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https://www.readbyqxmd.com/read/29666304/strategic-therapeutic-targeting-to-overcome-venetoclax-resistance-in-aggressive-b-cell-lymphomas
#1
Lan V Pham, Shengjian Huang, Hui Zhang, Jun Zhang, Taylor Bell, Shouhao Zhou, Elizabeth Pogue, Zhiyong Ding, Laura Lam, Jason R Westin, R Eric Davis, Ken H Young, L Jeffrey Medeiros, Richard J Ford, Krystle Nomie, Liang Zhang, Michael Wang
PURPOSE: B-cell lymphoma-2 (BCL-2), an anti-apoptotic protein often dysregulated in B-cell lymphomas, promotes cell survival and provides protection from stress. A recent Phase I first-in-human study of the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma showed an overall response rate of 44%. These promising clinical results prompted our examination of the biological effects and mechanism of action underlying venetoclax activity in aggressive B-cell lymphoma, including mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL)...
April 17, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29651129/venetoclax-rituximab-holds-substantial-promise-in-cll
#2
David Killock
No abstract text is available yet for this article.
April 12, 2018: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/29650729/venetoclax-after-idelalisib-relevant-progress-for-cll
#3
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
#4
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/29626063/ibrutinib-plus-venetoclax-may-be-effective-in-mantle-cell-lymphoma
#5
(no author information available yet)
Ibrutinib plus venetoclax is superior to monotherapy in patients with mantle-cell lymphoma.
April 6, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29622655/repurposing-tofacitinib-as-an-anti-myeloma-therapeutic-to-reverse-growth-promoting-effects-of-the-bone-marrow-microenvironment
#6
Christine Lam, Ian D Ferguson, Margarette C Mariano, Yu-Hsiu T Lin, Megan Murnane, Hui Liu, Geoffrey A Smith, Sandy W Wong, Jack Taunton, Jun O Liu, Constantine S Mitsiades, Byron C Hann, Blake T Aftab, Arun P Wiita
The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Activation of JAK/STAT signaling is thought to be a central component of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor FDA-approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Here, we validated in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated xenograft models of myeloma, that tofacitinib showed efficacy in myeloma models...
April 5, 2018: Haematologica
https://www.readbyqxmd.com/read/29606585/venetoclax-plus-rituximab-for-chronic-lymphocytic-leukaemia
#7
Robert Stirrups
No abstract text is available yet for this article.
March 29, 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29595064/accelerating-drug-development-in-pediatric-cancer-a-novel-phase-i-study-design-of-venetoclax-in-relapsed-refractory-malignancies
#8
Andrew E Place, Kelly Goldsmith, Jean-Pierre Bourquin, Mignon L Loh, Lia Gore, Daniel A Morgenstern, Yeshwant Sanzgiri, David Hoffman, Ying Zhou, Jeremy A Ross, Betty Prine, Mohamad Shebley, Megan McNamee, Thalia Farazi, Su Young Kim, Maria Verdugo, Leanne Lash-Fleming, C Michel Zwaan, Josef Vormoor
Venetoclax is a highly selective, potent BCL-2 inhibitor that is approved for some patients previously treated for chronic lymphocytic leukemia, and has shown promising activity in adult studies across several hematologic malignancies. Preclinical studies have demonstrated venetoclax activity in pediatric patient-derived xenograft models and cell lines; however, clinical studies in pediatric patients have yet to be conducted. The prognosis is poor for children with most relapsed/refractory malignancies, and limited treatment options result in unmet clinical need...
March 29, 2018: Future Oncology
https://www.readbyqxmd.com/read/29590547/ibrutinib-plus-venetoclax-for-the-treatment-of-mantle-cell-lymphoma
#9
COMPARATIVE STUDY
Constantine S Tam, Mary Ann Anderson, Christiane Pott, Rishu Agarwal, Sasanka Handunnetti, Rodney J Hicks, Kate Burbury, Gillian Turner, Juliana Di Iulio, Mathias Bressel, David Westerman, Stephen Lade, Martin Dreyling, Sarah-Jane Dawson, Mark A Dawson, John F Seymour, Andrew W Roberts
BACKGROUND: Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma. Complete response rates of 21% have been observed for each agent when administered as long-term continuous therapy. Preclinical models predict synergy in combination. METHODS: We conducted a single-group, phase 2 study of daily oral ibrutinib and venetoclax in patients, as compared with historical controls. Patients commenced ibrutinib monotherapy at a dose of 560 mg per day...
