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https://www.readbyqxmd.com/read/29910833/cryptococcal-meningoencephalitis-in-patients-with-mantle-cell-lymphoma-on-ibrutinib
#1
Kai Sun, Saro Kasparian, Swaminathan Iyer, Sai Ravi Pingali
Ibrutinib, a Bruton's tyrosine kinase inhibitor, has been increasingly widely used in relapsed and refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia [1, 2]. With its use becoming more common, there have been emerging case reports of opportunistic infections like cryptococcal infections [3-8]. These infections in patients receiving ibrutinib were mostly reported in patients with chronic lymphocytic leukaemia, who have poor immune reconstitution. Here, we report two cases of cryptococcal meningoencephalitis in patients with MCL on ibrutinib...
2018: Ecancermedicalscience
https://www.readbyqxmd.com/read/29907126/nf-%C3%AE%C2%BAb-signaling-and-its-relevance-to-the-treatment-of-mantle-cell-lymphoma
#2
REVIEW
Swathi Balaji, Makhdum Ahmed, Elizabeth Lorence, Fangfang Yan, Krystle Nomie, Michael Wang
Mantle cell lymphoma is an aggressive subtype of non-Hodgkin B cell lymphoma that is characterized by a poor prognosis determined by Ki67 and Mantle Cell International Prognostic Index scores, but it is becoming increasingly treatable. The majority of patients, especially if young, achieve a progression-free survival of at least 5 years. Mantle cell lymphoma can initially be treated with an anti-CD20 antibody in combination with a chemotherapy backbone, such as VR-CAP (the anti-CD20 monoclonal antibody rituximab administered with cyclophosphamide, doxorubicin, and prednisone) or R-CHOP (the anti-CD20 monoclonal antibody rituximab administered with cyclophosphamide, doxorubicin, vincristine, and prednisone)...
June 15, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29899297/molecular-mechanisms-of-disease-progression-in-primary-cutaneous-diffuse-large-b-cell-lymphoma-leg-type-during-ibrutinib-therapy
#3
Lucy C Fox, Costas K Yannakou, Georgina Ryland, Stephen Lade, Michael Dickinson, Belinda A Campbell, Henry Miles Prince
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is one of the well-recognized extranodal lymphomas commonly addicted to the B-cell receptor-MYD88 superpathway. We aimed to describe the genomic changes in a patient who progressed through treatment with ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor. An 80-year-old woman presented with multiply relapsed PCDLBCL-LT after multiple lines of chemoimmunotherapy and radiotherapy. Pre-treatment testing of the localized cutaneous tumor lesion on a lymphoid amplicon panel demonstrated an MYD88 p...
June 13, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29877241/-chronic-lymphocytic-leukemia-update-on-pathophysiology-and-management
#4
Junji Suzumiya
Chronic lymphocytic leukemia (CLL) is the most common hematological malignancy in the Western countries. Although a multi-step model has been proposed for the pathogenesis of CLL as well as other malignancies, the precise mechanism underlying the development of CLL remains complicated and unclear. In addition, several studies have investigated adverse prognostic factors, including gene abnormalities and the evolution of clones with the disease progression. FCR (fludarabine, cyclophosphamide, and rituximab) has been the standard first-line therapy for "fit" younger patients without TP53 abnormality/17p deletion...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/29869556/a-head-to-head-phase-iii-study-comparing-zanubrutinib-versus-ibrutinib-in-patients-with-waldenstr%C3%A3-m-macroglobulinemia
#5
Constantine S Tam, Veronique LeBlond, William Novotny, Roger G Owen, Alessandra Tedeschi, Siminder Atwal, Aileen Cohen, Jane Huang, Christian Buske
Waldenström macroglobulinemia (WM), an incurable B-cell malignancy, is sensitive to Bruton tyrosine kinase (BTK) inhibition with ibrutinib, a first-generation BTK inhibitor. Off-target effects of ibrutinib against TEC- and EGFR-family kinases are implicated in some adverse events. Patients with CXCR4WHIM and MYD88L265P mutations or who are MYD88WT have less sensitivity to ibrutinib than those with MYD88L265P and CXCR4WT disease. Zanubrutinib, a next-generation BTK inhibitor with potent preclinical activity in WM and minimal off-target effects, showed sustained BTK occupancy in peripheral blood mononuclear cells from patients with B-cell malignancies and promising responses in advanced WM...
