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Ibrutinib

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https://www.readbyqxmd.com/read/28223277/ventricular-arrhythmias-and-sudden-death-in-patients-taking-ibrutinib
#1
Benjamin L Lampson, Lijian Yu, Robert J Glynn, Jacqueline C Barrientos, Eric D Jacobsen, Versha Banerji, Jeffrey A Jones, Renata Walewska, Kerry J Savage, Gregory F Michaud, Javid J Moslehi, Jennifer R Brown
No abstract text is available yet for this article.
February 21, 2017: Blood
https://www.readbyqxmd.com/read/28216434/human-nlrp3-inflammasome-activity-is-regulated-by-and-potentially-targetable-via-btk
#2
Xiao Liu, Tica Pichulik, Olaf-Oliver Wolz, Truong-Minh Dang, Andrea Stutz, Carly Dillen, Magno Delmiro Garcia, Helene Kraus, Sabine Dickhöfer, Ellen Daiber, Lisa Münzenmayer, Silke Wahl, Nikolaus Rieber, Jasmin Kümmerle-Deschner, Amir Yazdi, Mirita Franz-Wachtel, Boris Macek, Markus Radsak, Sebastian Vogel, Berit Schulte, Juliane Sarah Walz, Dominik Hartl, Eicke Latz, Stephan Stilgenbauer, Bodo Grimbacher, Lloyd Miller, Cornelia Brunner, Christiane Wolz, Alexander N R Weber
BACKGROUND: The Nod-like receptor, NACHT, LRR and PYD domains-containing protein 3 (NLRP3), and Bruton's tyrosine kinase (BTK) are protagonists in innate and adaptive immunity, respectively: NLRP3 senses exogenous and endogenous insults leading to inflammasome activation, which occurs spontaneously in Muckle-Wells Syndrome (MWS); BTK mutations cause the genetic immunodeficiency X-linked agammaglobulinemia (XLA). However, to date few proteins that regulate NLRP3 inflammasome activity in human primary immune cells have been identified and clinically promising pharmacological targeting strategies remain elusive...
February 16, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28212557/using-high-sensitivity-sequencing-for-the-detection-of-mutations-in-btk-and-plc%C3%AE-2-genes-in-cellular-and-cell-free-dna-and-correlation-with-progression-in-patients-treated-with-btk-inhibitors
#3
Adam Albitar, Wanlong Ma, Ivan DeDios, Jeffrey Estella, Inhye Ahn, Mohammed Farooqui, Adrian Wiestner, Maher Albitar
Patients with chronic lymphocytic leukemia (CLL) that develop resistance to Bruton tyrosine kinase (BTK) inhibitors are typically positive for mutations in BTK or phospholipase c gamma 2 (PLCγ2). We developed a high sensitivity (HS) assay utilizing wild-type blocking polymerase chain reaction achieved via bridged and locked nucleic acids. We used this high sensitivity assay in combination with Sanger sequencing and next generation sequencing (NGS) and tested cellular DNA and cell-free DNA (cfDNA) from patients with CLL treated with the BTK inhibitor, ibrutinib...
February 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28203175/ibrutinib-is-effective-in-the-treatment-of-autoimmune-haemolytic-anaemia-in-mantle-cell-lymphoma
#4
Aliénor Galinier, Vincent Delwail, Mathieu Puyade
Autoimmune haemolytic anaemia (AIHA) in mantle cell lymphoma (MCL) is a rare but life-threatening complication. To date, there are no relevant data for treatment of AIHA in MCL. Ibrutinib, which has been approved for relapse/refractory MCL, is an immunomodulatory drug inhibiting Th2 activation and consequently the production of autoantibodies. We report a case of MCL with AIHA in which this form of anaemia was not controlled with the usual chemotherapy. Ibrutinib was used when MCL with AIHA relapsed, and it allowed rapid remission of AIHA and rapid discontinuation of steroid therapy...
January 2017: Case Reports in Oncology
https://www.readbyqxmd.com/read/28202458/sensitivity-to-pi3k-and-akt-inhibitors-is-mediated-by-divergent-molecular-mechanisms-in-subtypes-of-dlbcl
#5
Tabea Erdmann, Pavel Klener, James T Lynch, Michael Grau, Petra Vočková, Jan Molinsky, Diana Tuskova, Kevin Hudson, Urszula M Polanska, Michael Grondine, Michele Mayo, Beiying Dai, Matthias Pfeifer, Kristian Erdmann, Daniela Schwammbach, Myroslav Zapukhlyak, Annette M Staiger, German Ott, Wolfgang E Berdel, Barry R Davies, Francisco Cruzalegui, Marek Trneny, Peter Lenz, Simon T Barry, Georg Lenz
Activated B-cell-like (ABC) and germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (DLBCL) represent the two major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these two subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) alpha/delta (PI3Kα/δ) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs irrespective of their molecular subtype...
