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https://www.readbyqxmd.com/read/29650729/venetoclax-after-idelalisib-relevant-progress-for-cll
#1
Francesc Bosch, Michael Hallek
No abstract text is available yet for this article.
April 12, 2018: Blood
https://www.readbyqxmd.com/read/29644450/monitoring-and-management-of-toxicities-of-novel-b-cell-signaling-agents
#2
REVIEW
Joanna Rhodes, Anthony Mato, Jeff P Sharman
PURPOSE REVIEW: B cell signaling agents, including ibrutinib, idelalisib, and the BCL-2 inhibitor venetoclax have become an integral part of therapy for patients with non-Hodgkin's lymphomas. The toxicity profiles of these medications is distinct from chemoimmunotherapy. Here, we will review the mechanism of action of these drugs, their efficacy, and toxicity management. RECENT FINDINGS: Ibrutinib use is associated with increased risk of atrial fibrillation and bleeding which can be managed using dose interruptions and modifications...
April 11, 2018: Current Oncology Reports
https://www.readbyqxmd.com/read/29617050/transient-antagonism-of-anti-cd20-monoclonal-antibodies-and-pi3k-inhibitor-idelalisib-in-dlbcl-cell-lines
#3
Anna-Katharina Zoellner, Nico Peter, Yvonne Zimmermann, Grit Hutter, Wolfgang Hiddemann, Martin Dreyling
INTRODUCTION: PI3K inhibitors are evaluated for relapsed and refractory DLBCL patients. OBJECTIVE: Since rituximab has shown to influence BCR-signaling, we investigated the interaction of anti-CD20 antibody rituximab and the new type II glycoengineered anti-CD20 antibody obinutuzumab in combination with the PI3K delta inhibitor idelalisib. METHODS: Established DLBCL cell lines were treated with either rituximab or obinutuzumab alone, or in combination with PI3K delta inhibitor idelalisib...
April 4, 2018: European Journal of Haematology
https://www.readbyqxmd.com/read/29615799/idelalisib-impairs-trem-1-mediated-neutrophil-inflammatory-responses
#4
Astrid Alflen, Nicole Stadler, Pamela Aranda Lopez, Daniel Teschner, Matthias Theobald, Georg Heß, Markus P Radsak
Triggering receptor expressed on myeloid cells (TREM)-1 on polymorphonuclear neutrophils (PMN) regulates innate immune activation in infectious and non-infectious conditions. TREM-1 ligation activates phosphatidyl-inositol 3 kinase (PI3K) triggering all neutrophil effector functions. As idelalisib is a PI3K inhibitor in clinical use for the treatment of non-Hodgkin lymphomas, we asked whether this inhibitor affects PMN functionalities. We analyzed PMNs from healthy donors or lymphoma patients for oxidative burst, phagocytosis, activation markers and IL-8 release upon TREM-1 or TLR ligation ex vivo...
April 3, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29584544/drivers-of-treatment-patterns-in-patients-with-chronic-lymphocytic-leukemia-stopping-ibrutinib-or-idelalisib-therapies
#5
Anthony R Mato, Jennifer C Samp, Geneviève Gauthier, Emi Terasawa, Danielle M Brander
Novel therapies including kinase inhibitors (KI) have led to high and durable response in patients with chronic lymphocytic leukemia (CLL), however, some patients stop therapy. This study evaluates reasons for treatment changes among CLL patients who stopped KI in real-world practice. Sixty-nine US oncologists/hematologists provided patient-level data abstracted from charts of CLL adult patients who initiated a KI and later (1) switched to another anti-neoplastic regimen (Switched cohort), (2) discontinued the KI and remained untreated (Discontinued cohort), or (3) restarted the same KI after an interruption of ≥60 days (Restarted cohort)...
March 27, 2018: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29572333/risk-of-clinically-relevant-pharmacokinetic-based-drug-drug-interactions-with-drugs-approved-by-the-u-s-food-and-drug-administration-between-2013-and-2016
#6
Jingjing Yu, Zhu Zhou, Jessica Tay-Sontheimer, Rene H Levy, Isabelle Ragueneau-Majlessi
A total of 103 drugs (including 14 combination drugs) were approved by the U.S. Food and Drug Administration from 2013 to 2016. Pharmacokinetic-based drug interaction profiles were analyzed using the University of Washington Drug Interaction Database and the clinical relevance of these observations was characterized based on information from New Drug Application reviews. CYP3A was identified as a major contributor to clinical drug-drug interactions (DDIs), involved in approximately 2/3 of all interactions. Transporters (alone or with enzymes) were found to participate in about half of all interactions, although most of these were weak-to-moderate interactions...