June 5, 2018: Future Oncology
https://www.readbyqxmd.com/read/29862859/abbv-105-a-selective-and-irreversible-inhibitor-of-bruton-s-tyrosine-kinase-btk-is-efficacious-in-multiple-preclinical-models-of-inflammation
#6
Christian Goess, Christopher M Harris, Sara Murdock, Richard W McCarthy, Erik Sampson, Rachel Twomey, Suzanne Mathieu, Regina Mario, Matthew Perham, Eric R Goedken, Andrew J Long
OBJECTIVES: Bruton's Tyrosine Kinase (BTK) is a non-receptor tyrosine kinase required for intracellular signaling downstream of multiple immunoreceptors. We evaluated ABBV-105, a covalent BTK inhibitor, using in vitro and in vivo assays to determine potency, selectivity, and efficacy to validate the therapeutic potential of ABBV-105 in inflammatory disease. METHODS: ABBV-105 potency and selectivity were evaluated in enzymatic and cellular assays. The impact of ABBV-105 on B cell function in vivo was assessed using mechanistic models of antibody production...
June 2, 2018: Modern Rheumatology
https://www.readbyqxmd.com/read/29861875/the-b-cell-receptor-signaling-pathway-in-mantle-cell-lymphoma
#7
REVIEW
Maria I Merolle, Makhdum Ahmed, Krystle Nomie, Michael L Wang
Signal transduction through the constitutively activated B cell receptor (BCR) plays a key role in the pathogenesis of B-cell tumors by promoting survival and proliferation of malignant B cells. The BCR signaling pathway is known to be deregulated in Mantle Cell Lymphoma (MCL) due to mutations or epigenetic events that impact regulatory proteins. One such protein is Bruton's tyrosine kinase (BTK), an integral component of the BCR signaling pathway. The success of ibrutinib, a BTK inhibitor, and other drugs that target components of the BCR pathway is evidence that regulation of the BCR signaling pathway is an effective method of MCL treatment...
May 18, 2018: Oncotarget
https://www.readbyqxmd.com/read/29851546/ibrutinib-as-treatment-for-patients-with-relapsed-refractory-follicular-lymphoma-results-from-the-open-label-multicenter-phase-ii-dawn-study
#8
Ajay K Gopal, Stephen J Schuster, Nathan H Fowler, Judith Trotman, Georg Hess, Jing-Zhou Hou, Abdulraheem Yacoub, Michael Lill, Peter Martin, Umberto Vitolo, Andrew Spencer, John Radford, Wojciech Jurczak, James Morton, Dolores Caballero, Sanjay Deshpande, Gary J Gartenberg, Shean-Sheng Wang, Rajendra N Damle, Michael Schaffer, Sriram Balasubramanian, Jessica Vermeulen, Bruce D Cheson, Gilles Salles
Purpose The Bruton's tyrosine kinase inhibitor ibrutinib has demonstrated clinical activity in B-cell malignancies. The DAWN study assessed the efficacy and safety of single-agent ibrutinib in chemoimmunotherapy relapsed/refractory follicular lymphoma (FL) patients. Methods DAWN was an open-label, single-arm, phase II study of ibrutinib in patients with FL with two or more prior lines of therapy. Patients received ibrutinib 560 mg daily until progressive disease/unacceptable toxicity. The primary objective was independent review committee-assessed overall response rate (ORR; complete response plus partial response)...
May 31, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29851337/targeting-the-c481s-ibrutinib-resistance-mutation-in-bruton-s-tyrosine-kinase-using-protac-mediated-degradation
#9
Alexandru D Buhimschi, Haley A Armstrong, Momar Toure, Saul Jaime-Figueroa, Timothy L Chen, Amy M Lehman, Jennifer A Woyach, Amy J Johnson, John C Byrd, Craig M Crews
Inhibition of Bruton's tyrosine kinase (BTK) with the irreversible inhibitor ibrutinib has emerged as a transformative treatment option for patients with chronic lymphocytic leukemia (CLL) and other B-cell malignancies. Yet, more than 80% of CLL patients develop resistance due to a cysteine to serine mutation at the site covalently bound by ibrutinib (C481S). Currently, an effective treatment option for C481S patients exhibiting relapse to ibrutinib does not exist and these patients have poor outcomes. To address this, we have developed a PROteolysis TArgeting Chimera (PROTAC) that induces degradation of both wild-type and C481S mutant BTK...
May 31, 2018: Biochemistry
https://www.readbyqxmd.com/read/29808268/-bruton-tyrosine-kinase-inhibition-in-dermatology-and-allergology
#10
B Wedi
No abstract text is available yet for this article.
