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Venetoclax lymphoma

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https://www.readbyqxmd.com/read/28056525/venetoclax
#1
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...
December 1, 2016: 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
#2
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 (iNHL). In CLL, duvelisib monotherapy is associated with high iwCLL 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 (RNA seq, Nanostring, Affymetrix array, and real time RT-PCR) demonstrated increased expression of BCL2 along with several BH3-only pro-apoptotic genes...
December 26, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27993930/absorption-metabolism-and-excretion-of-a-novel-bcl-2-inhibitor-venetoclax-in-humans
#3
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 Maria de Morais, Anthony J Lee
Venetoclax (also known as ABT-199) is a B-cell lymphoma-2 (Bcl-2) family protein inhibitor and is currently in clinical development for the treatment of chronic lymphocytic leukaemia (CLL) and other hematological malignancies. The objective of this study was to characterize the absorption, metabolism, and excretion of venetoclax in humans. Following a single oral dose of 200 mg (100 μ - Ci) of [(14)C]venetoclax to four healthy volunteers, recovery of total radioactive dose was 100% (± 5%), with feces being the major route of elimination of the administered dose, whereas urinary excretion was minimal (<0...
December 19, 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27990281/mitochondrial-apoptosis-and-bh3-mimetics
#4
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
#5
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
#6
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
#7
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...
December 2, 2016: 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
#8
Suresh K Agarwal, Ahmed Hamed Salem, Alexey V Danilov, Beibei Hu, Soham Puvvada, Martin Gutierrez, David Chien, Lionel D Lewis, Shekman L Wong
AIM: To examine the effect of a strong CYP3A 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 through 11. Blood samples were collected predose and up to 96 hours after each venetoclax dose on Day 1 and Day 8...
November 2, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27854102/the-next-generation-of-targeted-molecules-for-the-treatment-of-chronic-lymphocytic-leukemia
#9
REVIEW
Deepa Jeyakumar, Susan O'Brien
With the recent approval of several new targeted therapies for chronic lymphocytic leukemia (CLL), there are now multiple options for its treatment. Inhibitors of Bruton tyrosine kinase (with ibrutinib being the first-in-class US Food and Drug Administration-approved agent) and phosphoinositide 3-kinase (with idelalisib as the first-in-class approved agent) are promising because they are generally well tolerated and highly effective against this malignancy. These agents may be particularly important in the treatment of older patients who are less able to tolerate the myelosuppression (and subsequent infections) associated with chemoimmunotherapy...
November 15, 2016: Oncology (Williston Park, NY)
https://www.readbyqxmd.com/read/27806433/targeting-bcl2-with-bh3-mimetics-basic-science-and-clinical-application-of-venetoclax-in-chronic-lymphocytic-leukemia-and-related-b-cell-malignancies
#10
A W Roberts, Dcs Huang
The intracellular protein B-cell-lymphoma-2 (BCL2) has been considered an attractive target for cancer therapy since the discovery of its function as a major promoter of cell survival (an anti-apoptotic) in the late 1980s. However, the challenges of targeting a protein-protein interaction delayed the discovery of fit-for-purpose molecules until the mid-2000s. Since then, a series of high affinity small organic molecules that inhibits the interaction of BCL2 with the apoptotic machinery, the so-called BH3-mimetics, have been developed...
January 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27697772/rational-targeted-therapies-to-overcome-microenvironment-dependent-expansion-of-mantle-cell-lymphoma
#11
David Chiron, Céline Bellanger, Antonin Papin, Benoit Tessoulin, Christelle Dousset, Sophie Maiga, Anne Moreau, Julie Esbelin, Valérie Trichet, Selina Chen-Kiang, Philippe Moreau, Cyrille Touzeau, Steven Le Gouill, Martine Amiot, Catherine Pellat-Deceunynck
Mantle cell lymphoma (MCL) accumulates in lymphoid organs, but disseminates early on in extranodal tissues. Although proliferation remains located in lymphoid organs only, suggesting a major role of the tumor ecosystem, few studies have assessed MCL microenvironment. We therefore cocultured primary circulating MCL cells from 21 patients several weeks ex vivo with stromal or lymphoid-like (CD40L) cells to determine which interactions could support their proliferation. We showed that coculture with lymphoid-like cells, but not stromal cells, induced cell-cycle progression, which was amplified by MCL-specific cytokines (insulin-like growth factor-1, B-cell activating factor, interleukin-6, interleukin-10)...
