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venetoclax

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https://www.readbyqxmd.com/read/28522442/bcl2-expression-in-dlbcl-reappraisal-of-immunohistochemistry-with-new-criteria-for-therapeutic-biomarker-evaluation
#1
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)...
May 18, 2017: Blood
https://www.readbyqxmd.com/read/28492339/venetoclax-for-the-treatment-of-patients-with-chronic-lymphocytic-leukemia
#2
Jennifer Crombie, Matthew S Davids
Venetoclax is a potent, selective inhibitor of BCL-2, a key regulator of the intrinsic pathway of apoptosis. In preclinical studies, venetoclax bound to BCL-2 with high affinity and rapidly induced apoptosis in chronic lymphocytic leukemia (CLL) cells. In early-phase clinical trials in CLL, venetoclax treatment led to tumor lysis syndrome in some patients with a large tumor burden, but this risk was subsequently mitigated by a revised study design that included lower initial dosing with intrapatient dose ramp-up and close tumor lysis syndrome monitoring and prophylaxis...
May 11, 2017: Future Oncology
https://www.readbyqxmd.com/read/28482721/the-potential-combination-of-bcl-2-inhibitors-and-ibrutinib-as-frontline-therapy-in-chronic-lymphocytic-leukemia
#3
Andrew Aw, Jennifer R Brown
The recent development of small molecule inhibitors targeted at the B-cell receptor (BCR) pathway and the anti-apoptotic protein BCL-2 has revolutionized the care of patients with chronic lymphocytic leukemia (CLL). While durable responses to the BCR inhibitor ibrutinib have been observed in both previously untreated and relapsed/refractory CLL patients, residual disease is common in patients treated with single-agent ibrutinib. Interest remains high in therapeutic combinations that may lead to better quality remissions...
May 9, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28473407/clinico-pathological-features-and-outcomes-of-progression-of-cll-on-the-bcl2-inhibitor-venetoclax
#4
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 chemo-immunotherapy. A limitation of this targeted therapy is progressive disease (PD) in some patients. To define the risk factors for progression, the clinico-pathological features of PD and the outcomes for patients after venetoclax failure, we analyzed 67 heavily pre-treated patients on three early phase clinical trials...
May 4, 2017: Blood
https://www.readbyqxmd.com/read/28468776/vulnerability-of-small-cell-lung-cancer-to-apoptosis-induced-by-the-combination-of-bet-bromodomain-proteins-and-bcl2-inhibitors
#5
Lloyd T Lam, Xiaoyu Lin, Emily J Faivre, Ziping Yang, Xiaoli Huang, Denise M Wilcox, Richard J Bellin, Sha Jin, Stephen K Tahir, Michael Mitten, Terry Magoc, Anahita Bhathena, Warren M Kati, Daniel H Albert, Yu Shen, Tamar Uziel
10% to 15% of all lung cancers are small cell lung cancer (SCLC). SCLC usually grows and metastasizes before it is diagnosed and relapses rapidly upon treatment. Unfortunately, no new targeted agent has been approved in the past 30 years for patients with SCLC. The BET (bromodomain and extra-terminal) proteins bind acetylated histones and recruit protein complexes to promote transcription initiation and elongation. BET proteins have been shown to regulate expression of key genes in oncogenesis such as MYC, CCND2, and BCL2L1 Here, we demonstrate that ~50% of SCLC cell lines are exquisitely sensitive to growth inhibition by the BET inhibitor, ABBV-075...
May 3, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28462890/multiple-myeloma-clinical-updates-from-the-american-society-of-hematology-annual-meeting-2016
#6
REVIEW
Evangelos Terpos
The novel clinical data for plasma cell neoplasms (smoldering myeloma, multiple myeloma (MM) and AL-amyloidosis) that were presented in the 2016 Annual Meeting of the American Society of Hematology are summarized here. Data from large phase 3 studies for newly diagnosed MM patients who are eligible for autologous transplantation (EMN02, MRC XI and StaMINA trials) are described along with the results of phase 2 studies using novel anti-myeloma drug combinations for induction, consolidation and maintenance as first line therapy...
March 18, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28453705/optimal-sequencing-of-ibrutinib-idelalisib-and-venetoclax-in-chronic-lymphocytic-leukemia-results-from-a-multicenter-study-of-683-patients
#7
A R Mato, B T Hill, N Lamanna, P M Barr, C S Ujjani, D M Brander, C Howlett, A P Skarbnik, B D Cheson, C S Zent, J J Pu, P Kiselev, K Foon, J Lenhart, S Henick Bachow, A M Winter, A-L Cruz, D F Claxton, A Goy, C Daniel, K Isaac, K H Kennard, C Timlin, M Fanning, L Gashonia, M Yacur, J Svoboda, S J Schuster, C Nabhan
Background: Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods: We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS)...
May 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28449207/targeting-anti-apoptotic-bcl2-family-proteins-in-haematological-malignancies-from-pathogenesis-to-treatment
#8
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/28448171/novel-investigational-drugs-active-as-single-agents-in-multiple-myeloma
#9
Mattia D'Agostino, Marco Salvini, Antonio Palumbo, Alessandra Larocca, Francesca Gay
Multiple myeloma (MM) is a hematologic malignancy characterized by proliferation of malignant plasma cells. patient outcome has improved markedly over the last decades due to the introduction of novel therapeutic agents such as bortezomib, thalidomide and lenalidomide. However, MM still remains largely incurable and patients eventually become refractory to available treatments. To address this unmet medical need, a variety of new molecules are currently being developed in preclinical models and/or are being investigated in clinical studies...
