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https://www.readbyqxmd.com/read/28439761/small-molecule-inhibitors-in-chronic-lymphocytic-lymphoma-and-b-cell-non-hodgkin-lymphoma
#1
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/28439132/idelalisib-and-rituximab-regimen
#2
A Kacee Barnett, J Aubrey Waddell, Dominic A Solimando
The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast...
March 2017: Hospital Pharmacy
https://www.readbyqxmd.com/read/28424165/suppression-of-b-cell-development-genes-is-key-to-glucocorticoid-efficacy-in-treatment-of-acute-lymphoblastic-leukemia
#3
Karina Kruth, Mimi Fang, Dawne N Shelton, Ossama Abu-Halawa, Ryan Mahling, Hongxing Yang, Jonathan S Weissman, Mignon L Loh, Markus Müschen, Sarah K Tasian, Michael C Bassik, Martin Kampmann, Miles A Pufall
Glucocorticoids (GCs), including dexamethasone (dex), are a central component of combination chemotherapy for childhood B-cell precursor acute lymphoblastic leukemia (B-ALL). GCs work by activating the glucocorticoid receptor (GR), a ligand-induced transcription factor, which in turn regulates genes that induce leukemic cell death. Which GR-regulated genes are required for GC cytotoxicity, which pathways affect their regulation, and how resistance arises are not well understood. Here we systematically integrate the transcriptional response of B-ALL to GCs with a next-generation shRNA screen to identify GC-regulated "effector" genes that contribute to cell death as well as genes that affect the sensitivity of B-ALL cells to dex...
April 19, 2017: Blood
https://www.readbyqxmd.com/read/28389687/advances-in-the-treatment-of-relapsed-refractory-chronic-lymphocytic-leukemia
#4
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/28348046/b-cell-lymphoma-patient-derived-xenograft-models-enable-drug-discovery-and-are-a-platform-for-personalized-therapy
#5
Liang Zhang, Krystle Nomie, Hui Zhang, Taylor Bell, Lan V Pham, Sabah Kadri, Jeremy Segal, Shaoying Li, Shouhao Zhou, David Santos, Shawana Richard, Shruti Sharma, Wendy Chen, Onyekachukwu Oriabure, Yang Liu, Shengjian Huang, Huifang Guo, Zhihong Chen, Wenjing Tao, Carrie Li, Jack Wang, Bingliang Fang, Jacqueline Wang, Lei Li, Maria Badillo, Makhdum Ahmed, Selvi Thirumurthi, Steven Y Huang, Yiping Shao, Laura Lam, Qing Yi, Lynn Wang, Michael Wang
PURPOSE: Patients with B-cell lymphomas often relapse after frontline therapy, and novel therapies are urgently needed to provide long-term remission. We established B-cell lymphoma PDX (patient-derived xenograft) models to assess their ability to mimic tumor biology and to identify B-cell lymphoma patient treatment options. EXPERIMENTAL DESIGN: We established the PDX models from 16 patients with diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, or Burkitt's lymphoma by inoculating the patient tumor cells into a human bone chip implanted into mice...
March 27, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28343293/pharmacokinetic-and-pharmacodynamic-considerations-in-the-treatment-of-chronic-lymphocytic-leukemia-ibrutinib-idelalisib-and-venetoclax
#6
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
#7
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/28327905/phase-ii-study-of-idelalisib-a-selective-inhibitor-of-pi3k%C3%AE-for-relapsed-refractory-classical-hodgkin-lymphoma
#8
A K Gopal, M A Fanale, C H Moskowitz, A R Shustov, S Mitra, W Ye, A Younes, A J Moskowitz
Background: The phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor idelalisib has been shown to block downstream intracellular signaling, reduce the production of prosurvival chemokines and induce apoptosis in classical Hodgkin lymphoma (HL) cell lines. It has also been shown to inhibit regulatory T cells and myeloid-derived suppressor cells in other tumor models. We hypothesized that inhibiting PI3Kδ would have both direct and indirect antitumor effects by directly targeting the malignant cells as well as modulating the inflammatory microenvironment...
January 24, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28325864/idelalisib-is-effective-in-patients-with-high-risk-follicular-lymphoma-and-early-relapse-after-initial-chemoimmunotherapy
#9
Ajay K Gopal, Brad S Kahl, Christopher R Flowers, Peter Martin, Stephen M Ansell, Esteban Abella-Dominicis, Brian Koh, Wei Ye, Paul M Barr, Gilles A Salles, Jonathan W Friedberg
No abstract text is available yet for this article.
