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https://www.readbyqxmd.com/read/28105602/ibrutinib-a-review-in-chronic-lymphocytic-leukaemia
#1
Emma D Deeks
Ibrutinib (Imbruvica(®)) is an oral irreversible inhibitor of Bruton's tyrosine kinase, a B-cell receptor (BCR) signalling kinase expressed by various haematopoietic cells, B-cell lymphomas and leukaemias. The drug is indicated for the treatment of certain haematological malignancies, including chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL), which are the focus of this review. In phase III CLL/SLL trials, ibrutinib monotherapy was more effective than chlorambucil in the first-line treatment of elderly patients (RESONATE-2) and more effective than ofatumumab in previously-treated adults (RESONATE)...
January 20, 2017: Drugs
https://www.readbyqxmd.com/read/28105149/t-14-18-q32-q21-in-chronic-lymphocytic-leukemia-patients-report-of-two-cases-and-a-literature-review
#2
Weifeng Chen, Yi Miao, Rong Wang, Yujie Wu, Hairong Qiu, Wei Xu, Jianyong Li, Lei Fan, Xin Xu
The chromosomal abnormality t(14;18)(q32;q21) is most commonly associated with germinal center-derived B-cell lymphomas, particularly follicular lymphoma (FL). Generally, it is considered a hallmark of FL. The t(14;18)(q32;q21) translocation is rare in chronic lymphocytic leukemia (CLL) and its prognostic significance remains unclear. In the present study, two cases of CLL with t(14;18)(q32;q21) were diagnosed using conventional cytogenetic analysis and fluorescence in situ hybridization. Both patients presented with leukemia and the morphological features and immunophenotypes were typical of CLL...
December 2016: Oncology Letters
https://www.readbyqxmd.com/read/28103725/a-phase-1-study-of-bortezomib-and-romidepsin-in-patients-with-chronic-lymphocytic-leukemia-small-lymphocytic-lymphoma-indolent-b-cell-lymphoma-peripheral-t-cell-lymphoma-or-cutaneous-t-cell-lymphoma
#3
Beata Holkova, Victor Yazbeck, Maciej Kmieciak, Prithviraj Bose, Shuo Ma, Amy Kimball, Mary Beth Tombes, Ellen Shrader, Wen Wan, Caryn Weir-Wiggins, Amanda Singh, Kevin T Hogan, Sarah Conine, Heidi Sankala, John D Roberts, Thomas C Shea, Steven Grant
A phase 1 study was conducted to determine the dose-limiting toxicities and maximum-tolerated dose (MTD) for bortezomib followed by romidepsin on days 1, 8, and 15 in patients with relapsed/refractory CLL/SLL or B- or T-cell lymphoma. Eighteen treated patients were evaluable for response. The MTD was 1.3 mg/m(2) bortezomib and 10 mg/m(2) romidepsin; median treatment duration was 3 cycles at this dose. The dose-limiting toxicities were grade 3 fatigue, vomiting, and chills. Two patients had partial responses, one lasting >2 years, 8 had stable disease, and 8 had progressive disease...
January 19, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28103279/aristaless-related-homeobox-arx-interacts-with-%C3%AE-catenin-bcl9-and-p300-to-regulate-canonical-wnt-signaling
#4
Il-Taeg Cho, Youngshin Lim, Jeffrey A Golden, Ginam Cho
Mutations in the Aristaless Related Homeobox (ARX) gene are associated with a spectrum of structural (lissencephaly) and functional (epilepsy and intellectual disabilities) neurodevelopmental disorders. How mutations in this single transcription factor can result in such a broad range of phenotypes remains poorly understood. We hypothesized that ARX functions through distinct interactions with specific transcription factors/cofactors to regulate unique target genes in different cell types. To identify ARX interacting proteins, we performed an unbiased proteomics screen and identified several components of the Wnt/β-catenin signaling pathway, including β-catenin (CTNNB1), B-cell CLL/lymphoma 9 (BCL9) and leucine rich repeat flightless interacting protein 2 (LRRFIP2), in cortical progenitor cells...
2017: PloS One
https://www.readbyqxmd.com/read/28102226/chronic-lymphocytic-leukaemia
#5
Thomas J Kipps, Freda K Stevenson, Catherine J Wu, Carlo M Croce, Graham Packham, William G Wierda, Susan O'Brien, John Gribben, Kanti Rai
Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5(+) B cells that is characterized by the accumulation of small, mature-appearing lymphocytes in the blood, marrow and lymphoid tissues. Signalling via surface immunoglobulin, which constitutes the major part of the B cell receptor, and several genetic alterations play a part in CLL pathogenesis, in addition to interactions between CLL cells and other cell types, such as stromal cells, T cells and nurse-like cells in the lymph nodes. The clinical progression of CLL is heterogeneous and ranges from patients who require treatment soon after diagnosis to others who do not require therapy for many years, if at all...
