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Venetoclax cll

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https://www.readbyqxmd.com/read/29899021/statins-enhance-efficacy-of-venetoclax-in-blood-cancers
#1
J Scott Lee, Andrew Roberts, Dennis Juarez, Thanh-Trang T Vo, Shruti Bhatt, Lee-Or Herzog, Sharmila Mallya, Richard J Bellin, Suresh K Agarwal, Ahmed Hamed Salem, Tu Xu, Jia Jia, Lingxiao Li, John R Hanna, Matthew S Davids, Angela G Fleischman, Susan O'Brien, Lloyd T Lam, Joel D Leverson, Anthony Letai, Jonathan H Schatz, David A Fruman
Statins have shown promise as anticancer agents in experimental and epidemiologic research. However, any benefit that they provide is likely context-dependent, for example, applicable only to certain cancers or in combination with specific anticancer drugs. We report that inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) using statins enhances the proapoptotic activity of the B cell lymphoma-2 (BCL2) inhibitor venetoclax (ABT-199) in primary leukemia and lymphoma cells but not in normal human peripheral blood mononuclear cells...
June 13, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29895707/comprehensive-safety-analysis-of-venetoclax-monotherapy-for-patients-with-relapsed-refractory-chronic-lymphocytic-leukemia
#2
Matthew S Davids, Michael Hallek, William Wierda, Andrew W Roberts, Stephan Stilgenbauer, Jeffrey A Jones, John F Gerecitano, Su Young Kim, Jalaja Potluri, Todd Busman, Andrea Best, Maria E Verdugo, Elisa Cerri, Monali Desai, Peter Hillmen, John F Seymour
PURPOSE: The oral BCL-2 inhibitor venetoclax is an effective therapy for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), including disease with high-risk genomic features such as chromosome 17p deletion (del[17p]) or progressive disease following B-cell receptor pathway inhibitors. EXPERIMENTAL DESIGN: We conducted a comprehensive analysis of the safety of 400mg daily venetoclax monotherapy in 350 patients with CLL using an integrated dataset from three phase-I/II studies...
June 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29880613/real-world-outcomes-and-management-strategies-for-venetoclax-treated-chronic-lymphocytic-leukemia-patients-in-the-united-states
#3
Anthony R Mato, Meghan Thompson, John N Allan, Danielle M Brander, John M Pagel, Chaitra S Ujjani, Brian T Hill, Nicole Lamanna, Frederick Lansigan, Ryan Jacobs, Mazyar Shadman, Alan P Skarbnik, Jeffrey J Pu, Paul M Barr, Alison R Sehgal, Bruce D Cheson, Clive S Zent, Hande H Tuncer, Stephen J Schuster, Peter V Pickens, Nirav N Shah, Andre Goy, Allison M Winter, Christine Garcia, Kaitlin Kennard, Krista Isaac, Colleen Dorsey, Lisa M Gashonia, Arun K Singavi, Lindsey E Roeker, Andrew Zelenetz, Annalynn Williams, Christina Howlett, Hanna Weissbrot, Naveed Ali, Sirin Khajavian, Andrea Sitlinger, Eve Tranchito, Joanna Rhodes, Joshua Felsenfeld, Neil Bailey, Bhavisha Patel, Timothy F Burns, Melissa Yacur, Mansi Malhotra, Jakub Svoboda, Richard R Furman, Chadi Nabhan
Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with CLL treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated IGHV, 45% del(17p), and 26...
June 7, 2018: Haematologica
https://www.readbyqxmd.com/read/29791237/the-future-of-chronic-lymphocytic-leukemia-potential-directions-from-ash-2017
#4
Stefano Molica
Novel targeted therapies - including ibrutinib, venetoclax, and idelalisib - have revolutionized the treatment landscape of chronic lymphocytic leukemia (CLL). Therefore, studying combinations of novel agents (NAs) with a distinct mechanism of action and nonoverlapping toxicities is challenging. Area covered: The 2017 American Society Hematology Annual Meeting has represented a showcase for several trials combining NAs. These studies are currently evaluating the efficacy NA plus anti-CD20 monoclonal antibody, NA plus NA (with or without anti-CD20 monoclonal antibody), and NA plus chemo-immunotherapy...
