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https://www.readbyqxmd.com/read/28427204/an-extensive-molecular-cytogenetic-characterization-in-high-risk-chronic-lymphocytic-leukemia-identifies-karyotype-aberrations-and-tp53-disruption-as-predictors-of-outcome-and-chemorefractoriness
#1
Gian Matteo Rigolin, Luca Formigaro, Maurizio Cavallari, Francesca Maria Quaglia, Enrico Lista, Antonio Urso, Emanuele Guardalben, Sara Martinelli, Elena Saccenti, Cristian Bassi, Laura Lupini, Maria Antonella Bardi, Eleonora Volta, Elisa Tammiso, Aurora Melandri, Massimo Negrini, Francesco Cavazzini, Antonio Cuneo
We investigated whether karyotype analysis and mutational screening by next generation sequencing could predict outcome in 101 newly diagnosed chronic lymphocytic leukemia patients with high-risk features, as defined by the presence of unmutated IGHV gene and/or 11q22/17p13 deletion by FISH and/or TP53 mutations. Cytogenetic analysis showed favorable findings (normal karyotype and isolated 13q14 deletion) in 30 patients, unfavorable (complex karyotype and/or 17p13/11q22 deletion) in 34 cases and intermediate (all other abnormalities) in 36 cases...
March 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28424451/prognostic-impact-of-notch1-myd88-and-sf3b1-mutations-in-polish-population-of-chronic-lymphocytic-leukemia-patients
#2
Maciej Putowski, Marta Podgórniak, Marta Piróg, Joanna Knap, Joanna Zaleska, Joanna Purkot, Jacek Zawiślak, Ewelina Zakrzewska, Agnieszka Karczmarczyk, Paulina Własiuk, Edyta Subocz, Krzysztof Giannopoulos
INTRODUCTION    Currently available prognostic factors determining the course of chronic lymphocytic leukemia (CLL) are not fully efficient especially for newly diagnosed patients. Investigation of molecular changes may help to clarify the reasons of the heterogeneity of the disease. Apart from already confirmed TP53 mutations, novel lesions: NOTCH1, SF3B1 and MYD88 might represent biomarkers of clinical relevance.  OBJECTIVES    The aim was to evaluate mutational status of NOTCH1, MYD88 and SF3B1 and to compare results with confirmed prognostic factors: ZAP-70, CD38 and IGHV mutation...
April 20, 2017: Polish Archives of Internal Medicine
https://www.readbyqxmd.com/read/28424415/clinicopathological-features-and-outcome-of-chronic-lymphocytic-leukaemia-in-chinese-patients
#3
Thomas Sau-Yan Chan, Yuh-Shan Lee, Ilaria Del Giudice, Marilisa Marinelli, Caterina Ilari, Luciana Cafforio, Anna Guarini, Daryl Tan, Colin Phipps, Yeow-Tee Goh, William Hwang, Allan Zhi-Kai Goh, Lisa Lai-Ping Siu, Saliangi Wu, Chun-Yin Ha, Shek-Ying Lin, Chi-Hang Kwok, Chi-Kuen Lau, Kit-Fai Wong, Robin Foà, Yok-Lam Kwong, Eric Tse
Chronic lymphocytic leukaemia (CLL) is uncommon in Chinese population and its biology, genetics and treatment outcome in Chinese patients have not been comprehensively investigated. In this study, we studied the clinicopathological features and outcome of 212 Chinese patients with newly diagnosed CLL in Hong Kong and Singapore. The median age at diagnosis was 64 years. The majority of patients presented with early-stage disease (Binet stage A, 56.1%). Del(13)(q14) was the most frequent abnormality (41.7%) detected by fluorescence in situ hybridization (FISH) analysis...