March 29, 2018: New England Journal of Medicine
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
#10
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/29562156/venetoclax-rituximab-in-relapsed-or-refractory-chronic-lymphocytic-leukemia
#11
RANDOMIZED CONTROLLED TRIAL
John F Seymour, Thomas J Kipps, Barbara Eichhorst, Peter Hillmen, James D'Rozario, Sarit Assouline, Carolyn Owen, John Gerecitano, Tadeusz Robak, Javier De la Serna, Ulrich Jaeger, Guillaume Cartron, Marco Montillo, Rod Humerickhouse, Elizabeth A Punnoose, Yan Li, Michelle Boyer, Kathryn Humphrey, Mehrdad Mobasher, Arnon P Kater
BACKGROUND: Venetoclax inhibits BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of chronic lymphocytic leukemia cells. We evaluated the efficacy of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. METHODS: In this randomized, open-label, phase 3 trial, we randomly assigned 389 patients to receive venetoclax for up to 2 years (from day 1 of cycle 1) plus rituximab for the first 6 months (venetoclax-rituximab group) or bendamustine plus rituximab for 6 months (bendamustine-rituximab group)...
March 22, 2018: New England Journal of Medicine
https://www.readbyqxmd.com/read/29561706/potential-of-bcl2-as-a-target-for-chronic-lymphocytic-leukemia-treatment
#12
Riccardo Moia, Fary Diop, Chiara Favini, Ahad Ahmed Kodipad, Gianluca Gaidano
Chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease. Deregulation of apoptosis is a major pathogenetic feature, and represents a therapeutic target. TP53 disrupted patients are categorized as high risk patients and are treated with novel target therapies. Among these new drugs, venetoclax, an orally bioavailable BCL2 inhibitor, has shown high efficacy also in relapsed/refractory CLL with TP53 disruption. Venetoclax has also been tested in combination with other drugs without compromising venetoclax dose and with a good safety profile...
March 21, 2018: Expert Review of Hematology
https://www.readbyqxmd.com/read/29559471/co-targeting-bcl-2-and-pi3k-induces-bax-dependent-mitochondrial-apoptosis-in-aml-cells
#13
Mohamed Rahmani, Jewel Nkwocha, Elisa Hawkins, Xinyan Pei, Rebecca E Parker, Maciej Kmieciak, Joel D Leverson, Deepak Sampath, Andrea Ferreira-Gonzalez, Steven Grant
Inhibitors targeting BCL-2 apoptotic proteins have significant potential for the treatment of acute myeloid leukemia (AML); however, complete responses are observed in only 20% of patients suggesting targeting BCL-2 alone is insufficient to yield durable responses. Here we assessed the efficacy of co-administration of the PI3K/mTOR inhibitor GDC-0980 or the p110β-sparing PI3K inhibitor taselisib with the selective BCL-2 antagonist venetoclax in AML cells. Tetracycline-inducible downregulation of BCL-2 significantly sensitized MV4-11 and MOLM-13 AML cells to PI3K inhibition...
March 20, 2018: Cancer Research
https://www.readbyqxmd.com/read/29545346/efficacy-of-the-combination-of-venetoclax-and-hypomethylating-agents-in-relapsed-refractory-acute-myeloid-leukemia
#14
Ibrahim Aldoss, Dongyun Yang, Ahmed Aribi, Haris Ali, Karamjeet Sandhu, Monzr M Al Malki, Mathew Mei, Amandeep Salhotra, Samer Khaled, Ryotaro Nakamura, David Snyder, Margaret O'Donnell, Anthony A Stein, Stephen J Forman, Guido Marcucci, Vinod Pullarkat
No abstract text is available yet for this article.
