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Venetoclax lymphoma

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https://www.readbyqxmd.com/read/28439761/small-molecule-inhibitors-in-chronic-lymphocytic-lymphoma-and-b-cell-non-hodgkin-lymphoma
#1
REVIEW
Allison Rosenthal
PURPOSE OF REVIEW: The purpose of this review is to summarize the available literature for the use of small molecule inhibitors in chronic lymphocytic leukemia and B cell non-Hodgkin lymphoma. RECENT FINDINGS: Ibrutinib, idelalisib, and venetoclax are small molecule inhibitors that have revolutionized therapeutic options for patients with CLL, particularly for those with high-risk disease including 17p deletion. These drugs are increasingly finding application in a variety of subtypes of B cell NHL...
April 24, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/28416490/preclinical-characterization-of-bet-family-bromodomain-inhibitor-abbv-075-suggests-combination-therapeutic-strategies
#2
Mai H Bui, Xiaoyu Lin, Daniel H Albert, Leiming Li, Lloyd T Lam, Emily J Faivre, Scott Warder, Xiaoli Huang, Denise Wilcox, Cherrie K Donawho, George S Sheppard, Le Wang, Steve Fidanze, John K Pratt, Dachun Liu, Lisa Hasvold, Tamar Uziel, Xin Lu, Fred Kohlhapp, Guowei Fang, Steven W Elmore, Saul H Rosenberg, Keith F McDaniel, Warren M Kati, Yu Shen
ABBV-075 is a potent and selective BET family bromodomain inhibitor that recently entered Phase I clinical trials. Comprehensive preclinical characterization of ABBV-075 demonstrated broad activity across cell lines and tumor models representing a variety of hematological malignancies and solid tumor indications. In most cancer cell lines derived from solid tumors, ABBV-075 triggers prominent G1 cell cycle arrest without extensive apoptosis. In this study, we show that ABBV-075 efficiently triggers apoptosis in acute myeloid leukemia (AML), non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM) cells...
April 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28389687/advances-in-the-treatment-of-relapsed-refractory-chronic-lymphocytic-leukemia
#3
REVIEW
C Shustik, I Bence-Bruckler, R Delage, C J Owen, C L Toze, S Coutre
Treatment of chronic lymphocytic leukemia (CLL) has advanced with the introduction of chemoimmunotherapy (CIT) agents that have improved the outcomes of frontline therapy. However, most treated patients will relapse and require subsequent therapy. This review focuses on recent advances in the treatment of relapsed or refractory CLL. Until recently, treatment options for relapsed CLL were of limited efficacy. Retreatment with fludarabine, cyclophosphamide, and rituximab (FCR) was recommended for patients with a durable response to first-line FCR, although acquired genetic aberrations, impaired marrow reserve, and comorbidities often made this suboptimal therapy for many patients...
April 7, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/28331288/development-of-venetoclax-for-therapy-of-lymphoid-malignancies
#4
REVIEW
Huayuan Zhu, Alexandru Almasan
B-cell lymphoma-2 (BCL-2) family dysfunction and impairment of apoptosis are common in most B-cell lymphoid malignancies. Venetoclax (Venclexta™, formerly ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor, which mimics its BCL-2 homology 3-domain to induce apoptosis. It was approved for treatment of previously treated chronic lymphocytic leukemia (CLL) patients with 17p deletion early in 2016. It has also been in clinical trials for other B-cell lymphoid malignancies. Unlike the other recently approved targeted agents idelalisib and ibrutinib, so far there has been no relapse reported in some patients...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28288710/possible-novel-agents-in-marginal-zone-lymphoma
#5
REVIEW
Pier Luigi Zinzani, Alessandro Broccoli
Efficacy, safety and mechanisms of action of novel agents in marginal zone lymphoma patients, both with a nodal and extranodal presentation, are reviewed. Data on lenalidomide, bortezomib and (90)yttrium-ibrutumomab tiuxetan are obtained from trials specifically designed for patients affected by marginal zone lymphoma and with various disease presentations. The role of targeted agents, such as obinutuzumab, ibrutinib and idelalisib, and of some very new drugs (venetoclax, copanlisib, ublituximab and TGR-1202) is also discussed, taking into account the most relevant experiences in patients with indolent non-Hodgkin's lymphomas...
