiated. Methods: To identify tumor clonotype(s), tumor DNA extracted from archival paraffin-embedded tissue underwent PCR amplification of IgH-VDJ, IgH-DJ and IgKappa/Lambda regions using universal consensus primers. CtDNA levels were measured pre-LD, 0, 7, 14, 21, 28, 56, 90, 180, 270, and 365 days following Axi-cel infusion. PET-CT scans were obtained at baseline, Day 28, Month 3, 6, and 12 with response assessed per Lugano criteria. Deauville 1-3 was considered PET-negative. The protocol prespecified that patients with less than Day 28 follow-up be excluded from analysis. Any detectable ctDNA was considered MRD positive. Results: Here we report on the pre-planned analysis of the first 50 study patients with at least a Day 28 MRD assessment and 3 months of follow up. An additional 4 patients with at least 3 months of follow-up but who did not have a Day 28 MRD assessment were also included. Baseline characteristics and clinical outcomes of patients were similar to ZUMA-1 and a real-world analysis of 295 patient who received Axi-cel (Nastoupil et al ASH 2018). The median age was 61 years old (range 19-76) (53.7% male, 46.3% female) and 59% of patients received 3 or more prior lines of therapy (range 1-6). After a median follow-up of 7.5 months, the best overall response rate was 87% (47 of 54) and complete response rate was 57% (31 of 54). The median OS was not reached and median PFS was 4.6 months (panel A). At Day 28, 56% (28 of 50) of patients were MRD negative (MRD-neg) and 44% (22 of 50) were MRD positive (MRD-pos). As compared to MRD-pos, MRD-neg correlated with improved median PFS (not reached vs. 2.96 months, p&lt;0.0001) and median OS (not reached vs.7.4 months, p=0.0005) (panels B and C). By PET assessment on Day 28, 46% (25 of 54) of patients were PET-negative (PET-neg) and 54% (28 of 54) were PET-positive (PET-pos). When compared to PET-pos patients, PET-neg patients demonstrated an improved median PFS (not reached vs. 3.1 months, p=0.0007) and median OS (both not reached, p=0.0096). MRD and PET-CT on Day 28 were able to identify patients relapsed by 6 months with similar sensitivity, 71% (95% CI: 48-89%) and 77% (95% CI: 55% to 92%), respectively. However, Day 28 MRD status had improved specificity as compared to Day 28 PET status, 94% (95% CI: 71% to 99%) versus 63% (95% CI: 38% to 83%). Day 28 MRD assessment was particularly helpful in identifying high-risk patients in the Day 28 PET-pos subgroups of patients with a PR (n=20) or SD (n=3) (panel D). This subgroup of patients with MRD-pos (n=13) had an inferior median PFS compared to those who were MRD-neg (n=10) (3.1 months vs. not reached, p=0.0033). Of note, one MRD-neg patient died without disease at 4.5 months. After excluding those (n=4) with progressive disease on Day 28 (all MRD-pos), 72% (16 of 22) of patients were MRD-pos at least 2 months prior to radiographic progression and 86% (19 of 22) were MRD-pos at least 1 month prior to radiographic progression. Conclusion: MRD monitoring using high-throughput sequencing of ctDNA has the potentially to make an impact on the clinical management of patients undergoing Axi-cel therapy. Furthermore, ctDNA is an informative tool to compare CAR19 therapies that vary by costimulatory domains or production methods. This technology potentially overcomes fundamental limitations of DLBCL imaging (cost, radiation exposure & limited repetition) and may minimize the need for surveillance PET-CT scans. These results provide a rationale for designing MRD-based risk-adaptive CAR T cell clinical trials. Figure Disclosures Kirsch: Adaptive Biotechnologies: Employment. Jacob:Adaptive Biotechnologies: Employment, Other: shareholder. Mullins:Adaptive Biotechnologies: Employment. Lee:Adaptive Biotechnologies: Employment, Equity Ownership. Mackall:Obsidian: Research Funding; Lyell: Consultancy, Equity Ownership, Other: Founder, Research Funding; Nektar: Other: Scientific Advisory Board; PACT: Other: Scientific Advisory Board; Bryologyx: Other: Scientific Advisory Board; Vor: Other: Scientific Advisory Board; Roche: Other: Scientific Advisory Board; Adaptimmune LLC: Other: Scientific Advisory Board; Glaxo-Smith-Kline: Other: Scientific Advisory Board; Allogene: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Locke:Cellular BioMedicine Group Inc.: Consultancy; Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor. Miklos:Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; AlloGene: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; Becton Dickinson: Research Funding.
31
Groll, Andreas H., Hisham Abdel-Azim, Thomas Lehrnbecher, et al. "Safety, Tolerability, and Pharmacokinetics (PK) of Posaconazole (POS) Intravenous (IV) Solution and Oral Powder for Suspension in Children With Neutropenia." Open Forum Infectious Diseases 4, suppl_1 (2017): S296. http://dx.doi.org/10.1093/ofid/ofx163.681.
Full textAbstract:
Abstract Background POS, a triazole antifungal approved for prophylaxis and treatment of adults with invasive fungal infections, is available as an IV solution and 2 oral formulations: an oral suspension and a tablet with improved bioavailability. A novel powder for oral suspension (PFS) has been developed to offer the bioavailability of the tablet in a formulation optimized for weight-based dosing in children. The objective of this study is to evaluate the safety, tolerability, and PK of POS IV and POS PFS in pediatric patients (patients) aged 2 to 17 y with documented or expected neutropenia. Methods This is an ongoing, nonrandomized, multicenter, open-label, sequential dose-escalation study evaluating POS IV and POS PFS. Pts are divided into 2 age groups: 2 to &lt;7 and 7 to 17 y. Each age group includes 2 dose cohorts: 3.5 mg/kg/d and 4.5 mg/kg/d. Patients received 10–28 d of POS initially as IV solution with the option to switch to PFS after 10 d for the remainder of the treatment period. PK sampling was conducted after 7–10 days on each formulation. Target PK exposure was ~90% of patients with Cavg 500–2,500 ng/mL. Cavg is defined as AUC over a dosing interval. Results 57 of 66 patients (86%) who received POS IV were PK evaluable; 35 patients (53%) received POS PFS, of whom 30 (86%) were PK evaluable. Table 1 shows Cavg and proportion in target range of PK-evaluable patients by dose cohort and age group. The safety profiles of POS IV and PFS were similar to those previously reported for adults treated with oral/IV POS. Conclusion POS PFS resulted in lower POS exposure than IV across age groups at both dose levels. POS exposure was substantially lower in the younger age group for both IV and PFS. At 4.5 mg/kg, the patients in this study achieved the predefined target but did not achieve systemic exposures (mean Cavg) comparable to those seen in adults with POS IV or tablet. These results suggest that study of POS IV and PFS dosing &gt;4.5 mg/kg/d is warranted. Disclosures A. H. Groll, Merck Sharp & Dohme: Consultant, Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee and Speaker honorarium. T. Lehrnbecher, Merck/MSD: Scientific Advisor and Speaker’s Bureau, Speaker honorarium. Astellas: Scientific Advisor and Speaker’s Bureau, Speaker honorarium. Basilea: Scientific Advisor, Consulting fee. Gilead: Investigator, Scientific Advisor and Speaker’s Bureau, Research grant and Speaker honorarium.Pfizer: Speaker’s Bureau, Speaker honorarium. W. Steinbach, Merck: Consultant, Consulting fee. Astellas: Consultant, Consulting fee. Gilead: Consultant, Consulting fee. R. Murray, Merck: Employee, Salary. A. Paschke, Merck: Employee, Salary. E. Mangin, Merck: Employee, Salary. G. A. Winchell, Merck: Research Contractor, Consulting fee. C. J. Bruno, Merck: Employee and Shareholder, Salary and Stock.
32
Mills, Anthony, Elizabeth A. Martin, Chih-Chin Liu, Martine Drolet, and Peter Sklar. "1011. Efficacy and Safety of Doravirine in Treatment-Naïve Adults ≥50 Years Old With HIV-1." Open Forum Infectious Diseases 7, Supplement_1 (2020): S533—S534. http://dx.doi.org/10.1093/ofid/ofaa439.1197.
