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Venetoclax cll

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https://www.readbyqxmd.com/read/29034364/microenvironmental-agonists-generate-de-novo-phenotypic-resistance-to-combined-ibrutinib-plus-venetoclax-in-cll-and-mcl
#1
Kallesh D Jayappa, Craig A Portell, Vicki L Gordon, Brian J Capaldo, Stefan Bekiranov, Mark J Axelrod, L Kyle Brett, Julia D Wulfkuhle, Rosa I Gallagher, Emanuel F Petricoin, Timothy P Bender, Michael E Williams, Michael J Weber
De novo resistance and rapid recurrence often characterize responses of B-cell malignancies to ibrutinib (IBR), indicating a need to develop drug combinations that block compensatory survival signaling and give deeper, more durable responses. To identify such combinations, we previously performed a combinatorial drug screen and identified the Bcl-2 inhibitor venetoclax (VEN) as a promising partner for combination with IBR in Mantle Cell Lymphoma (MCL). We have opened a multi-institutional clinical trial to test this combination...
June 13, 2017: Blood Advances
https://www.readbyqxmd.com/read/29025288/-state-of-the-art-molecular-diagnostics-and-therapy-of-chronic-lymphocytic-leukaemia-in-the-era-of-new-targeted-therapies
#2
Tímea Gurbity Pálfi, Viktória Fésüs, Csaba Bödör, Zita Borbényi
Chronic lymphoid leukaemia (CLL) has a heterogeneous clinical course depending on many clinical and molecular prognostic markers, which play an important role in the selection of the best treatment option. So far, TP53 disruption is the key prognostic and predictive factor assisting treatment decisions, especially in the era of novel therapies. Asymptomatic patients in early stages of the disease will still benefit from watchful waiting. In the frontline setting, chemoimmunotherapy is still the standard care in the majority of standard risk CLL patients...
October 2017: Orvosi Hetilap
https://www.readbyqxmd.com/read/28984869/bcl2-and-mir-15-16-from-gene-discovery-to-treatment
#3
REVIEW
Yuri Pekarsky, Veronica Balatti, Carlo M Croce
In 1984, we investigated the t(14;18) chromosomal translocations that frequently occur in patients with follicular lymphoma. We first identified a locus on chromosome 18 involved in these translocations with the chromosome 14 containing the immunoglobulin heavy chain locus. Within this region on chromosome 18, we then discovered a gene that we called BCL2, which was activated by the translocations. Since that time, many studies determined that BCL2 is one of the most important oncogenes involved in cancer by inhibiting apoptosis...
October 6, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28978838/chronic-lymphocytic-leukemia-biology-disease-progression-and-current-treatment-strategies
#4
Takahiro Yano
Chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and accumulation of mature CD5-positive, CD10-negative, CD20 weakly positive, and CD23-positive B-cells within blood, bone marrow, lymph nodes, and spleen. In proliferation centers, the survival and growth of CLL cells requires a permissive microenvironment comprising T-cells, macrophages, and stromal cells. FISH analysis has revealed that almost 80% of CLL cases carry chromosomal abnormalities including the most frequent del (13q14) and the strongest poor prognostic factor del (17p), both related to TP53 mutations...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28972395/venetoclax-for-the-treatment-of-chronic-lymphocytic-leukemia
#5
Massimo Gentile, Annamaria Petrungaro, Giuseppina Uccello, Ernesto Vigna, Anna Grazia Recchia, Nadia Caruso, Sabrina Bossio, Laura De Stefano, Angela Palummo, Francesca Storino, Massimo Martino, Fortunato Morabito
Venetoclax, an orally bioavailable inhibitor of BCL-2, was approved in 2016 by the United States Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL) patients with 17p deletion [del(17p)], who have received at least one prior therapy. Areas covered: We focus on the mechanism of action of venetoclax and on the clinical trial data that led to the approval of venetoclax for CLL patients. We also review the studies in which this drug has being explored in combination with other anti-CLL drugs...