March 2017: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/28209992/from-basic-apoptosis-discoveries-to-advanced-selective-bcl-2-family-inhibitors
#6
REVIEW
Avi Ashkenazi, Wayne J Fairbrother, Joel D Leverson, Andrew J Souers
Members of the B cell lymphoma 2 (BCL-2) gene family have a central role in regulating programmed cell death by controlling pro-apoptotic and anti-apoptotic intracellular signals. In cancer, apoptosis evasion through dysregulation of specific BCL-2 family genes is a recurring event; accordingly, selective inhibition of specific anti-apoptotic BCL-2 family proteins represents an exciting therapeutic opportunity. A combination of nuclear magnetic resonance (NMR)-based screening and structure-based drug design has yielded the first bona fide BCL-2 homology 3 (BH3) mimetics, including the BCL-2 and BCL-XL dual antagonist navitoclax, which is the first BCL-2 family inhibitor to show efficacy in patients with cancer...
April 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/28205194/novel-and-expanded-oncology-drug-approvals-of-2016-part-2-new-options-in-the-management-of-hematologic-malignancies
#7
REVIEW
Todd C Knepper, James Saller, Christine M Walko
The recent past has brought pharmacotherapeutic advances that benefit patients with hematologic malignancies. In 2016, two novel hematology drugs were approved and four previously approved hematology drugs were granted expanded use for the treatment of appropriate patient populations by the US Food and Drug Administration. These new approvals and indications represent significant steps forward in patient management: they include the first-in-class B-cell lymphoma 2 inhibitor, venetoclax, the newest targeted therapy available for the treatment of hematologic malignancies; and nivolumab, the first immune checkpoint inhibitor to be approved for treatment of a hematologic malignancy...
February 15, 2017: Oncology (Williston Park, NY)
https://www.readbyqxmd.com/read/28139404/venetoclax-active-and-safe-in-non-hodgkin-lymphoma
#8
Manjulika Das
No abstract text is available yet for this article.
March 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28130250/the-bcl2-inhibitor-venetoclax-is-active-in-non-hodgkin-lymphoma
#9
(no author information available yet)
Venetoclax has single-agent antitumor activity in a range of non-Hodgkin lymphoma (NHL) subtypes.
March 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28100580/venetoclax-in-patients-with-previously-treated-chronic-lymphocytic-leukemia
#10
Andrew W Roberts, Stephan Stilgenbauer, John F Seymour, David C S Huang
Venetoclax is the first BCL2 inhibitor to enter routine clinical practice. It is an orally bioavailable small molecule that binds BCL2 very specifically. Acting as a pharmacological mimic of the proteins that initiate apoptosis (a so-called BH3-mimetic), venetoclax rapidly induces apoptosis in chronic lymphocytic leukemia (CLL) cells which express high levels of BCL2 and rely on it to maintain their survival. As a single agent, daily venetoclax treatment induced durable responses in 79% of patients with relapsed or refractory CLL or small lymphocytic lymphoma in a Phase 1 study, including complete remissions in 20% of patients...
January 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28095146/phase-i-first-in-human-study-of-venetoclax-in-patients-with-relapsed-or-refractory-non-hodgkin-lymphoma
#11
Matthew S Davids, Andrew W Roberts, John F Seymour, John M Pagel, Brad S Kahl, William G Wierda, Soham Puvvada, Thomas J Kipps, Mary Ann Anderson, Ahmed Hamed Salem, Martin Dunbar, Ming Zhu, Franklin Peale, Jeremy A Ross, Lori Gressick, Monali Desai, Su Young Kim, Maria Verdugo, Rod A Humerickhouse, Gary B Gordon, John F Gerecitano
Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts...
