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https://www.readbyqxmd.com/read/29444501/quercetin-therapy-for-selected-patients-with-pim1-kinase-positive-chronic-lymphocytic-leukemia-small-lymphocytic-lymphoma-a-pilot-study
#1
Beverly W Baron, Michael J Thirman, Mihai C Giurcanu, Joseph M Baron
We reported that PIM1 kinase is expressed in the lymphocytes of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Quercetin, a naturally occurring flavonoid, is a dietary supplement and inhibits many kinases, including PIM1, in vitro. Under an Institutional Review Board-approved protocol, we performed an open-label, single-arm pilot study to evaluate the antitumor activity of quercetin in patients with CLL/SLL. Q-ForceTM chews were administered orally, 500 mg twice daily, for 3 months...
February 14, 2018: Acta Haematologica
https://www.readbyqxmd.com/read/29440231/-ex-vivo-activity-of-cytotoxic-drugs-and-targeted-agents-in-small-intestinal-nets
#2
Kosmas Daskalakis, Olov Norlen, Andreas Karakatsanis, Per Hellman, Rolf Larsson, Peter Nygren, Peter Stalberg
Small intestinal endocrine tumours (SI-NETs) are generally considered resistant to systemic treatment. To date, predictive markers for drug activity are lacking. Tumour samples from 27 patients with SI-NETs were analyzed ex vivo for sensitivity to a panel of cytotoxic drugs and targeted agents using a short-term total cell kill assay. Samples of renal cancer, colorectal cancer (CRC), ovarian cancer, and chronic lymphocytic leukemia (CLL) were included for comparison. For the SI-NET subset, drug sensitivity was analyzed in relation to clinico-pathological variables and pre-treatment biomarkers...
February 12, 2018: Endocrine-related Cancer
https://www.readbyqxmd.com/read/29427646/epigenetic-deregulation-in-chronic-lymphocytic-leukemia-clinical-and-biological-impact
#3
REVIEW
Larry Mansouri, Justyna Anna Wierzbinska, Christoph Plass, Richard Rosenquist
Deregulated transcriptional control caused by aberrant DNA methylation and/or histone modifications is a hallmark of cancer cells. In chronic lymphocytic leukemia (CLL), the most common adult leukemia, the epigenetic 'landscape' has added a new layer of complexity to our understanding of this clinically and biologically heterogeneous disease. Early studies identified aberrant DNA methylation, often based on single gene promoter analysis with both biological and clinical impact. Subsequent genome-wide profiling studies revealed differential DNA methylation between CLLs and controls and in prognostics subgroups of the disease...
February 7, 2018: Seminars in Cancer Biology
https://www.readbyqxmd.com/read/29427355/rituximab-cladribine-and-cyclophosphamide-rcc-induction-with-rituximab-maintenance-in-chronic-lymphocytic-leukemia-palg-cll4-ml21283-trial
#4
Tadeusz Robak, Jerzy Blonski, Aleksander Bartłomiej Skotnicki, Magdalena Piotrowska, Tomasz Wróbel, Justyna Rybka, Janusz Kłoczko, Łukasz Bołkun, Bożena Katarzyna Budziszewska, Urszula Walczak, Anatoly Uss, Marta Fidecka, Piotr Smolewski
OBJECTIVES: PALG CLL4 is the first, randomized, phase IIIb study with cladribine, cyclophosphamide and rituximab (RCC) induction and subsequent maintenance with rituximab in previously untreated chronic lymphocytic leukemia (CLL) patients. METHODS: The induction treatment consisted of six RCC cycles regimen. Patients with complete response (CR) or partial response (PR) after an induction phase were randomized into a maintenance arm with rituximab or an observational arm...
