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Venetoclax cll

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https://www.readbyqxmd.com/read/27913471/sequencing-of-chronic-lymphocytic-leukemia-therapies
#1
Jacqueline C Barrientos
It is an unprecedented time for the treatment of patients with chronic lymphocytic leukemia (CLL) with the recent approval of several targeted agents for use in frontline, relapsed, refractory, and high-risk disease. Traditionally, frontline management of CLL has been a combination of chemotherapy (fludarabine, cyclophosphamide, bendamustine, or chlorambucil) with an anti-CD20 monoclonal antibody (rituximab, ofatumumab, obinutuzumab). The current landscape is rapidly evolving with the advent of therapies that demonstrate selective inhibition of important pathways necessary for CLL proliferation and survival...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27889784/targeted-therapy-of-cll
#2
Othman Al-Sawaf, Kirsten Fischer, Barbara Eichhorst, Michael Hallek
The landscape of chronic lymphocytic leukemia (CLL) has undergone profound changes in the past years. First, the addition of CD20-targeting antibodies to conventional chemotherapy has improved the therapeutic outcome in the majority of CLL patients. Since the establishment of the critical role of the B cell receptor signaling pathway in the pathogenesis of CLL, several agents have been developed to target this pathway. Ibrutinib and idelalisib, 2 potent kinase inhibitors, have both become available for CLL therapy in the first and second line...
2016: Oncology Research and Treatment
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
#3
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
#4
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/27808579/predictive-and-prognostic-biomarkers-in-the-era-of-new-targeted-therapies-for-chronic-lymphocytic-leukemia
#5
Davide Rossi, Bernhard Gerber, Georg Stüssi
Treatment options for chronic lymphocytic leukemia (CLL) have improved with the introduction of the B-cell receptor inhibitors ibrutinib and idelalisib, and of the BCL2 inhibitor venetoclax. While awaiting the results of head to head comparisons between novel agents and chemoimmunotherapy, predictive biomarkers can assist physicians in treatment tailoring. Though novel agents have modified the landscape of predictors at the time of treatment requirement, the usefulness of historical CLL prognostic biomarkers is still up-to-date when considering anticipation of time to first treatment...
November 3, 2016: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/27806433/targeting-bcl2-with-bh3-mimetics-basic-science-and-clinical-application-of-venetoclax-in-cll-and-related-b-cell-malignancies
#6
Andrew W Roberts, David C S 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...
November 2, 2016: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27796157/management-of-elderly-and-unfit-patients-with-chronic-lymphocytic-leukemia
#7
Francesca R Mauro, Adriano Salaroli, Maria D Caputo, Gioia Colafigli, Luigi Petrucci, Melissa Campanelli, Antonietta Ferretti, Anna R Guarini, Robin Foà
About 75% of patients with chronic lymphocytic leukemia (CLL) are more than 65 years at the time of diagnosis. Treatment of the elderly remains complicated due to multiple factors, such as comorbidities, decline in functional reserve and fitness. Since chronological age by itself cannot properly predict life expectancy and treatment tolerance, an accurate assessment of the fitness status is of crucial importance for an optimal treatment choice. Areas covered: This review will discuss the most relevant aspects concerning the issues experienced in the management of elderly/unfit patients with CLL...
December 2016: Expert Review of Hematology
https://www.readbyqxmd.com/read/27742072/current-state-of-hematopoietic-cell-transplantation-in-cll-as-smart-therapies-emerge
#8
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
https://www.readbyqxmd.com/read/27742065/current-strategies-to-create-tailored-and-risk-adapted-therapies-for-cll-patients
#9
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
https://www.readbyqxmd.com/read/27697994/the-dual-syk-jak-inhibitor-cerdulatinib-antagonises-b-cell-receptor-and-microenvironmental-signaling-in-chronic-lymphocytic-leukemia
#10
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
https://www.readbyqxmd.com/read/27695617/the-potential-of-venetoclax-abt-199-in-chronic-lymphocytic-leukemia
#11
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/27638334/impact-of-venetoclax-exposure-on-clinical-efficacy-and-safety-in-patients-with-relapsed-or-refractory-chronic-lymphocytic-leukemia
#12
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
#13
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/27558232/pharmacokinetics-of-venetoclax-a-novel-bcl-2-inhibitor-in-patients-with-relapsed-or-refractory-chronic-lymphocytic-leukemia-or-non-hodgkin-s-lymphoma
#14
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
https://www.readbyqxmd.com/read/27535975/bcl2-inhibitors-as-anticancer-drugs-a-plethora-of-misleading-bh3-mimetics
#15
REVIEW
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
https://www.readbyqxmd.com/read/27521330/treatment-of-chronic-lymphocytic-leukemia-with-del-17p-tp53-mutation-allogeneic-hematopoietic-stem-cell-transplantation-or-bcr-signaling-inhibitors
#16
REVIEW
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
https://www.readbyqxmd.com/read/27504063/pharmaceutical-approval-update
#17
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
https://www.readbyqxmd.com/read/27499136/hox-gene-expression-predicts-response-to-bcl-2-inhibition-in-acute-myeloid-leukemia
#18
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
https://www.readbyqxmd.com/read/27491497/new-treatment-approaches-in-cll-challenges-and-opportunities-in-the-elderly
#19
REVIEW
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
https://www.readbyqxmd.com/read/27466751/venetoclax-venclexta-for-chronic-lymphocytic-leukemia
#20
(no author information available yet)
No abstract text is available yet for this article.
August 1, 2016: Medical Letter on Drugs and Therapeutics
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