February 15, 2017: Blood
https://www.readbyqxmd.com/read/28199309/phosphatidylinositol-3-kinase-%C3%AE-blockade-increases-genomic-instability-in-b-cells
#6
Mara Compagno, Qi Wang, Chiara Pighi, Taek-Chin Cheong, Fei-Long Meng, Teresa Poggio, Leng-Siew Yeap, Elif Karaca, Rafael B Blasco, Fernanda Langellotto, Chiara Ambrogio, Claudia Voena, Adrian Wiestner, Siddha N Kasar, Jennifer R Brown, Jing Sun, Catherine J Wu, Monica Gostissa, Frederick W Alt, Roberto Chiarle
Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation. In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation...
February 15, 2017: Nature
https://www.readbyqxmd.com/read/28197963/a-concise-review-of-autoimmune-cytopenias-in-chronic-lymphocytic-leukemia
#7
REVIEW
Mazie Tsang, Sameer A Parikh
Chronic lymphocytic leukemia (CLL) is frequently associated with autoimmune complications such as autoimmune hemolytic anemia, immune thrombocytopenia, pure red cell aplasia, and autoimmune granulocytopenia. It is critical to diagnose cytopenias from these secondary complications of CLL accurately, since prognosis and therapy are substantially different from patients who have cytopenias due to extensive bone marrow infiltration by CLL. The pathogenesis of autoimmune cytopenias in CLL is complex; and it involves antigen presentation by CLL cells to polyclonal B cells resulting in production of autoantibody, and alteration of the T cell milieu tilting the balance in favor of an autoimmune response...
February 14, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/28193034/leveraging-gas-phase-fragmentation-pathways-for-improved-identification-and-selective-detection-of-targets-modified-by-covalent-probes
#8
Scott B Ficarro, Christopher M Browne, Joseph D Card, William M Alexander, Tinghu Zhang, Eunyoung Park, Randall McNally, Sirano Dhe-Paganon, Hyuk-Soo Seo, Ilaria Lamberto, Michael J Eck, Sara J Buhrlage, Nathanael S Gray, Jarrod A Marto
The recent approval of covalent inhibitors for multiple clinical indications has reignited enthusiasm for this class of drugs. As interest in covalent drugs has increased, so too has the need for analytical platforms that can leverage their mechanism-of-action to characterize modified protein targets. Here we describe novel gas phase dissociation pathways which yield predictable fragment ions during MS/MS of inhibitor-modified peptides. We find that these dissociation pathways are common to numerous cysteine-directed probes as well as the covalent drugs, Ibrutinib and Neratinib...
December 20, 2016: Analytical Chemistry
https://www.readbyqxmd.com/read/28185174/current-treatment-of-chronic-lymphocytic-leukemia
#9
REVIEW
Krzysztof Jamroziak, Bartosz Puła, Jan Walewski
A number of new treatment options have recently emerged for chronic lymphocytic leukemia (CLL) patients, including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, phosphatidylinositol-3-kinase (PI3K) delta isoform inhibitor idelalisib combined with rituximab, the Bcl-2 antagonist venetoclax, and the new anti-CD20 antibodies obinutuzumab and ofatumumab. Most of these agents are already included into treatment algorithms defined by international practice guidelines, but more clinical investigations are needed to answer still remaining questions...
January 2017: Current Treatment Options in Oncology
https://www.readbyqxmd.com/read/28182323/ibrutinib-associated-bleeding-pathogenesis-management-and-risk-reduction-strategies
#10
REVIEW
Joseph J Shatzel, Sven R Olson, Derrick L Tao, Owen J T McCarty, Alexey V Danilov, Thomas G DeLoughery
Ibrutinib is an irreversible inhibitor of Bruton's tyrosine kinase (Btk) that has proven to be an effective therapeutic agent for multiple B-cell mediated lymphoproliferative disorders. Ibrutinib, however, carries an increased bleeding risk compared to standard chemotherapy. Bleeding events range from minor mucocutaneous bleeding to life-threatening hemorrhage, due in large part to the effects of ibrutinib on several distinct platelet signaling pathways. There is currently minimal data to guide clinicians regarding the use of ibrutinib in patients at high risk for bleeding or on anticoagulant or antiplatelet therapy...