February 10, 2018: European Journal of Haematology
https://www.readbyqxmd.com/read/29415595/reasons-for-initiation-of-treatment-and-predictors-of-response-for-patients-with-rai-stage-0-1-chronic-lymphocytic-leukemia-cll-receiving-first-line-therapy-an-analysis-of-the-connect%C3%A2-cll-cohort-study
#5
Christopher R Flowers, Chadi Nabhan, Neil E Kay, Anthony Mato, Nicole Lamanna, Charles M Farber, Matthew S Davids, Pavel Kiselev, Arlene S Swern, Kristen Sullivan, E Dawn Flick, Jeff P Sharman
A 'watch-and-wait' strategy is recommended for most patients with early-stage chronic lymphocytic leukemia (CLL) prior to treatment initiation. In the Connect® CLL registry, a prospective observational cohort study of 1494 patients treated in 199 US centers, median time to first-line treatment initiation was 3.8, 1.5, and 0.6 years for patients with Rai stage 0, 1, and ≥2, respectively. Only 60% of patients with Rai stage 0/1 underwent FISH/cytogenetic testing prior to initiation of a new line of therapy...
February 7, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29408410/the-role-of-mtor-mediated-signaling-in-the-regulation-of-cellular-migration
#6
REVIEW
Ailsa K Holroyd, Alison M Michie
Mechanistic target for rapamycin (mTOR) is a serine/threonine protein kinase that forms two distinct complexes mTORC1 and mTORC2, integrating mitogen and nutrient signals to regulate cell survival and proliferation; processes which are commonly deregulated in human cancers. mTORC1 and mTORC2 have divergent molecular associations and cellular functions: mTORC1 regulates in mRNA translation and protein synthesis, while mTORC2 is involved in the regulation of cellular survival and metabolism. Through AKT phosphorylation/activation, mTORC2 has also been reported to regulate cell migration...
February 3, 2018: Immunology Letters
https://www.readbyqxmd.com/read/29407973/small-molecule-mcl-1-inhibitors-emerging-anti-tumor-agents
#7
Yichao Wan, Ningning Dai, Zilong Tang, Hao Fang
The anti-apoptotic members of B-cell lymphoma-2 (Bcl-2) proteins family, such as Bcl-2 and myeloid cell leukemia-1 (Mcl-1), are the key regulators of the intrinsic pathway of apoptosis and overexpressed in many tumor cells, which have been confirmed as potential drug targets for cancers. A number of Bcl-2 proteins inhibitors have been developed and conducted clinical trials, but no Mcl-1 inhibitors are presented in the clinics. In addition, Mcl-1 is an important reason for the resistance to radio- and chemotherapies, including inhibitors that target other Bcl-2 family members...
January 30, 2018: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29393986/rituximab-in-combination-with-chemotherapy-for-the-treatment-of-chronic-lymphocytic-leukaemia-in-clinical-practice
#8
Marcel Reiser, Steffen Dörfel, Manfred Hensel, Mark Hoesl, Wolf-Oliver Jordan, Michael Koenigsmann, Dirk Meyer, Dietmar Reichert, Andreas Schwarzer, Moritz Marquardt, Kerstin Kellershohn, Kathleen Jentsch-Ullrich
OBJECTIVES: This study was conducted to investigate the real-world effectiveness and tolerability of rituximab-containing chemoimmunotherapies, which have become the standard of care for chronic lymphocytic leukaemia (CLL), particularly for physically fit patients. Furthermore, current treatment patterns in clinical practice were documented, and an unselected real-life population was compared with older, comorbid patients. METHODS: Prospective, multicentre, observational, study with rituximab-containing chemoimmunotherapy in CLL patients...
February 2, 2018: European Journal of Haematology
https://www.readbyqxmd.com/read/29390159/improving-shared-decision-making-in-chronic-lymphocytic-leukemia-through-multidisciplinary-education
#9
Gabrielle B Rocque, Courtney P Williams, Karina I Halilova, Uma Borate, Bradford E Jackson, Emily S Van Laar, Maria Pisu, Thomas W Butler, Randall S Davis, Amitkumar Mehta, Sara J Knight, Monika M Safford
New treatments for chronic lymphocytic leukemia (CLL) with excellent response rates and varying toxicity profiles have emerged in recent years, creating an opportunity for a patient's personal preferences to contribute to treatment decisions. We conducted a prospective, quasi-experimental pre- and post-evaluation of a multilevel educational program and its impact on knowledge of CLL and shared decision-making (SDM). We educated patients, lay navigators, nurses/advanced practice providers (APPs), and physicians...
