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Venetoclax cll

Mohamed A Kharfan-Dabaja, Jessica El-Asmar, Farrukh T Awan, Mehdi Hamadani, Ernesto Ayala
Novel therapies targeting various kinases downstream of the B-cell receptor have emerged along with monoclonal antibodies and BCL-2 antagonists, and are changing the therapeutic landscape of chronic lymphocytic leukemia. However, cure remains unattainable unless eligible patients are offered an allogeneic hematopoietic cell transplant. Access to allogeneic hematopoietic cell transplantation has expanded considerably with availability of reduced intensity conditioning regimens which is capable offering durable remissions even in poor-risk disease...
March 2016: Best Practice & Research. Clinical Haematology
Paula Cramer, Barbara Eichhorst, Hans Christian Reinhardt, Michael Hallek
Given the current dynamics in the development of novel agents for CLL therapy, the task to find optimal, non-toxic combinations has become the primary goal. This article gives an update of the most interesting novel drugs. The strategy of the German CLL Study Group to use these agents in combinations is described in detail, highlighting the strategy and first results of a recently started series of phase II combination trials, the BXX series using agents such as bendamustine, idelalisib, ibrutinib, obinutuzumab, ofatumumab and venetoclax...
March 2016: Best Practice & Research. Clinical Haematology
Matthew D Blunt, Stefan Koehrer, Rachel Dobson, Marta Larrayoz, Sarah Wilmore, Alice Hayman, Jack Parnell, Lindsay D Smith, Andrew Davies, Peter Wm Johnson, Pamela B Conley, Anjali Pandey, Jonathan C Strefford, Freda K Stevenson, Graham Packham, Francesco Forconi, Greg P Coffey, Jan Burger, Andrew J Steele
PURPOSE: B-cell receptor (BCR)-associated kinase inhibitors such as ibrutinib have revolutionised the treatment of chronic lymphocytic leukemia (CLL). However, these agents are not curative and resistance is already emerging in a proportion of patients. Interleukin-4 (IL-4), expressed in CLL lymph nodes, can augment BCR-signalling and reduce the effectiveness of BCR-kinase inhibitors. Therefore simultaneous targeting of the IL-4- and BCR-signalling pathways by cerdulatinib, a novel dual Syk/JAK inhibitor currently in clinical trials (NCT01994382), may improve treatment responses in patients...
October 3, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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
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
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
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 now approved in the United States for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least one 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
Ryan S Soderquist, Alan Eastman
Antiapoptotic BCL2 proteins play a major role in tumor cell survival. Hence, BCL2 inhibitors have been developed as direct inducers of apoptosis. ABT-199 (venetoclax) received breakthrough therapy designation from the FDA due to its apparent efficacy in CLL and AML. However, resistance to ABT-199 is mediated by other BCL2 proteins including BCLXL and MCL1. Considerable effort has been expended seeking novel "BH3 mimetics" that inhibit all of these BCL2 proteins. While many BH3 mimetics inhibit BCL2 proteins in vitro, they fail to directly inhibit them in intact cells...
September 2016: Molecular Cancer Therapeutics
Emili Montserrat, Peter Dreger
The treatment of patients with chronic lymphocytic leukemia (CLL) whose tumor presents the del(17p)/TP53 mutation is a major challenge. Treatment with chemo(immuno)therapy, immunomodulators, or the anti-CD52 monoclonal antibody alemtuzumab produces transient, unsatisfactory responses. Reduced-intensity-conditioning allotransplantation produces sustained progression-free survival and overall survival (40%-60% at 5 years), equivalent to the cure of the disease, even in cases with adverse biomarkers. Unfortunately, despite improvements in this procedure, the non-relapse mortality continues to be high (15%-30%), and only highly selected patients (young, physically fit, with treatment-sensitive disease, not heavily pretreated, and with a fully matched donor) may benefit from the intervention without incurring unacceptable treatment-related risks...
August 2016: Clinical Lymphoma, Myeloma & Leukemia
Michele B Kaufman
Venetoclax (Venclexta) for chronic lymphocytic leukemia; riboflavin 5'-phosphate solutions (Photrexa Viscous and Photrexa) for progressive keratoconus; and pimavanserin (Nuplazid) for Parkinson's disease psychosis.
