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17p chronic lymphocytic leukemia

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https://www.readbyqxmd.com/read/29024486/development-of-locus-specific-sub-clone-separation-by-fluorescence-in-situ-hybridization-in-suspension-in-chronic-lymphocytic-leukemia
#1
Cuc H Do, Sheree Bailey, Cindy Macardle, Lauren A Thurgood, Karen M Lower, Bryone J Kuss
Intra-tumor genetic heterogeneity is a hallmark of cancer. The ability to monitor and analyze these sub-clonal cell populations can be considered key to successful treatment, particularly in the modern era of targeted therapies. Although advances in sequencing technologies have significantly improved our ability to analyze the mutational landscape of tumors, this utility is reduced when considering small, but clinically significant sub-clones, that is, those representing <10% of the tumor burden. We have developed a high-throughput method that utilizes a 17-probe labeled bacterial artificial chromosome contig to quantify sub-clonal populations of cells based on deletion of a single locus...
October 11, 2017: Cytometry. Part A: the Journal of the International Society for Analytical Cytology
https://www.readbyqxmd.com/read/28993409/malt1-inhibition-is-efficacious-in-both-na%C3%A3-ve-and-ibrutinib-resistant-chronic-lymphocytic-leukemia
#2
Nakhle S Saba, Deanna H Wong, Georges Tanios, Jessica R Iyer, Patricia Lobelle-Rich, Eman L Dadashian, Delong Liu, Lorena Fontan, Erik K Flemington, Cydney M Nichols, Chingiz Underbayev, Hana Safah, Ari Melnick, Adrian Wiestner, Sarah E M Herman
The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2, a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma...
October 9, 2017: Cancer Research
https://www.readbyqxmd.com/read/28989588/cytogenetic-abnormalities-with-interphase-fish-method-and-clinical-manifestation-in-chronic-lymphocytic-leukemia-patients-in-north-east-of-iran
#3
Hossein Rahimi, Mohammad Hadi Sadeghian, Mohammad Reza Keramati, Amir Hossein Jafarian, Sepideh Shakeri, Seyyede Fatemeh Shams, Neda Motamedi, Maryam Sheikhi, Hossein Ayatollahi
Background: Chronic lymphocytic leukemia (CLL) is one of the most prevalent adult leukemias. This malignancy is known by lymphocytosis for a duration of more than 3 months. In fact, it is a heterogeneous clinical disease with changeable progression. Chromosomal aberrations are significant parameters to predict result and survival rate and find treatment strategies for each patient. Cytogenetic methods are known as sensitive and relatively new procedures to detect abnormalities in genome. Materials and Methods: In order to identify CLL-related chromosomal abnormalities, 48 CLL patients included 38 Men and 10 Women with mean age of 58...
July 1, 2017: International Journal of Hematology-oncology and Stem Cell Research
https://www.readbyqxmd.com/read/28978838/chronic-lymphocytic-leukemia-biology-disease-progression-and-current-treatment-strategies
#4
Takahiro Yano
Chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and accumulation of mature CD5-positive, CD10-negative, CD20 weakly positive, and CD23-positive B-cells within blood, bone marrow, lymph nodes, and spleen. In proliferation centers, the survival and growth of CLL cells requires a permissive microenvironment comprising T-cells, macrophages, and stromal cells. FISH analysis has revealed that almost 80% of CLL cases carry chromosomal abnormalities including the most frequent del (13q14) and the strongest poor prognostic factor del (17p), both related to TP53 mutations...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28972395/venetoclax-for-the-treatment-of-chronic-lymphocytic-leukemia
#5
Massimo Gentile, Annamaria Petrungaro, Giuseppina Uccello, Ernesto Vigna, Anna Grazia Recchia, Nadia Caruso, Sabrina Bossio, Laura De Stefano, Angela Palummo, Francesca Storino, Massimo Martino, Fortunato Morabito
Venetoclax, an orally bioavailable inhibitor of BCL-2, was approved in 2016 by the United States Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL) patients with 17p deletion [del(17p)], who have received at least one prior therapy. Areas covered: We focus on the mechanism of action of venetoclax and on the clinical trial data that led to the approval of venetoclax for CLL patients. We also review the studies in which this drug has being explored in combination with other anti-CLL drugs...