January 30, 2018: Translational Behavioral Medicine
https://www.readbyqxmd.com/read/29386193/brd4-profiling-identifies-critical-chronic-lymphocytic-leukemia-oncogenic-circuits-and-reveals-sensitivity-to-plx51107-a-novel-structurally-distinct-bet-inhibitor
#10
Hatice Gulcin Ozer, Dalia El-Gamal, Ben Powell, Zachary A Hing, James S Blachly, Bonnie Harrington, Shaneice Mitchell, Nicole R Grieselhuber, Katie Williams, Tzung-Huei Lai, Lapo Alinari, Robert A Baiocchi, Lindsey Brinton, Elizabeth Baskin, Matthew Cannon, Larry Beaver, Virginia M Goettl, David M Lucas, Jennifer A Woyach, Deepa Sampath, Amy M Lehman, Lianbo Yu, Jiazhong Zhang, Yan Ma, Ying Zhang, Wayne Spevak, Songyuan Shi, Paul Severson, Rafe Shellooe, Heidi Carias, Garson Tsang, Ken Dong, Todd Ewing, Adhirai Marimuthu, Christina Tantoy, Jason Walters, Laura Sanftner, Hamid Rezaei, Marika Nespi, Bernice Matusow, Gaston Habets, Prabha Ibrahim, Chao Zhang, Ewy A Mathé, Gideon Bollag, John C Byrd, Rosa Lapalombella
Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is over-expressed in CLL and is enriched proximal to genes up-regulated or de novo expressed in CLL with known function in disease pathogenesis and progression. These genes, including key members of the BCR signaling pathway, provide rationale for this therapeutic approach to identify new targets in alternative types of cancer...
January 31, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29382644/venetoclax-data-prompt-rethink-of-cll-therapy
#11
(no author information available yet)
The BCL2 inhibitor venetoclax is approved in the United States for only a subset of patients with refractory chronic lymphocytic leukemia. However, in light of data presented at the American Society of Hematology 2017 Annual Meeting, clinicians are thinking ahead to administering the drug more broadly-in combinations and as a first-line therapy-for other patients with the disease.
January 30, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29358183/clinical-implications-of-cancer-gene-mutations-in-patients-with-chronic-lymphocytic-leukemia-treated-with-lenalidomide
#12
Koichi Takahashi, Boyu Hu, Feng Wang, Yuanqing Yan, Ekaterina Kim, Candida Vitale, Keyur P Patel, Paolo Strati, Curtis Gumbs, Latasha Little, Samantha Tippen, Xingzhi Song, Jianhua Zhang, Nitin Jain, Philip Thompson, Guillermo Garcia-Manero, Hagop Kantarjian, Zeev Estrov, Kim-Anh Do, Michael Keating, Jan A Burger, Alessandra Ferrajoli, P Andrew Futreal, William G Wierda
Lenalidomide is clinically active in chronic lymphocytic leukemia (CLL), but its effectiveness in the context of the CLL mutational landscape is unknown. We performed targeted capture sequencing of 295 cancer genes in specimens from 102 CLL patients with treatment-naïve disease (TN patients) and 186 CLL patients with relapsed/refractory disease (R/R patients) who received lenalidomide-based therapy at our institution. The most frequently mutated gene was SF3B1 (15%), followed by NOTCH1 (14%) and TP53 (14%), with R/R patients having significantly more TP53 mutations than TN patients...