February 9, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28180067/-hemophagocytic-lymphohistiocytosis-after-ebv-reactivation-and-ibrutinib-treatment-in-relapsed-refractory-chronic-lymphocytic-leukemia
#11
Maurizio Cavallari, Maria Ciccone, Simonetta Falzoni, Francesco Cavazzini, Luca Formigaro, Francesco Di Virgilio, Antonella Rotola, Gian Matteo Rigolin, Antonio Cuneo
Hemophagocytic Lymphohistiocytosis (HLH) is a rare syndrome characterized by ineffective T-cell and NK response. We report the clinical course of a patient with relapsed CLL who developed acute symptoms soon after starting ibrutinib. Hyperpyrexia, splenomegaly, hyperferritinemia, hypertriglyceridemia, cytopenias, and a typical cytokine pattern, i.e. high interleukin (IL)-6, IL10 and IL18, were consistent with a diagnosis of HLH. Coexistent Epstein Barr virus reactivation was documented. Ibrutinib-induced impairment of NK degranulation, associated with EBV reactivation and CLL-related immunodeficiency may have contributed to the development of HLH in our patient...
2017: Leukemia Research Reports
https://www.readbyqxmd.com/read/28178345/pi3k%C3%AE-inhibitor-idelalisib-in-combination-with-btk-inhibitor-ono-gs-4059-in-diffuse-large-b-cell-lymphoma-with-acquired-resistance-to-pi3k%C3%AE-and-btk-inhibitors
#12
Anella Yahiaoui, Sarah A Meadows, Rick A Sorensen, Zhi-Hua Cui, Kathleen S Keegan, Robert Brockett, Guang Chen, Christophe Quéva, Li Li, Stacey L Tannheimer
Activated B-cell-like diffuse large B-cell lymphoma relies on B-cell receptor signaling to drive proliferation and survival. Downstream of the B-cell receptor, the key signaling kinases Bruton's tyrosine kinase and phosphoinositide 3-kinase δ offer opportunities for therapeutic intervention by agents such as ibrutinib, ONO/GS-4059, and idelalisib. Combination therapy with such targeted agents could provide enhanced efficacy due to complimentary mechanisms of action. In this study, we describe both the additive interaction of and resistance mechanisms to idelalisib and ONO/GS-4059 in a model of activated B-cell-like diffuse large B-cell lymphoma...
2017: PloS One
https://www.readbyqxmd.com/read/28171884/optimal-sequencing-of-ibrutinib-idelalisib-and-venetoclax-in-chronic-lymphocytic-leukemia-results-from-a-multi-center-study-of-683-patients
#13
A R Mato, B T Hill, N Lamanna, P M Barr, C S Ujjani, D M Brander, C Howlett, A P Skarbnik, B D Cheson, C S Zent, J J Pu, P Kiselev, K Foon, J Lenhart, S Henick Bachow, A M Winter, A-L Cruz, D F Claxton, A Goy, C Daniel, K Isaac, K H Kennard, C Timlin, M Fanning, L Gashonia, M Yacur, J Svoboda, S J Schuster, C Nabhan
No abstract text is available yet for this article.
January 25, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28171709/long-term-outcomes-for-patients-with-chronic-lymphocytic-leukemia-who-discontinue-ibrutinib
#14
Preetesh Jain, Philip A Thompson, Michael Keating, Zeev Estrov, Alessandra Ferrajoli, Nitin Jain, Hagop Kantarjian, Jan A Burger, Susan O'Brien, William G Wierda
BACKGROUND: Ibrutinib is a Bruton tyrosine kinase inhibitor and is approved for the treatment of patients with chronic lymphocytic leukemia (CLL) in frontline and relapsed/refractory settings. The authors previously reported poor outcomes for patients who discontinued ibrutinib; however, long-term outcomes were not reported. METHODS: Data from 320 patients who received ibrutinib on clinical studies between 2010 and 2015 at The University of Texas MD Anderson Cancer Center were retrospectively analyzed...