Full textAbstract:
Abstract Background Nearly 50% of people living with HIV in the US are ≥50 years old. Older people are more likely to have late-stage HIV infection at diagnosis, greater risk for cardiovascular disease and certain cancers, and concurrent medications for common age-related conditions. Doravirine (DOR) is a next-generation NNRTI with activity against first-generation NNRTI-associated mutations, a neutral impact on lipids, and few drug-drug interactions with commonly used medications. Methods We compared Week 96 results from DOR Phase 2 and Phase 3 trials (P007, P018, and P021) in treatment-naïve adults ≥50 vs &lt; 50 years old. 855 participants received DOR 100mg +2 NRTIs in P007 & P018 or fixed combination DOR/3TC/TDF in P021; 383 participants received ritonavir-boosted darunavir (DRV) +2 NRTIs in P018; and 472 received efavirenz (EFV) 600mg +FTC/TDF in P007 or fixed combination EFV/FTC/TDF in P021. Participants who took ≥1 dose of study drug were included; the Observed Failure approach was used for missing efficacy data. All analyses were done by descriptive statistics. Results Of 1710 participants, 187 (11%) were 50-70 (median 54) years old at study entry. Baseline characteristics and treatment outcomes are summarized below for participants &lt; 50 vs ≥50 years old. The older cohort had more women, more participants with AIDS, and lower median CD4+ T-cell counts than the younger cohort, whereas baseline HIV-1 RNA was similar between age cohorts. Hypertension and use of analgesics were more common in older participants. In each treatment group, the older cohort had a higher proportion of participants with HIV-1 RNA&lt; 50 copies/mL at week 96 and fewer discontinuations due to lack of efficacy than the younger cohort. Mean change in CD4+ T-cell count was similar between age cohorts in the DOR and DRV groups and was lower for older participants in the EFV group. Rates of drug-related AEs and serious drug-related AEs were similar between age cohorts across all treatment groups. Discontinuations due to drug-related AEs were similar between age cohorts in the DOR group and were slightly higher for older participants in the DRV and EFV groups. Conclusion DOR is a beneficial option for adults ≥50 years old, given its similar efficacy and favorable safety profile compared to younger adults. Doravirine Phase 2 and Phase 3 Trials in Treatment-Naïve Adults Disclosures Anthony Mills, MD, Gilead (Grant/Research Support, Advisor or Review Panel member)Janssen Pharmaceutica (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Shionogi (Grant/Research Support)ViiV Healthcare (Grant/Research Support, Advisor or Review Panel member) Elizabeth A. Martin, DO, MPH, MBA, Merck & Co., Inc. (Employee) Chih-Chin Liu, PhD, Merck & Co., Inc. (Employee) Martine Drolet, BPharm, LPH, MBA, Merck & Co., Inc. (Employee) Peter Sklar, MD, MPH, Merck & Co., Inc. (Employee)
33
Ison, Michael G., Simon Portsmouth, Yuki Yoshida, Takao Shishido, Frederick Hayden, and Takeki Uehara. "LB16. Phase 3 Trial of Baloxavir Marboxil in High-Risk Influenza Patients (CAPSTONE-2 Study)." Open Forum Infectious Diseases 5, suppl_1 (2018): S764—S765. http://dx.doi.org/10.1093/ofid/ofy229.2190.
Full textAbstract:
Abstract Background Baloxavir marboxil (BXM), an oral selective cap-dependent endonuclease inhibitor, is effective and safe for treating acute influenza in otherwise healthy patients. Method We conducted an international, randomized, double-blind, placebo (PLC)- and oseltamivir (Os)-controlled treatment study in patients at higher risk (HR) of influenza complications. Inclusion criteria included age ≥12 years, fever + influenza symptoms of ≤48 hours duration, and presence of at least 1 HR factor adapted from CDC criteria. Patients were randomized (1:1:1) to a single oral dose of BXM (40/80 mg for BW &lt;/≥80 kg), PLC, or 75 mg Os BID for 5 days. The primary endpoint was time to improvement of influenza symptoms (TTIIS) in those with RT-PCR confirmed influenza (ITTI population). Secondary endpoints included infectious virus detection in serial nasopharyngeal swabs, prescription of antibiotics, and influenza-related complications. Result Among 2,184 randomized patients, 1,163(53%) comprised the ITTI population (47.9% A/H3N2, 6.9% A/H1N1, 41.6% B). The most common risk factors were asthma or chronic lung disease (39.2%) and age ≥65 years (27.4%). TTIIS was significantly shorter in BXM than PLC (median 73.2 hours vs. 102.3 hours, P &lt; 0.0001) and numerically shorter than Os (81.0 hours, P = 0.8347). TTIIS in BXM patients with A/H3N2 virus (median: 75.4 hours) was significantly shorter than in PLC (100.4 hours; P =0.0141) and was significantly shorter in patients with influenza B (74.6 hours) than in either PLC (100.6 hours; P = 0.0138) or Os (101.6 hours; P = 0.0251). Median time to cessation of viral shedding in BXM patients was 48 hours, significantly less than 96 hours in both PLC and Os patients. Systemic antibiotic use and influenza-related complications were significantly fewer in BXM (3.4% and 2.8%, resp.) than PLC (7.5% and 10.4%; P = 0.0112, and P &lt; 0.0001). The incidence of any (25.1–29.7%) or serious adverse events (0.7–1.2%) did not differ significantly across the groups. Conclusion BXM was well-tolerated and associated with faster recovery and reduced risk of complications in HR influenza patients compared with PLC. It proved superior to Os in shortening the duration of virus replication and in resolving influenza B illness. Oral BXM is a promising treatment option for patients with risk factors for influenza complications. Disclosures M. G. Ison, Romark: Investigator, Research support. Shionogi: Scientific Advisor, Paid DSMB Member. Emergent BioScience: Investigator, Research support. Janssen: Investigator and Scientific Advisor, Consulting fee and Research support. GlaxoSmithKlein: Scientific Advisor, Paid DSMB Member. VirBio: Consultant, Consulting fee. Seqirus: Consultant, Consulting fee. S. Portsmouth, Shionogi Inc.: Employee, Salary. Y. Yoshida, Shionogi & Co., Ltd.: Employee, Salary. T. Shishido, Shionogi & Co., Ltd.: Employee, Salary. F. Hayden, Shionogi & Co., Ltd.: Scientific Advisor, Consulting fee (donated) and travel support for attending 6th ESWI meeting, 10–13 September 2017, Latvia, to present phase 3 OWH results. .T. Uehara, Shionogi & Co., Ltd.: Employee, Salary.
34
Zamora, Danniel, Elizabeth Duke, Hu Xie, et al. "194. Combinatorial Polyfunctionality Analysis of Antigen-specific T-cell Subsets (COMPASS) as a Predictor for Clinically Significant CMV Infection in the Letermovir Era." Open Forum Infectious Diseases 7, Supplement_1 (2020): S225—S226. http://dx.doi.org/10.1093/ofid/ofaa439.504.
Full textAbstract:
Abstract Background Increased CMV reactivation is observed following discontinuation of letermovir prophylaxis after hematopoietic cellular transplantation (HCT) and decreased CMV-specific polyfunctional T-cell immunity has been proposed as a possible mechanism (BBMT 2020;26:S68). COMPASS is a novel analytical tool that integrates polyfunctional T-cell cytokine responses into a single score value (Nat Biotechnol 2015;33:610). We employed COMPASS for the first time in the HCT setting to determine if CMV-specific immunodeficiency is associated with late CMV events in a prospective cohort of allogeneic HCT recipients receiving either letermovir or preemptive therapy. Methods Peripheral blood mononuclear cells were collected 3 months post-HCT and assessed with a 13-color intracellular cytokine staining (ICS) assay that includes 5 functional markers. Intermediate early-1 (IE-1) antigen and phosphoprotein 65 (pp65) were used to stimulate polyfunctional T-cell responses that were defined using COMPASS generated polyfunctionality scores (PFS). CMV DNAemia was monitored by weekly plasma PCR and patients who reactivated were treated with preemptive therapy per institutional standards. Cumulative incidence of clinically significant CMV infection (cs-CMV; ≥500 IU/mL or CMV disease) by day 270 was assessed. Univariable and multivariable Cox regression were used to estimate the association of polyfunctional T-cell responses (upper quartile versus lower 3 quartiles) with cs-CMV infection by day 270 post-HCT. Results 56 letermovir recipients and 93 preemptive controls were evaluated. Time to first clinically significant CMV (cs-CMV) infection after HCT and among day 100 survivors in both groups is shown in Figure 1. COMPASS PFS at 3 months were significantly lower in letermovir recipients (Figure 2). After adjusting for CMV infection before day 100, CD4 and CD8 PFS to IE-1 and pp65 below the upper quartile were associated with higher risk of late cs-CMV infection, with IE-1 CD8 PFS reaching statistical significance (Figure 3). Conclusion Our findings demonstrate that COMPASS is a valuable tool to evaluate multiple, T-cell cytokine responses to CMV in HCT recipients. COMPASS appears to be useful to identify patients at risk for late cs-CMV infection. Disclosures Elizabeth Duke, MD, Merck (Grant/Research Support) Michael Boeckh, MD PhD, AlloVir (Consultant)EvrysBio (Advisor or Review Panel member, Other Financial or Material Support, share options)Gilead (Consultant, Grant/Research Support)GSK (Consultant)Helocyte (Advisor or Review Panel member, Shareholder)Lophius (Grant/Research Support)Merck (Consultant, Grant/Research Support)SymBio (Consultant)VirBio (Consultant, Grant/Research Support)
35
Jackson, Edward, Piyali Chatterjee, Susan Smith, Karen Badal, and David E. Griffith. "1330. Diagnosis and Management of NTM Lung Disease: Effect of Online Educational Interventions on Infectious Disease Specialist Knowledge." Open Forum Infectious Diseases 5, suppl_1 (2018): S406. http://dx.doi.org/10.1093/ofid/ofy210.1163.