December 15, 2016: Blood
https://www.readbyqxmd.com/read/27695617/the-potential-of-venetoclax-abt-199-in-chronic-lymphocytic-leukemia
#12
Gilad Itchaki, Jennifer R Brown
Venetoclax (VEN, ABT-199/GDC-0199) is an orally bioavailable BH3-mimetic that specifically inhibits the anti-apoptotic B-cell lymphoma/leukemia 2 (BCL2) protein. Although BCL2 overexpression is not genetically driven in chronic lymphocytic leukemia (CLL), it is nearly universal and represents a highly important and prevalent mechanism of apoptosis evasion, making it an attractive therapeutic target. This review summarizes the role of BCL2 in CLL pathogenesis, the development path targeting its inhibition prior to VEN, and the preclinical and clinical data regarding the effectiveness and safety of VEN...
October 2016: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/27661108/acquired-resistance-to-venetoclax-abt-199-in-t-14-18-positive-lymphoma-cells
#13
Juraj Bodo, Xiaoxian Zhao, Lisa Durkin, Andrew J Souers, Darren C Phillips, Mitchell R Smith, Eric D Hsi
The chromosomal translocation t(14;18) in follicular lymphoma (FL) is a primary oncogenic event resulting in BCL-2 over-expression. This study investigates activity of the BH3 mimetic venetoclax (ABT-199), which targets BCL-2, and mechanisms of acquired resistance in FL.The sensitivity of FL cells to venetoclax treatment correlated with BCL-2/BIM ratio. Cells with similar expression of anti-apoptotic proteins, but with higher levels of BIM were more sensitive to the treatment. Venetoclax induced dissociation of BCL-2/ BIM complex and a decrease in mitochondrial potential...
September 20, 2016: Oncotarget
https://www.readbyqxmd.com/read/27638334/impact-of-venetoclax-exposure-on-clinical-efficacy-and-safety-in-patients-with-relapsed-or-refractory-chronic-lymphocytic-leukemia
#14
Kevin J Freise, Aksana K Jones, Doerthe Eckert, Sven Mensing, Shekman L Wong, Rod A Humerickhouse, Walid M Awni, Ahmed Hamed Salem
BACKGROUND: Venetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that restores apoptosis in cancer cells and has demonstrated efficacy in a variety of hematological malignancies. OBJECTIVE: The objective of this research was to characterize the relationship between venetoclax exposures and efficacy and safety in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). METHODS: A total of 272 and 338 patients from four clinical studies were pooled for the exposure-efficacy and exposure-safety analyses, respectively...
September 15, 2016: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/27586967/venetoclax-does-not-prolong-the-qt-interval-in-patients-with-hematological-malignancies-an-exposure-response-analysis
#15
Kevin J Freise, Martin Dunbar, Aksana K Jones, David Hoffman, Sari L Heitner Enschede, Shekman Wong, Ahmed Hamed Salem
PURPOSE: Venetoclax (ABT-199/GDC-0199) is a selective first-in-class B cell lymphoma-2 inhibitor being developed for the treatment of hematological malignancies. The aim of this study was to determine the potential of venetoclax to prolong the corrected QT (QTc) interval and to evaluate the relationship between systemic venetoclax concentration and QTc interval. METHODS: The study population included 176 male and female patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 105) or non-Hodgkin's lymphoma (n = 71) enrolled in a phase 1 safety, pharmacokinetic, and efficacy study...
October 2016: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/27582059/targeting-bcl-2-and-abl-lyn-in-philadelphia-chromosome-positive-acute-lymphoblastic-leukemia
#16
Jessica T Leonard, Joelle S J Rowley, Christopher A Eide, Elie Traer, Brandon Hayes-Lattin, Marc Loriaux, Stephen E Spurgeon, Brian J Druker, Jeffrey W Tyner, Bill H Chang
Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) remains a challenge. Although the addition of targeted tyrosine kinase inhibitors (TKIs) to standard cytotoxic therapy has greatly improved upfront treatment, treatment-related morbidity and mortality remain high. TKI monotherapy provides only temporary responses and renders patients susceptible to the development of TKI resistance. Thus, identifying agents that could enhance the activity of TKIs is urgently needed. Recently, a selective inhibitor of B cell lymphoma 2 (BCL-2), ABT-199 (venetoclax), has shown impressive activity against hematologic malignancies...