January 22, 2018: Blood
https://www.readbyqxmd.com/read/29352719/prognostic-testing-patterns-and-outcomes-of-chronic-lymphocytic-leukemia-patients-stratified-by-fluorescence-in-situ-hybridization-cytogenetics-a-real-world-clinical-experience-in-the-connect-cll-registry
#13
Anthony Mato, Chadi Nabhan, Neil E Kay, Nicole Lamanna, Thomas J Kipps, David L Grinblatt, Christopher R Flowers, Charles M Farber, Matthew S Davids, Pavel Kiselev, Arlene S Swern, Shriya Bhushan, Kristen Sullivan, E Dawn Flick, Jeff P Sharman
INTRODUCTION: Prognostic genetic testing is recommended for patients with chronic lymphocytic leukemia (CLL) to guide clinical management. Specific abnormalities, such as del(17p), del(11q), and unmutated IgHV, can predict the depth and durability of the response to CLL therapy. PATIENTS AND METHODS: In the present analysis of the Connect CLL Registry (ClinicalTrials.gov identifier, NCT01081015), a prospective observational cohort study of patients treated across 199 centers, the patterns of prognostic testing and outcomes of patients with unfavorable-risk genetics were analyzed...
December 6, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29333021/efficacy-and-safety-of-ibrutinib-in-indian-patients-with-relapsed-or-refractory-chronic-lymphocytic-leukemia-and-mantle-cell-lymphoma-cases-from-a-named-patient-program
#14
Mohan B Agarwal, Dinesh Bhurani, Chirag Shah, Nitin Sood, Manish Singhal, Anil Kamat, Subash Chezhian, Suryaprakash Mishra, Dinesh Nagrale
Context: This named patient program evaluated the safety and efficacy of ibrutinib, a selective inhibitor of Bruton's tyrosine kinase in Indian patients with relapsed/refractory chronic lymphocytic leukemia (CLL, with/without chromosome 17 deletion [del17p]) and mantle cell lymphoma (MCL). Subjects and Methods: The eight enrolled patients (relapsed/refractory CLL: n = 6 [4/6 patients with del17p] and relapsed/refractory MCL: n = 2) had median age of 55 years (range, 52-60) and had received a median of 3 (CLL patients) and 4 (MCL patients) prior therapies...
October 2017: Indian Journal of Medical and Paediatric Oncology
https://www.readbyqxmd.com/read/29318593/optimising-outcomes-for-patients-with-chronic-lymphocytic-leukaemia-on-ibrutinib-therapy-european-recommendations-for-clinical-practice
#15
John G Gribben, Francesc Bosch, Florence Cymbalista, Christian H Geisler, Paolo Ghia, Peter Hillmen, Carol Moreno, Stephan Stilgenbauer
Ibrutinib is indicated in Europe for the treatment of several B-cell malignancies, including chronic lymphocytic leukaemia (CLL). However, despite the high efficacy and favourable toxicity profile of ibrutinib, recent data suggest that it is not always administered optimally in clinical practice, with an increased tendency for dose reduction and a higher frequency of discontinuation. An expert panel of European haematologists was convened to identify practical issues pertinent to physicians involved in the therapeutic management of ibrutinib-treated CLL patients and here we outline the findings...
January 9, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29317997/experience-with-ibrutinib-for-first-line-use-in-patients-with-chronic-lymphocytic-leukemia
#16
REVIEW
Gilad Itchaki, Jennifer R Brown
Ibrutinib is the first in-class, orally administered, Bruton's tyrosine kinase (BTK) inhibitor that abrogates the critical signaling downstream of the B-cell receptor (BCR). This signaling is required for B-cell survival, proliferation and interaction with the microenvironment. Ibrutinib proved active in preclinical models of lymphoproliferative diseases and achieved impressive response rates in heavily pretreated relapsed and refractory (R/R) patients with chronic lymphocytic leukemia (CLL). Ibrutinib prolonged survival compared to standard therapy and mitigated the effect of most poor prognostic factors in CLL, thus becoming the main therapeutic option in high-risk populations...