Full textAbstract:
Abstract Background Diagnosis and management of nontuberculous mycobacterial (NTM) lung disease is challenging for clinicians due to its rarity and the need for complicated, multidrug antibiotic regimens. The objective of this study was to determine whether online educational interventions can effectively address knowledge gaps among ID specialists regarding diagnosis and treatment of patients with NTM lung disease. Methods Two educational interventions, consisting of a text-based activity with interactive questions, and a video-based discussion between two experts, were developed and made available online. Educational impact of each intervention was assessed using a 3-question repeated pairs pre-/post-assessment study design. Data from a sampling of learners were collected from September 11, 2017 through January 17, 2018. Statistical analyses included a paired (within-physician) two-tailed t-test and McNemar’s χ2 statistic, with Cramer’s V to determine the overall effect of each intervention. Results Overall, a total of 1,273 ID specialist learners participated in the two activities from launch through April 30, 2018. Analysis demonstrated a significant improvement (P &lt; 0.05) in overall knowledge with considerable educational impact (V = 0.195 and 0.259). Improvements in specific areas included (figure). Despite gains in knowledge, additional gaps were also identified: (1) Regarding treatment of M. abscessus lung disease, 18% were unable to discern between guideline recommended therapies for M. abscessus and MAC complex NTM, and an additional 14% would treat with a less aggressive, noncurative regimen (n = 211), and (2) regarding treatment of fibrocavitary MAC complex NTM; nearly one-third (31%) would treat a using a thrice-weekly regimen, despite an indication for a daily regimen (n = 114). Conclusion Participation in interactive text-based as well as video-based activities improved the ability of ID specialists to make evidence-based decisions in the care of NTM lung disease. The findings also uncovered educational needs that warrant further education in selecting appropriate therapeutic regimens particularly in cases where aggressive therapy is indicated. Disclosures E. Jackson, Medscape: Employee, Salary. P. Chatterjee, Medscape: Employee, Salary. S. Smith, BioFire Diagnostics: Independent Medical Education, Educational grant. K. Badal, Medscape: Employee, Salary. D. E. Griffith, Aradigm Corporation: Advisor/consultant and Speaker’s Bureau, Consulting fee and Speaker honorarium. Bayer Healthcare Pharmaceuticals: Advisor/consultant, Consulting fee. Grifols: Advisor/consultant and Speaker’s Bureau, Consulting fee and Speaker honorarium. Insmed Incorporated: Advisor/consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Grant recipient and Speaker honorarium.
36
Jain, Michael D., Hua Zhao, Reginald Atkins, et al. "Tumor Inflammation and Myeloid Derived Suppressor Cells Reduce the Efficacy of CD19 CAR T Cell Therapy in Lymphoma." Blood 134, Supplement_1 (2019): 2885. http://dx.doi.org/10.1182/blood-2019-131041.
Full textAbstract:
Introduction: Approximately 60% of Large B cell Lymphoma (LBCL) patients that receive CD19 CAR T cell therapy with axicabtagene ciloleucel (axi-cel) experience lymphoma progression (Locke et al. Lancet Oncol. 2019) and the likelihood of response to subsequent therapy is low (Spiegel, Dahiya et al. ASCO 2019). Target loss of CD19 is observed in less than a third of patients experiencing relapse. Alternative mechanisms of resistance to axi-cel are poorly understood. Lymphoma patients with elevated serum markers of systemic inflammation, such as ferritin and IL-6, have worse outcomes following axi-cel (Locke, Neelapu et al. Mol.Ther.2017; Faramand et al. ASH 2018). We hypothesized that suppressive monocytic myeloid derived suppressor cells (M-MDSCs), which are associated with worse chemotherapy outcomes in LBCL (Azzaoui et al. Blood 2016), and tumor driven inflammation may be present and responsible for decreased efficacy of axi-cel in LBCL. Methods: LBCL patients undergoing axi-cel treatment were enrolled onto prospective sample collection protocols. Patients were stratified for analysis into ongoing responders (complete response or partial response) or relapsed (progressive disease) after a minimum of 3 months follow-up (range 3 - 15 months). M-MDSCs, defined as a Lin-, CD11b+, CD33+, CD15-, CD14+, HLA-DRlow population, were sorted from leftover apheresis material after collection for axi-cel manufacture. M-MDSC ability to suppress proliferation of autologous T cells stimulated with CD3/CD28 coated beads was measured by 3H thymidine incorporation. Circulating peripheral blood M-MDSCs, quantified by % of live cells by flow cytometry, were measured at the time of apheresis and serially after axi-cel infusion until day 30. In vitro mouse experiments utilized a CD19-CD28 CAR and cytokine-induced bone marrow MDSCs (Thevenot et al. Immunity 2014). Cytokines were measured by ELISA and cytotoxicity against CD19 bearing cell lines used xCELLigence real-time cell analysis, as we have done previously (Li et al. JCI Insight 2018).Tumor biopsies were taken within 1 month prior to infusion of axi-cel. Limited gene expression profiling of tumor microenvironment (TME) genes used the Nanostring IO360 panel (770 genes). Analysis used nSolver to identify cell types, GSEA and differential gene expression between groups. Results: First, we demonstrated that M-MDSCs sorted from patient apheresis material suppressed the proliferation of autologous T cells (n=6). We next enumerated M-MDSCs in the peripheral blood (n = 32). M-MDSC numbers initially decreased after lymphodepleting chemotherapy but recovered to baseline levels by day +10. The level of M-MDSCs following CAR T cell therapy strongly correlated with pre-CAR T baseline levels (R = 0.871, p <0.0001), suggesting that the number of M-MDSCs present during CAR T cell expansion is dependent on factors already present before therapy began. M-MDSC levels were significantly higher in patients who subsequently relapsed, both at baseline (p= 0.01) and after axi-cel (p=0.04), as compared to patients with durable response. Mouse MDSCs were able to suppress CAR T cell IFN-gamma excretion (p<0.0001) and cytotoxicity (p<0.0001) in vitro. To evaluate the role of the TME we interrogated limited set gene expression profiling on patient (n=27) pre-axi-cel tumor biopsies. By cell type scoring, the macrophage gene score was significantly higher in patients who relapsed after CAR T therapy (p <0.001). By differential gene expression and gene set enrichment, patients who relapsed had a significantly higher expression (p <0.01) of multiple genes indicative of chronic interferon (IFN) signaling including higher levels of OAS2, OAS3, IFI6 and IFIT1, as well as the IFN-stimulated macrophage gene SIGLEC-1/CD169. Conclusions: Systemic inflammatory myeloid cytokines, circulating M-MDSCs in the blood and chronic IFN in the TME all associate with LBCL relapse after axi-cel CAR T cell therapy. Our observations support that CAR T cells can be suppressed by baseline patient and tumor-related factors and strategies to overcome these factors should be targeted to improve patient outcomes. MDJ and HZ contributed equally. Disclosures Jain: Kite/Gilead: Consultancy. Bachmeier:Kite/Gilead: Speakers Bureau. Chavez:Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals, Inc.: Speakers Bureau. Shah:Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Kite/Gilead: Honoraria; Celgene/Juno: Honoraria; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; AstraZeneca: Honoraria. Mullinax:Iovance: Research Funding. Davila:Celgene: Research Funding; GlaxoSmithKline: Consultancy; Precision Biosciences: Consultancy; Novartis: Research Funding; Atara: Research Funding; Bellicum: Consultancy; Adaptive: Consultancy; Anixa: Consultancy. Locke:Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy.
37
Jacobs, Miriam T., Michael D. Jain, Jay Y. Spiegel, et al. "Characteristics and Outcomes of Patients Who Did Not Develop CRS after Axicabtagene Ciloleucel for Relapsed/Refractory Large B-Cell Lymphoma: Results from the US Lymphoma CAR-T Consortium." Blood 134, Supplement_1 (2019): 1583. http://dx.doi.org/10.1182/blood-2019-131168.