March 21, 2017: Blood
https://www.readbyqxmd.com/read/28325601/design-and-synthesis-of-novel-6-aryl-substituted-4-anilinequinazoline-derivatives-as-potential-pi3k%C3%AE-inhibitors
#10
Minhang Xin, Yuan-Yuan Hei, Hao Zhang, Ying Shen, San-Qi Zhang
In this study, a series of new 6-aryl substituted 4-anilinequinazolines was designed and synthesized as PI3Kδ inhibitors based on our reported chemical structures. The preliminary structure-activity relationship (SAR) was established, and compounds 13h and 13k displayed most potent PI3Kδ inhibitory activities with the IC50 values of 9.3nM and 9.7nM, respectively. Compound 13h demonstrated similar anti-proliferative profiles to idelalisib against three human B cell lines. Three key hydrogen bonding interactions were found in the docking of 13h with PI3Kδ enzyme...
May 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28314699/safety-and-tolerability-of-idelalisib-lenalidomide-and-rituximab-in-relapsed-and-refractory-lymphoma-the-alliance-for-clinical-trials-in-oncology-a051201-and-a051202-phase-1-trials
#11
Sonali M Smith, Brandelyn N Pitcher, Sin-Ho Jung, Nancy L Bartlett, Nina Wagner-Johnston, Steven I Park, Kristy L Richards, Amanda F Cashen, Anthony Jaslowski, Scott E Smith, Bruce D Cheson, Eric Hsi, John P Leonard
BACKGROUND: A new generation of biological and targeted agents might potentially replace traditional cytotoxic agents in lymphoma. Lenalidomide plus rituximab was felt to be a safe and promising backbone based on available data. Idelalisib is an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor that has promising activity as a monotherapy in refractory indolent lymphomas. The primary objective of these two trials was to determine the maximum tolerated dose of lenalidomide in combination with rituximab and idelalisib in relapsed follicular and mantle cell lymphoma...
April 2017: Lancet Haematology
https://www.readbyqxmd.com/read/28298527/dual-inhibition-of-bruton-s-tyrosine-kinase-and-phosphoinositide-3-kinase-p110%C3%AE-as-a-therapeutic-approach-to-treat-non-hodgkin-s-b-cell-malignancies
#12
Jennifer Alfaro, Felipe Pérez de Arce, Sebastián Belmar, Glenda Fuentealba, Patricio Avila, Gonzalo Ureta, Camila Flores, Claudia Acuña, Luz Delgado, Diana Gaete, Brahmam Pujala, Anup Barde, Anjan K Nayak, T V R Upendra, Dhananjay Patel, Shailender Chauhan, Vijay K Sharma, Stacy Kanno, Ramona G Almirez, David T Hung, Sarvajit Chakravarty, Roopa Rai, Sebastián Bernales, Kevin P Quinn, Son M Pham, Emma McCullagh
Although new targeted therapies, such as ibrutinib and idelalisib, have made a large impact on non-Hodgkin's lymphoma (NHL) patients, the disease is often fatal because patients are initially resistant to these targeted therapies, or because they eventually develop resistance. New drugs and treatments are necessary for these patients. One attractive approach is to inhibit multiple parallel pathways that drive the growth of these hematologic tumors, possibly prolonging the duration of the response and reducing resistance...
May 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28295729/targeting-of-b-cell-receptor-signalling-in-b-cell-malignancies
#13
M Jerkeman, M Hallek, M Dreyling, C Thieblemont, E Kimby, L Staudt
Pharmacological agents that inhibit enzymes of the B-cell receptor (BCR) pathway are of increasing importance in the treatment of B-cell malignancies. These include inhibitors of Bruton tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K), splenic tyrosine kinase and protein kinase Cβ. Two agents are already approved in the USA and Europe: ibrutinib, a BTK inhibitor, for the treatment of chronic lymphatic leukaemia (CLL), mantle cell lymphoma (MCL) and Waldenström's macroglobulinemia; and idelalisib, a PI3Kδ inhibitor, for the treatment of CLL and follicular lymphoma...
March 14, 2017: Journal of Internal Medicine
https://www.readbyqxmd.com/read/28288710/possible-novel-agents-in-marginal-zone-lymphoma
#14
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
https://www.readbyqxmd.com/read/28257752/efficacy-and-safety-of-idelalisib-in-combination-with-ofatumumab-for-previously-treated-chronic-lymphocytic-leukaemia-an-open-label-randomised-phase-3-trial
#15
Jeffrey A Jones, Tadeusz Robak, Jennifer R Brown, Farrukh T Awan, Xavier Badoux, Steven Coutre, Javier Loscertales, Kerry Taylor, Elisabeth Vandenberghe, Malgorzata Wach, Nina Wagner-Johnston, Loic Ysebaert, Lyndah Dreiling, Ronald Dubowy, Guan Xing, Ian W Flinn, Carolyn Owen
BACKGROUND: Idelalisib, a selective inhibitor of PI3Kδ, is approved for the treatment of patients with relapsed chronic lymphocytic leukaemia (CLL) in combination with rituximab. We aimed to assess the efficacy and safety of idelalisib in combination with a second-generation anti-CD20 antibody, ofatumumab, in a similar patient population. METHODS: In this global, open-label, randomised, controlled phase 3 trial, we enrolled patients with relapsed CLL progressing less than 24 months from last therapy...