March 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28424162/pembrolizumab-in-patients-with-chronic-lymphocytic-leukemia-with-richter-s-transformation-and-relapsed-cll
#4
Wei Ding, Betsy R LaPlant, Timothy G Call, Sameer A Parikh, Jose F Leis, Rong He, Tait D Shanafelt, Sutapa Sinha, Jennifer Le-Rademacher, Andrew L Feldman, Thomas M Habermann, Thomas E Witzig, Gregory A Wiseman, Yi Lin, Erik Asmus, Grzegorz S Nowakowski, Michael J Conte, Deborah A Bowen, Casey N Aitken, Daniel L Van Dyke, Patricia T Greipp, Xin Liu, Xiaosheng Wu, Henan Zhang, Charla R Secreto, Shulan Tian, Esteban Braggio, Linda E Wellik, Ivana Micallef, David S Viswanatha, Huihuang Yan, Asher A Chanan-Khan, Neil E Kay, Haidong Dong, Stephen M Ansell
CLL patients progressed early on ibrutinib often develop Richter's transformation (RT) with short survival about 4 months. Preclinical studies suggest that programmed death 1 (PD-1) pathway is critical to inhibit immune surveillance in CLL. This phase 2 study MC1485 (NCT02332980) was designed to test the efficacy and safety of pembrolizumab, a humanized PD-1-blocking antibody, at a dose of 200 mg every 3 weeks in relapsed and transformed CLL. Twenty-five patients including 16 relapsed CLL and 9 RT (all proven diffuse large cell lymphoma) patients were enrolled and 60% received prior ibrutinib...
April 19, 2017: Blood
https://www.readbyqxmd.com/read/28421390/ofatumumab-combined-with-chlorambucil-for-previously-untreated-chronic-lymphocytic-leukemia-a-phase-i-ii-open-label-study-in-japan
#5
Kiyohiko Hatake, Michinori Ogura, Kohichi Takada, Masafumi Taniwaki, Fanghong Zhang, Taizo Fujita, Kiyoshi Ando
Elderly/comorbid patients with chronic lymphocytic leukemia (CLL) require low-toxicity treatments. Internationally, the standard treatment for such patients is chlorambucil and an anti-CD20 therapy; however, chlorambucil is not approved in Japan. The aim of the present study was to evaluate the safety, efficacy and pharmacokinetics of ofatumumab in combination with chlorambucil in Japanese patients with previously untreated CLL who were inappropriate for fludarabine-based therapy. Ten patients were enrolled and treated in this study, all of whom received at least one dose of the study drugs...
April 18, 2017: International Journal of Hematology
https://www.readbyqxmd.com/read/28419476/cortactin-a-lyn-substrate-is-a-checkpoint-molecule-at-the-intersection-of-bcr-and-cxcr4-signalling-pathway-in-chronic-lymphocytic-leukaemia-cells
#6
Veronica Martini, Cristina Gattazzo, Federica Frezzato, Valentina Trimarco, Marco Pizzi, Giorgia Chiodin, Filippo Severin, Edoardo Scomazzon, Vincenza Guzzardo, Deborah Saraggi, Flavia Raggi, Leonardo Martinello, Monica Facco, Andrea Visentin, Francesco Piazza, Anna Maria Brunati, Gianpietro Semenzato, Livio Trentin
Cortactin (CTTN) is a substrate of the Src kinase Lyn that is known to play an actin cytoskeletal regulatory role involved in cell migration and cancer progression following its phosphorylation at Y421. We recently demonstrated that Cortactin is overexpressed in patients with chronic lymphocytic leukaemia (CLL). This work was aimed at defining the functional role of Cortactin in these patients. We found that Cortactin is variably expressed in CLL patients both in the peripheral blood and lymph nodes and that its expression correlates with the release of matrix metalloproteinase 9 (MMP-9) and the motility of neoplastic cells...
April 17, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28418900/therapeutic-inhibition-of-usp7-pten-network-in-chronic-lymphocytic-leukemia-a-strategy-to-overcome-tp53-mutated-deleted-clones
#7
Giovanna Carrà, Cristina Panuzzo, Davide Torti, Guido Parvis, Sabrina Crivellaro, Ubaldo Familiari, Marco Volante, Deborah Morena, Marcello Francesco Lingua, Mara Brancaccio, Angelo Guerrasio, Pier Paolo Pandolfi, Giuseppe Saglio, Riccardo Taulli, Alessandro Morotti
Chronic Lymphocytic Leukemia (CLL) is a lymphoproliferative disorder with either indolent or aggressive clinical course. Current treatment regiments have significantly improved the overall outcomes even if higher risk subgroups - those harboring TP53 mutations or deletions of the short arm of chromosome 17 (del17p) - remain highly challenging. In the present work, we identified USP7, a known de-ubiquitinase with multiple roles in cellular homeostasis, as a potential therapeutic target in CLL. We demonstrated that in primary CLL samples and in CLL cell lines USP7 is: i) over-expressed through a mechanism involving miR-338-3p and miR-181b deregulation; ii) functionally activated by Casein Kinase 2 (CK2), an upstream interactor known to be deregulated in CLL; iii) effectively targeted by the USP7 inhibitor P5091...