Full textAbstract:
M.T.J. and M.D.J. contributed equally; A.G. and F.L.L. contributed equally. Introduction Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 CAR T-cell therapy that is approved for the treatment of adults with relapsed or refractory large B-cell lymphoma (LBCL) who have failed at least two prior systemic lines of therapy. In the ZUMA-1 trial that led to axi-cel approval, 93% of patients developed cytokine release syndrome (CRS) (Neelapu, Locke et al. NEJM 2018). CRS is a non-antigen-specific toxicity that occurs as a result of CAR T and bystander immune cell activation. Whether lack of development of CRS after treatment with axi-cel is associated with inferior lymphoma outcomes is unknown. Here we evaluate the outcomes of patients that did not develop CRS after receiving axi-cel in a large multicenter cohort. Methods and Results The US Lymphoma CAR T Consortium includes seventeen US academic centers that contribute data independently of manufacturers. As of 8/31/2018, 300 patients were apheresed with intent to manufacture standard of care axi-cel for LBCL. In this study, we analyzed the modified intent-to-treat (mITT) population of 276 patients receiving CAR T infusion with a median follow up of 9 months. In this group, 25 patients (9%) did not develop CRS and 251 patients (91%) developed CRS following axi-cel infusion. CRS was graded according to Lee criteria (Lee et al. Blood 2014) or CARTOX (Neelapu SS et al. Nat Rev Clin Oncol. 2018). At baseline, a higher proportion of patients in the no CRS group had ECOG score of 0-1 (no CRS group 100% vs. CRS group 82%, p= 0.019) and IPI score of 0-2 (no CRS group 72% vs. CRS group 46%, p = 0.019) After CAR T cell infusion, patients who did not develop CRS had a lower chance of developing grade 3 or higher neurotoxicity (no CRS group 4% vs. CRS group 35%, p=0.001), lower rates of ICU admission (no CRS group 8% vs. CRS group 35%, p = 0.006), and shorter length of hospital stay (median 10 days for no CRS group vs 14 days for CRS group, p &lt; 0.001). Of the 25 patients who had grade 0 CRS, 23 (92%%) also had grade 0 neurotoxicity. In univariate analysis, no CRS was associated with lower complete response (CR) rate (no CRS group 40% vs. CRS group 66%, p=0.015) but no statistically significant difference in overall response rate (ORR) (no CRS group 72% vs. CRS group 84%, p= 0.158). In relation to CRS there was no difference in treatment related mortality among the two groups (CRS group 4% vs. no CRS group 4.4%, p = 0.85). In multivariate analysis correcting for confounding features, no CRS was associated with statistically significant lower complete response rate (p = 0.002), but there was no significant difference in ORR (p = 0.13), overall survival (P=0.15), progression free survival (P=0.16), and time to progression (P= 0.14) between the two groups (figure 1.). Conclusions In this large cohort of LBCL patients receiving axi-cel with median follow up of 9 months, patients that did not develop CRS, compared with those that developed CRS, achieved lower rates of complete response but there was no difference in overall response rate, progression free survival, time to progression, overall survival, and treatment related mortality between the two groups. Disclosures Jain: Kite/Gilead: Consultancy. Nastoupil:Bayer: Honoraria; TG Therapeutics: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; Spectrum: Honoraria. Lunning:Spectrum: Consultancy; Seattle Genetics: Consultancy; Portola: Consultancy; OncLive: Consultancy; Novartis: Consultancy; Kite: Consultancy; Gilead Sciences, Inc.: Consultancy; DAVA: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; TG Therapeutics: Consultancy, Research Funding; MiRagen: Research Funding; Juno Therapeutics: Consultancy, Research Funding; Janssen Scientific Affairs, LLC: Consultancy, Research Funding; Curis: Research Funding; VANIUM: Consultancy; Verastem: Consultancy. Reagan:Kite, A Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Oluwole:Pfizer: Consultancy; Spectrum: Consultancy; Gilead Sciences: Consultancy; Bayer: Consultancy. McGuirk:Novartis: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum Pharmaceuticals: Research Funding; Fresenius Biotech: Research Funding; Astellas: Research Funding. Deol:Agios: Other: Advisory board; Novartis: Other: Advisory board; Kite: Other: Advisory board. Sehgal:Juno/Celgene: Research Funding; Merck: Research Funding; Kite/Gilead: Research Funding. Goy:Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; University of Nebraska: Research Funding; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hakensackumc: Research Funding; Hackensack University Medical Center, RCCA: Employment; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; Takeda: Other: Grants outside of the submitted work; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Genentech: Other: Grants outside of the submitted work, Research Funding. Hill:Kite: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celegene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Research Funding; TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding. Andreadis:Juno: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Roche: Equity Ownership; Jazz Pharmaceuticals: Consultancy; Kite: Consultancy; Gilead: Consultancy; Genentech: Consultancy, Employment; Pharmacyclics: Research Funding; Merck: Research Funding. Munoz:Incyte: Research Funding; Portola: Research Funding; AstraZeneca: Speakers Bureau; Fosunkite: Speakers Bureau; Pfizer: Consultancy; Alexion: Consultancy; Bristol-Myers Squibb: Consultancy; Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau. Chavez:Janssen Pharmaceuticals, Inc.: Speakers Bureau; Genentech: Speakers Bureau; Kite Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Bennani:Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Purdue Pharma: Other: Advisory board. Vose:Acerta Pharma: Honoraria, Other: Grants, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; Kite Pharma: Honoraria, Other: Grants, Research Funding; Novartis: Research Funding; Seattle Genetics: Research Funding; AbbVie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Legend Pharmaceuticals: Honoraria. Miklos:Becton Dickinson: Research Funding; Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; AlloGene: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Neelapu:Poseida: Research Funding; Cellectis: Research Funding; Precision Biosciences: Consultancy; Cell Medica: Consultancy; Novartis: Consultancy; Incyte: Consultancy; Celgene: Consultancy, Research Funding; Allogene: Consultancy; Acerta: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; BMS: Research Funding; Merck: Consultancy, Research Funding; Karus: Research Funding. Ghobadi:Wugen: Consultancy; Celgene: Consultancy; EUSA: Consultancy; Kite Pharma a Gilead Company: Consultancy, Research Funding, Speakers Bureau. Locke:Novartis: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy; Kite: Other: Scientific Advisor.
38
Schuster, Stephen J., Richard T. Maziarz, Solveig G. Ericson, et al. "Consensus Grading of Cytokine Release Syndrome (CRS) in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (r/r DLBCL) Treated with Tisagenlecleucel on the JULIET Study." Blood 132, Supplement 1 (2018): 4190. http://dx.doi.org/10.1182/blood-2018-99-113052.
Full textAbstract:
Abstract Introduction: Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy achieves rapid and durable responses in patients with r/r DLBCL, although unique potential toxicities require specialized management. Cytokine release syndrome (CRS) is the most commonly observed adverse event of special interest associated with CAR T-cell therapy. Two CRS grading scales have been used in different clinical trials of CAR T-cell therapy: the Penn scale (Porter, Sci Transl Med, 2015; Porter, J Hematol & Oncol, 2018) and the Lee scale (Lee, Blood, 2014; Neelapu, Nat Rev Clin Oncol, 2017). To better inform management of CRS and develop best practices, we assessed concordance and differences between the two scales by using the Lee scale to regrade observed CRS events in r/r DLBCL patients treated with tisagenlecleucel, who were previously graded per protocol using the Penn scale. Methods: Individual patient level data from the JULIET trial, a single-arm, open-label, multicenter, global phase 2 trial of tisagenlecleucel in adult patients with r/r DLBCL (NCT02445248), were used in this study. Four medical experts who had managed DLBCL patients using different CAR T-cell therapy protocols and products independently reviewed the data, while blinded to the original Penn grading, and re-graded CRS for JULIET patients using the Lee scale. Re-grading assessments and disagreements in the assigned Lee grade were discussed and reconciled among reviewers during a live meeting. As per the investigational charter, the most conservative final assessment of any expert reviewer determined the final grading for any individual case. For example, if an event was graded as 2, 3, 3 and 4, then grade 4 would be the final grading. Results: As of December. 8, 2017, 111 patients with r/r DLBCL were infused with tisagenlecleucel in the JULIET trial. Sixty-four (58%) patients had CRS graded according to the Penn scale and each case was re-graded using the Lee scale based on JULIET data collected prospectively (e.g., CRS-related symptoms, oxygen supplementation, intervention for hypotension, and organ toxicities). Using the Lee scale, 63 (57%) patients were considered to have any grade CRS by investigators, including grade 1 events in 26 (23%), grade 2 in 18 (16%), grade 3 in 10 (9%), and grade 4 in 9 (8%) (Figure 1). One patient with grade 1 per Penn scale was re-graded to grade 0 due to absence of documented fever or symptoms requiring intervention. Compared to Penn grades, the Lee scale provided the same grade for 39 patients, a lower grade for 20 patients, and a higher grade for 5 patients. Among 64 patients re-graded, 59 (92%) had fever, 27 (42%) had oxygen supplementation (3 with grade 1, 6 grade 2, 9 grade 3, and 9 grade 4 per Lee scale) and 7 (11%) had concurrent infections. Of 29 (45%) patients requiring intervention for hypotension (13 with grade 2, 7 grade 3, and 9 grade 4 per Lee scale), 28 had fluid resuscitation and 10 received high dose/combination vasopressors. In addition, 8 of 9 patients re-graded as Lee grade 4 were intubated. As for anti-cytokine therapy, only 17 patients received tocilizumab (1 for grade 1, 2 for grade 2, 5 for grade 3, and 9 for grade 4 CRS per Lee scale) and 12 patients received corticosteroids (2 for grade 2, 1 for grade 3, and 9 for grade 4 CRS per Lee scale). Conclusions: Different CAR-T studies in DLBCL patients have used different approaches (Lee and Penn scales) for grading CRS and had different thresholds for tocilizumab treatment of CRS. Harmonization of grading CRS between studies permits a more accurate comparison of observations and outcomes. In this analysis, patients with r/r DLBCL receiving tisagenlecleucel in the JULIET trial, which used the Penn scale to grade CRS, were re-graded by expert consensus using the Lee scale. Using the Lee scale, more patients were categorized as grade 1 (Lee vs. Penn: 26 vs. 17), fewer patients as grades 2 and 3 (18 vs. 23, and 10 vs. 15, respectively), and the same number of patients as grade 4 (9 vs. 9) compared to the Penn scale. The re-grading of the JULIET CRS data using the Lee scale makes it possible to perform comparative analyses of CRS outcomes from clinical trials using different CAR-T products and could be used to develop best practice guidelines. Disclosures Schuster: Pfizer: Membership on an entity's Board of Directors or advisory committees; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; OncLive: Honoraria; Genentech: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Physician's Education Source, LLC: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Maziarz:Athersys, Inc.: Patents & Royalties; Kite Therapeutics: Honoraria; Juno Therapeutics: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ericson:Novartis Pharmaceuticals Corporation: Employment. Rusch:Novartis Pharmaceuticals Corporation: Employment. Romanov:Novartis Pharmaceuticals Corporation: Employment. Locke:Cellular BioMedicine Group Inc.: Consultancy; Novartis Pharmaceuticals: Other: Scientific Advisor; Kite Pharma: Other: Scientific Advisor. Maloney:Janssen Scientific Affairs: Honoraria; Roche/Genentech: Honoraria; Seattle Genetics: Honoraria; GlaxoSmithKline: Research Funding; Juno Therapeutics: Research Funding.