May 28, 2018: Der Hautarzt; Zeitschrift Für Dermatologie, Venerologie, und Verwandte Gebiete
https://www.readbyqxmd.com/read/29781323/targeting-the-b-cell-receptor-pathway-a-review-of-current-and-future-therapies-for-non-hodgkin-s-lymphoma
#11
Thomas D Rodgers, Patrick M Reagan
The B-cell receptor (BCR) pathway is a crucial aspect of mature lymphocytes and is maintained in B-cell neoplasms. Many small module inhibitors targeting kinases within the BCR pathway are approved, with others in development, offering alternative treatment options to standard chemoimmunotherapy. Areas Covered: This review covers both approved inhibitors and investigational inhibitors of spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK), and phosphoinositide-3-kinase (PI3K) in the treatment of B-cell lymphomas...
May 20, 2018: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/29777941/characterization-of-the-binding-of-a-novel-antitumor-drug-ibrutinib-with-human-serum-albumin-insights-from-spectroscopic-calorimetric-and-docking-studies
#12
Bin Tang, Peixiao Tang, Jiawei He, Hongqin Yang, Hui Li
Ibrutinib (IBR) is a novel Bruton's tyrosine kinase inhibitor and shows good efficacy for several B-cell malignancies. In the current study, the molecular mechanism of the interaction between IBR and the transport protein human serum albumin (HSA) was ascertained by spectroscopic, calorimetric, and docking studies. Detailed investigations on affinity parameter, binding model, conformational change, and site selectivity were implemented by receptor-based and ligand-based analysis. An unusual fluorescence co-quenching (mutual quenching) was observed in the binding of IBR to HSA, followed by a static mechanism...
May 16, 2018: Journal of Photochemistry and Photobiology. B, Biology
https://www.readbyqxmd.com/read/29743179/a-cd19-cd3-bispecific-antibody-for-effective-immunotherapy-of-chronic-lymphocytic-leukemia-in-the-ibrutinib-era
#13
Hannah R Robinson, Junpeng Qi, Erika M Cook, Cydney Nichols, Eman L Dadashian, Chingiz Underbayev, Sarah E M Herman, Nakhle S Saba, Keyvan Keyvanfar, Clare Sun, Inhye E Ahn, Sivasubramanian Baskar, Christoph Rader, Adrian Wiestner
The Bruton's tyrosine kinase inhibitor ibrutinib induces high rates of clinical response in chronic lymphocytic leukemia (CLL). However, there remains a need for adjunct treatments to deepen response and to overcome drug resistance. Blinatumomab, a CD19/CD3 bispecific antibody (bsAb) designed in the BiTE® format, is FDA approved for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Due to its short half-life of 2.1 hours, blinatumomab requires continuous intravenous dosing for efficacy...
May 9, 2018: Blood
https://www.readbyqxmd.com/read/29742076/update-on-hairy-cell-leukemia
#14
Robert J Kreitman, Evgeny Arons
Hairy cell leukemia (HCL) is a chronic B-cell malignancy with multiple treatment options, including several that are investigational. Patients present with pancytopenia and splenomegaly, owing to the infiltration of leukemic cells expressing CD22, CD25, CD20, CD103, tartrate-resistant acid phosphatase (TRAP), annexin A1 (ANXA1), and the BRAF V600E mutation. A variant lacking CD25, ANXA1, TRAP, and the BRAF V600E mutation, called HCLv, is more aggressive and is classified as a separate disease. A molecularly defined variant expressing unmutated immunoglobulin heavy variable 4-34 (IGHV4-34) is also aggressive, lacks the BRAF V600E mutation, and has a phenotype of HCL or HCLv...
March 2018: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/29741794/targeting-bruton-s-tyrosine-kinase-for-the-treatment-of-b-cell-associated-malignancies-and-autoimmune-diseases-preclinical-and-clinical-developments-of-small-molecule-inhibitors
#15
Zhen Zhang, Daoguang Zhang, Yang Liu, Dezhi Yang, Fansheng Ran, Michael L Wang, Guisen Zhao
B cell receptor (BCR) signaling plays a key role in B cell development and function. Aberrant BCR signaling has been confirmed as a central driver for the pathogenesis of various B cell malignancies. Bruton's tyrosine kinase (BTK) is a vital component of BCR signaling and exhibits overexpression in various B cell leukemias and lymphomas. Inhibiting BTK has been proved as an efficient way for B cell malignancy intervention. Remarkable achievements have been made in the pursuit of selective BTK inhibitors, represented by the success of the irreversible BTK inhibitors, ibrutinib and acalabrutinib...