November 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28945711/venetoclax-management-and-care-for-patients-with-relapsed-or-refractory-chronic-lymphocytic-leukemia%C3%A2
#6
Heather Brumbaugh Paradis, Debbie Alter, Diane Llerandi
BACKGROUND: Venetoclax (Venclexta™) is a potent, selective, orally available, small-molecule B-cell lymphoma 2 inhibitor that achieves response rates of about 80% and has an acceptable safety profile for patients with relapsed or refractory chronic lymphocytic leukemia (CLL).
. OBJECTIVES: The aim was to describe treatment management considerations when caring for patients using venetoclax.
. METHODS: A review was done of safety and management considerations based on current clinical practice and 240 patients with CLL who received venetoclax monotherapy on clinical trials from 2011-2016...
October 1, 2017: Clinical Journal of Oncology Nursing
https://www.readbyqxmd.com/read/28942659/novel-synthetic-drugs-currently-in-clinical-development-for-chronic-lymphocytic-leukemia
#7
Pawel Robak, Tadeusz Robak
Over the last few years, several new synthetic drugs, particularly Bruton's tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K) and BCL-2 inhibitors have been developed and investigated in chronic lymphocytic leukemia (CLL). Areas covered: This review highlights key aspects of BTK, PI3K and BCL-2 inhibitors that are currently at various stages of preclinical and clinical development in CLL. A literature review of the MEDLINE database for articles in English concerning CLL, B-cell receptor, BCL-2 antagonists, BTK inhibitors and PI3K inhibitors, was conducted via PubMed...
November 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28851760/tumor-lysis-syndrome-in-chronic-lymphocytic-leukemia-with-novel-targeted-agents
#8
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/28838268/rational-combination-strategies-to-enhance-venetoclax-activity-and-overcome-resistance-in-hematologic-malignancies
#9
Steven Grant
Venetoclax (ABT-199) is a Bcl-2-specific BH3-mimetic that has shown significant promise in certain subtypes of CLL as well as in several other hematologic malignancies. As in the case of essentially all targeted agents, intrinsic or acquired resistance to this agent generally occurs, prompting the search for new strategies capable of circumventing this problem. A logical approach to this challenge involves rational combination strategies designed to disable preexisting or induced compensatory survival pathways...
August 24, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28826693/chimeric-antigen-receptor-t-cell-therapy-for-chronic-lymphocytic-leukemia-a-narrative-review
#10
REVIEW
Anthony R Mato, Meghan C Thompson, Chadi Nabhan, Jakub Svoboda, Stephen J Schuster
The treatment landscape for chronic lymphocytic leukemia (CLL) is changing rapidly. Novel targeted agents such as ibrutinib, venetoclax, and idelalisib have had a significant effect on first-line, relapsed/refractory, and high-risk disease. Despite these advances, there are continuous needs for new treatment options, especially for patients in whom these novel therapies fail or those who cannot tolerate these novel therapies. In 2011, Porter et al reported the first successful use of autologous chimeric antigen receptor T cells (CARTs) directed against cluster of differentiation (CD)19 in 3 refractory CLL patients...
July 21, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28782884/chronic-lymphocytic-leukemia-2017-update-on-diagnosis-risk-stratification-and-treatment
#11
REVIEW
Michael Hallek
DISEASE OVERVIEW: Chronic lymphocytic leukemia (CLL) is the commonest leukemia in western countries. The disease typically occurs in elderly patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that impair apoptosis of clonal B cells. DIAGNOSIS: The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B lymphocytes, which identify a clonal B-cell population carrying the CD5 antigen and B-cell markers...