March 23, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29571669/chronic-lymphocytic-leukemia-and-infection-risk-in-the-era-of-targeted-therapies-linking-mechanisms-with-infections
#7
REVIEW
Talal Hilal, Juan C Gea Banacloche, Jose F Leis
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the world. Patient with CLL are at particular risk for infections due to inherent disease-related immune dysfunction in addition to the effect of certain systemic therapies on the immune system. The advent of B-cell receptor (BCR) inhibitors such as ibrutinib and idelalisib has led to a practice change that utilizes these targeted agents in the treatment of CLL, either in place of chemoimmunotherapy (CIT) or in later line settings. In this paper, we review the pathophysiology of immune dysfunction in CLL, the spectrum of immunodeficiency with the various therapeutic agents along with prevention strategies with a focus on targeted therapies...
March 16, 2018: Blood Reviews
https://www.readbyqxmd.com/read/29569483/pathological-assessment-of-gastrointestinal-biopsies-from-patients-with-idelalisib-associated-diarrhea-and-colitis
#8
Cecilia Cs Yeung, David M Hockenbery, Maria Westerhoff, Steven E Coutre, Ruth H Sedlak, Ronald L Dubowy, Veerendra Munugalavadla, Kerry Taylor, Francesc Bosch
AIM: Idelalisib (IDELA) treatment is associated with diarrhea/colitis (incidence of ∼15% grade ≥3). We performed a retrospective analysis of gastrointestinal biopsies from 29 patients treated with IDELA across 9 clinical trials. METHODS: A central core laboratory performed histopathologic review, immunohistochemistry, and droplet digital PCR viral studies. These results were correlated with tissue immune profiling data and morphologic features per modified Geboes score...
March 23, 2018: Future Oncology
https://www.readbyqxmd.com/read/29563327/inhibition-of-the-%C3%AE-subunit-of-phosphoinositide-3-kinase-pi3k-in-heart-increases-late-sodium-current-and-is-arrhythmogenic
#9
Tao Yang, David F Meoli, Javid Moslehi, Dan M Roden
While inhibition of phosphoinositide 3-kinase (PI3K) is an emerging strategy in cancer therapy, we and others have reported that this action can also contribute to drug-induced Q-T prolongation and arrhythmias by increasing cardiac late sodium current (INaL). Previous studies in mice implicate the PI3K-α isoform as the major effector of the INaL action. Here, we have determined the effects of new anticancer drugs targeting specific PI3K isoforms on INaL and action potentials (APs) in mouse cardiomyocytes and CHO cells...
March 21, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29536777/introduction-of-pyrrolidineoxy-or-piperidineamino-group-at-the-4-position-of-quinazoline-leading-to-novel-quinazoline-based-phosphoinositide-3-kinase-delta-pi3k%C3%AE-inhibitors
#10
Minhang Xin, Weiming Duan, Yifan Feng, Yuan-Yuan Hei, Hao Zhang, Ying Shen, Hong-Yi Zhao, Shuai Mao, San-Qi Zhang
Phosphoinositide 3-kinase Delta (PI3Kδ) plays a key role in B-cell signal transduction and inhibition of PI3Kδ was confirmed to have clinical benefit in certain types of activation of B-cell malignancies. Herein, we reported a novel series of 4-pyrrolidineoxy or 4-piperidineamino substituted quinazolines, showing potent PI3Kδ inhibitory activities. Among these compounds, 12d, 14b and 14c demonstrated higher potency against PI3Kδ with the half maximal inhibitory concentration (IC50 ) values of 4.5, 3.0, and 3...
December 2018: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/29534936/novel-6-aryl-substituted-4-pyrrolidineaminoquinazoline-derivatives-as-potent-phosphoinositide-3-kinase-delta-pi3k%C3%AE-inhibitors
#11
Minhang Xin, Weiming Duan, Yifan Feng, Yuan-Yuan Hei, Hao Zhang, Ying Shen, Hong-Yi Zhao, Shuai Mao, San-Qi Zhang
In this study, a novel series of 6-aryl substituted 4-pyrrolidineaminoquinazoline derivatives were designed and evaluated as potent PI3Kδ inhibitors. The preliminary SAR was established, and compounds 12d, 20a and 20c displayed leading potent PI3Kδ inhibition, with IC50 values of 4.5, 2.7 and 3.1 nM, respectively, that were comparable to idelalisib (IC50  = 2.7 nM). Moreover, these three compounds showed favorable PI3Kδ isoform selectivity over PI3Kα, PI3Kβ, and PI3Kγ, and showed distinct anti-proliferation profiles against four human B cell lines of Ramos, Raji, RPMI-8226 and SU-DHL-6...
