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Wei-Ge Wang, Xiao-Yan Zhou, Xiao-Qiu Li
No abstract text is available yet for this article.
June 2018: Annals of Translational Medicine
Amelia Bercusson, Thomas Colley, Anand Shah, Adilia Warris, Darius Armstrong-James
No abstract text is available yet for this article.
July 18, 2018: Blood
Christopher David Swan, Thomas Gottlieb
We report a case of Cryptococcus neoformans pulmonary infection complicated by empyema in a 79-year-old man with diffuse large B-cell lymphoma treated with R-CHOP and ibrutinib. A literature review identified 25 cases of cryptococcal pleural disease published since 1980. Most cases were caused by the C. neoformans species in immunocompromised hosts with an exudative pleural effusion and lymphocyte-predominant infiltrate. The cryptococcal antigen test was often positive when pleural fluid and serum were tested...
July 18, 2018: BMJ Case Reports
Sean D Reiff, Elizabeth M Muhowski, Daphne Guinn, Amy Lehman, Catherine A Fabian, Carolyn Cheney, Rose Mantel, Lisa Smith, Amy J Johnson, Wendy B Young, Adam R Johnson, Lichuan Liu, John C Byrd, Jennifer A Woyach
The clinical success of ibrutinib validates Bruton tyrosine kinase (BTK) inhibition as an effective strategy for treating hematologic malignancies including chronic lymphocytic leukemia (CLL). Despite ibrutinib's ability to produce durable remissions in patients, acquired resistance can develop, mostly commonly by mutation of C481 of BTK in the ibrutinib binding site. Here, we characterize a novel BTK inhibitor, GDC-0853, to evaluate its preclinical efficacy in treatment naïve and ibrutinib resistant CLL. GDC-0853 is unique among reported BTK inhibitors in that it does not rely upon covalent reaction with C481 to stabilize its occupancy within BTK's ATP binding site...
July 17, 2018: Blood
Tianfeng Li, Yi Deng, Yu Shi, Ruijun Tian, Yonglong Chen, Lin Zou, Julhash U Kazi, Lars Rönnstrand, Bo Feng, Sun On Chan, Wai Yee Chan, Jianmin Sun, Hui Zhao
Aberrant activation of anaplastic lymphoma kinase (ALK) can cause sporadic and familial neuroblastoma. Using a proteomics approach, we identified Bruton's tyrosine kinase (BTK) as a novel ALK interaction partner, and the physical interaction was confirmed by co-immunoprecipitation. BTK is expressed in neuroblastoma cell lines and tumor tissues. Its high expression correlates with poor relapse-free survival probability of neuroblastoma patients. Mechanistically, we demonstrated that BTK potentiates ALK-mediated signaling in neuroblastoma, and increases ALK stability by reducing ALK ubiquitination...
July 16, 2018: Oncogene
Takaharu Suzuki, Shukuko Miyakoshi, Ayako Nanba, Takayoshi Uchiyama, Keisuke Kawamoto, Sadao Aoki
Ibrutinib (IBR) covalently binds to the active site of Bruton's tyrosine kinase (BTK) and is used for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL). Approximately 5-10% of CLL is complicated by autoimmune cytopenia (AIC), such as autoimmune hemolytic anemia (AIHA). Several cases of AIC have reportedly demonstrated improvement during IBR treatment. However, in our case, the patient developed AIHA during oral IBR treatment. As AIHA is exacerbated by the increased number of CLL cells in the peripheral blood, it may have developed because of disease progression rather than IBR use...
July 14, 2018: Journal of Clinical and Experimental Hematopathology: JCEH
Sen Chen, Changmeng Cai, Adam G Sowalsky, Huihui Ye, Fen Ma, Xin Yuan, Nicholas I Simon, Nathanael S Gray, Steven P Balk
Prostate cancer (PCa) responds to therapies that suppress androgen receptor (AR) activity (androgen deprivation therapy, ADT) but invariably progresses to castration-resistant prostate cancer (CRPC). The Tec family nonreceptor tyrosine kinase BMX is activated downstream of phosphatidylinositol-3 kinase and has been implicated in regulation of multiple pathways and in the development of cancers including PCa. However, its precise mechanisms of action, and particularly its endogenous substrates, remain to be established...