August 31, 2016: Science Translational Medicine
https://www.readbyqxmd.com/read/27558232/pharmacokinetics-of-venetoclax-a-novel-bcl-2-inhibitor-in-patients-with-relapsed-or-refractory-chronic-lymphocytic-leukemia-or-non-hodgkin-lymphoma
#17
Ahmed Hamed Salem, Suresh K Agarwal, Martin Dunbar, Sari L Heitner Enschede, Rod A Humerickhouse, Shekman L Wong
Venetoclax is a selective BCL-2 inhibitor that is approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. The aim of this analysis was to characterize venetoclax pharmacokinetics in the plasma and urine of patients with hematological malignancies and evaluate the effect of dose proportionality, accumulation, weak and moderate CYP3A inhibitors, as well as low- and high-fat meals on venetoclax pharmacokinetics...
August 25, 2016: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27520294/efficacy-and-biological-correlates-of-response-in-a-phase-ii-study-of-venetoclax-monotherapy-in-patients-with-acute-myelogenous-leukemia
#18
Marina Konopleva, Daniel A Pollyea, Jalaja Potluri, Brenda Chyla, Leah Hogdal, Todd Busman, Evelyn McKeegan, Ahmed Hamed Salem, Ming Zhu, Justin L Ricker, William Blum, Courtney D DiNardo, Tapan Kadia, Martin Dunbar, Rachel Kirby, Nancy Falotico, Joel Leverson, Rod Humerickhouse, Mack Mabry, Richard Stone, Hagop Kantarjian, Anthony Letai
: We present a phase II, single-arm study evaluating 800 mg daily venetoclax, a highly selective, oral small-molecule B-cell leukemia/lymphoma-2 (BCL2) inhibitor in patients with high-risk relapsed/refractory acute myelogenous leukemia (AML) or unfit for intensive chemotherapy. Responses were evaluated following revised International Working Group (IWG) criteria. The overall response rate was 19%; an additional 19% of patients demonstrated antileukemic activity not meeting IWG criteria (partial bone marrow response and incomplete hematologic recovery)...
October 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27260335/venetoclax-first-global-approval
#19
Emma D Deeks
Venetoclax (Venclexta™) is an oral selective inhibitor of the prosurvival protein BCL-2 and therefore restores the apoptotic ability of malignant cells. The drug arose from research by Abbott Laboratories (now AbbVie) during a collaboration with Genentech and is being co-developed by AbbVie and Genentech/Roche primarily for the treatment of haematological malignancies. Venetoclax is approved in the USA for use as monotherapy in patients with chronic lymphocytic leukaemia (CLL) with the 17p deletion (as detected by an approved FDA test) who have received at least one prior therapy, and is awaiting approval for similar indications in the EU and Canada...
June 2016: Drugs
https://www.readbyqxmd.com/read/27233802/clinical-predictors-of-venetoclax-pharmacokinetics-in-chronic-lymphocytic-leukemia-and-non-hodgkin-s-lymphoma-patients-a-pooled-population-pharmacokinetic-analysis
#20
Aksana K Jones, Kevin J Freise, Suresh K Agarwal, Rod A Humerickhouse, Shekman L Wong, Ahmed Hamed Salem
Venetoclax (ABT-199/GDC-0199) is a selective, potent, first-in-class BCL-2 inhibitor that restores apoptosis in cancer cells and has demonstrated clinical efficacy in a variety of hematological malignancies. The objective of this analysis was to characterize the population pharmacokinetics of venetoclax and identify demographic, pathophysiologic, and treatment factors that influence its pharmacokinetics. Plasma concentration samples from 505 subjects enrolled in 8 clinical studies were analyzed using non-linear mixed-effects modeling...
September 2016: AAPS Journal
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