39
Sun, Li, and Ning Cheng. "Impacts of Sense of Career Calling and Perceived Career Development Opportunities on Work Engagement: A Case Study of Undergraduate Academic Advisor." International Journal of Business and Management 16, no. 8 (2021): 37. http://dx.doi.org/10.5539/ijbm.v16n8p37.
Full textAbstract:
This article studies the impacts of sense of career calling and perception of career development opportunities on work engagement, taking academic advisors as survey object. An online questionnaire survey was carried out on academic advisors of colleges and universities in Henan Province, China. Purposive sampling is used for the convenience of data collection, and a total of 400 valid questionnaires were received. SPSS statistical software is used to conduct descriptive analysis, independent sample t-test, and regression analysis of sample data. Research results show that academic advisors have a higher sense of career calling, perception of career development opportunities, and work engagement. Married teachers have a higher sense of career calling, perception of career development opportunities, and work engagement. Sense of career calling and perceived career development opportunities have a significant positive impact on work engagement, and career mission has a greater impact on work engagement than perceived career development opportunities. This research can help college administrators and decision makers realize the importance of the psychological needs of academic advisors in improving work engagement.
40
Flamm, Jason A., Thanes Vanig, Joseph Gathe, et al. "Efficacy and Safety of Tenofovir Alafenamide vs. Tenofovir Disoproxil Fumarate in HIV-infected, Virologically Suppressed Black and Non-Blacks Adults Through Week 96: Subgroup Analysis of a Randomized Switch Study." Open Forum Infectious Diseases 4, suppl_1 (2017): S427—S428. http://dx.doi.org/10.1093/ofid/ofx163.1079.
Full textAbstract:
Abstract Background Black adults are disproportionately affected by HIV. Methods We conducted a 96-week subgroup analysis by race (Black vs. non-Black) for efficacy (pre-specified) and safety (post-hoc) from a randomized, double blind, active-controlled study in virologically suppressed HIV-infected individuals who switched to emtricitabine/tenofovir alafenamide (FTC/TAF) from FTC/tenofovir disoproxil fumarate (FTC/TDF) vs. continuing FTC/TDF while remaining on the same third agent. Results Of 663 treated patients, 136 (20.5%) self-identified as Black (FTC /TAF &#x2028;n = 69, FTC /TDF n = 67). Baseline viral load, CD4 counts, renal laboratory parameters, and bone mineral density (BMD) were similar between the two arms within Blacks and non-Blacks. For Blacks, virologic success by FDA snapshot algorithm at week 96: FTC /TAF 87.0% vs. FTC /TDF 88.1%; for non-Blacks 89.0% vs. 89.7%. Few participants discontinued study drug due to adverse events in either subgroups (FTC/TAF vs. FTC/TDF: Black 0 vs.. 1.5%; non-Black, 3.0% vs. 1.1%). In assessment of renal and bone safety using estimated glomerular filtration rate (eGFR), renal biomarkers, and BMD, there were differences between two arms that generally favored FTC/TAF over FTC/TDF (Table). In the overall population, no cases of Fanconi syndrome or proximal renal tubulopathy occurred with FTC/TAF; one FTC/TDF participant discontinued study drug due to proximal tubulopathy. Conclusion In virologically suppressed Black adults, FTC/TAF demonstrated improvements in renal and bone safety over FTC/TDF with similar sustained efficacy at week 96. These results support switching to FTC/TAF from FTC/TDF for the treatment of HIV-1 infection in Black adults. Disclosures J. A. Flamm, Gilead: Investigator, Research support; T. Vanig, Gilead: Consultant, Investigator and Speaker’s Bureau, Consulting fee, Research support and Speaker honorarium; J. Gathe, Gilead: Investigator, Research support; C. Kinder, Gilead: Investigator, Research support; M. Para, Gilead: Investigator, Research grant and Research support; B. Rashbaum, Gilead: Investigator and Shareholder, Research support and Speaker honorarium; S. Segal-Maurer, Gilead Sciences: Consultant, Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee, Research support and Speaker honorarium; Janssen Therapeutics: Speaker’s Bureau, Speaker honorarium; D. Shamblaw, Gilead: Investigator, Research support; M. Wohlfeiler, Gilead: Investigator, Research support; B. Young, Gilead Sciences: Independent Contractor, Investigator, Research Contractor and Scientific Advisor, Consulting fee, Research support and Speaker honorarium; Merck & Co: Scientific Advisor and Speaker’s Bureau, Consulting fee, Research support and Speaker honorarium; ViiV Healthcare: Scientific Advisor, Research grant; C. Zurawski, Gilead: Investigator, Research grant; M. S. Rhee, Gilead: Employee and Shareholder, Salary
41
Baick, John S. "Cracks in the Foundation: Frederick T. Gates, the Rockefeller Foundation, and the China Medical Board." Journal of the Gilded Age and Progressive Era 3, no. 1 (2004): 59–89. http://dx.doi.org/10.1017/s1537781400000621.
Full textAbstract:
As his lengthy career neared an end, Rockefeller advisor Frederick T. Gates made a bold and unsuccessful proposal to the trustees of the Rockefeller Foundation in 1924, asking them to invest $265 million in the China Medical Board. Founded in 1914, the China Medical Board (CMB) was one of the earliest ventures of the Rockefeller Foundation, the most prominent of the Progressive Era's giant secular philanthropic foundations. The CMB was also the last major philanthropic effort by Gates, the man most responsible for shifting the Rockefellers from denominational charity to international philanthropy. After a decade in existence, the CMB had not come close to realizing the hopes of its founder. Only with this massive, unprecedented infusion of capital, Gates explained, could his dream “spring into existence full panoplied.” This dream was never fully realized because of its astonishingly grandiose scale and complexity: its goal was to make Chinese medical care the finest in the world, and in the process close the chasm that he saw between denominational Christianity and the needs of the modern world. Although the story of the China Medical Board is the story of a failed vision, it also affords a glimpse of the cracks at the base of modern American philanthropy.
42
Lidam, Robert Ngendang A., Yupiter H. P. Manurung, M. Ridhwan, et al. "Angular Distortion Analysis on Multipassed Welding of Combined Joint Types Using Thermo-Elastic-Plastic FEM." Advanced Materials Research 314-316 (August 2011): 315–18. http://dx.doi.org/10.4028/www.scientific.net/amr.314-316.315.
Full textAbstract:
A 2D and 3D thermo-elastic-plastic (TEP) FE Analysis has been developed to simulate the angular distortion induced by Gas Metal Arc Welding (GMAW) process on combination of butt and T-joint with thickness of 9 mm. The material used in this study was low alloy Manganese Carbon steel S355J2G3. In this research, SYSWELD 2010 with its computation management tool known as Multipassed Welding Advisor (MPA) was used to analyze the distortion behaviour of combined joint types. To model the heat source of GMAW, Goldak’s double ellipsoid representation which is available within this FEA code was selected. The final objective of this research is hence aimed to be base line study to provide preliminary information in preparing the tools or equipments for experimental investigation.
43
Marty, Francisco M., Prashant Malhotra, Robert L. Gottlieb, et al. "72. Remdesivir vs Standard Care in Patients with Moderate covid-19." Open Forum Infectious Diseases 7, Supplement_1 (2020): S166—S167. http://dx.doi.org/10.1093/ofid/ofaa439.382.
