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Yali Chen, Qianxiang Zhou, Lei Zhang, Ran Wang, Meihua Jin, Yuling Qiu, Dexin Kong
Increasing resistance of imatinib, a BCR-ABL tyrosine kinase inhibitor, hinders its use in the therapy of chronic myeloid leukemia (CML). The PI3K pathway is known to be closely involved in BCR-ABL transformation and the tumorigenesis of CML, suggesting that PI3K may be a potential target for CML therapy. Idelalisib, a specific inhibitor of PI3K p110δ, has been approved for the treatment of chronic lymphocytic leukemia (CLL). However, the antileukemia effect of idelalisib on CML remains unknown. In the present study, the antileukemia activity of idelalisib alone or in combination with imatinib was investigated by use of K562 cells...
October 17, 2016: Oncology Reports
Deepa Jeyakumar, Susan O'Brien
Inhibitors of the B cell receptor (BCR) represent an attractive therapeutic option for patients with chronic lymphocytic leukemia. Recently approved inhibitors of Bruton's tyrosine kinase (ibrutinib) and phosphatidylinositol 3-kinase (idelalisib), are promising agents because they are generally well tolerated and highly effective. These agents may be particularly important in the treatment of older patients who are less able to tolerate the myelosuppression (and infections) associated with chemoimmunotherapy...
March 2016: Best Practice & Research. Clinical Haematology
Brian Koffman, Andrew Schorr
The 21st century has seen rapid, positive changes in the management of chronic lymphocytic leukaemia from the patient's perspective. New prognostic and predictive markers have ushered in the start of more precise and individualized therapy. For the first time, combined therapy [fludarabine, cyclophosphamide and rituximab] has been shown to prolong life significantly. Clinical trials have become more adaptive, faster and more patient friendly. Perhaps the greatest change of all is the development of novel oral agents (ibrutinib and idelalisib) and powerful monoclonal antibodies that offer robust and durable disease control...
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
Preeti Vyas, Divya Vohora
Recent findings have publicized phosphoinositide-3-kinases (PI3Ks) as novel therapeutic targets, which are also purported to be involved in the complex pathophysiology of inflammatory and various other diseases. They are recognized to participate in the inflammatory cellular responses by modulating the growth, development and proliferation of various immune cells and hence, affect the release of various cytokines and other inflammatory mediators involved in these manifestations. The review presents a brief synopsis of the PI3K/AKT/mTOR signalling pathway along with the current and future prospects of targeting PI3Ks for various diseases, like malignant, autoimmune, inflammatory, cardiovascular, neurological disorders etc...
October 13, 2016: Current Drug Targets
Jing Du, Martin Neuenschwander, Yong Yu, J Henry M Däbritz, Nina-Rosa Neuendorff, Kolja Schleich, Aitomi Bittner, Maja Milanovic, Gregor Beuster, Silke Radetzki, Edgar Specker, Maurice Reimann, Frank Rosenbauer, Stephan Mathas, Philipp Lohneis, Michael Hummel, Bernd Dörken, Jens Peter von Kries, Soyoung Lee, Clemens A Schmitt
Classical Hodgkin's lymphoma (cHL), although originating from B-cells, is characterized by the virtual lack of gene products whose expression constitutes the B-cell phenotype. Epigenetic repression of B-cell-specific genes via promoter hypermethylation and histone deacetylation as well as compromised expression of B-cell-committed transcription factors were previously reported to contribute to the lost B-cell phenotype in cHL. Restoring the B-cell phenotype may not only correct a central malignant property, but render cHL susceptible to clinically established antibody therapies targeting B-cell surface receptors or small compounds interfering with B-cell receptor signaling...
October 12, 2016: Blood
Anthony R Mato, Chadi Nabhan, Paul M Barr, Chaitra S Ujjani, Brian T Hill, Nicole Lamanna, Alan P Skarbnik, Christina Howlett, Jeffrey J Pu, Alison R Sehgal, Lauren E Strelec, Alexandra Vandegrift, Danielle M Fitzpatrick, Clive S Zent, Tatyana Feldman, Andre Goy, David F Claxton, Spencer Henick Bachow, Gurbakhash Kaur, Jakub Svoboda, Sunita Dwivedy Nasta, David Porter, Daniel J Landsburg, Stephen J Schuster, Bruce D Cheson, Pavel Kiselev, Andrew M Evens
B Cell receptor (BCR) kinase inhibitor (KI) therapy represents a paradigm shift in Chronic Lymphocytic Leukemia (CLL) management, but data on practice patterns after KI discontinuation and optimal sequencing are limited. We conducted a multicenter, retrospective, comprehensive analysis on 178 CLL patients (ibrutinib=143; idelalisib=35) who discontinued KI therapy. We examined responses, toxicity, post-KI therapies, and overall survival (OS). Patients had a median of 3 prior therapies (range 0-11); del17p (34%), p53 mutation (27%), del11q (33%), and complex karyotype (29%)...
September 6, 2016: Blood
Sina Oppermann, Avery J Lam, Stephanie Tung, Yonghong Shi, Lindsay McCaw, Guizhei Wang, Jarkko Ylanko, Brian Leber, David Andrews, David E Spaner
Glucorticoids (GCs) such as dexamethasone (DEX) remain important treatments for Chronic Lymphocytic Leukemia (CLL) but the mechanisms are poorly understood and resistance is inevitable. Proliferation centers (PC) in lymph nodes and bone marrow offer protection against many cytotoxic drugs and circulating CLL cells were found to acquire resistance to DEX-mediated killing in conditions encountered in PCs including stimulation by toll-like receptor agonists and interactions with stromal cells. The resistant state was associated with impaired glucocorticoid receptor-mediated gene expression, autocrine activation of STAT3 through Janus Kinases (JAKs), and increased glycolysis...