March 2017: Lancet Haematology
https://www.readbyqxmd.com/read/28257435/idelalisib-and-caffeine-reduce-suppression-of-t-cell-responses-mediated-by-activated-chronic-lymphocytic-leukemia-cells
#16
Barry D Hock, Sean A MacPherson, Judith L McKenzie
Chronic lymphocytic leukemia (CLL) is associated with T cell dysfunction. Activated CLL cells are found within the lymphoid tumor micro-environment and overcoming immuno-suppression induced by these cells may improve anti-CLL immune responses. However, the mechanisms by which activated CLL cells inhibit T cell responses, and reagents targeting such mechanisms have not been identified. Here we demonstrate that the ability of in vitro activated CLL cells to suppress T cell proliferation is not reversed by the presence of ecto-nuclease inhibitors or blockade of IL-10, PD-1 and CTLA-4 pathways...
2017: PloS One
https://www.readbyqxmd.com/read/28254430/anti-tumor-activity-of-pi3k-%C3%AE-inhibitor-in-hematologic-malignant-cells-shedding-new-light-on-resistance-to-idelalisib
#17
Davood Bashash, Ava Safaroghli-Azar, Maryam Dadashi, Majid Safa, Majid Momeny, Seyed H Ghaffari
Genetic and laboratory experiments have brought remarkable advances in management of human malignancies, which not only revolutionized the understanding of the disease, but also led to development of novel and effective targeted therapies against specific deregulated pathways. This study aimed to investigate anti-cancer effects of Idelalisib, a potent PI3K-δ inhibitor, in a panel of hematological cell lines. The resulting data showed that Idelalisib decreased cell survival in all the tested cell lines; however, as compared to NB4, viability of other cell lines, irrespective of their molecular characteristics or even the compensatory activation of MEK/ERK pathway, was inhibited at higher concentrations...
February 22, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/28245410/-research-progress-of-novel-small-molecule-drugs-in-the-treatment-of-chronic-lymphocytic-leukemia-review
#18
Jing-Qiao Qiao, Miao He, Shu-Ting Zhang, Hai Bai
Chronic lymphocytic leukemia (CLL), the most frequent adult leukemia in Western population, is characterized by accumulation of mature-looking CD5(+)/19(+)/23(+) B cells in peripheral blood, bone marrow, and lymphatic organs. Over the last 20 years, there has been a dramatic change in therapy for CLL, the complete response rate increased from the initial <5% to the current 40%-50%, this remarkable improvement has been attributable to combination of chemoimmunotherapy agents that have contributed to the backbone of therapy for patients with CLL...
February 2017: Zhongguo Shi Yan Xue Ye Xue za Zhi
https://www.readbyqxmd.com/read/28236475/update-of-the-grupo-espa%C3%A3-ol-de-leucemia-linfoc%C3%A3-tica-cr%C3%A3-nica-clinical-guidelines-of-the-management-of-chronic-lymphocytic-leukemia
#19
José A García-Marco, Julio Delgado, José A Hernández-Rivas, Ángel Ramírez Payer, Javier Loscertales Pueyo, Isidro Jarque, Pau Abrisqueta, Pilar Giraldo, Rafael Martínez, Lucrecia Yáñez, Mª José Terol, Marcos González, Francesc Bosch
BACKGROUND AND OBJECTIVE: The broad therapeutic arsenal and the biological heterogeneity of patients with chronic lymphocytic leukemia (CLL) makes it difficult to standardize treatment for CLL patients with specific clinical settings in routine clinical practice. These considerations prompted us to elaborate the present consensus document, which constitutes an update of the previous version published in 2013, mainly focusing on novel treatment strategies that have been developed over last 5 years, namely B-cell receptor inhibitors (ibrutinib and idelalisib), anti-CD20 monoclonal antibodies (ofatumumab and obinutuzumab), and Bcl-2 inhibitors (venetoclax)...
February 21, 2017: Medicina Clínica
https://www.readbyqxmd.com/read/28217252/primary-mucosa-associated-lymphoid-tissue-lymphoma-of-the-liver-a-report-of-two-cases-and-review-of-the-literature
#20
Ifeyinwa E Obiorah, Lynt Johnson, Metin Ozdemirli
Mucosa-associated lymphoid tissue (MALT) lymphoma of the liver is a very rare condition and thus the diagnosis may be challenging. The clinical presentation is usually variable, ranging from minimal clinical symptoms to severe end stage liver disease. In this paper, we describe the clinicopathologic findings in two cases of primary hepatic MALT lymphoma. One case is an 80-year-old female with no underlying chronic liver disease and the second case is a 30-year-old female with autoimmune hepatitis complicated by MALT lymphoma...
January 28, 2017: World Journal of Hepatology
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