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Venetoclax lymphoma

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https://www.readbyqxmd.com/read/28914567/chemotherapy-free-triple-combination-of-obinutuzumab-venetoclax-and-idasanutlin-antitumor-activity-in-xenograft-models-of-non-hodgkin-lymphoma
#1
Frank Herting, Thomas Friess, Pablo Umaña, Steven Middleton, Christian Klein
No abstract text is available yet for this article.
September 15, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28851760/tumor-lysis-syndrome-in-chronic-lymphocytic-leukemia-with-novel-targeted-agents
#2
Bruce D Cheson, Sari Heitner Enschede, Elisa Cerri, Monali Desai, Jalaja Potluri, Nicole Lamanna, Constantine Tam
Tumor lysis syndrome (TLS) is an uncommon but potentially life-threatening complication associated with the treatment of some cancers. If left untreated, TLS may result in acute renal failure, cardiac dysrhythmia, neurologic complications, seizures, or death. Tumor lysis syndrome is most commonly observed in patients with hematologic malignancies with a high proliferation rate undergoing treatment with very effective therapies. In chronic lymphocytic leukemia (CLL), historically, TLS has been observed less often, owing to a low proliferation rate and slow response to chemotherapy...
August 29, 2017: Oncologist
https://www.readbyqxmd.com/read/28797193/exposure-response-evaluations-of-venetoclax-efficacy-and-safety-in-patients-with-non-hodgkin-lymphoma
#3
Apurvasena Parikh, Sathej Gopalakrishnan, Kevin J Freise, Maria E Verdugo, Rajeev M Menon, Sven Mensing, Ahmed Hamed Salem
Exposure-response analyses were performed for a venetoclax monotherapy study in 106 patients with varying subtypes of non-Hodgkin lymphoma (NHL) (NCT01328626). Logistic regression, time-to-event, and progression-free survival (PFS) analyses were used to evaluate the relationship between venetoclax exposure, NHL subtype and response, PFS, or occurrence of serious adverse events. Trends for small increases in the probability of response with increasing venetoclax exposures were identified, and became more evident when assessed by NHL subtype...
August 10, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28741496/targeting-bcl-2-like-proteins-to-kill-cancer-cells
#4
REVIEW
Suzanne Cory, Andrew W Roberts, Peter M Colman, Jerry M Adams
Mutations that impair apoptosis contribute to cancer development and reduce the effectiveness of conventional anti-cancer therapies. These insights and understanding of how the B cell lymphoma (BCL)-2 protein family governs apoptosis have galvanized the search for a new class of cancer drugs that target its pro-survival members by mimicking their natural antagonists, the BCL-2 homology (BH)3-only proteins. Successful initial clinical trials of the BH3 mimetic venetoclax/ABT-199, specific for BCL-2, have led to its recent licensing for refractory chronic lymphocytic leukemia and to multiple ongoing trials for other malignancies...
August 2016: Trends in Cancer
https://www.readbyqxmd.com/read/28724540/targeting-bcl-2-in-b-cell-lymphomas
#5
REVIEW
Matthew S Davids
The B-cell leukemia/lymphoma-2 (BCL-2) family of proteins governs the intrinsic pathway of mitochondrial apoptosis. Dysregulation of BCL-2 has long been known to be a crucial part of the pathophysiology of B-cell lymphomas; however, several early attempts to target this pathway therapeutically were unsuccessful because of toxicity, lack of efficacy, or both. Recently, a highly potent and selective oral BCL-2 antagonist, venetoclax, was approved in chronic lymphocytic leukemia, where it has proven to be highly active, even in patients with high-risk del(17p) disease...
August 31, 2017: Blood
https://www.readbyqxmd.com/read/28696175/venetoclax-a-novel-b-cell-lymphoma-2-inhibitor-for-chronic-lymphocytic-leukemia-and-other-hematologic-malignancies
#6
Jacqueline L Olin, Carrie L Griffiths, Morgan B Smith
Patients with chronic lymphocytic leukemia with the 17p deletion have a poor prognosis and treatment options are limited. Venetoclax, a novel B-cell lymphoma-2 inhibitor, has been approved for treatment-experienced chronic lymphocytic leukemia patients with the 17p deletion. A phase 1 dose-escalation study to 400 mg daily showed overall response rates across all doses of 79% with a complete response achieved in 20%. A phase 2 multicenter open-label study demonstrated overall response rate of 79.4% of patients (95% confidence interval 70...
January 1, 2017: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/28691866/safety-and-pharmacodynamics-of-venetoclax-abt-199-in-a-randomized-single-and-multiple-ascending-dose-study-in-women-with-systemic-lupus-erythematosus
#7
P Lu, R Fleischmann, C Curtis, S Ignatenko, S H Clarke, M Desai, S L Wong, K M Grebe, K Black, J Zeng, J Stolzenbach, J K Medema
Objective The anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) may contribute to the pathogenesis of systemic lupus erythematosus. The safety, tolerability, and pharmacodynamics of the selective Bcl-2 inhibitor venetoclax (ABT-199) were assessed in women with systemic lupus erythematosus. Methods A phase 1, double-blind, randomized, placebo controlled study evaluated single ascending doses (10, 30, 90, 180, 300, and 500 mg) and multiple ascending doses (2 cycles; 30, 60, 120, 240, 400, and 600 mg for 1 week, and then 3 weeks off per cycle) of orally administered venetoclax...