November 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28925785/risk-adjusted-therapy-in-chronic-lymphocytic-leukemia-a-phase-ii-cancer-trials-ireland-ctrial-ie-icorg-07-01-study-of-fludarabine-cyclophosphamide-and-rituximab-therapy-evaluating-response-adapted-abbreviated-frontline-therapy-with-fcr-in-non-del-17p-cll
#6
Niamh Appleby, David O'Brien, Fiona M Quinn, Liam Smyth, Johanna Kelly, Imelda Parker, Kathleen Scott, Mary R Cahill, Gerard Crotty, Helen Enright, Brian Hennessy, Andrew Hodgson, Maeve Leahy, Hilary O'Leary, Michael O'Dwyer, Amjad Hayat, Elisabeth A Vandenberghe
Minimal residual disease negative complete response (MRD-negative CR) provides an early marker for time to treatment failure (TTF) in CLL treated with fludarabine, cyclophosphamide, and rituximab (FCR). MRD was assessed after four FCR cycles (FCR4); MRD-negative CR patients discontinued treatment. Fifty-two patients (35M; 17F) were enrolled. Eighteen (18/52; 34.6%) patients reached MRD-negative CR after FCR4 and 29/52 (55.8%) were MRD-negative CR at end of treatment (EOT). Median TTF was 71.1 months (95% CI 61...
September 19, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28888994/chronic-lymphocytic-leukemia-with-isochromosome-17q-an-aggressive-subgroup-associated-with-tp53-mutations-and-complex-karyotypes
#7
Rosa Collado, Anna Puiggros, José Antonio López-Guerrero, Ma José Calasanz, Ma José Larráyoz, David Ivars, Zaida García-Casado, Eugènia Abella, Ma Teresa Orero, Elisabet Talavera, Ana Carla Oliveira, Jesús Ma Hernández-Rivas, María Hernández-Sánchez, Elisa Luño, Alberto Valiente, Javier Grau, Inmaculada Portal, Santiago Gardella, Anna Camino Salgado, Ma Teresa Giménez, Ma Teresa Ardanaz, Andrea Campeny, José Julio Hernández, Sara Álvarez, Blanca Espinet, Félix Carbonell
Although i(17q) [i(17q)] is frequently detected in hematological malignancies, few studies have assessed its clinical role in chronic lymphocytic leukemia (CLL). We recruited a cohort of 22 CLL patients with i(17q) and described their biological characteristics, mutational status of the genes TP53 and IGHV and genomic complexity. Furthermore, we analyzed the impact of the type of cytogenetic anomaly bearing the TP53 defect on the outcome of CLL patients and compared the progression-free survival (PFS) and overall survival (OS) of i(17q) cases with those of a group of 38 CLL patients harboring other 17p aberrations...
September 6, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28782884/chronic-lymphocytic-leukemia-2017-update-on-diagnosis-risk-stratification-and-treatment
#8
REVIEW
Michael Hallek
DISEASE OVERVIEW: Chronic lymphocytic leukemia (CLL) is the commonest leukemia in western countries. The disease typically occurs in elderly patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that impair apoptosis of clonal B cells. DIAGNOSIS: The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B lymphocytes, which identify a clonal B-cell population carrying the CD5 antigen and B-cell markers...
September 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28780145/what-is-the-role-of-chemotherapy-in-patients-with-chronic-lymphocytic-leukemia
#9
REVIEW
Bruce D Cheson
The current standard treatment for patients with chronic lymphocytic leukemia who require therapy is chemoimmunotherapy. However, the availability of an increasing number of targeted agents and combination warrants a reassessment of that approach. The high rate of durable responses with ibrutinib in relapsed refractory patients has established its role in this setting; however, because of its impressive efficacy as initial treatment, it should be considered as part of the algorithm in appropriate patients. There is virtually no role for chemotherapy in the relapsed or refractory setting, but, instead, consideration of active agents including idelalisib plus rituximab, or, particularly venetoclax...
July 12, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28751718/two-mouse-models-reveal-an-actionable-parp1-dependence-in-aggressive-chronic-lymphocytic-leukemia
#10
Gero Knittel, Tim Rehkämper, Darya Korovkina, Paul Liedgens, Christian Fritz, Alessandro Torgovnick, Yussor Al-Baldawi, Mona Al-Maarri, Yupeng Cun, Oleg Fedorchenko, Arina Riabinska, Filippo Beleggia, Phuong-Hien Nguyen, F Thomas Wunderlich, Monika Ortmann, Manuel Montesinos-Rongen, Eugen Tausch, Stephan Stilgenbauer, Lukas P Frenzel, Marco Herling, Carmen Herling, Jasmin Bahlo, Michael Hallek, Martin Peifer, Reinhard Buettner, Thorsten Persigehl, H Christian Reinhardt
Chronic lymphocytic leukemia (CLL) remains an incurable disease. Two recurrent cytogenetic aberrations, namely del(17p), affecting TP53, and del(11q), affecting ATM, are associated with resistance against genotoxic chemotherapy (del17p) and poor outcome (del11q and del17p). Both del(17p) and del(11q) are also associated with inferior outcome to the novel targeted agents, such as the BTK inhibitor ibrutinib. Thus, even in the era of targeted therapies, CLL with alterations in the ATM/p53 pathway remains a clinical challenge...