July 16, 2018: Cancer Research
Chris J Kapelios, Maria S Bonou, Panagiotis Diamantopoulos, Maria K Angelopoulou, Constantina Masoura, John Barbetseas, Nora-Athina Viniou
Ibrutinib is a drug used in several lymphohyperplastic diseases. Its use is associated with an increased risk of atrial fibrillation. New-onset atrial fibrillation in this setting is a true challenge as several antiarrhythmic drugs are not indicated and long-term anticoagulation has several limitations. Herein, we describe our experience in treating a 55-year-old patient receiving ibrutinib who presented with new-onset atrial fibrillation and borderline arterial pressure. Since first-line therapies, electrical cardioversion and ablation, could not be performed, rhythm control with intravenous administration of amiodarone was attempted and led to prompt sinus rhythm restoration...
January 1, 2018: Journal of Oncology Pharmacy Practice
Helen Yu, Hoa Truong, Scott A Mitchell, Albert Liclican, John J Gosink, Wanying Li, Julie Lin, Joy Y Feng, Juliane M Jürgensmeier, Andrew Billin, Ren Xu, Scott Patterson, Nikos Pagratis
Bruton's tyrosine kinase (BTK) is a clinically validated target for B-cell leukemias and lymphomas with FDA-approved small-molecule inhibitors ibrutinib and acalabrutinib. Tirabrutinib (GS-4059/ONO-4059, Gilead Sciences, Inc., Foster City, CA) is a second-generation, potent, selective, irreversible BTK inhibitor in clinical development for lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL). An accurate pharmacodynamic assay to assess tirabrutinib target coverage in phase 1/2 clinical studies will inform dose and schedule selection for advanced clinical evaluation...
July 1, 2018: SLAS Discovery
Kaoru Harada, Joel P Brook, Francis M Lobo
No abstract text is available yet for this article.
July 12, 2018: Annals of Allergy, Asthma & Immunology
Changyuan Wang, Si Li, Qiang Meng, Xiuli Sun, Hua Li, Xiaohong Shu, Huijun Sun, Kexin Liu, Zhihao Liu, Xiaodong Ma
A new family of diphenylpyrimidine derivatives bearing an amino acid substituent were identified as potent BTK inhibitors. Among them, compound 7b, which features an l-proline substituent, was identified as the strongest BTK inhibitor, with an IC50 of 8.7 nM. Compound 7b also displayed similar activity against B-cell lymphoma cell lines as ibrutinib. Moreover, 7b exhibited low cytotoxic activity against normal PBMC cells. In addition, the acridine orange/ethidium bromide (AO/EB) staining assay, Western blot analysis and flow cytometry analysis also showed its effectiveness in interfering with B-cell lymphoma cell growth...
July 6, 2018: Bioorganic & Medicinal Chemistry
William J Archibald, Philip J Meacham, AnnaLynn M Williams, Andrea M Baran, Adrienne I Victor, Paul M Barr, Deepak M Sahasrahbudhe, Clive S Zent
Melanoma is significantly more common and is associated with a poorer prognosis in patients with an underlying B-cell malignancy. This study reports on the management of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) and a subsequent diagnosis of melanoma. In the Wilmot Cancer Institute CLL cohort, which includes 470 patients followed for 2849 person-years, 18 patients (3.8%) developed 22 melanomas. Fourteen melanomas were invasive, a significantly higher rate as compared with the age and sex matched general population (standardized incidence ratio [SIR] 6...
July 6, 2018: Leukemia Research
Amir Yosef, Emily Z Touloukian, Vinod E Nambudiri
Bruton tyrosine kinase plays a critical role in hastening cell proliferation. Bruton tyrosine kinase inhibitors are a class of immunotheraputic agents that disrupt this signaling pathway. Ibrutinib, a novel Bruton tyrosine kinase inhibitor approved by the Food and Drug Administration (FDA) for the treatment of Waldenstrom macroglobulinemia in patients who have failed treatment with other agents, has emerged as an important therapeutic agent in the management of Waldenstrom macroglobulinemia and other plasma cell dyscrasias...
January 1, 2018: Journal of Oncology Pharmacy Practice
Carlos Aguilar
: Ibrutinib is the first drug of a new family of Bruton's tyrosine kinases (Btk)-inhibiting agents, which have proved to be useful for the treatment of several B-cell lymphoid malignancies. This drug is associated to an increased bleeding risk from initial clinical trials especially in association with warfarin. Although Btk plays an important role in platelet signalling, increased bleeding tendency in patients on ibrutinib is more complex than Btk inhibition alone and is because of several antiplatelet mechanisms, namely inhibition of Btk and Tec kinases, which play a key role in platelet activation downstream of the collagen GPVI and Glycoprotein Ib...