August 25, 2016: Oncotarget
Jorge J Castillo, Joshua N Gustine, Kirsten Meid, Toni Dubeau, Guang Yang, Lian Xu, Zachary R Hunter, Steven P Treon
No abstract text is available yet for this article.
August 26, 2016: Leukemia & Lymphoma
Marc Sorigue, Josep-Maria Ribera, Cristina Motlló, Juan-Manuel Sancho
Despite the improvement in prognosis since the advent of rituximab, follicular lymphoma is still incurable and remains the cause of death of most afflicted patients. With the expanding knowledge of the pathogenesis of B-cell malignancies, in the last few years a plethora of new therapies acting through a variety of mechanisms have shown promising results. This review attempts to analyze the evidence available on these new drugs, which include new monoclonal antibodies and immunoconjugates, the anti-angiogenic and immunomodulatory agent lenalidomide, the proteasome inhibitor bortezomib, inhibitors of B-cell receptor pathway enzymes, such as ibrutinib, idelalisib, duvelisib and entospletinib, BCL2 inhibitors and checkpoint inhibitors...
October 2016: Leukemia Research
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
Arjun Gupta, Hsiao C Li
No abstract text is available yet for this article.
2016: BMJ Case Reports
S Eldfors, H Kuusanmäki, M Kontro, M M Majumder, A Parsons, H Edgren, T Pemovska, O Kallioniemi, K Wennerberg, N Gökbuget, T Burmeister, K Porkka, C A Heckman
TCF3-PBX1 (E2A-PBX1) is a recurrent gene fusion in B-cell precursor lymphoblastic leukemia (BCP-ALL), which is caused by the translocation t(1;19)(q23;p13). TCF3-PBX1 BCP-ALL patients typically benefit from chemotherapy; however, many relapse and subsequently develop resistant disease with few effective treatment options. Mechanisms driving disease progression and therapy resistance have not been studied in TCF3-PBX1 BCP-ALL. Here, we aimed to identify novel treatment options for TCF3-PBX1 BCP-ALL by profiling leukemia cells from a relapsed patient, and determine molecular mechanisms underlying disease pathogenesis and progression...
July 27, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Yazan F Madanat, Mitchell R Smith, Alexandru Almasan, Brian T Hill
Chronic lymphocytic leukemia, small lymphocytic lymphoma, and follicular lymphoma are indolent B-cell lymphoproliferative disorders that mainly affect an older population. Although the majority of patients in need of treatment derive significant benefit from conventional chemotherapeutic agents as well as monoclonal antibodies, less toxic and more effective treatments are needed. Novel agents that inhibit the B-cell receptor signaling pathway have shown promising outcomes in these disorders. Idelalisib is a potent selective oral inhibitor of phosphatidylinositol 3-kinase delta and has shown significant clinical activity in B-cell malignancies...
2016: Blood and Lymphatic Cancer: Targets and Therapy
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
Qingshan Yang, Lisa S Chen, Min Jin Ha, Kim-Anh Do, Sattva S Neelapu, Varsha Gandhi
PURPOSE: PI3 Kinase is a critical node in the B-cell receptor pathway which is responsible for survival and proliferation of B-cell malignancies. Idelalisib, a PI3Kδ-isoform specific inhibitor, has been approved to treat B-cell malignancies. While biological activity of the drug has been evaluated, molecular mechanisms and signaling pathway disruption leading to the biological effects of idelalisib are not yet well-defined. Prior laboratory reports have identified transcription and translation as the primary events for attenuation of PI3Kα isoform...
June 24, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
(no author information available yet)
No abstract text is available yet for this article.
April 2016: Australian Prescriber
Jacqueline C Barrientos
Idelalisib is a first-in-class selective oral PI3Kδ inhibitor for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma, a predominantly elderly population with high comorbidity. The drug promotes apoptosis in primary CLL cells ex vivo, independent of common prognostic markers and inhibits CLL cell homing, migration and adhesion to cells in the microenvironment. Idelalisib has shown efficacy with acceptable safety as monotherapy and combination therapy in relapsed/refractory CLL...
September 2016: Future Oncology
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
Richard J Jones, Tawin Iempridee, Xiaobin Wang, Hans C Lee, Janet E Mertz, Shannon C Kenney, Heather C Lin, Veerabhadran Baladandayuthapani, Christopher W Dawson, Jatin J Shah, Donna M Weber, Robert Z Orlowski
PURPOSE: Lenalidomide, thalidomide, and pomalidomide (LTP) are immunomodulatory agents approved for use in multiple myeloma, but in some settings, especially with alkylating agents, an increase in Hodgkin lymphoma and other secondary primary malignancies (SPM) has been noted. Some of these malignancies have been linked to Epstein-Barr virus (EBV), raising the possibility that immunomodulatory drugs disrupt latent EBV infection. EXPERIMENTAL DESIGN: We studied the ability of LTP to reactivate latently infected EBV-positive cell lines in vitro and in vivo, and evaluated the EBV viral load in archived serum samples from patients who received a lenalidomide, thalidomide, and dexamethasone (LTD) combination...
October 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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