January 1, 2017: Lupus
https://www.readbyqxmd.com/read/28665232/integrating-novel-drugs-to-chemoimmunotherapy-in-diffuse-large-b-cell-lymphoma
#8
Annalisa Chiappella, Elisa Santambrogio, Alessia Castellino, Maura Nicolosi, Umberto Vitolo
Diffuse Large B-cell Lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL), with an incidence in Europe of 3.8/100.000/year. A multi-drugs chemoimmunotherapy regimen, containing rituximab, cyclophosphamide, vincristine, doxorubicin and prednisone (R-CHOP) administrated every 21 days, is the standard therapy for DLBCL patients. The discovery of several biological features of DLBCL has encouraged the introduction of novel drugs in the treatment. Areas covered: In this article, the use of standard therapies will be reviewed and will be investigated adoption of novel drugs such as Bortezomib, Bruton's tyrosine kinase, IMiDs, Venetoclax, mTOR inhibitors and other biological agents...
August 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28663582/bet-protein-proteolysis-targeting-chimera-protac-exerts-potent-lethal-activity-against-mantle-cell-lymphoma-cells
#9
B Sun, W Fiskus, Y Qian, K Rajapakshe, K Raina, K G Coleman, A P Crew, A Shen, D T Saenz, C P Mill, A J Nowak, N Jain, L Zhang, M Wang, J D Khoury, C Coarfa, C M Crews, K N Bhalla
Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and NFkB target genes, which undermines the growth and survival of MCL cells. However, BETi treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4, which potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells...
June 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28653191/microrna-dysregulation-to-identify-novel-therapeutic-targets
#10
Carlo M Croce
This paper describes how we discovered the juxtaposition of the MYC gene to the human immunoglobulin loci and how that finding was extended to characterize molecularly the t(14;18) chromosome translocation of follicular lymphoma and to clone the BCL2 gene. BCL2 is also overexpressed in CLL, the most common human leukemia. We discovered that most of human CLLs have a deletion of two microRNAs residing in the same polycistronic RNA, miR-15a and miR-16-1, and that these two microRNAs are negative regulators of BCL2...
June 27, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28619982/jak1-2-and-bcl2-inhibitors-synergize-to-counteract-bone-marrow-stromal-cell-induced-protection-of-aml
#11
Riikka Karjalainen, Tea Pemovska, Mihaela Popa, Minxia Liu, Komal K Javarappa, Muntasir M Majumder, Bhagwan Yadav, David Tamborero, Jing Tang, Dmitrii Bychkov, Mika Kontro, Alun Parsons, Minna Suvela, Mireia Mayoral Safont, Kimmo Porkka, Tero Aittokallio, Olli Kallioniemi, Emmet McCormack, Bjørn T Gjertsen, Krister Wennerberg, Jonathan Knowles, Caroline A Heckman
The bone marrow (BM) provides a protective microenvironment to support the survival of leukemic cells and influence their response to therapeutic agents. In acute myeloid leukemia (AML), the high rate of relapse may in part be a result of the inability of current treatment to effectively overcome the protective influence of the BM niche. To better understand the effect of the BM microenvironment on drug responses in AML, we conducted a comprehensive evaluation of 304 inhibitors, including approved and investigational agents, comparing ex vivo responses of primary AML cells in BM stroma-derived and standard culture conditions...
August 10, 2017: Blood
https://www.readbyqxmd.com/read/28578655/potential-mechanisms-of-resistance-to-venetoclax-and-strategies-to-circumvent-it
#12
Stephen K Tahir, Morey L Smith, Paul Hessler, Lisa Roberts Rapp, Kenneth B Idler, Chang H Park, Joel D Leverson, Lloyd T Lam
BACKGROUND: Venetoclax (ABT-199), a first-in-class orally bioavailable BCL-2-selective inhibitor, was recently approved by the FDA for use in patients with 17p-deleted chronic lymphocytic leukemia who have received prior therapy. It is also being evaluated in numerous clinical trials for treating patients with various hematologic malignancies. As with any targeted cancer therapy, it is critically important to identify potential mechanisms of resistance, both for patient stratification and developing strategies to overcome resistance, either before it develops or as it emerges...
June 2, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28566329/venetoclax-synergizes-with-radiotherapy-for-treatment-of-b-cell-lymphomas
#13
Shyril O'Steen, Damian J Green, Ajay K Gopal, Johnnie J Orozco, Aimee L Kenoyer, Yukang Lin, D Scott Wilbur, Donald K Hamlin, Darrell R Fisher, Mark D Hylarides, Theodore A Gooley, Amelia Waltman, Brian G Till, Oliver W Press
Constitutive B-cell receptor signaling leads to overexpression of the antiapoptotic BCL-2 protein and is implicated in the pathogenesis of many types of B-cell non-Hodgkin lymphoma (B-NHL). The BCL-2 small-molecule inhibitor venetoclax shows promising clinical response rates in several lymphomas, but is not curative as monotherapy. Radiotherapy is a rational candidate for combining with BCL-2 inhibition, as DNA damage caused by radiotherapy increases the activity of pro-apoptotic BCL-2 pathway proteins, and lymphomas are exquisitely sensitive to radiation...