May 8, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28439761/small-molecule-inhibitors-in-chronic-lymphocytic-lymphoma-and-b-cell-non-hodgkin-lymphoma
#10
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/28419431/moving-beyond-maximum-tolerated-dose-for-targeted-oncology-drugs-use-of-clinical-utility-index-to-optimize-venetoclax-dosage-in-multiple-myeloma-patients
#11
Kevin J Freise, Aksana K Jones, Maria E Verdugo, Rajeev M Menon, Paulo C Maciag, Ahmed Hamed Salem
Exposure-response analyses of venetoclax in combination with bortezomib and dexamethasone in previously treated patients with multiple myeloma (MM) were performed on a Phase 1b venetoclax dose-ranging study. Logistic regression models were utilized to determine relationships, identify sub-populations with different responses and optimize the venetoclax dosage that balanced both efficacy and safety. Bortezomib refractory status and number of prior treatments were identified to impact the efficacy response to venetoclax treatment...
April 17, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28416490/preclinical-characterization-of-bet-family-bromodomain-inhibitor-abbv-075-suggests-combination-therapeutic-strategies
#12
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/28400475/an-ex-vivo-platform-for-the-prediction-of-clinical-response-in-multiple-myeloma
#13
Ariosto S Silva, Maria D Silva, Praneeth Sudalagunta, Allison I Distler, Timothy Jacobson, Aunshka Collins, Tuan Nguyen, Jinming Song, Dung-Tsa Chen, Lu Chen, Christopher L Cubitt, Rachid Baz, Lia Perez, Dmitri Rebatchouk, William Dalton, James Greene, Robert A Gatenby, Robert J Gillies, Eduardo Sontag, Mark B Meads, Kenneth Shain
Multiple myeloma (MM) remains treatable but incurable. Despite a growing armamentarium of effective agents, choice of therapy, especially in relapse, still relies almost exclusively on clinical acumen. We have developed a system, EMMA (Ex vivo Mathematical Myeloma Advisor), consisting of patient-specific mathematical models parameterized by an ex vivo assay that reverse engineers the intensity and heterogeneity of chemosensitivity of primary cells from MM patients, allowing us to predict clinical response to up to 31 drugs within 5 days post-bone marrow biopsy...
April 11, 2017: Cancer Research
https://www.readbyqxmd.com/read/28398276/bcl-2-as-a-therapeutic-target-in-chronic-lymphocytic-leukemia
#14
REVIEW
Catherine Daniel, Anthony R Mato
Venetoclax (formerly ABT-199) was recently approved in the United States for the treatment of patients who have relapsed or refractory chronic lymphocytic leukemia (CLL) with the 17p deletion. Venetoclax has demonstrated marked activity as monotherapy as well as in combination with cytotoxic chemotherapies, B-cell receptor inhibitors, and anti-CD20 monoclonal antibodies across the spectrum of CLL. The potency of venetoclax has been associated with a unique ability to induce deep (minimal residual disease-negative) complete remissions that appear to be durable...
March 2017: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/28389687/advances-in-the-treatment-of-relapsed-refractory-chronic-lymphocytic-leukemia
#15
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/28343293/pharmacokinetic-and-pharmacodynamic-considerations-in-the-treatment-of-chronic-lymphocytic-leukemia-ibrutinib-idelalisib-and-venetoclax
#16
REVIEW
Madeline Waldron, Allison Winter, Brian T Hill
Management of chronic lymphocytic leukemia has changed markedly over the last several years with the emergence of several novel oral agents targeting B-cell receptor and Bcl-2 signaling pathways. For patients requiring treatment, ibrutinib, idelalisib, and venetoclax offer unique clinical benefits with a different set of therapeutic considerations compared with traditional parenteral therapy. Despite the conveniences afforded by oral therapy, these agents also carry unique logistical obstacles. Drug interactions with agents that are metabolized via the cytochrome P450 3A4 pathway are possible with all three agents...
March 25, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28331288/development-of-venetoclax-for-therapy-of-lymphoid-malignancies
#17
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/28331083/maintenance-of-the-hiv-reservoir-is-antagonized-by-selective-bcl2-inhibition
#18
Nathan W Cummins, Amy M Sainski-Nguyen, Sekar Natesampillai, Fatma Aboulnasr, Scott Kaufmann, Andrew D Badley
Decay of the HIV reservoir is slowed over time in part by expansion of the pool of HIV infected cells. This expansion reflects homeostatic proliferation of infected cells by IL-7 or antigenic stimulation, as well as new rounds of infection of susceptible target cells. As novel therapies are being developed to accelerate the decay of the latent HIV reservoir, it will be important to identify interventions that prevent expansion and/or repopulation of the latent HIV reservoir. Our previous studies showed that HIV protease cleaves the host protein procaspase 8 to generate Casp8p41, which can bind and activate BAK to induce apoptosis of infected cells...
March 22, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28325865/venetoclax-and-obinutuzumab-in-chronic-lymphocytic-leukemia
#19
Kirsten Fischer, Othman Al-Sawaf, Anna-Maria Fink, Mark Dixon, Jasmin Bahlo, Simon Warburton, Thomas J Kipps, Robert Weinkove, Sue Robinson, Till Seiler, Stephen Opat, Carolyn Owen, Javier López, Kathryn Humphrey, Rod Humerickhouse, Eugen Tausch, Lukas Frenzel, Barbara Eichhorst, Clemens-M Wendtner, Stephan Stilgenbauer, Anton W Langerak, Jacque J M van Dongen, Sebastian Boettcher, Matthias Ritgen, Valentin Goede, Mehrdad Mobasher, Michael Hallek
No abstract text is available yet for this article.
March 21, 2017: Blood
https://www.readbyqxmd.com/read/28288710/possible-novel-agents-in-marginal-zone-lymphoma
#20
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
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