February 7, 2017: Cancer
https://www.readbyqxmd.com/read/28167659/targeting-btk-with-ibrutinib-in-relapsed-refractory-marginal-zone-lymphoma
#15
Ariela Noy, Sven de Vos, Catherine Thieblemont, Peter Martin, Christopher R Flowers, Franck Morschhauser, Graham P Collins, Shuo Ma, Morton Coleman, Shachar Peles, Stephen Smith, Jacqueline C Barrientos, Alina Smith, Brian Munneke, Isaiah Dimery, Darrin M Beaupre, Robert Chen
Marginal zone lymphoma (MZL) is a heterogeneous B-cell malignancy for which no standard treatment exists. MZL is frequently linked to chronic infection, which may induce B-cell receptor (BCR) signaling resulting in aberrant B-cell survival and proliferation. We conducted a multicenter, open-label, phase 2 study to evaluate the efficacy and safety of ibrutinib in previously treated MZL. Patients with histologically-confirmed MZL of all subtypes who received ≥1 prior therapy with an anti-CD20 antibody-containing regimen were treated with ibrutinib 560 mg orally once daily until progression or unacceptable toxicity...
February 6, 2017: Blood
https://www.readbyqxmd.com/read/28163195/positive-selection-of-type-ii-collagen-reactive-cd80-high-marginal-zone-b-cells-in-dba-1-mice
#16
Chanho Park, In Seong Kho, Jeong In Yang, Min-Jung Kim, Sunhoo Park, Hoon-Suk Cha, Jaejoon Lee, Tae Jin Kim
To investigate whether dysregulated selection of autoreactive marginal zone (MZ) B cells is involved in autoimmune diseases, we examined MZ B cell profile in multiple strains of mice, and found that type II collagen (CII)-reactive autoreactive CD80(high) MZ B cells spontaneously developed in the DBA/1, but not in C57BL/6 mice. CD80(high) MZ B cells that were characteristically found in DBA/1 mice expressed higher levels of TACI, SLAM3, and SLAM6 than the usual CD80(low) MZ B cells. Notably, the CD80(high) MZ B cells were more sensitive to ibrutinib, a Bruton's tyrosine kinase inhibitor, than CD80(low) MZ or follicular B cells and their transient depletion via intravenous injection of ibrutinib significantly delayed the induction of collagen-induced arthritis (CIA)...
February 2, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28157216/ibrutinib-in-previously-treated-chronic-lymphocytic-leukemia-patients-with-autoimmune-cytopenias-in-the-resonate-study
#17
M Montillo, S O'Brien, A Tedeschi, J C Byrd, C Dearden, D Gill, J R Brown, J C Barrientos, S P Mulligan, R R Furman, F Cymbalista, C Plascencia, S Chang, E Hsu, D F James, P Hillmen
No abstract text is available yet for this article.
February 3, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/28156016/severe-pneumonia-associated-with-ibrutinib-monotherapy-for-cll-and-lymphoma
#18
Natalia Kreiniz, Jacob Bejar, Aaron Polliack, Tamar Tadmor
In recent years, there have been major advances in the treatment of chronic lymphocytic leukemia (CLL) particularly since the development of novel therapeutic agents, mostly "biological drugs." One of the obvious advantages of these agents is the decreased rate of infectious complications occurring during the course of therapy, compared to the use of standard immuno-chemotherapy regimens. Here, we describe 3 patients with CLL and 1 with mantle cell lymphoma who developed severe life-threatening pneumonias, during monotherapy with ibrutinib...
February 3, 2017: Hematological Oncology
https://www.readbyqxmd.com/read/28152955/real-world-treatment-patterns-health-care-resource-utilization-hru-and-costs-among-patients-with-waldenstrom-macroglobulinemia-wm-initiating-therapy
#19
Lorie Ellis, Stephanie Korrer, Stacey DaCosta Byfield
: 17 Background: WM is a rare, indolent B-cell lymphoma with 1000 to 1500 new cases diagnosed annually in the US. The disease is incurable with current therapy. Prior to January 2015 when ibrutinib was approved by the US FDA for WM, there were no therapies approved in this indication. This study describes initial systemic anti-cancer therapy (SACT) and HRU among WM patients (pts). METHODS: A retrospective study using a large, national US claims database from 1/2007-10/2013 was conducted...
March 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28146266/how-i-manage-patients-with-hairy-cell-leukaemia
#20
REVIEW
Philip A Thompson, Farhad Ravandi
Patients with hairy cell leukaemia (HCL) have highly favourable outcomes after purine analogue therapy. However, most patients subsequently relapse and require re-treatment. A minority of patients develop purine analogue-refractory disease. Targeted therapies have improved outcomes for such patients. Recently, the BRAF V600E mutation was identified in most patients with classical HCL, resulting in constitutive mitogen-activated protein kinase pathway activation; impressive responses are achieved in heavily pre-treated patients with BRAF inhibition...
February 1, 2017: British Journal of Haematology
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