July 10, 2018: Blood Coagulation & Fibrinolysis: An International Journal in Haemostasis and Thrombosis
Gerald Illerhaus, Elisabeth Schorb, Benjamin Kasenda
Primary central nervous system lymphoma (PCNSL) is a rare aggressive extranodal Non- Hodgkin Lymphoma. Despite high remission rates can be achieved with high-dose methotrexate based immunochemotherapy, risk of relapse and associated death is still substantial in at least a third of patients. Novel agents for treating lymphoid malignancies have substantially enriched treatment options for PCNSL. We herein systematically review the existing clinical evidence of novel agents in treatment of PCNSL, summarize ongoing studies, and discuss perspectives...
July 9, 2018: Blood
Aya Maeda, Yuki Nishida, Marla Weetall, Liangxian Cao, Arthur Branstrom, Jo Ishizawa, Takenobu Nii, Wendy D Schober, Yoshiaki Abe, Kosei Matsue, Mariko Yoshimura, Shinya Kimura, Kensuke Kojima
Despite the development of the novel Bruton tyrosine kinase inhibitor ibrutinib, mantle cell lymphoma (MCL) remains an incurable B-cell non-Hodgkin lymphoma. BMI-1 is required for the self-renewal and maintenance of MCL-initiating stem cells. Upregulation of BMI-1 has been reported in MCL patients, especially in those with refractory/relapsed disease. We studied the effects of a novel small-molecule selective inhibitor of BMI1 expression, PTC596, in MCL cells. Eight MCL cell lines and patient-derived samples were exposed to PTC596...
June 19, 2018: Oncotarget
David Wanner, Michael Steurer
At ASH (American Society of Hematology) 2017 three out of a plethora of trials showed remarkable and promising results. The combinations of venetoclax with rituximab and ibrutinib with venetoclax convinced with striking efficacy together with a manageable safety profile in relapsed/refractory setting as well as in first line therapy of high-risk disease. These two combinations are potential new standard treatment options in chronic lymphocytic leukemia.
2018: Memo
Kyle Crassini, Yandong Shen, Michael O'Dwyer, Michael O'Neill, Richard Christopherson, Stephen Mulligan, O Giles Best
Despite significant advances in treatment, chronic lymphocytic leukaemia (CLL) remains an incurable disease. Ibrutinib and idelalisib, which inhibit Bruton Tyrosine kinase (BTK) and phosphoinositol-3 (PI3) kinase-δ respectively, have become important treatment options for the disease and demonstrate the potential of targeting components of the B-cell receptor-signalling pathway. IBL-202 is a dual inhibitor of the PIM and PI3 kinases. Synergy between the pan-PIM inhibitor, pPIMi, and idelalisib against a range of haematological cell lines and primary CLL cells supports the rationale for preclinical studies of IBL-202 in CLL...
July 5, 2018: British Journal of Haematology
Filipa Mousinho, Tatiana Mendes, Paula Sousa E Santos, Maria João Acosta, José Pereira, Maria Arroz, Cândido Silva, Ana Paula Azevedo, Rita Oliveira, Martinha Chorão, Fernando Lima
Early-stage chronic lymphocytic leukemia (CLL) with neurologic involvement is a rare condition and should require a careful follow-up. Although no standard protocol exists for this condition, intrathecal chemotherapy, combined with systemic chemoimmunotherapy, has been used previously. This case describes the treatment of a patient with CLL and symptomatic compromise of the central nervous system. Our results suggest that a combination of chemotherapy, radiotherapy, and ibrutinib, administered sequentially over a 2-year period, led to a near-complete resolution of the cerebral spinal fluid neoplastic infiltration...
2018: Case Reports in Hematology
Pankaj Dwivedi, David E Muench, Michael Wagner, Mohammad Azam, H Leighton Grimes, Kenneth D Greis
Granulocyte-colony stimulating factor receptor (G-CSFR) controls myeloid progenitor proliferation and differentiation to neutrophils. Mutations in CSF3R (encoding G-CSFR) have been reported in patients with chronic neutrophilic leukemia (CNL) and acute myeloid leukemia (AML); however, despite years of research, the malignant downstream signaling of the mutated G-CSFRs is not well understood. Here, we used a quantitative phospho-tyrosine analysis to generate a comprehensive signaling map of G-CSF induced tyrosine phosphorylation in the normal versus mutated (proximal: T618I and truncated: Q741x) G-CSFRs...
July 5, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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