Full textAbstract:
Abstract Background Remdesivir (RDV) shortens time to recovery time in patients with severe COVID-19. Its effect in patients with moderate COVID-19 remains unclear. Methods We conducted an open-label, phase 3 trial (NCT04252664) involving hospitalized patients with confirmed SARS-CoV-2 infection, evidence of pulmonary infiltrates, and oxygen saturation &gt;94% on room air. Patients were randomly assigned 1:1:1 to receive up to 5d or 10d of RDV with standard of care (SoC), or SoC alone; patients could be discharged prior to completing per-protocol assigned treatment duration. RDV was dosed intravenously at 200 mg on d1, 100 mg daily thereafter. Patients were evaluated daily while hospitalized, and via telephone if discharged. The primary endpoint was clinical status on d11 assessed on a 7-point ordinal scale. Results regarding the primary endpoint are expected to be published before IDWeek 2020; we plan to present d28 results at the meeting. Results In total, 584 patients underwent randomization and started their assigned treatment (191, 5d RDV; 193, 10d RDV; 200, SoC). By d11, ³ 2 point improvement on the ordinal scale occurred in 70% of patients in the 5d arm, 65% in the 10d arm, and 61% in the SoC arm. Patients in the 5d RDV arm were significantly more likely to have an improvement in clinical status than those receiving SoC (odds ratio [OR], 1.65; 95% confidence interval [CI], 1.09–2.48; P=0.017); OR of improvement for the 10d RDV arm compared to SoC was 1.31 (95% CI, 0.88–1.95]; p=0.183). This improvement in the 5-day arm over the SOC arm was noted from d6 through d11. We observed a peak of discharges corresponding with the assigned treatment duration of RDV, with increased discharges at d6 in the 5-day arm and at d11 in the 10-day arm. A worsening of clinical status of ≥ 1 point in the ordinal scale was observed more commonly in the SoC am (n=19, 10%) versus the 5d RDV (n=7, 4%) and 10d RDV (n=9, 5%). Conclusion RDV for up to 5 days was superior to SoC in improving the clinical status of patients with moderate COVID-19 by d11. We will report d28 outcomes at the meeting. Disclosures Francisco M. Marty, MD, Allovir (Consultant)Amplyx (Consultant)Ansun (Scientific Research Study Investigator)Avir (Consultant)Cidara (Scientific Research Study Investigator)F2G (Consultant, Scientific Research Study Investigator)Kyorin (Consultant)Merck (Consultant, Grant/Research Support, Scientific Research Study Investigator)New England Journal of Medicine (Other Financial or Material Support, Honorarium for Video)Regeneron (Consultant, Scientific Research Study Investigator)ReViral (Consultant)Scynexis (Scientific Research Study Investigator)Symbio (Consultant)Takeda (Scientific Research Study Investigator)United Medical (Consultant)WHISCON (Scientific Research Study Investigator) Prashant Malhotra, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Robert L. Gottlieb, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Karen T. Tashima, MD, Bristol-Myers Squibb (Research Grant or Support)Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator)GlaxoSmithKline (Research Grant or Support)Merck (Research Grant or Support)Tibotec (Research Grant or Support)Viiv Healthcare (Research Grant or Support) Massimo Galli, MD, Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Other Financial or Material Support, Personal fees) Louis Yi Ann Chai, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Devi SenGupta, MD, Gilead Sciences Inc. (Employee, Shareholder) Robert H. Hyland, MD, Gilead Sciences Inc. (Employee, Shareholder) Hongyuan Wang, PhD, Gilead Sciences Inc. (Employee, Shareholder) Lijie Zhong, PhD, Gilead Sciences Inc. (Employee, Shareholder) Huyen Cao, MD, Gilead Sciences Inc. (Employee, Shareholder) Anand Chokkalingam, PhD, Gilead Sciences (Employee) Anu Osinusi, MD, Gilead Sciences (Employee) Diana M. Brainard, MD, Gilead Sciences (Employee) Michael Brown, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Ane Josune Goikoetxea, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Mamta Jain, MD, Gilead Sciences Inc. (Scientific Research Study Investigator, Research Grant or Support)GlaxoSmithKline (Advisor or Review Panel member)Janssen (Research Grant or Support)Merck (Research Grant or Support) David Shu Cheong Hui, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Enos Bernasconi, MD, Gilead Sciences Inc. (Scientific Research Study Investigator) Christoph Spinner, MD, AbbVie (Advisor or Review Panel member, Other Financial or Material Support, Travel)Bristol-Myers Squibb (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel)Gilead Sciences Inc. (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member, Other Financial or Material Support, Travel)Janssen (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel)MSD (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel)Viiv Healthcare (Grant/Research Support, Advisor or Review Panel member, Other Financial or Material Support, Travel)
44
Lodise, Thomas P., Susan L. Rosenkranz, Matthew Finnemeyer, et al. "The Emperor’s New Clothes: Prospective Observational Evaluation of the Association between the Day 2 Vancomycin Exposure and Failure Rates among Adult Hospitalized Patients with MRSA Bloodstream Infections (PROVIDE)." Open Forum Infectious Diseases 4, suppl_1 (2017): S30—S31. http://dx.doi.org/10.1093/ofid/ofx162.074.
Full textAbstract:
Abstract Background Current guidelines recommend vancomycin (VAN) dosing to achieve AUC/MIC ratio ≥400 for patients (pts) with serious MRSA bloodstream infections (BSI), but supporting data were largely derived in single center retrospective studies. A recent study using a Bayesian approach to estimate the VAN AUC found that patients with MRSA BSI who had an AUCDAY2/MICBMD ≥ 650 or an AUCDAY2/MICETEST ≥ 320 had lower incidences of failure (Clin Infect Dis 59:666, 2014). This study prospectively evaluated if these VAN AUCDAY2/MIC targets were associated with lower incidences of failure (PROVIDE, Award number UM1AI104681, Antibacterial Resistance Leadership Group). Methods Prospective, multi-center (n = 14), observational study (2014–2106) of hospitalized adults with confirmed MRSA BSI treated with VAN ≥ 72h. Exclusion: (1) neutropenia; (2) cystic fibrosis; (3) renal replacement therapy; (4) APACHE-II score &gt; 25; (5) previous MRSA BSI within 60 days. VAN exposures were estimated using maximum a posteriori probability procedure in ADAPT 5. MICBMD and MICETEST were performed at a central laboratory. Outcomes: failure (30-day mortality or MRSA BSI ≥ 7 days); acute kidney injury (AKI), ≥1.5 × increase in serum creatinine (Scr) among patients with a baseline SCR &lt; 2.0mg/dl. The study was powered at 80% to detect a 17.5% difference in failure between AUCDAY2/MIC groups. Results Among the 265 evaluable patients, mean (SD) age was 61 (17) and APACHE-II was 12 (6). Endocarditis was definite/possible in 29%. The MIC50/90 by BMD and ETEST were 1/1 and 1.5/1.5mg/l, respectively. Failure occurred in 18%; 26% had AKI. Mean (SD) VAN duration was 18 (14) days. Mean (SD) AUCDAY2 was 586.9 (235.5) and 44% and 73% of patients achieved an AUCDAY2/MICBMD ≥ 650 and AUCDAY2/MICETEST ≥ 320. In the multivariate analyses (Figure 1), failure was not significantly different between AUCDAY2/MIC groups. In contrast, AKI was significantly more common in patients with an AUCDAY2/ MICETEST &gt; = 320. Conclusion Achievement of higher VAN AUCDAY2/MIC exposures for patients with MRSA BSIs were not associated with better outcomes and were found to result in increased AKI. Clinicians should assess the benefits vs. risks of using VAN regimens that confer high AUCDAY2/MIC exposures for patients with MRSA BSIs. Disclosures T. P. Lodise Jr., allergan: Consultant, Grant Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee and Speaker honorarium; medicines company: Consultant, Grant Investigator, Scientific Advisor and Speaker’s Bureau, Consulting fee, Research support and Speaker honorarium; melinta: Consultant, Consulting fee; motif: Consultant and Scientific Advisor, Consulting fee; paratek: Consultant and Scientific Advisor, Consulting fee; nabriva: Consultant, Consulting fee; M. J. Zervos, Merck, Inc.: Investigator, Research grant; M. Scheetz, Bayer: Scientific Advisor, Consulting fee; V. Fowler Jr., Pfizer, Novartis, Galderma, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Cubist, Basilea, Affinergy, Janssen, xBiotech, Contrafect: Consultant, Consulting fee; NIH, Basilea, MedImmune, Cerexa/Forest/Actavis/Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist/Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius: Grant Investigator, Research grant; Green Cross, Cubist, Cerexa, Durata, Theravance; Debiopharm: Consultant, Consulting fee; UpToDate: author on several chapters, Royalties
45
Freifeld, Alison G., Andrea Zimmer, Christopher Arnold, et al. "1016. Bloodstream Infection Survey in High-Risk Oncology Patients (BISHOP) With Fever and Neutropenia (FN): Predictors for Morbidity and Mortality." Open Forum Infectious Diseases 5, suppl_1 (2018): S302—S303. http://dx.doi.org/10.1093/ofid/ofy210.853.