July 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28562380/pharmacokinetics-of-venetoclax-in-patients-with-17p-deletion-chronic-lymphocytic-leukemia
#14
Ahmed Hamed Salem, Martin Dunbar, Suresh K Agarwal
Venetoclax is a first-in-class orally available, B-cell lymphoma (BCL)-2 inhibitor indicated for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) harboring the 17p deletion. We used a novel approach for evaluating venetoclax pharmacokinetics using only sparse sampling in 155 patients enrolled in a phase 2, multicenter, open-label study in CLL patients with the 17p deletion. Patients received venetoclax doses within 30 min after the completion of breakfast or the first meal of the day, with no specific recommendations for the fat content in the meal...
September 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28536906/current-status-of-bruton-s-tyrosine-kinase-inhibitor-development-and-use-in-b-cell-malignancies
#15
REVIEW
Andrew Aw, Jennifer R Brown
The B-cell receptor (BCR) pathway plays an important role in the survival, proliferation and trafficking of cancer cells in a variety of B-cell malignancies. Recently, a number of agents have been developed to target various components of the BCR pathway. One such target is Bruton's tyrosine kinase (BTK), a Tec family kinase member found near the cell membrane that is involved in upstream BCR signaling. The biological function of BTK in several B-cell lymphoid malignancies has led to the development of the oral BTK inhibitor ibrutinib...
July 2017: Drugs & Aging
https://www.readbyqxmd.com/read/28522442/bcl2-expression-in-dlbcl-reappraisal-of-immunohistochemistry-with-new-criteria-for-therapeutic-biomarker-evaluation
#16
Naoko Tsuyama, Seiji Sakata, Satoko Baba, Yuko Mishima, Noriko Nishimura, Kyoko Ueda, Masahiro Yokoyama, Yasuhito Terui, Kiyohiko Hatake, Masanobu Kitagawa, Naoki Ishizuka, Naoto Tomita, Kengo Takeuchi
Overexpression of the BCL2 is associated with a poor prognosis in diffuse large B-cell lymphoma (DLBCL). The assessment of MYC immunohistochemistry (IHC) is becoming optimized, whereas the criteria for BCL2 positivity are highly variable. Furthermore, data on the frequency and prognostic value of BCL2 positivity are conflicting. We aimed to evaluate BCL2 expression by IHC and assess the prognostic significance of the histopathologically scored BCL2 expression in 456 patients with DLBCL uniformly treated with standard immunochemotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, R-CHOP)...
July 27, 2017: Blood
https://www.readbyqxmd.com/read/28473407/clinicopathological-features-and-outcomes-of-progression-of-cll-on-the-bcl2-inhibitor-venetoclax
#17
Mary Ann Anderson, Constantine Tam, Thomas E Lew, Surender Juneja, Manu Juneja, David Westerman, Meaghan Wall, Stephen Lade, Alexandra Gorelik, David C S Huang, John F Seymour, Andrew W Roberts
The BCL2 inhibitor venetoclax achieves responses in ∼79% of patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (RR-CLL/SLL), irrespective of risk factors associated with poor response to chemoimmunotherapy. A limitation of this targeted therapy is progressive disease (PD) in some patients. To define the risk factors for progression, the clinicopathological features of PD, and the outcomes for patients after venetoclax failure, we analyzed 67 heavily pretreated patients on 3 early phase clinical trials...
June 22, 2017: Blood
https://www.readbyqxmd.com/read/28449207/targeting-anti-apoptotic-bcl2-family-proteins-in-haematological-malignancies-from-pathogenesis-to-treatment
#18
REVIEW
Meike Vogler, Harriet S Walter, Martin J S Dyer
The B-cell lymphoma 2 (BCL2) family of proteins comprise key regulators of apoptosis and are implicated in the pathogenesis of many malignancies, including lymphomas and leukaemias. Targeting of BCL2 proteins can be directly toxic to tumour cells or render them more sensitive to chemotherapy. Inhibition of the anti-apoptotic functions of BCL2 proteins using structure-based design to produce specific inhibitors of protein-protein interactions has been achieved for BCL2, MCL1 and BCL-XL (also termed BCL2L1), providing an armamentarium of new targeted therapies called BH3-mimetics...
April 27, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28439761/small-molecule-inhibitors-in-chronic-lymphocytic-lymphoma-and-b-cell-non-hodgkin-lymphoma
#19
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...
June 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/28416490/preclinical-characterization-of-bet-family-bromodomain-inhibitor-abbv-075-suggests-combination-therapeutic-strategies
#20
Mai H Bui, Xiaoyu Lin, Daniel H Albert, Leiming Li, Lloyd T Lam, Emily J Faivre, Scott E 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 hematologic 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 lymphoma, and multiple myeloma cells...
June 1, 2017: Cancer Research
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