September 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28780145/what-is-the-role-of-chemotherapy-in-patients-with-chronic-lymphocytic-leukemia
#12
REVIEW
Bruce D Cheson
The current standard treatment for patients with chronic lymphocytic leukemia who require therapy is chemoimmunotherapy. However, the availability of an increasing number of targeted agents and combination warrants a reassessment of that approach. The high rate of durable responses with ibrutinib in relapsed refractory patients has established its role in this setting; however, because of its impressive efficacy as initial treatment, it should be considered as part of the algorithm in appropriate patients. There is virtually no role for chemotherapy in the relapsed or refractory setting, but, instead, consideration of active agents including idelalisib plus rituximab, or, particularly venetoclax...
July 12, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28750119/minimal-residual-disease-in-chronic-lymphocytic-leukemia-in-the-era-of-novel-agents-a-review
#13
Meghan Thompson, Danielle Brander, Chadi Nabhan, Anthony Mato
Importance: The landscape of chronic lymphocytic leukemia (CLL) treatment has changed considerably since the first reported assessment of minimal residual disease (MRD) by flow cytometry in 1992. Chemoimmunotherapy (CIT) combinations have become the standard of care for most patients, and novel targeted agents are rapidly being incorporated into the front-line and relapsed settings. Minimal residual disease status has been shown to be a predictor of both progression-free survival (PFS) and overall survival (OS) at the time of response assessment following CIT, but less is known about the relationship between MRD and outcomes after novel oral therapeutics...
July 27, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28741496/targeting-bcl-2-like-proteins-to-kill-cancer-cells
#14
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
#15
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/28715249/durable-molecular-remissions-in-chronic-lymphocytic-leukemia-treated-with-cd19-specific-chimeric-antigen-receptor-modified-t-cells-after-failure-of-ibrutinib
#16
Cameron J Turtle, Kevin A Hay, Laïla-Aïcha Hanafi, Daniel Li, Sindhu Cherian, Xueyan Chen, Brent Wood, Arletta Lozanski, John C Byrd, Shelly Heimfeld, Stanley R Riddell, David G Maloney
Purpose We evaluated the safety and feasibility of anti-CD19 chimeric antigen receptor-modified T (CAR-T) cell therapy in patients with chronic lymphocytic leukemia (CLL) who had previously received ibrutinib. Methods Twenty-four patients with CLL received lymphodepleting chemotherapy and anti-CD19 CAR-T cells at one of three dose levels (2 × 10(5), 2 × 10(6), or 2 × 10(7) CAR-T cells/kg). Nineteen patients experienced disease progression while receiving ibrutinib, three were ibrutinib intolerant, and two did not experience progression while receiving ibrutinib...
September 10, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28705863/fischer-k-al-sawaf-o-fink-a-m-et-al-venetoclax-and-obinutuzumab-in-chronic-lymphocytic-leukemia-blood-2017-129-19-2702-2705
#17
(no author information available yet)
No abstract text is available yet for this article.
July 13, 2017: Blood
https://www.readbyqxmd.com/read/28696175/venetoclax-a-novel-b-cell-lymphoma-2-inhibitor-for-chronic-lymphocytic-leukemia-and-other-hematologic-malignancies
#18
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/28670929/exploiting-the-pro-apoptotic-function-of-noxa-as-a-therapeutic-modality-in-cancer
#19
REVIEW
Jeroen E Guikema, Martine Amiot, Eric Eldering
Direct targeting of Bcl-2 members for therapeutic purposes in cancer has become a clinical reality with the FDA approval of ABT-199/Venetoclax. Other highly specific BH3-mimetics are in pre-clinical development. Understanding the functional interactions among the Bcl-2 family is of prime importance to fully exploit their potential. NOXA is considered a rather weak BH3-only member but it has unexplored potential in various settings, which are of relevance in cancer. NOXA is best known as a selective inhibitor of MCL1, itself overexpressed in many cancers, and this protein pair forms an important rheostat in many forms of cell stress...
August 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28653191/microrna-dysregulation-to-identify-novel-therapeutic-targets
#20
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
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