January 19, 2017: Nature Reviews. Disease Primers
https://www.readbyqxmd.com/read/28100842/prognostic-value-of-thymidine-kinase-activity-in-patients-with-chronic-lymphocytic-leukemia
#6
Piotr Stelmach, Jerzy Z Błoński
Thymidine kinase (TK) activity is a marker of biological activity that allows the indolent and aggressive forms of chronic lymphocytic leukemia (CLL) to be distinguished. The aims of the study were to determine the relationship between TK activity and clinical status and prognosis, as well as to compare its activity with that of other prognostic and predictive factors. TK activity was measured in patient sera at the time of diagnosis using the DiviTum method, with the mean value being 439 Du/L. A correlation was found between TK activity and risk of disease progression (p=0...
December 30, 2016: Postȩpy Higieny i Medycyny Doświadczalnej
https://www.readbyqxmd.com/read/28100580/venetoclax-in-patients-with-previously-treated-chronic-lymphocytic-leukemia
#7
Andrew W Roberts, Stephan Stilgenbauer, John F Seymour, David C S Huang
Venetoclax is the first BCL2 inhibitor to enter routine clinical practice. It is an orally bioavailable small molecule that binds BCL2 very specifically. Acting as a pharmacological mimic of the proteins that initiate apoptosis (a so-called BH3-mimetic), venetoclax rapidly induces apoptosis in chronic lymphocytic leukemia (CLL) cells which express high levels of BCL2 and rely on it to maintain their survival. As a single agent, daily venetoclax treatment induced durable responses in 79% of patients with relapsed or refractory CLL or small lymphocytic lymphoma in a Phase 1 study, including complete remissions in 20% of patients...
January 18, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28097289/binding-of-cll-subset-4-b-cell-receptor-immunoglobulins-to-viable-human-memory-b-lymphocytes-requires-a-distinctive-igkv-somatic-mutation
#8
Rosa Catera, Yun Liu, Chao Gao, Xiao-Jie Yan, Amanda Magli, Steven L Allen, Jonathan E Kolitz, Kanti R Rai, Charles C Chu, Ten Feizi, Kostas Stamatopoulos, Nicholas Chiorazzi
Amino acid replacement mutations in certain CLL stereotyped B-cell receptor (BCR) immunoglobulins (IGs) at defined positions within antigen-binding sites strongly imply antigen selection. Prime examples of this are CLL subset 4 BCR IGs using IGHV4-34/IGHD5-18/IGHJ6 and IGKV2-30/IGKJ2 rearrangements. Conspicuously and unlike most CLL IGs, subset 4 IGs do not bind apoptotic cells. By testing the (auto)antigenic reactivities of subset 4 IGs toward viable lymphoid-lineage cells and specific autoantigens typically bound by IGHV4-34(+) IGs, we found IGs from both subset 4 and non-subset 4 IGHV4-34-expressing CLL cases bind naïve B cells...
January 12, 2017: Molecular Medicine
https://www.readbyqxmd.com/read/28096995/response-to-ibrutinib-in-chronic-lymphocytic-leukemia-improves-in-quality-with-time
#9
Stefano Molica, Guido Carillio, Caterina Battaglia
Unlike chemoimmunotherapy regimens, which are given for a defined period, ibrutinib, a first-in-class Bruton's kinase inhibitor, allows most patients with CLL to remain on treatment for an extended period. Our experience, supported by sequential CT scan images, suggests that long-term ibrutinib promotes a high response rate that improves in quality with time.