March 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28416773/changes-in-t-cell-subpopulations-and-cytokine-network-during-early-period-of-ibrutinib-therapy-in-chronic-lymphocytic-leukemia-patients-the-significant-decrease-in-t-regulatory-cells-number
#8
Monika Podhorecka, Aneta Goracy, Agnieszka Szymczyk, Malgorzata Kowal, Blanca Ibanez, Olga Jankowska-Lecka, Arkadiusz Macheta, Aleksandra Nowaczynska, Elzbieta Drab-Urbanek, Sylwia Chocholska, Dariusz Jawniak, Marek Hus
B cell receptor (BCR) stimulation signal plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL), and kinase inhibitors directed toward the BCR pathway are now the promising anti-leukemic drugs. Ibrutinib, a Bruton tyrosine kinase inhibitor, demonstrates promising clinical activity in CLL. It is reported that ibrutinib, additionally to directly targeting leukemic cells, also inhibits the interactions of these cells with T cells, macrophages and accessory cells. Assessment of these mechanisms is important because of their non -direct anti-leukemic effects and to identify possible side effects connected with long-term drug administration...
March 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/28412730/the-long-noncoding-rna-trerna-decreases-dna-damage-and-is-associated-with-poor-response-to-chemotherapy-in-chronic-lymphocytic-leukemia
#9
Cecelia R Miller, Amy S Ruppert, Sydney Fobare, Timothy L Chen, Chaomei Liu, Amy Lehman, James S Blachly, Xiaoli Zhang, David M Lucas, Michael R Grever, Martin S Tallman, Ian W Flinn, Laura Z Rassenti, Thomas J Kipps, Deepa Sampath, Kevin R Coombes, Erin K Hertlein
The study of long noncoding RNAs (lncRNAs) is an emerging area of cancer research, in part due to their ability to serve as disease biomarkers. However, few studies have investigated lncRNAs in chronic lymphocytic leukemia (CLL). We have identified one particular lncRNA, treRNA, which is overexpressed in CLL B-cells. We measured transcript expression in 144 CLL patient samples and separated samples into high or low expression of treRNA relative to the overall median. We found that high expression of treRNA is significantly associated with shorter time to treatment...
February 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28408842/spotlight-on-ibrutinib-and-its-potential-in-frontline-treatment-of-chronic-lymphocytic-leukemia
#10
REVIEW
Maliha Khan, Jamie L Gibbons, Alessandra Ferrajoli
Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the adult population. Current efforts are focused on better understanding the intricate pathophysiology of the disease to develop successful targeted therapies. Ibrutinib is emerging as an important agent in this new age of targeted treatment for CLL. As a Bruton's tyrosine kinase inhibitor, it blocks the signaling pathway that malignant B-lymphocytes need for growth and maturation. Ibrutinib's role in therapy was further expanded recently when the US Food and Drug Administration approved its use in both frontline and salvage treatment for patients with CLL...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28402581/akt-inhibitor-mk-2206-in-combination-with-bendamustine-and-rituximab-in-relapsed-or-refractory-chronic-lymphocytic-leukemia-results-from-the-n1087-alliance-study
#11
Jeremy T Larsen, Tait D Shanafelt, Jose F Leis, Betsy LaPlant, Tim Call, Adam Pettinger, Curtis Hanson, Charles Erlichman, Thomas Matthew Habermann, Craig Reeder, Daniel Nikcevich, Deborah Bowen, Michael Conte, Justin Boysen, Charla Secreto, Connie Lesnick, Renee Tschumper, Diane Jelinek, Neil E Kay, Wei Ding
Akt is a downstream target of B cell receptor signaling and is a central regulator of CLL cell survival. We aim to investigate the safety and efficacy of the Akt inhibitor MK-2206 in combination with bendamustine and rituximab (BR) in relapsed and/or refractory CLL in a phase I/II study. A standard phase I design was used with cohorts of three plus three patients to determine the maximum tolerated dose (MTD) of MK-2206 in combination with BR in relapsed CLL. Single-agent MK-2206 (weekly dosed) was administered one-week in advance before BR on cycle 1 and subsequently was given with BR at the same time for cycle 2-6...