March 10, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28089635/venetoclax-plus-rituximab-in-relapsed-or-refractory-chronic-lymphocytic-leukaemia-a-phase-1b-study
#12
John F Seymour, Shuo Ma, Danielle M Brander, Michael Y Choi, Jacqueline Barrientos, Matthew S Davids, Mary Ann Anderson, Anne W Beaven, Steven T Rosen, Constantine S Tam, Betty Prine, Suresh K Agarwal, Wijith Munasinghe, Ming Zhu, L Leanne Lash, Monali Desai, Elisa Cerri, Maria Verdugo, Su Young Kim, Rod A Humerickhouse, Gary B Gordon, Thomas J Kipps, Andrew W Roberts
BACKGROUND: Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab. METHODS: Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial...
February 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28056525/venetoclax-a-first-in-class-oral-bcl-2-inhibitor-for-the-management-of-lymphoid-malignancies
#13
Amber C King, Tim J Peterson, Troy Z Horvat, Mabel Rodriguez, Laura A Tang
OBJECTIVE: To review the pharmacology, efficacy, and safety of venetoclax for treatment of lymphoid malignancies. DATA SOURCES: A literature search was performed of PubMed and MEDLINE databases (2005 to September 2016), abstracts from the American Society of Hematology and the American Society of Clinical Oncology, and ongoing studies from clinicaltrials.gov. Searches were performed utilizing the following key terms: venetoclax, ABT-199, GDC-199, obatoclax, GX15-070, BCL-2 inhibitor, navitoclax, ABT-263, and Venclexta...
May 2017: Annals of Pharmacotherapy
https://www.readbyqxmd.com/read/28017967/duvelisib-treatment-is-associated-with-altered-expression-of-apoptotic-regulators-that-helps-in-sensitization-of-chronic-lymphocytic-leukemia-cells-to-venetoclax-abt-199
#14
V M Patel, K Balakrishnan, M Douglas, T Tibbitts, E Y Xu, J L Kutok, M Ayers, A Sarkar, R Guerrieri, W G Wierda, S O'Brien, N Jain, H M Stern, V Gandhi
Duvelisib, an oral dual inhibitor of PI3K-δ and PI3K-γ, is in phase III trials for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin's lymphoma. In CLL, duvelisib monotherapy is associated with high iwCLL (International Workshop on Chronic Lymphocytic Leukemia) and nodal response rates, but complete remissions are rare. To characterize the molecular effect of duvelisib, we obtained samples from CLL patients on the duvelisib phase I trial. Gene expression studies (RNAseq, Nanostring, Affymetrix array and real-time RT-PCR) demonstrated increased expression of BCL2 along with several BH3-only pro-apoptotic genes...
February 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27993930/metabolism-and-disposition-of-a-novel-b-cell-lymphoma-2-inhibitor-venetoclax-in-humans-and-characterization-of-its-unusual-metabolites
#15
Hong Liu, Melissa J Michmerhuizen, Yanbin Lao, Katty Wan, Ahmed Hamed Salem, James Sawicki, Michael Serby, Srirajan Vaidyanathan, Shekman L Wong, Suresh Agarwal, Martin Dunbar, Jens Sydor, Sonia M de Morais, Anthony J Lee
Venetoclax (ABT-199), a B-cell lymphoma-2 (Bcl-2) protein inhibitor, is currently in clinical development for the treatment of hematologic malignancies. We characterized the absorption, metabolism, and excretion of venetoclax in humans. After a single oral dose of [(14)C]venetoclax to healthy volunteers, the recovery of total radioactive dose was 100%, with feces being the major route of elimination of the administered dose, whereas urinary excretion was minimal (<0.1%). The extent of absorption was estimated to be at least 65%...
March 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27990281/mitochondrial-apoptosis-and-bh3-mimetics
#16
REVIEW
Haiming Dai, X Wei Meng, Scott H Kaufmann
The BCL2-selective BH3 mimetic venetoclax was recently approved for the treatment of relapsed, chromosome 17p-deleted chronic lymphocytic leukemia (CLL) and is undergoing extensive testing, alone and in combination, in lymphomas, acute leukemias, and solid tumors. Here we summarize recent advances in understanding of the biology of BCL2 family members that shed light on the action of BH3 mimetics, review preclinical and clinical studies leading to the regulatory approval of venetoclax, and discuss future investigation of this new class of antineoplastic agent...