Full textAbstract:
Abstract Background Blood stream infection (BSI) during neutropenia is associated with high risk for morbidity and mortality in patients with hematologic malignancies receiving chemotherapy or undergoing hematopoietic cell transplant (HCT). We sought to identify factors associated with increased risk for critical illness (CI) morbidities within 7 days of BSI with index FN following chemotherapy. Methods A prospective ongoing survey among 14 high-volume US cancer centers submitting clinical and microbiologic data from consecutive HM patients with blood stream infection (BSI) during first FN after cytotoxic chemotherapy or HCT. We evaluated factors influencing poor outcomes defined as critical illness (need for pressor support, mechanical ventilation, new pneumonia or new BSI) within 7 days of BSI with index FN. Concordance between antibiotic and BSI isolate was determined by investigator (AZ, AF) interpretation of susceptibility reports provided by each center compared with the initial antimicrobial regimen (IAR) used, for single organism bacteremias only. Results Among 294 FN bacteremic episodes (93 HCT) were 336 bacterial pathogens (48.5% Gram-negative [GN], 46.5% Gram-positive [GP], and 6% anaerobes). Death occurred in 11/294 (4%) and 41/294 (14%) had CI by day 8. At FN presentation, mean MASCC score of those with CI vs. those without was 16.9 vs. 18.6 (P = 0.03) and there was a trend toward higher mean PITT scores for patients with CI by day 8 vs. those without (1.54 vs. 0.82 (P = 0.08)). Among GN bacteremias, 15% developed CI vs. 14.5% in nonviridans group Streptococci (VGS) GP bacteremias, and 10.9% in VGS bacteremias (NS). Among patients with single organism bacteremias (88% of all BSI), mismatch of IAR coverage with isolate susceptibilities occurred in 16.7% (38/227). Among patients whom IAR was active vs. inactive against BSI isolate, 16% vs 14.3%, respectively, developed CI (P = 0.81). Conclusion These data indicate that the MASCC score applied to high-risk inpatients may be a predictor for CI in the first week after bacteremia FN. The PITT shows less correlation with poor outcomes. There was no association between isolate type (GN, GP, or VGS) and CI. Notably there was no association between mismatched BSI susceptibility and antimicrobial spectrum of the IAR and early CI. Disclosures A. G. Freifeld, Merck: Investigator, Research grant. A. Zimmer, Merck: Investigator, Research grant. S. Pergam, Merck: Consultant, Consulting fee. Chimerix: Consultant, Consulting fee. K. V. Rolston, Merck: Investigator, Research grant. JMI Laboratories: Investigator, Research grant. Shionogi (Japan): Investigator, Research grant. S. Shoham, Merck: Investigator and Scientific Advisor, Consulting fee and Grant recipient. Astellas: Investigator, Grant recipient. Shionogi (Japan): Investigator, Grant recipient. Gilead: Investigator, Grant recipient. Shire: Investigator, Grant recipient. T. J. Walsh, Merck: Grant Investigator, Research grant. Atellas: Consultant, Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Gilead: Scientific Advisor, Consulting fee. Allergan: Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Scynexis: Grant Investigator, Research grant. Amplyx: Grant Investigator, Research grant. Shionogi: Scientific Advisor, Consulting fee. J. A. Young, GSK: Investigator, The University of Minnesota is reimbursed for contract costs associated with conducting clinical trials of vaccine. I receive no personal financial benefit. Y. Zhang, Merck: Investigator, Research grant. J. Meza, Merck: Investigator, Research grant.
46
Bergin, Stephen P., Adrian Coles, Sara B. Calvert, et al. "872. PROPHETIC: Predicting Pneumonia in Hospitalized Patients in the ICU—A Model and Scoring System." Open Forum Infectious Diseases 5, suppl_1 (2018): S25. http://dx.doi.org/10.1093/ofid/ofy209.056.
Full textAbstract:
Abstract Background Prospectively identifying patients at highest risk for hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) by implementing a risk assessment scoring tool may help focus prevention efforts, optimize the screening process to improve clinical trial feasibility, and enhance development of new antibacterial agents. Methods Within the intensive care units (ICU) of 28 US hospitals, between February 6, 2016 and October 7, 2016, patients hospitalized &gt;48 hours and receiving high levels of respiratory support were prospectively followed for meeting the definition of HABP/VABP recommended in US FDA draft guidance. Patient demographics, medical comorbidities, and treatment exposures were recorded. The association between candidate risk factors and odds of developing HABP/VABP was evaluated with a multivariable logistic regression model. Risk factors were selected using backward selection with α = 0.1 for model inclusion. A web-based scoring system was developed to estimate the risk of HABP/VABP from the risk factors identified. Results A total of 5,101 patients were enrolled, of whom 1,005 (20%) developed HABP/VABp. 4,613 patients were included in the model, excluding 488 (10%) with HABP/VABP at or before enrollment. There are 15 variables included in the model. APACHE II admission score &gt;20 (P &lt; 0.001, OR 2.14, 95% CI 2.00–2.29), admission diagnosis of trauma (P &lt; 0.001, OR 3.31, 95% CI 1.90–5.74), frequent oral or lower respiratory tract suctioning (P &lt; 0.001, OR 2.33, 95% CI 1.81–2.99), and receipt of enteral nutrition (P &lt; 0.001, OR 2.31, 95% CI 1.69–3.16) were the key drivers of increased pneumonia risk. The model demonstrated excellent discrimination (bias-corrected C-statistic 0.861, 95% CI 0.843–0.880). The web-based scoring system can be accessed via this link: https://ctti-habpvabp.shinyapps.io/web_based_tool/. Conclusion Using a web-based scoring system, ICU patients at highest risk for developing HABP/VABP can be accurately identified. Prospective implementation of this tool may assist in focusing additional prevention efforts on the highest risk patients and enhance new drug development for HABP/VABP. Disclosures S. P. Bergin, CTTI: Investigator and Scientific Advisor, Research support and Travel to study related meetings. A. Coles, CTTI: Investigator and Scientific Advisor, Salary. S. B. Calvert, CTTI: Employee, Salary. M. J. Zervos, CTTI: Investigator, Research support. A. C. Bardossy, CTTI: Investigator, Research support. M. Kollef, CTTI: Investigator, Research support. M. J. Durkin, CTTI: Investigator, Research support. M. Sims, CTTI: Investigator, Research support. C. Greenshields, CTTI: Investigator, Research support. B. A. Kabchi, CTTI: Investigator, Research support. H. K. Donnelly, CTTI: Collaborator and Scientific Advisor, Research support and Salary. P. Tenaerts, CTTI: Employee, Salary. P. Gu, CTTI: Collaborator, Research support and Salary. V. G. Fowler Jr., CTTI: Investigator and Scientific Advisor, Research support and Salary. Merck: Consultant, Grant Investigator and Scientific Advisor, Consulting fee, Grant recipient and Research support. Cerexa/Actavis/Allegan: Grant Investigator, Grant recipient. Pfizer: Consultant and Grant Investigator, Consulting fee and Grant recipient. Advanced Liquid Logics: Grant Investigator, Grant recipient. NIH: Investigator, Grant recipient, Research support and Salary. MedImmune: Consultant and Grant Investigator, Consulting fee and Grant recipient. Basilea: Consultant and Grant Investigator, Consulting fee and Grant recipient. Karius: Grant Investigator, Grant recipient. Contrafect: Consultant and Grant Investigator, Consulting fee and Grant recipient. Regeneron: Grant Investigator, Grant recipient. Genentech: Consultant and Grant Investigator, Consulting fee and Grant recipient. Achaogen: Consultant, Consulting fee. Astellas: Consultant, Consulting fee. Arsanis: Consultant, Consulting fee. Affinergy: Consultant, Consulting fee. Bayer: Consultant, Consulting fee. Cerexa: Consultant, Consulting fee. Cubist: Consultant, Consulting fee. Debiopharm: Consultant, Consulting fee. Durata: Consultant, Consulting fee. Grifols: Consultant, Consulting fee. Medicines Co.: Consultant, Consulting fee. Novartis: Consultant, Consulting fee. Novadigm: Consultant, Consulting fee. Theravance: Consultant, Consulting fee and Speaker honorarium. xBiotech: Consultant, Consulting fee. Green Cross: Consultant, Speaker honorarium. T. L. Holland, CTTI: Investigator and Scientific Advisor, Research support and Salary.
47
Faramand, Rawan, Hiroshi Kotani, Dylan Morrissey, et al. "Prediction of CAR T-Related Toxicities in R/R DLBCL Patients Treated with Axicabtagene Ciloleucel Using Point of Care Cytokine Measurements." Blood 132, Supplement 1 (2018): 95. http://dx.doi.org/10.1182/blood-2018-99-116539.