June 2018: Expert Review of Hematology
https://www.readbyqxmd.com/read/29767411/mek1-2-inhibition-by-binimetinib-is-effective-as-a-single-agent-and-potentiates-the-actions-of-venetoclax-and-abt-737-under-conditions-that-mimic-the-chronic-lymphocytic-leukaemia-cll-tumour-microenvironment
#5
Kyle Crassini, Yandong Shen, William S Stevenson, Richard Christopherson, Chris Ward, Stephen P Mulligan, O Giles Best
The survival and proliferation of chronic lymphocytic leukaemia (CLL) cells is driven by multiple signalling pathways, including those mediated by the B cell, Toll-like and chemokine receptors. Many of these pathways converge on the same signalling molecules, including those involved in the Raf-1/MEK/Erk1/2-MAPK pathway. We investigated the effects of the MEK1/2 (also termed MAP2K1/2) inhibitor, binimetinib, against CLL cells cultured under conditions that mimic aspects of the tumour microenvironment. Binimetinib blocked CLL cell survival induced by stroma-conditioned media and phorbol myristylate (PMA)...
May 16, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29759975/restoring-the-switch-for-cancer-cell-death-targeting-the-apoptosis-signaling-pathway
#6
REVIEW
Clement Chung
PURPOSE: The relevance of apoptosis to cancer development and pharmacologic agents that target this pathway in selected malignancies are described. SUMMARY: Apoptosis is a tightly regulated biological process mediated by both proapoptotic (i.e., prodeath) and antiapoptotic (i.e., prosurvival) proteins. While apoptosis represents a well-established effector mechanism induced by conventional chemotherapy in many malignancies, the development of apoptosis-based targeted therapy is relatively new...
May 14, 2018: American Journal of Health-system Pharmacy: AJHP
https://www.readbyqxmd.com/read/29752258/how-and-when-i-do-allogeneic-transplant-in-cll
#7
John G Gribben
Allogenic stem cell transplantation (allo-SCT) has been considered the treatment of choice for high-risk patients with chronic lymphocytic leukemia (CLL) and the only approach offered with curative intent in this disease. The availability novel agents including the B cell receptor inhibitors (BCRi) ibrutinib, acalabrutinib and idelalisib, as well as venetoclax which targets the BCL2 pathway and the success of these agents in treating high-risk disease patients has made it more difficult to assess who and when in their treatment course allo-SCT should be considered...
May 11, 2018: Blood
https://www.readbyqxmd.com/read/29747654/bcl-2-as-therapeutic-target-for-hematological-malignancies
#8
REVIEW
Guilherme Fleury Perini, Glaciano Nogueira Ribeiro, Jorge Vaz Pinto Neto, Laura Tojeiro Campos, Nelson Hamerschlak
Disruption of the physiologic balance between cell proliferation and cell death is an important step of cancer development. Increased resistance to apoptosis is a key oncogenic mechanism in several hematological malignancies and, in many cases, especially in lymphoid neoplasias, has been attributed to the upregulation of BCL-2. The BCL-2 protein is the founding member of the BCL-2 family of apoptosis regulators and was the first apoptosis modulator to be associated with cancer. The recognition of the important role played by BCL-2 for cancer development and resistance to treatment made it a relevant target for therapy for many diseases, including solid tumors and hematological neoplasias...
May 11, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29728204/chronic-lymphocytic-leukemia-diagnosis-and-treatment
#9
REVIEW
Paolo Strati, Nitin Jain, Susan O'Brien
The complexity of the treatment of patients with chronic lymphocytic leukemia has increased substantially over the past several years as a consequence of the advent of novel biological agents such as ibrutinib, idelalisib, and venetoclax, as well as increasingly potent anti-CD20 monoclonal antibodies. In addition, the identification of molecular predictive markers and the introduction of more sensitive and sophisticated techniques to assess minimal residual disease have allowed optimization of the use of chemoimmunotherapy and targeted therapies and may become standard of care in the future...