January 2017: Clinical Case Reports
https://www.readbyqxmd.com/read/28096407/development-of-chronic-allergic-responses-by-dampening-bcl6-mediated-suppressor-activity-in-memory-t-helper-2-cells
#10
Takashi Ogasawara, Masahiko Hatano, Hisae Satake, Jun Ikari, Toshibumi Taniguchi, Nobuhide Tsuruoka, Haruko Watanabe-Takano, Lisa Fujimura, Akemi Sakamoto, Hirokuni Hirata, Kumiya Sugiyama, Yasutsugu Fukushima, Susumu Nakae, Kenji Matsumoto, Hirohisa Saito, Takeshi Fukuda, Kazuhiro Kurasawa, Koichiro Tatsumi, Takeshi Tokuhisa, Masafumi Arima
Mice deficient in the transcriptional repressor B-cell CLL/lymphoma 6 (Bcl6) exhibit similar T helper 2 (TH2) immune responses as patients with allergic diseases. However, the molecular mechanisms underlying Bcl6-directed regulation of TH2 cytokine genes remain unclear. We identified multiple Bcl6/STAT binding sites (BSs) in TH2 cytokine gene loci. We found that Bcl6 is modestly associated with the BSs, and it had no significant effect on cytokine production in newly differentiated TH2 cells. Contrarily, in memory TH2 (mTH2) cells derived from adaptively transferred TH2 effectors, Bcl6 outcompeted STAT5 for binding to TH2 cytokine gene loci, particularly Interleukin4 (Il4) loci, and attenuated GATA binding protein 3 (GATA3) binding to highly conserved intron enhancer regions in mTH2 cells...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28096240/coevolution-of-leukemia-and-host-immune-cells-in-chronic-lymphocytic-leukemia
#11
Noelia Purroy, C J Wu
Cumulative studies on the dissection of changes in driver genetic lesions in cancer across the course of the disease have provided powerful insights into the adaptive mechanisms of tumors in response to the selective pressures of therapy and environmental changes. In particular, the advent of next-generation-sequencing (NGS)-based technologies and its implementation for the large-scale comprehensive analyses of cancers have greatly advanced our understanding of cancer as a complex dynamic system wherein genetically distinct subclones interact and compete during tumor evolution...
January 17, 2017: Cold Spring Harbor Perspectives in Medicine
https://www.readbyqxmd.com/read/28096090/how-i-manage-ibrutinib-refractory-chronic-lymphocytic-leukemia
#12
Jennifer A Woyach
The introduction of the Bruton's Tyrosine Kinase inhibitor ibrutinib has dramatically changed the management of chronic lymphocytic leukemia. Although responses have been durable in the majority of patients, relapses do occur, especially in the high risk patient population. Most relapses occur as the result of acquired mutations in BTK and PLCG2, which may facilitate success with alternative targeted therapies. As outcomes following ibrutinib relapse have been reported to be poor, specific strategies are needed for this patient population...
January 17, 2017: Blood
https://www.readbyqxmd.com/read/28092772/the-expression-of-endothelin-1-in-chronic-lymphocytic-leukemia-is-controlled-by-epigenetic-mechanisms-and-extracellular-stimuli
#13
Silvia Martinelli, Rossana Maffei, Stefania Fiorcari, Chiara Quadrelli, Patrizia Zucchini, Stefania Benatti, Leonardo Potenza, Mario Luppi, Roberto Marasca
Endothelin-1 (ET-1) is a hormone peptide widely expressed and is involved in several biological processes, important not only for normal cell function but also for tumor development, including cell proliferation, invasion, metastasis, angiogenesis and osteogenesis. In accordance, ET-1 was already shown to contribute to the growth and progression of many different solid cancers. We recently demonstrated that ET-1 has a role in the pathogenesis of chronic lymphocytic leukemia (CLL) where it is abnormally expressed...
December 30, 2016: Leukemia Research
https://www.readbyqxmd.com/read/28091403/chronic-lymphocytic-leukemia-prognostic-index-a-new-integrated-scoring-system-to-predict-the-time-to-first-treatment-in-chinese-patients-with-chronic-lymphocytic-leukemia
#14
Heng Li, Shu-Hua Yi, Wen-Jie Xiong, Hui-Min Liu, Rui Lyu, Ting-Yu Wang, Wei Liu, Shi-Zhen Zhong, Zhen Yu, De-Hui Zou, Yan Xu, Gang An, Zeng-Jun Li, Lu-Gui Qiu
BACKGROUND: The established clinical staging systems (Rai/Binet) of chronic lymphocytic leukemia (CLL) cannot accurately predict the appropriate treatment of patients in the earlier stages. In the past two decades, several prognostic factors have been identified to predict the outcome of patients with CLL, but only a few studies investigated more markers together. To predict the time to first treatment (TTFT) in patients of early stages, we evaluated the prognostic role of conventional markers as well as cytogenetic abnormalities and combined them together in a new prognostic scoring system, the CLL prognostic index (CLL-PI)...