July 28, 2017: Nature Communications
https://www.readbyqxmd.com/read/28728469/characterizing-patients-with-multiple-chromosomal-aberrations-detected-by-fish-in-chronic-lymphocytic-leukemia
#11
Isabel González-Gascón Y Marín, María Hernández-Sanchez, Ana Eugenia Rodríguez-Vicente, Anna Puiggros, Rosa Collado, Elisa Luño, Teresa González, Neus Ruiz-Xivillé, Margarita Ortega, Eva Gimeno, Carolina Muñoz, Maria Stefania Infante, Julio Delgado, María Teresa Vargas, Marcos González, Francesc Bosch, Blanca Espinet, Jesús María Hernández-Rivas, José Ángel Hernández
We analyzed the features of chronic lymphocytic leukemia (CLL) with multiple abnormalities (MA) detected by FISH. A local database including 2095 CLL cases was used and 323 with MA (15.4%) were selected. MA was defined by the presence of two or more alterations (deletions of 13q14 (13q-), 11q22 (11q-), 17p13 (17p-) or trisomy 12 (+12)). The combination of 13q- with 11q- and 13q- with 17p-, accounted for 58.2% of the series, in contrast to 11q- with 17p- (3.7%). Patients carrying MA since diagnosis presented a short time to first therapy(TTFT) (27 months) and overall survival (OS) (76 months)...
July 21, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28724540/targeting-bcl-2-in-b-cell-lymphomas
#12
REVIEW
Matthew S Davids
The B-cell leukemia/lymphoma-2 (BCL-2) family of proteins governs the intrinsic pathway of mitochondrial apoptosis. Dysregulation of BCL-2 has long been known to be a crucial part of the pathophysiology of B-cell lymphomas; however, several early attempts to target this pathway therapeutically were unsuccessful because of toxicity, lack of efficacy, or both. Recently, a highly potent and selective oral BCL-2 antagonist, venetoclax, was approved in chronic lymphocytic leukemia, where it has proven to be highly active, even in patients with high-risk del(17p) disease...
August 31, 2017: Blood
https://www.readbyqxmd.com/read/28715249/durable-molecular-remissions-in-chronic-lymphocytic-leukemia-treated-with-cd19-specific-chimeric-antigen-receptor-modified-t-cells-after-failure-of-ibrutinib
#13
Cameron J Turtle, Kevin A Hay, Laïla-Aïcha Hanafi, Daniel Li, Sindhu Cherian, Xueyan Chen, Brent Wood, Arletta Lozanski, John C Byrd, Shelly Heimfeld, Stanley R Riddell, David G Maloney
Purpose We evaluated the safety and feasibility of anti-CD19 chimeric antigen receptor-modified T (CAR-T) cell therapy in patients with chronic lymphocytic leukemia (CLL) who had previously received ibrutinib. Methods Twenty-four patients with CLL received lymphodepleting chemotherapy and anti-CD19 CAR-T cells at one of three dose levels (2 × 10(5), 2 × 10(6), or 2 × 10(7) CAR-T cells/kg). Nineteen patients experienced disease progression while receiving ibrutinib, three were ibrutinib intolerant, and two did not experience progression while receiving ibrutinib...
September 10, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28696175/venetoclax-a-novel-b-cell-lymphoma-2-inhibitor-for-chronic-lymphocytic-leukemia-and-other-hematologic-malignancies
#14
Jacqueline L Olin, Carrie L Griffiths, Morgan B Smith
Patients with chronic lymphocytic leukemia with the 17p deletion have a poor prognosis and treatment options are limited. Venetoclax, a novel B-cell lymphoma-2 inhibitor, has been approved for treatment-experienced chronic lymphocytic leukemia patients with the 17p deletion. A phase 1 dose-escalation study to 400 mg daily showed overall response rates across all doses of 79% with a complete response achieved in 20%. A phase 2 multicenter open-label study demonstrated overall response rate of 79.4% of patients (95% confidence interval 70...
January 1, 2017: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/28694085/baseline-characteristics-predicting-very-good-outcome-of-allogeneic-hematopoietic-cell-transplantation-in-young-patients-with-high-cytogenetic-risk-chronic-lymphocytic-leukemia%C3%A2-a-retrospective-analysis-from-the-chronic-malignancies-working-party-of-the-ebmt
#15
Michel van Gelder, Dimitris Ziagkos, Liesbeth de Wreede, Anja van Biezen, Peter Dreger, Martin Gramatzki, Matthias Stelljes, Niels Smedegaard Andersen, Nicolaas Schaap, Antonin Vitek, Dietrich Beelen, Vesa Lindström, Jürgen Finke, Jacob Passweg, Matthias Eder, Maciej Machaczka, Julio Delgado, William Krüger, Luděk Raida, Gerard Socié, Pavel Jindra, Boris Afanasyev, Eva Wagner, Yves Chalandon, Anja Henseler, Stefan Schoenland, Nicolaus Kröger, Johannes Schetelig
BACKGROUND: Patients with genetically high-risk relapsed/refractory chronic lymphocytic leukemia have shorter median progression-free survival (PFS) with kinase- and BCL2-inhibitors (KI, BCL2i). Allogeneic hematopoietic stem cell transplantation (alloHCT) may result in sustained PFS, especially in younger patients because of its age-dependent non-relapse mortality (NRM) risk, but outcome data are lacking for this population. PATIENTS AND METHODS: Risk factors for 2-year NRM and 8-year PFS were identified in patients < 50 years in an updated European Society for Blood and Marrow Transplantation registry cohort (n = 197; median follow-up, 90...