May 2018: Mayo Clinic Proceedings
https://www.readbyqxmd.com/read/29715056/venetoclax-for-patients-with-chronic-lymphocytic-leukemia-with-17p-deletion-results-from-the-full-population-of-a-phase-ii-pivotal-trial
#10
Stephan Stilgenbauer, Barbara Eichhorst, Johannes Schetelig, Peter Hillmen, John F Seymour, Steven Coutre, Wojciech Jurczak, Stephen P Mulligan, Anna Schuh, Sarit Assouline, Clemens-Martin Wendtner, Andrew W Roberts, Matthew S Davids, Johannes Bloehdorn, Talha Munir, Sebastian Böttcher, Lang Zhou, Ahmed Hamed Salem, Monali Desai, Brenda Chyla, Jennifer Arzt, Su Young Kim, Maria Verdugo, Gary Gordon, Michael Hallek, William G Wierda
Purpose Venetoclax is an orally bioavailable B-cell lymphoma 2 inhibitor. US Food and Drug Administration and European Medicines Agency approval for patients with 17p deleted relapsed/refractory chronic lymphocytic leukemia [del(17p) CLL] was based on results from 107 patients. An additional 51 patients were enrolled in a safety expansion cohort. Extended analysis of all enrolled patients, including the effect of minimal residual disease (MRD) negativity on outcome, is now reported. Patients and Methods Overall, 158 patients with relapsed/refractory or previously untreated (n = 5) del(17p) CLL received venetoclax 400 mg per day after an initial dose ramp up...
May 1, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29709246/infections-in-patients-with-chronic-lymphocytic-leukaemia-mitigating-risk-in-the-era-of-targeted-therapies
#11
REVIEW
Benjamin W Teh, Constantine S Tam, Sasanka Handunnetti, Leon J Worth, Monica A Slavin
Chronic lymphocytic leukaemia (CLL) is the most common leukaemia with infections a leading cause of morbidity and mortality. Recently there has been a paradigm shift from the use of chemo-immunotherapies to agents targeting specific B-lymphocyte pathways. These agents include ibrutinib, idelalisib and venetoclax. In this review, the risks and timing of infections associated with these agents are described, taking into account disease and treatment status. Treatment with ibrutinib as monotherapy or in combination with chemo-immunotherapies is not associated with additional risk for infection...
April 23, 2018: Blood Reviews
https://www.readbyqxmd.com/read/29651129/venetoclax-rituximab-holds-substantial-promise-in-cll
#12
David Killock
No abstract text is available yet for this article.
June 2018: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/29650729/venetoclax-after-idelalisib-relevant-progress-for-cll
#13
Francesc Bosch, Michael Hallek
No abstract text is available yet for this article.
April 12, 2018: Blood
https://www.readbyqxmd.com/read/29595064/accelerating-drug-development-in-pediatric-cancer-a-novel-phase-i-study-design-of-venetoclax-in-relapsed-refractory-malignancies
#14
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/29562156/venetoclax-rituximab-in-relapsed-or-refractory-chronic-lymphocytic-leukemia
#15
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
#16
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...
May 2018: Expert Review of Hematology
https://www.readbyqxmd.com/read/29520705/targeting-bcl-2-in-hematologic-malignancies
#17
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/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-hematooncology
#19
REVIEW
Jana Mihalyova, Tomas Jelinek, Katerina Growkova, Matous Hrdinka, Michal Simicek, Roman Hajek
Inhibitors of antiapoptotic proteins of the BCL2 family can successfully restart the deregulated process of apoptosis in malignant cells. Whereas nonselective agents have been limited by their affinity to different BCL2 members, 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 leukemia (CLL) with 17p deletion. Extension of indications can be expected in monotherapy and in combination regimens...
May 2018: Experimental Hematology
https://www.readbyqxmd.com/read/29465308/cll2-bxx-phase-ii-trials-sequential-targeted-treatment-for-eradication-of-minimal-residual-disease-in-chronic-lymphocytic-leukemia
#20
Paula Cramer, Julia von Tresckow, Jasmin Bahlo, Anja Engelke, Petra Langerbeins, Anna-Maria Fink, Kirsten Fischer, Clemens-Martin Wendtner, Karl-Anton Kreuzer, Stephan Stilgenbauer, Sebastian Böttcher, Barbara Eichhorst, Michael Hallek
AIM: Four Phase II trials (clinical trials numbers: NCT02345863, NCT02401503, NCT02445131 and NCT02689141) evaluate a different combination of targeted agents in an all-comer population of approximately 60 patients with chronic lymphocytic leukemia irrespective of prior treatment, physical fitness and genetic risk factors. Patients with a higher tumor load start with a debulking treatment with bendamustine. The subsequent induction and maintenance treatment with an anti-CD20 antibody (obinutuzumab or ofatumumab) and a targeted oral agent (ibrutinib, idelalisib or venetoclax) are continued until achievement of a complete response and minimal residual disease negativity...
March 2018: Future Oncology
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