2016: F1000Research
https://www.readbyqxmd.com/read/27982454/relationship-between-venetoclax-exposure-rituximab-coadministration-and-progression-free-survival-in-patients-with-relapsed-or-refractory-chronic-lymphocytic-leukemia-demonstration-of-synergy
#17
Kevin J Freise, Aksana K Jones, Rajeev M Menon, Maria E Verdugo, Rod A Humerickhouse, Walid M Awni, Ahmed Hamed Salem
Venetoclax is indicated at a dosage of 400 mg daily (QD) for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. Ongoing trials are evaluating venetoclax in combination with CD20 targeting monoclonal antibodies, such as rituximab. The objective of this research was to characterize the relationship between venetoclax exposures and progression-free survival (PFS) and to evaluate the effect of rituximab coadministration on PFS in patients with relapsed or refractory (R/R) CLL/small lymphocytic lymphoma (SLL)...
December 16, 2016: Hematological Oncology
https://www.readbyqxmd.com/read/27913204/the-selective-bcl-2-inhibitor-venetoclax-a-bh3-mimetic-does-not-dysregulate-intracellular-ca-2-signaling
#18
Tamara Vervloessem, Hristina Ivanova, Tomas Luyten, Jan B Parys, Geert Bultynck
Anti-apoptotic B cell-lymphoma-2 (Bcl-2) proteins are emerging as therapeutic targets in a variety of cancers for precision medicines, like the BH3-mimetic drug venetoclax (ABT-199), which antagonizes the hydrophobic cleft of Bcl-2. However, the impact of venetoclax on intracellular Ca(2+) homeostasis and dynamics in cell systems has not been characterized in detail. Here, we show that venetoclax did not affect Ca(2+)-transport systems from the endoplasmic reticulum (ER) in permeabilized cell systems. Venetoclax (1μM) did neither trigger Ca(2+) release by itself nor affect agonist-induced Ca(2+) release in a variety of intact cell models...
November 30, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27910036/evaluation-of-the-pharmacokinetic-interaction-between-venetoclax-a-selective-bcl-2-inhibitor-and-warfarin-in-healthy-volunteers
#19
Ahmed Hamed Salem, Beibei Hu, Kevin J Freise, Suresh K Agarwal, Dilraj S Sidhu, Shekman L Wong
BACKGROUND AND OBJECTIVE: Venetoclax is a selective, B-cell lymphoma-2 inhibitor that has demonstrated clinical efficacy in a variety of hematological malignancies. In vitro data indicated weak cytochrome P450 (CYP) 2C9 inhibition by venetoclax; however, it is not predicted to cause clinically relevant inhibition due to high plasma protein binding. A Phase 1 study was conducted in healthy volunteers to evaluate the effect of venetoclax on warfarin pharmacokinetics. METHODS: Subjects received a single oral dose of 5 mg warfarin on day 1 of both periods 1 and 2, separated by a 14 days washout...
March 2017: Clinical Drug Investigation
https://www.readbyqxmd.com/read/27859472/effect-of-ketoconazole-a-strong-cyp3a-inhibitor-on-the-pharmacokinetics-of-venetoclax-a-bcl-2-inhibitor-in-patients-with-non-hodgkin-lymphoma
#20
Suresh K Agarwal, Ahmed Hamed Salem, Alexey V Danilov, Beibei Hu, Soham Puvvada, Martin Gutierrez, David Chien, Lionel D Lewis, Shekman L Wong
AIMS: To examine the effect of a strong cytochrome P450 (CYP) 3A inhibitor, ketoconazole, on the pharmacokinetics, safety and tolerability of venetoclax. METHODS: Twelve patients with non-Hodgkin lymphoma (NHL) were enrolled in this Phase 1, open-label, fixed-sequence study. Patients received a single 50 mg dose of venetoclax orally on Day 1 and Day 8, and a 400 mg once daily dose of ketoconazole on Days 5-11. Blood samples were collected predose and up to 96 h after each venetoclax dose on Day 1 and Day 8...
April 2017: British Journal of Clinical Pharmacology
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