August 2016: P & T: a Peer-reviewed Journal for Formulary Management
M Kontro, A Kumar, M M Majumder, S Eldfors, A Parsons, T Pemovska, J Saarela, B Yadav, D Malani, Y Fløisand, M Höglund, K Remes, B T Gjertsen, O Kallioniemi, K Wennerberg, C A Heckman, K Porkka
Inhibitors of BCL-2 such as venetoclax (ABT-199) and navitoclax (ABT-263) are clinically explored in several cancer types, including acute myeloid leukemia (AML), to selectively induce apoptosis in cancer cells. To identify robust biomarkers for BCL-2 inhibitor sensitivity, we evaluated the ex vivo sensitivity of fresh leukemic cells from 73 diagnosed and relapsed/refractory AML patients, then comprehensively assessed if the responses correlated to specific mutations or gene expression signatures. Compared to samples from healthy donor controls (non-sensitive) and chronic lymphocytic leukemia (CLL) patients (highly-sensitive), AML samples exhibited variable responses to BCL-2 inhibition...
August 8, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Barbara Eichhorst, Michael Hallek, Valentin Goede
The majority of patients with chronic lymphocytic leukemia (CLL) are over 70years old. These patients vary in their vulnerability toward treatment efforts. Heterogeneity in fitness of older patients with CLL is mainly determined by individual differences in physiological aging and pathological conditions such as comorbidities and geriatric syndromes. Various options exist to treat older patients with CLL outside and inside clinical trials. Among these are new treatment approaches, including chemoimmunotherapy with engineered CD20 antibodies (e...
September 2016: Journal of Geriatric Oncology
(no author information available yet)
No abstract text is available yet for this article.
August 1, 2016: Medical Letter on Drugs and Therapeutics
Bernard L Marini, Lisa Samanas, Anthony J Perissinotti
Treatment options for chronic lymphocytic leukemia, the most common leukemia in the United States, have expanded rapidly in recent years. While traditional chemoimmunotherapy still remains a mainstay for young, fit patients, a number of novel targeted therapies have emerged that have changed the therapeutic landscape. Two innovative anti-CD20 monoclonal antibodies, obinutuzumab and ofatumomamab, have demonstrated activity in chronic lymphocytic leukemia and represent well-tolerated options in upfront management of elderly patients or in those with significant comorbidities...
June 29, 2016: Journal of Oncology Pharmacy Practice
Seong Lin Khaw, Santi Suryani, Kathryn Evans, Jennifer Richmond, Alissa Robbins, Raushan T Kurmasheva, Catherine A Billups, Stephen W Erickson, Yuelong Guo, Peter J Houghton, Malcolm A Smith, Hernan Carol, Andrew W Roberts, David C S Huang, Richard B Lock
The clinical success of the BCL-2-selective BH3-mimetic venetoclax in patients with poor prognosis chronic lymphocytic leukemia (CLL) highlights the potential of targeting the BCL-2-regulated apoptotic pathway in previously untreatable lymphoid malignancies. By selectively inhibiting BCL-2, venetoclax circumvents the dose-limiting, BCL-XL-mediated thrombocytopenia of its less selective predecessor navitoclax, while enhancing efficacy in CLL. We have previously reported the potent sensitivity of many high-risk childhood acute lymphoblastic leukemia (ALL) xenografts to navitoclax...
September 8, 2016: Blood
Douglas R Green
Venetoclax is a BH3 mimetic approved for treating chronic lymphocytic leukemia. Cancer cells are resistant to apoptosis but "primed for death" by elevated BCL-2, which binds to pro-apoptotic proteins and holds them in check. Venetoclax releases this antagonism and is the first approved drug to target a protein-protein interaction.
June 16, 2016: Cell
Sina Oppermann, Jarkko Ylanko, Yonghong Shi, Santosh Hariharan, Christopher C Oakes, Patrick M Brauer, Juan C Zúñiga-Pflücker, Brian Leber, David E Spaner, David W Andrews
Novel agents such as the Bcl-2 inhibitor venetoclax (ABT-199) are changing treatment paradigms for chronic lymphocytic leukemia (CLL) but important problems remain. Although some patients exhibit deep and durable responses to venetoclax as a single agent, other patients harbor subpopulations of resistant leukemia cells that mediate disease recurrence. One hypothesis for the origin of resistance to venetoclax is by kinase-mediated survival signals encountered in proliferation centers that may be unique for individual patients...
August 18, 2016: Blood
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
Jennifer R Brown, Michael J Hallek, John M Pagel
During the past 5 years, rapid therapeutic advances have changed the landscape of chronic lymphocytic leukemia (CLL) therapy. This disease has traditionally been treated using cytotoxic chemotherapy regimens in combination with anti-CD20 antibody treatment, and recent long-term follow-up data from multiple centers suggest that fit patients with CLL with favorable disease features-particularly mutated immunoglobulin heavy chain variable region (IGHV) genes-derive very long-term benefit from the most potent of these regimens, namely the fludarabine, cyclophosphamide, and rituximab (FCR) regimen...
2016: American Society of Clinical Oncology Educational Book
Harriet S Walter, Gilles A Salles, Martin J S Dyer
No abstract text is available yet for this article.
June 2, 2016: New England Journal of Medicine
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