May 9, 2018: Archiv der Pharmazie
https://www.readbyqxmd.com/read/29737219/use-of-acalabrutinib-in-patients-with-mantle-cell-lymphoma
#16
Farrukh T Awan, Wojciech Jurczak
Acalabrutinib, a selective, Bruton tyrosine kinase (BTK) inhibitor, was granted accelerated approval by the FDA on 31 October 2017 for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Areas covered: This narrative review provides an overview of acalabrutinib, its use in clinical practice and potential future developments. Expert commentary: BTK inhibitors have demonstrated efficacy in patients with relapsed or refractory MCL. To prepare patients for therapy, all preexisting infections should be diagnosed and treated, and infection prophylaxis undertaken...
May 8, 2018: Expert Review of Hematology
https://www.readbyqxmd.com/read/29725548/a-case-report-of-nongerminal-center-b-cell-type-diffuse-large-b-cell-lymphoma-treated-to-complete-response-with-rituximab-and-ibrutinib
#17
Geoffrey Shouse, Miemie Thinn
Diffuse large B-cell lymphoma (DLBCL) is a molecularly heterogeneous disease consisting of different subtypes with varying clinical behaviors. For example, the activated B-cell-like (ABC) type of DLBCL has lower cure rates with traditional chemotherapy regimens. The molecular pathway promoting tumorigenic growth of the ABC type includes a dependence on intracellular signaling by Bruton's agammaglobulinemia tyrosine kinase (BTK). This specific pathway has led to the investigation of the utility of ibrutinib in treatment of this type of lymphoma at relapse or in combination with standard chemotherapy...
2018: Case Reports in Hematology
https://www.readbyqxmd.com/read/29720040/severe-arthritic-syndrome-due-to-ibrutinib-use-for-chronic-lymphocytic-leukemia
#18
Constantin A Dasanu
Although newer targeted agents improve survival in cancer patients, they have also been linked with unusual side effects. The most common side effects of Bruton tyrosine kinase inhibitors include fatigue, nausea, diarrhea, bruising, and cytopenias. We describe herein a case of an unusually severe articular syndrome with the use of ibrutinib in a patient with 17 p minus chronic lymphocytic leukemia. The severity of this side effect led to permanent discontinuation of this agent. As the causality ibrutinib-arthralgia seems legitimate, we expect further similar cases to surface in patients treated with Bruton tyrosine kinase inhibitors...
January 1, 2018: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/29717662/the-role-of-bruton-s-tyrosine-kinase-in-immune-cell-signaling-and-systemic-autoimmunity
#19
Jasper Rip, Esmee K Van Der Ploeg, Rudi W Hendriks, Odilia B J Corneth
Bruton's tyrosine kinase (BTK) is an intracellular signaling molecule first identified as the molecule affected in X-linked agammaglobulinemia (XLA) patients, who almost completely lack peripheral B cells and serum immunoglobulins. BTK is crucial for B cell development and various B cell functions, including cytokine and natural antibody production. Importantly, it is also expressed in numerous other cells, including monocytes, macrophages, granulocytes, dendritic cells, and osteoclasts. A few rare cases of autoimmune disease in XLA patients have been described...
2018: Critical Reviews in Immunology
https://www.readbyqxmd.com/read/29715023/discovery-of-4-7-diamino-5-4-phenoxyphenyl-6-methylene-pyrimido-5-4-b-pyrrolizines-as-novel-bruton-s-tyrosine-kinase-btk-inhibitors
#20
Yu Xue, Peiran Song, Zilan Song, Aoli Wang, Linjiang Tong, Mei-Yu Geng, Jian Ding, Qingsong Liu, Liping Sun, Hua Xie, Ao Zhang
An alternative medicinal chemistry approach was conducted on BTK inhibitor 1 (ibrutinib) by merging the pyrazolo[3,4-d]pyrimidine component into a tricyclic skeleton. Two types of compounds were prepared, and their biochemical activities on BTK as well as stereochemistry effects were determined. Structural optimization focusing on the reactive binding group to BTK Cys481 and on the metabolic site guided by metabolic study were conducted. 7S was identified as the most potent showing an IC50 value of 0.4 nM against BTK and 16 nM against BTK-dependent TMD8 cells...
May 1, 2018: Journal of Medicinal Chemistry
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