Full textAbstract:
Abstract Introduction: One of the main complications of adoptive T cell therapy (ACT) is the en-masse activation of tumor-reactive T cells inducing a large release of cytokines followed by activation of other immune cells leading to adverse events. These are classified as a cytokine release syndrome (CRS) or neurotoxicity described as a CAR T Related Encephalopathy Syndrome (CRES). Several biomarkers have been associated with CRS and/or neurotoxicity such as LDH, ferritin and CRP. Cytokines have also been associated with CRS and and/or CRES, but present approaches rely on retrospective study of collected biomarkers. Here, we report the results of cytokine analysis using a point of care (POC) device to predict immune-related toxicities in patients with relapsed/refractory (R/R)DLBCL treated with axicabtagene ciloleucel (axi-cel). Methods: Patients with R/R DLBCL treated with commercial axi-cel were included in this study. Baseline serum samples were collected prior to lymphodepleting chemotherapy and then daily during hospitalization. To select which cytokines to monitor, we retrospectively analyzed 38 serum cytokines in a cohort of 53 patients with R/R B cell acute lymphoblastic leukemia (B-ALL) who were treated with 19-28z CAR T cells. The patients were divided into those requiring treatment with tocilizumab and/or steroids versus those who did not require treatment. We observed several cytokines, including IL-2, IL-6, IL-15 and IFNg, which were significantly elevated in patients with CRS and/or CRES requiring treatment (Figure 1a). Based on this analysis and results of published studies, eight serum proteins were selected in our study including IL-1b, IL-2, IL-6, IL-15, IFNg, TNFa, and angiopoietin-1 &2. We monitored these proteins using a POC device that allows for rapid daily monitoring with a turnaround time of two hours. We established that the results from the POC device strongly correlate with a current gold standard device(Luminex), which has a typical two day turn around time. CRS and CRES were prospectively graded using revised Lee criteria (Lee et al Blood 2014) and the CARTOX group (Neelapu et al. NRCO 2017) respectively by an experienced clinical team and confirmed by chart review retrospectively. Results: A total of 20 patients with R/R DLBCL treated with commercial axi-cel were identified. Median age 64 years ( range 43-73) with 80% male.In our cohort, grades 1-3 CRS were observed in 45%, 40% and 5% respectively. There were no observed grade 0 or grade 4 CRS. There were two patients (10%) who died in the setting of severe toxicity. Patients with grade 5 CRS had higher levels of IL-6 and angiopoietin 2/angiopoietin 1 ratio at day one, which correlated with severity of toxicity r=0.52 (p= 0.039) , and r=0.53 (p=0.033) respectively (Fig. 1b). Furthermore, patients with high grades CRS had elevated levels of IL-15 at day seven (r=0.83, p=0.006). The majority of patients (55%) had grade 1-2 CRES.There were no significant correlations between serum cytokine levels and CRES or between those who required tocilizumab/steroids vs. those who did not, likely due to the small sample size. In select cases, daily monitoring of cytokines using the POC device provided clinical insight that wasn't evident from standard biomarkers. For example, one patient who developed delayed CRS had high serum levels of IL-6 but did not have elevated levels of CRP(Fig.1c). Discussion: In this analysis of 20 patients, we observed a correlation between severe CRS and elevated serum cytokine levels of IL-6 and angiopoietin 2/angiopoietin 1 ratio at day one suggesting that these biomarkers may be utilized to predict severe toxicity in patients treated with ACT. While this study is limited by small sample size, our observations correlate with previously published biomarkers data in patients enrolled in clinical trials. To our knowledge this is the first reported cytokine data using commercial axi-cel. Monitoring of cytokines using a POC device is feasible and will be useful clinically. High risk patients may be identified early and help guide intervention in real time, for example day one elevated IL-6 levels might inform earlier use of tocilizumab. We continue to enroll patients to validate cytokines as predictive biomarkers with the goal of informing the development of preventative strategies to mitigate CAR T cell therapy immune related adverse events. Disclosures Locke: Cellular BioMedicine Group Inc.: Consultancy; Kite Pharma: Other: Scientific Advisor; Novartis Pharmaceuticals: Other: Scientific Advisor. Brentjens:Juno Therapeutics, a Celgene Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Park:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Kite Pharma: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Shire: Consultancy. Davila:Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees.
48
do Carmo Santos, Nelcí, Vinícius G. da Paixão, and Samuel S. da Rocha Pita. "New Trypanosoma cruzi Trypanothione Reductase Inhibitors Identification using the Virtual Screening in Database of Nucleus Bioassay, Biosynthesis and Ecophysiology (NuBBE)." Anti-Infective Agents 17, no. 2 (2019): 138–49. http://dx.doi.org/10.2174/2211352516666180928130031.
Full textAbstract:
Background: American trypanosomiasis, also known as Chagas disease, is caused by the protozoan Trypanosoma cruzi (T. cruzi) and affects approximately 10 to 12 million, primarily in Latin America. Since its discovery in 1909, there is no effective treatment for its chronic phase, with benzonidazole being the only anti-trypanosoma drug used in Brazil, despite the absence of conclusive evidence to prove its efficacy and safety. Thus, it is necessary to develop new drugs that are more effective and selective against Trypanosoma cruzi. Methods: The T. cruzi enzyme Trypanothione Reductase (TcTR) is a validated target for the discovery of new antiprotozoal compounds and we employed the Virtual Screening technique on the database of Nucleus of Bioassays, Biosynthesis and Ecophysiology (NuBBE), aiming to search for new chemical moieties against T. cruzi. From these we selected the 10 best ligand energies interactions and verified their interaction profile with the main TcTR sites through the AuPosSOM server (https://www.biomedicale.univ-paris5.fr/aupossom). Results and Conclusion: Finally, we analyzed some pharmacokinetics and toxicological information through the servers Aggregator Advisor (http://advisor.bkslab.org), Pred-hERG 4.0 (http://labmol.com.br/predherg) and pkCSM (http://biosig.unimelb.edu.au/pkcsm/prediction) which we expect will be useful in in vitro preclinical trials.</P>
49
Kaliszewska, Małgorzata. "DETERMINANTS AND DILEMMAS IMPACTING THE COOPERATION OF FAMILY AND SCHOOL IN CONVEYING COMMUNITY VALUES FROM THE PERSPECTIVE OF THE LITERARY OUTPUT OF TERESA ŚLIWIŃSKA, A TEACHER FROM POZNAŃ. BIOGRAPHICAL RESEARCH." Zeszyty Naukowe Wyższej Szkoły Humanitas w Sosnowcu. Pedagogika 20 (June 10, 2019): 295–307. http://dx.doi.org/10.5604/01.3001.0013.2314.
Full textAbstract:
Researching biography does not only mean exploring the course and trajectory of human life but also understanding people’s life projects, see goals that have been achieved or abandoned and the legacy if there remains any. The article presents one of the areas of pedagogical activity of Teresa Śliwińska: a teacher, headmistress, methodological advisor and community activist, which is a concern for building a school community. The subject of our paper in view of T. Śliwiśka’s literary output is the selected examples on passing on community (collective) values to students, such as religious, family and patriotic values by teachers and parents together. We have not only analyzed values themselves, but also the conditions and dilemmas accompanying the process of passing on the values and the cooperation of the school and home environments.
50
E Segaloff, Hannah, Joshua G. Petrie, Ryan E. Malosh, et al. "Influenza Vaccination and Treatment with Antiviral Agents Among Hospitalized Adults in the 2014–2015 and 2015–2016 Influenza Seasons." Open Forum Infectious Diseases 4, suppl_1 (2017): S316—S317. http://dx.doi.org/10.1093/ofid/ofx163.740.
Full textAbstract:
Abstract Background Vaccination and treatment with neuraminidase inhibitors can reduce incidence and severity of influenza. Observational studies suggest antiviral treatment reduces influenza symptom duration and severe outcomes among hospitalized patients. The interaction of the effects of vaccination and antiviral treatment against severe influenza has not been established. Methods We used data from a test-negative influenza vaccine effectiveness study. The parent study enrolled adults admitted to two hospitals in Michigan with an acute respiratory illness of ≤10 days duration during the 2014–2015 and 2015–2016 influenza seasons. Respiratory swabs from enrolled patients were tested for influenza by RT-PCR; influenza-positive individuals were included in this analysis. We evaluated predictors of vaccination and antiviral treatment using logistic regression. We also assessed the association between antiviral treatment and hospital length of stay (LOS) using linear regression models stratified by vaccination status. Results We included 200 individuals in the analysis; 103 (51.5%) were vaccinated and 135 (67.5%) were treated with antivirals. Significant predictors of vaccination included age ≥65, white race, a Charlson comorbidity index (CCI) score ≥3, study site, and increased past-year health care visits. Antiviral treatment varied by study site and was more common in the 2015–2016 season and among those aged 18–49. Vaccination was not associated with antiviral treatment or with time from illness onset to treatment. Antiviral treatment was associated with reduced LOS (percent change in LOS: −23.6% (−39.2%, −4.1%), P = 0.02) among vaccinated participants but not among unvaccinated participants (21.1% (−10.9%, 64.8%), P = 0.22) after adjustment for sex, age, influenza subtype, site, CCI, frailty, and past-year health care contacts. When an interaction term was used in lieu of stratification the interaction was significant (P = 0.01). This difference in antiviral effectiveness by vaccination status held across age groups, but was most dramatic for those aged 18–49. Conclusion Vaccinated individuals were more likely than unvaccinated individuals to benefit from antiviral treatment. This finding warrants confirmation in other populations. Disclosures A. S. Monto, sanofi pasteur: Grant Investigator, Research grant. Novartis: Consultant, Consulting fee. Protein Sciences: Consultant, Consulting fee. E. T. Martin, Pfizer: Scientific Advisor, Research grant. Merck: Scientific Advisor, Research grant. Multiparty Group For Advice on Science: Scientific Advisor, Research grant.