2017: Chinese Medical Journal
https://www.readbyqxmd.com/read/28089635/venetoclax-plus-rituximab-in-relapsed-or-refractory-chronic-lymphocytic-leukaemia-a-phase-1b-study
#15
John F Seymour, Shuo Ma, Danielle M Brander, Michael Y Choi, Jacqueline Barrientos, Matthew S Davids, Mary Ann Anderson, Anne W Beaven, Steven T Rosen, Constantine S Tam, Betty Prine, Suresh K Agarwal, Wijith Munasinghe, Ming Zhu, L Leanne Lash, Monali Desai, Elisa Cerri, Maria Verdugo, Su Young Kim, Rod A Humerickhouse, Gary B Gordon, Thomas J Kipps, Andrew W Roberts
BACKGROUND: Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab. METHODS: Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial...
January 12, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/28089461/chronic-lymphocytic-leukemia-in-association-with-a-ranula-a-report-and-review-of-the-literature
#16
Scott M Peters, Chang Han, Angela J Yoon, Elizabeth M Philipone
Chronic lymphocytic leukemia (CLL), an indolent neoplasm of B lymphocytes, is the most common adult leukemia in the Western Hemisphere. Despite this, however, the intraoral presentation of CLL is quite rare. We report the case of an 83-year-old woman with CLL incidentally involving minor salivary glands in association with a ranula (floor-of-mouth mucocele).
November 22, 2016: Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
https://www.readbyqxmd.com/read/28089238/ruxolitinib-for-symptom-control-in-patients-with-chronic-lymphocytic-leukaemia-a-single-group-phase-2-trial
#17
Preetesh Jain, Michael Keating, Sarah Renner, Charles Cleeland, Huang Xuelin, Graciela Nogueras Gonzalez, David Harris, Ping Li, Zhiming Liu, Ivo Veletic, Uri Rozovski, Nitin Jain, Phillip Thompson, Prithviraj Bose, Courtney DiNardo, Alessandra Ferrajoli, Susan O'Brien, Jan Burger, William Wierda, Srdan Verstovsek, Hagop Kantarjian, Zeev Estrov
BACKGROUND: Disease-related symptoms impair the quality of life of patients with chronic lymphocytic leukaemia (CLL) who do not require systemic therapy. Available therapies are not specifically aimed at symptom control. Because stimulation of the B-cell receptor activates JAK2 in CLL cells and the JAK2 inhibitor ruxolitinib improves symptoms in patients with myelofibrosis, we postulated that ruxolitinib would improve disease-related symptoms in patients with CLL. We did a phase 2 trial of ruxolitinib to test this hypothesis...
January 11, 2017: Lancet Haematology
https://www.readbyqxmd.com/read/28089237/cll-when-the-target-of-treatment-is-disease-related-symptoms
#18
Stefano Molica, Emili Montserrat
No abstract text is available yet for this article.
January 11, 2017: Lancet Haematology
https://www.readbyqxmd.com/read/28088788/dual-syk-jak-inhibition-overcomes-ibrutinib-resistance-in-chronic-lymphocytic-leukemia-cerdulatinib-but-not-ibrutinib-induces-apoptosis-of-tumor-cells-protected-by-the-microenvironment
#19
Ailin Guo, Pin Lu, Greg Coffey, Pamela Conley, Anjali Pandey, Y Lynn Wang
Ibrutinib (BTK inhibitor) has generated remarkable responses in CLL. However, the drug, to a large extent, does not cause cell death directly and does not eradicate CLL malignant clones. Inability to eradicate CLL has fostered resistance generation. Once patients become resistant, they do poorly with a median survival of 3-4 months. Novel therapeutic strategies are needed to prevent resistance, improve treatment outcome and ultimately cure the disease. Herein, we explore dual targeting of the BCR and JAK-STAT pathways with a novel single agent, cerdulatinib, which selectively inhibits both SYK (a BCR component) and JAK kinases...
January 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28081486/front-line-treatment-of-cll-in-the-era-of-novel-agents
#20
REVIEW
Tadeusz Robak, Stephan Stilgenbauer, Alessandra Tedeschi
Although chemoimmunotherapy prolongs survival and as such, is the standard of care for treatment-naïve patients, its effectiveness may be reduced by associated toxicity and dose reductions. In addition, it has been associated with the development of myelosuppression and secondary neoplasms; treatments are hence needed which offer greater survival and lowered toxicity. A range of new targeted agents, ibrutinib, idelalisib and venetoclax, have demonstrated such a balance in a second-line setting, offering CLL patients durable remissions and a modest toxicity profile...
December 30, 2016: Cancer Treatment Reviews
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