April 12, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28398276/bcl-2-as-a-therapeutic-target-in-chronic-lymphocytic-leukemia
#12
REVIEW
Catherine Daniel, Anthony R Mato
Venetoclax (formerly ABT-199) was recently approved in the United States for the treatment of patients who have relapsed or refractory chronic lymphocytic leukemia (CLL) with the 17p deletion. Venetoclax has demonstrated marked activity as monotherapy as well as in combination with cytotoxic chemotherapies, B-cell receptor inhibitors, and anti-CD20 monoclonal antibodies across the spectrum of CLL. The potency of venetoclax has been associated with a unique ability to induce deep (minimal residual disease-negative) complete remissions that appear to be durable...
March 2017: Clinical Advances in Hematology & Oncology: H&O
https://www.readbyqxmd.com/read/28395851/efficacy-and-safety-of-bendamustine-and-ibrutinib-in-previously-untreated-patients-with-chronic-lymphocytic-leukemia-indirect-comparison
#13
REVIEW
Iga Andrasiak, Justyna Rybka, Wanda Knopinska-Posluszny, Tomasz Wrobel
Bendamustine and ibrutinib are commonly used in the treatment of patients suffering from chronic lymphocytic leukemia (CLL). In this study we compare efficacy and safety bendamustine versus ibrutinib therapy in previously untreated patients with CLL. Because there are no head-to-head comparisons between bendamustine and ibrutinib, we performed indirect comparison using Bucher method. A systematic literature review was performed and 2 studies published before June 2016 were taken into analysis. Treatment with ibrutinib significantly improves PFS determined by investigator (HR of 0...
March 7, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28395515/long-term-safety-experience-with-bendamustine-for-injection-in-a-real-world-setting
#14
Peter Martin, Paul M Barr, Leonard James, Ashutosh Pathak, Brad Kahl
BACKGROUND: Bendamustine hydrochloride (bendamustine) was approved for first-line treatment of patients with chronic lymphocytic leukemia (CLL) and relapsed indolent B-cell non-Hodgkin's lymphoma (NHL). Pharmacovigilance data have been collected since bendamustine's approval to enhance understanding of its long-term safety profile. Here we provide an overview of the pharmacovigilance data for bendamustine that have led to label updates related to safety and administration since its approval...
April 11, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28389687/advances-in-the-treatment-of-relapsed-refractory-chronic-lymphocytic-leukemia
#15
REVIEW
C Shustik, I Bence-Bruckler, R Delage, C J Owen, C L Toze, S Coutre
Treatment of chronic lymphocytic leukemia (CLL) has advanced with the introduction of chemoimmunotherapy (CIT) agents that have improved the outcomes of frontline therapy. However, most treated patients will relapse and require subsequent therapy. This review focuses on recent advances in the treatment of relapsed or refractory CLL. Until recently, treatment options for relapsed CLL were of limited efficacy. Retreatment with fludarabine, cyclophosphamide, and rituximab (FCR) was recommended for patients with a durable response to first-line FCR, although acquired genetic aberrations, impaired marrow reserve, and comorbidities often made this suboptimal therapy for many patients...
April 7, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/28388253/lenalidomide-in-the-treatment-of-chronic-lymphocytic-leukemia
#16
Gilad Itchaki, Jennifer R Brown
Lenalidomide is an immunomodulatory drug (IMiD) with a unique mode of action (MOA) that may vary across disease-type. It is currently approved in multiple myeloma (MM), myelodysplastic syndrome (MDS) and mantle cell lymphoma (MCL), yet is also clinically active in a host of lymphoproliferative diseases, including chronic lymphocytic leukemia (CLL). Due to its protean effects on the immune system, lenalidomide may be particularly appealing in CLL, which is distinct in its ability to evade immune recognition and cause immunosuppression...