March 2, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29529009/quantification-of-idelalisib-in-human-plasma-by-ultra-performance-liquid-chromatography-coupled-to-mass-spectrometry-in-negative-ionization-mode
#12
Huu H Huynh, Clara Roessle, Hélène Sauvageon, Alain Plé, Isabelle Madelaine, Catherine Thieblemont, Samia Mourah, Lauriane Goldwirt
BACKGROUND: Idelalisib is the first orally active selective phosphatidylinositol 3-kinase delta inhibitor approved by Food and Drug Administration and European Medicines Agency in 2014 for the treatment of several types of blood cancer. Idelalisib is widely used as a monotherapy or in combination with rituximab, bendamustine, or ofatumumab with a significant efficacy. However, idelalisib has shown increased risk of infection and a higher frequency of serious adverse events. It may be useful to determine idelalisib concentration in human plasma to adjust dose and to manage adverse effects in clinical practice...
April 2018: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/29523661/idelalisib-and-rituximab-in-17p-deletion-positive-splenic-marginal-zone-lymphoma
#13
Aby Z Philip
Splenic marginal zone lymphoma (SMZL) is a rare indolent B-cell malignancy involving the spleen and bone marrow. Various cytogenetic abnormalities with prognostic value have been identified in SMZL. Complexity of karyotype, 14q aberrations, and TP53 deletions have been found to be poor prognostic indicators. We report an unusual case of SMZL with a complex karyotype including 17p deletion, primarily refractory to 2 chemoimmunotherapy regimens, that responded well to treatment with phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitors idelalisib and rituximab...
March 2018: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/29508857/targeting-the-pi3k-pathway-in-cancer-are-we-making-headway
#14
REVIEW
Filip Janku, Timothy A Yap, Funda Meric-Bernstam
The PI3K-AKT-mTOR pathway is one of the most frequently dysregulated pathways in cancer and, consequently, more than 40 compounds that target key components of this signalling network have been tested in clinical trials involving patients with a range of different cancers. The clinical development of many of these agents, however, has not advanced to late-phase randomized trials, and the antitumour activity of those that have been evaluated in comparative prospective studies has typically been limited, or toxicities were found to be prohibitive...
March 6, 2018: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/29507689/single-cell-profiling-of-phospho-protein-levels-in-chronic-lymphocytic-leukemia
#15
Ida K Myhrvold, Andrea Cremaschi, Johanne U Hermansen, Geir E Tjønnfjord, Ludvig A Munthe, Kjetil Taskén, Sigrid S Skånland
Chronic lymphocytic leukemia (CLL) has a high incidence and a steeply growing prevalence in the Western world. The heterogeneity of the disease necessitates individual mapping of biology and predicted drug response in each patient as basis for administration of tailored treatments. Cell signaling aberrations may serve as biological indicators for suitable therapy. By applying phospho-specific flow cytometry, we mapped basal and induced phosphorylation levels of 20 phospho-epitopes on proteins relevant to B-cell signaling in B cells from 22 CLL patients and 25 normal controls...
February 6, 2018: Oncotarget
https://www.readbyqxmd.com/read/29479062/distinct-roles-for-phosphoinositide-3-kinases-%C3%AE-and-%C3%AE-in-malignant-b-cell-migration
#16
Ahmed Y Ali, Xun Wu, Nour Eissa, Sen Hou, Jean-Eric Ghia, Thomas T Murooka, Versha Banerji, James B Johnston, Francis Lin, Spencer B Gibson, Aaron J Marshall
The PI 3-kinases (PI3K) are essential mediators of chemokine receptor signaling necessary for migration of chronic lymphocytic leukemia (CLL) cells and their interaction with tissue-resident stromal cells. While the PI3Kδ-specific inhibitor idelalisib shows efficacy in treatment of CLL and other B cell malignancies, the function of PI3Kγ has not been extensively studied in B cells. Here, we assess whether PI3Kγ has non-redundant functions in CLL migration and adhesion to stromal cells. We observed that pharmaceutical PI3Kγ inhibition with CZC24832 significantly impaired CLL cell migration, while dual PI3Kδ/γ inhibitor duvelisib had a greater impact than single isoform-selective inhibitors...