October 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28605616/managing-patients-with-tp53-deficient-chronic-lymphocytic-leukemia
#16
Jennifer Edelmann, John G Gribben
Patients with chronic lymphocytic leukemia (CLL) having a chromosomal loss on the short arm of chromosome 17 including the TP53 gene locus (17p deletion) and/or having mutations in TP53 have a short overall survival and, until recently, limited treatment options. The recent introduction of two novel substance classes, B-cell receptor inhibitors and BH3 mimetics, into CLL treatment has provided enormous clinical progress in this previously difficult-to-treat patient subgroup characterized by high risk for treatment failure with standard chemoimmunotherapy and rapid disease progression...
June 2017: Journal of Oncology Practice
https://www.readbyqxmd.com/read/28604954/-detection-of-genomic-abnormalities-among-105-patients-with-chronic-lymphocytic-leukemia-using-fluorescence-in-situ-hybridization
#17
Huanping Wang, Huan Xu, Zhimei Chen, Jiyu Lou, Jie Jin
OBJECTIVE: To assess the value of fluorescence in situ hybridization (FISH) for the detection of genomic abnormalities among patients with chronic lymphocytic leukemia (CLL). METHODS: Interphase FISH was performed on bone marrow samples derived from 105 patients with CLL at the time of diagnosis using probes for D13S319/13q14, ATM/11q22, P53/17p13 and CEP12. The abnormalities and prognostic factors were analyzed. Overall survival of the patients was calculated. RESULTS: The FISH assay has detected genomic abnormalities in 81 (77...
June 10, 2017: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
https://www.readbyqxmd.com/read/28578655/potential-mechanisms-of-resistance-to-venetoclax-and-strategies-to-circumvent-it
#18
Stephen K Tahir, Morey L Smith, Paul Hessler, Lisa Roberts Rapp, Kenneth B Idler, Chang H Park, Joel D Leverson, Lloyd T Lam
BACKGROUND: Venetoclax (ABT-199), a first-in-class orally bioavailable BCL-2-selective inhibitor, was recently approved by the FDA for use in patients with 17p-deleted chronic lymphocytic leukemia who have received prior therapy. It is also being evaluated in numerous clinical trials for treating patients with various hematologic malignancies. As with any targeted cancer therapy, it is critically important to identify potential mechanisms of resistance, both for patient stratification and developing strategies to overcome resistance, either before it develops or as it emerges...
June 2, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28562380/pharmacokinetics-of-venetoclax-in-patients-with-17p-deletion-chronic-lymphocytic-leukemia
#19
Ahmed Hamed Salem, Martin Dunbar, Suresh K Agarwal
Venetoclax is a first-in-class orally available, B-cell lymphoma (BCL)-2 inhibitor indicated for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) harboring the 17p deletion. We used a novel approach for evaluating venetoclax pharmacokinetics using only sparse sampling in 155 patients enrolled in a phase 2, multicenter, open-label study in CLL patients with the 17p deletion. Patients received venetoclax doses within 30 min after the completion of breakfast or the first meal of the day, with no specific recommendations for the fat content in the meal...
September 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28559149/chronic-lymphocytic-leukemia-patients-with-deletion-11q-have-a-short-time-to-requirement-of-first-line-therapy-but-long-overall-survival-results-of-a-population-based-cohort-in-british-columbia-canada
#20
Jennifer Goy, Tanya L Gillan, Helene Bruyere, Steven J T Huang, Monica Hrynchak, Aly Karsan, Khaled Ramadan, Joseph Connors, Cynthia L Toze, Alina S Gerrie
BACKGROUND: Chronic lymphocytic leukemia (CLL) patients with 11q22.3 deletion (11q-) have an aggressive clinical course, and thus selection of first-line therapy in this group is important. This study aimed to improve our understanding of real-world practice patterns and outcomes of CLL patients with 11q- in a population-based setting. PATIENTS AND METHODS: The British Columbia CLL Database was used to identify patients with 11q-. Overall survival (OS) and treatment-free survival (TFS) were assessed after adjustment for prognostic factors...
May 8, 2017: Clinical Lymphoma, Myeloma & Leukemia
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