April 7, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28373262/impact-of-ibrutinib-dose-adherence-on-therapeutic-efficacy-in-patients-with-previously-treated-cll-sll
#17
Paul M Barr, Jennifer R Brown, Peter Hillmen, Susan O'Brien, Jacqueline C Barrientos, Nishitha M Reddy, Steven Coutre, Stephen P Mulligan, Ulrich Jaeger, Richard R Furman, Florence Cymbalista, Marco Montillo, Claire Dearden, Tadeusz Robak, Carol Moreno, John M Pagel, Jan A Burger, Samuel Suzuki, Juthamas Sukbuntherng, George Cole, Danelle F James, John C Byrd
Ibrutinib, an oral inhibitor of Bruton's tyrosine kinase (BTK), at a once-daily dose of 420 mg achieved BTK active-site occupancy in patients with CLL that was maintained at 24 hours. It is unknown if intermittent interruption of ibrutinib therapy contributes to altered clinical outcomes. We therefore evaluated the effect of ibrutinib dose adherence on patient outcomes in the phase 3 RESONATE(TM) trial. The overall mean dose intensity (DI) was 95% with median treatment duration of ~9 months. Pharmacokinetic assessment of ibrutinib exposure at 420 mg dose suggested similar exposure regardless of patient weight or age...
April 3, 2017: Blood
https://www.readbyqxmd.com/read/28370385/familial-chronic-lymphocytic-leukemia-in-israel-a-disproportionate-distribution-among-ashkenazi-jews
#18
Mor Zada, Daniele Lerner, Yuval Piltz, Chava Perry, Irit Avivi, Yair Herishanu
BACKGROUND: Relatives of patients with chronic lymphocytic leukemia (CLL) are at increased risk of developing CLL. Familial CLL is defined as more than one case of CLL among blood relatives, a phenomenon reported in approximately 5-10% of all CLL patients. OBJECTIVE: Given the known predisposition of CLL among Ashkenazi Jews, we studied the features of familial CLL in an Israeli population. METHODS: This is a retrospective study, in which we reviewed the demographics, clinical characteristics and outcomes of a total of 332 patients with CLL/small lymphocytic lymphoma...
March 31, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28368400/interferon-%C3%AE-is-a-stat1-dependent-direct-inducer-of-bcl6-expression-in-imatinib-treated-chronic-myeloid-leukemia-cells
#19
H S Madapura, N Nagy, D Ujvari, T Kallas, M C L Kröhnke, S Amu, M Björkholm, L Stenke, P K Mandal, J S McMurray, M Keszei, L S Westerberg, H Cheng, F Xue, G Klein, E Klein, D Salamon
B-cell CLL/lymphoma 6 (BCL6) exerts oncogenic effects in several human hematopoietic malignancies including chronic myeloid leukemia (CML), where BCL6 expression was shown to be essential for CML stem cell survival and self-renewal during imatinib mesylate (IM) treatment. As several lines of evidence suggest that interferon γ (IFNγ) production in CML patients might have a central role in the response to tyrosine kinase inhibitor (TKI) therapy, we analyzed if IFNγ modulates BCL6 expression in CML cells. Although separate IFNγ or IM treatment only slightly upregulated BCL6 expression, combined treatment induced remarkable BCL6 upregulation in CML lines and primary human CD34+ CML stem cells...
April 3, 2017: Oncogene
https://www.readbyqxmd.com/read/28350342/the-role-of-pi3k-isoforms-in-regulating-bone-marrow-microenvironment-signaling-focusing-on-acute-myeloid-leukemia-and-multiple-myeloma
#20
REVIEW
Rachel E Piddock, Kristian M Bowles, Stuart A Rushworth
Despite the development of novel treatments in the past 15 years, many blood cancers still remain ultimately fatal and difficult to treat, particularly acute myeloid leukaemia (AML) and multiple myeloma (MM). While significant progress has been made characterising small-scale genetic mutations and larger-scale chromosomal translocations that contribute to the development of various blood cancers, less is understood about the complex microenvironment of the bone marrow (BM), which is known to be a key player in the pathogenesis of chronic lymphocytic leukaemia (CLL), AML and MM...
March 28, 2017: Cancers
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