January 31, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29477250/chronic-lymphocytic-leukaemia
#17
REVIEW
Michael Hallek, Tait D Shanafelt, Barbara Eichhorst
Important advances in understanding the pathogenesis of chronic lymphocytic leukaemia in the past two decades have led to the development of new prognostic tools and novel targeted therapies that have improved clinical outcome. Chronic lymphocytic leukaemia is the most common type of leukaemia in developed countries, and the median age at diagnosis is 72 years. The criteria for initiating treatment rely on the Rai and Binet staging systems and on the presence of disease-related symptoms. For many patients with chronic lymphocytic leukaemia, treatment with chemotherapy and anti-CD20 monoclonal antibodies is the standard of care...
February 21, 2018: Lancet
https://www.readbyqxmd.com/read/29465308/cll2-bxx-phase-ii-trials-sequential-targeted-treatment-for-eradication-of-minimal-residual-disease-in-chronic-lymphocytic-leukemia
#18
Paula Cramer, Julia von Tresckow, Jasmin Bahlo, Anja Engelke, Petra Langerbeins, Anna-Maria Fink, Kirsten Fischer, Clemens-Martin Wendtner, Karl-Anton Kreuzer, Stephan Stilgenbauer, Sebastian Böttcher, Barbara Eichhorst, Michael Hallek
AIM: Four Phase II trials (Clinical Trials numbers: NCT02345863, NCT02401503, NCT02445131 and NCT02689141) evaluate a different combination of targeted agents in an all-comer population of approximately 60 patients with chronic lymphocytic leukemia irrespective of prior treatment, physical fitness and genetic risk factors. Patients with a higher tumor load start with a debulking treatment with bendamustine. The subsequent induction and maintenance treatment with an anti-CD20 antibody (obinutuzumab or ofatumumab) and a targeted oral agent (ibrutinib, idelalisib or venetoclax) are continued until achievement of a complete response and minimal residual disease negativity...
February 21, 2018: Future Oncology
https://www.readbyqxmd.com/read/29454849/escmid-study-group-for-infections-in-compromised-hosts-esgich-consensus-document-on-the-safety-of-targeted-and-biological-therapies-an-infectious-diseases-perspective-intracellular-signaling-pathways-tyrosine-kinase-and-mtor-inhibitors
#19
REVIEW
Mark Reinwald, Jose T Silva, Nicolas J Mueller, Jesús Fortún, Christian Garzoni, Johan W de Fijter, Mario Fernández-Ruiz, Paolo Grossi, Jose María Aguado
BACKGROUND: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. AIMS: To review, from an Infectious Diseases perspective, the safety profile of therapies targeting different intracellular signaling pathways and to suggest preventive recommendations. SOURCES: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family...
February 15, 2018: Clinical Microbiology and Infection
https://www.readbyqxmd.com/read/29453281/the-pi3k%C3%AE-selective-inhibitor-idelalisib-minimally-interferes-with-immune-effector-function-mediated-by-rituximab-or-obinutuzumab-and-significantly-augments-b-cell-depletion-in-vivo
#20
Adam Palazzo, Sylvia Herter, Laura Grosmaire, Randy Jones, Christian R Frey, Florian Limani, Marina Bacac, Pablo Umana, Robert J Oldham, Michael J E Marshall, Kerry L Cox, Anna H Turaj, Mark S Cragg, Christian Klein, Matthew J Carter, Stacey Tannheimer
Idelalisib is a highly selective oral inhibitor of PI3Kδ indicated for the treatment of patients with relapsed chronic lymphocytic leukemia in combination with rituximab. Despite additive clinical effects, previous studies have paradoxically demonstrated that targeted therapies potentially negatively affect anti-CD20 mAb effector mechanisms. To address these potential effects, we investigated the impact of PI3Kδ inhibition by idelalisib on the effector mechanisms of rituximab and obinutuzumab. At clinically relevant concentrations, idelalisib minimally influenced rituximab- and obinutuzumab-mediated Ab-dependent cellular cytotoxicity and phagocytosis on human lymphoma cell lines, while maintaining the superiority of obinutuzumab-mediated Ab-dependent cellular cytotoxicity...
February 16, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
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