March 15, 2018: Haematologica
https://www.readbyqxmd.com/read/29543073/epigenetic-therapy-azacytidine-and-decitabine-in-acute-myeloid-leukemia
#15
Stephan R Bohl, Lars Bullinger, Frank G Rücker
The majority of patients with acute myeloid leukemia (AML) are older and exhibit a poor prognosis even after intensive therapy. Inducing differentiation and apoptosis of leukemic blasts by DNA-hypomethylating agents, like e.g. azacytidine (AZA) and decitabine (DAC), represent well-tolerated alternative treatment approaches. Both agents show convincing response as single agents in AML. However, there is a lack of knowledge regarding molecular mechanisms and predictive biomarkers for these agents. Areas covered: This review will (i) provide an overview of the current knowledge of molecular mechanisms underlying the action of these drugs, (ii) report promising predictive biomarkers, (iii) elude on new combined treatment options, and (iv) discuss novel approaches to improve outcomes...
March 27, 2018: Expert Review of Hematology
https://www.readbyqxmd.com/read/29520705/targeting-bcl-2-in-hematologic-malignancies
#16
Nadia Khan, Brad Kahl
Resistance to apoptosis is one of the hallmarks of cancer and members of the B-cell lymphoma 2 (BCL-2) family of proteins are central regulators of apoptosis. Many cancers become resistant to chemotherapy and apoptosis by up-regulating BCL-2 and other family members, making these proteins attractive targets for cancer therapy. Venetoclax is an orally administered, small-molecule apoptosis stimulant that targets BCL-2 proteins by acting as a BCL-2 homology domain 3 (BH3) mimetic. The drug is approved in the USA and EU as a monotherapy for the for the treatment of certain patients with chronic lymphocytic leukemia (CLL) and is in phase III clinical development for multiple myeloma (MM), and in phase II or I/II clinical trials for acute myeloid leukemia, and several B-cell malignancies, including diffuse large B-cell lymphoma, Waldenstrom's macroglobulinaemia, follicular lymphoma, and mantle-cell lymphoma...
March 8, 2018: Targeted Oncology
https://www.readbyqxmd.com/read/29483097/patient-customized-drug-combination-prediction-and-testing-for-t-cell-prolymphocytic-leukemia-patients
#17
Liye He, Jing Tang, Emma I Andersson, Sanna Timonen, Steffen Koschmieder, Krister Wennerberg, Satu Mustjoki, Tero Aittokallio
The molecular pathways that drive cancer progression and treatment resistance are highly redundant and variable between individual patients with the same cancer type. To tackle this complex rewiring of pathway crosstalk, personalized combination treatments targeting multiple cancer growth and survival pathways are required. Here we implemented a computational-experimental drug combination prediction and testing (DCPT) platform for efficient in silico prioritization and ex vivo testing in patient-derived samples to identify customized synergistic combinations for individual cancer patients...
February 26, 2018: Cancer Research
https://www.readbyqxmd.com/read/29480432/frontline-therapy-of-cll-evolving-treatment-paradigm
#18
REVIEW
Craig S Boddy, Shuo Ma
PURPOSE OF REVIEW: Chronic lymphocytic leukemia (CLL) has multiple current frontline therapy options, including chemoimmunotherapy (CIT) and most recently, ibrutinib. Here, we review the most recent updates in the frontline treatment of CLL, including updates in CIT, updates in targeted therapies, and ongoing clinical trials. RECENT FINDINGS: Ibrutinib was FDA-approved for the upfront treatment of CLL in 2016 after being studied in older patients and those with 17p deletions or TP53 mutations...
April 2018: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/29477371/venetoclax-a-new-wave-in-haemato-oncology
#19
REVIEW
Jana Mihalyova, Tomas Jelinek, Katerina Growkova, Matous Hrdinka, Michal Simicek, Roman Hajek
Inhibitors of anti-apoptotic proteins of the BCL2 family can successfully restart the deregulated process of apoptosis in malignant cells. While non-selective agents have been limited by their affinity to different BCL2 members, and thus inducing excessive toxicity, the highly selective BCL2 inhibitor, venetoclax (ABT-199, Venclexta™), has an acceptable safety profile. To date, it has been approved in monotherapy for the treatment of relapsed or refractory chronic lymphocytic leukaemia (CLL) with 17p deletion...
February 22, 2018: Experimental Hematology
https://www.readbyqxmd.com/read/29477250/chronic-lymphocytic-leukaemia
#20
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
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