January 2018: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/29317636/the-expression-of-inhibitor-of-bruton-s-tyrosine-kinase-gene-is-progressively-up-regulated-in-the-clinical-course-of-chronic-lymphocytic-leukaemia-conferring-resistance-to-apoptosis
#17
Francesco Albano, Federico Chiurazzi, Selena Mimmi, Eleonora Vecchio, Arianna Pastore, Clementina Cimmino, Camilla Frieri, Enrico Iaccino, Antonio Pisano, Gaetanina Golino, Giuseppe Fiume, Massimo Mallardo, Giuseppe Scala, Ileana Quinto
Chronic lymphocytic leukaemia (CLL) is the most common B-cell malignancy with a variable clinical outcome. Biomarkers of CLL progression are required for optimising prognosis and therapy. The Inhibitor of Bruton's tyrosine kinase-isoform α (IBTKα) gene encodes a substrate receptor of Cullin 3-dependent E3 ubiquitin ligase, and promotes cell survival in response to the reticulum stress. Searching for novel markers of CLL progression, we analysed the expression of IBTKα in the peripheral blood B-cells of CLL patients, before and after first line therapy causing remission...
January 9, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29317454/casein-kinase-1-is-a-therapeutic-target-in-chronic-lymphocytic-leukemia
#18
Pavlina Janovska, Jan Verner, Jiri Kohoutek, Lenka Bryjova, Michaela Gregorova, Marta Dzimkova, Hana Skabrahova, Tomasz Radaszkiewicz, Petra Ovesna, Olga Vondalova Blanarova, Tereza Nemcova, Zuzana Hoferova, Katerina Vasickova, Lucie Smyckova, Alexander Egle, Sarka Pavlova, Lucie Poppova, Karla Plevova, Sarka Pospisilova, Vitezslav Bryja
Casein kinase (CK) 1δ/ε is a key component of non-canonical Wnt signaling pathways, which were shown previously to drive pathogenesis of chronic lymphocytic leukemia (CLL). In this study we investigated thoroughly the effects of CK1δ/ε inhibition on the primary CLL cells and analyzed the therapeutic potential in vivo using two murine model systems based on the Eµ-TCL1-induced leukemia (syngeneic adoptive transfer model and spontaneous disease development), which resemble closely the human CLL. We can demonstrate that CK1δ/ε inhibitor PF-670462 significantly blocks microenvironmental interactions - chemotaxis, invasion and communication with stromal cells in primary CLL cells in all major subtypes of CLL...
January 9, 2018: Blood
https://www.readbyqxmd.com/read/29316456/disease-characteristics-and-clinical-outcomes-in-patients-aged-less-than-40-with-chronic-lymphocytic-leukemia
#19
Bartlomiej M Getta, Sean Devlin, Jae H Park, Martin S Tallman, Ellin Berman
Outcomes in very young CLL patients (age ≤40) are not well characterized. We compared 71 consecutive patients aged ≤40 with 142 "older" matched patients >40 from our institution and used SEER database as an independent comparison group. Patients in the two age groups were diagnosed at similar Rai stage. At diagnosis, very young patients had a similar rate of adverse cytogenetics, IGHV mutation and ZAP70 expression and had lower beta-2-microglobulin and a lower incidence of second malignancies...
February 2018: Leukemia Research
https://www.readbyqxmd.com/read/29305552/venetoclax-for-patients-with-chronic-lymphocytic-leukemia-who-progressed-during-or-after-idelalisib-therapy
#20
Steven Coutre, Michael Choi, Richard R Furman, Herbert Eradat, Leonard Heffner, Jeffrey A Jones, Brenda Chyla, Lang Zhou, Suresh Agarwal, Tina Waskiewicz, Maria Verdugo, Rod A Humerickhouse, Jalaja Potluri, William G Wierda, Matthew S Davids
B-cell receptor pathway inhibitors (BCRi) have transformed treatment for chronic lymphocytic leukemia (CLL); however, efficacy of therapies for patients whose disease is refractory to/relapses after (R/R) BCRi is unknown. Venetoclax is a selective, orally bioavailable BCL-2 inhibitor with activity in patients with CLL, including those who are heavily pretreated or have 17p deletion. This phase 2 study prospectively evaluated venetoclax in patients with R/R CLL after ibrutinib or idelalisib; here we report on patients who received idelalisib as the last BCRi prior to enrollment...
January 5, 2018: Blood
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