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https://www.readbyqxmd.com/read/29025288/-state-of-the-art-molecular-diagnostics-and-therapy-of-chronic-lymphocytic-leukaemia-in-the-era-of-new-targeted-therapies
#1
Tímea Gurbity Pálfi, Viktória Fésüs, Csaba Bödör, Zita Borbényi
Chronic lymphoid leukaemia (CLL) has a heterogeneous clinical course depending on many clinical and molecular prognostic markers, which play an important role in the selection of the best treatment option. So far, TP53 disruption is the key prognostic and predictive factor assisting treatment decisions, especially in the era of novel therapies. Asymptomatic patients in early stages of the disease will still benefit from watchful waiting. In the frontline setting, chemoimmunotherapy is still the standard care in the majority of standard risk CLL patients...
October 2017: Orvosi Hetilap
https://www.readbyqxmd.com/read/29024486/development-of-locus-specific-sub-clone-separation-by-fluorescence-in-situ-hybridization-in-suspension-in-chronic-lymphocytic-leukemia
#2
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/28994094/novel-prognostic-molecular-factors-a-quantum-leap-in-the-field-of-chronic-lymphocytic-leukemia
#3
Ewelina Zakrzewska, Marta Pirog, Joanna Purkot, Krzysztof Giannopoulos
Cytogenetic lesions do not completely explain clinical heterogeneity of chronic lymphocytic leukemia (CLL). The 2016 revision of the World Health Organization classification 2008 introduced that molecular lesions of TP53, NOTCH1, SF3B1 and BIRC3 have potential clinical relevance and could be integrated into an updated risk profile. The negative clinical implications of TP53 disruptions are well constituted and patients with these mutations should be considered for novel, small molecule signal transduction inhibitors therapies...
October 10, 2017: Folia Histochemica et Cytobiologica
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/28975027/second-lung-malignancy-and-richter-syndrome-in-chronic-lymphocytic-leukemia-case-report-and-literature-review
#5
Ghassen Soussi, Selsabil Daboussi, Samira Mhamdi, Zied Moatemri, Hela Ghedira, Chiraz Aichaouia, Mohsen Khadhraoui, Faouzi El Mezni, Rezaik Cheikh
BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most frequent lymphoproliferative disease. Transformation into Richter disease and occurrence of second malignancies involving the lungs are rare complications. The hallmarks of any thoracic involvement are still unknown. CASE PRESENTATION: We report a case of a 56-year-old male patient, with history of tobacco smoking, who presented with recurrent hemoptysis, fatigue and weight loss. Physical examination was normal except a slightly enlarged supraclavicular lymph node...
2017: Multidisciplinary Respiratory Medicine
https://www.readbyqxmd.com/read/28972595/ibrutinib-modulates-the-immunosuppressive-cll-microenvironment-through-stat3-mediated-suppression-of-regulatory-b-cell-function-and-inhibition-of-the-pd-1-pd-l1-pathway
#6
K Kondo, H Shaim, P A Thompson, J A Burger, M Keating, Z Estrov, D Harris, E Kim, A Ferrajoli, M Daher, R Basar, M Muftuoglu, N Imahashi, A Alsuliman, C Sobieski, E Gokdemir, W Wierda, N Jain, E Liu, E J Shpall, K Rezvani
Ibrutinib, a covalent inhibitor of Bruton Tyrosine Kinase (BTK), is approved for treatment of patients with relapsed/refractory or treatment-naïve CLL. Besides directly inhibiting BTK, ibrutinib possesses immunomodulatory properties through targeting multiple signaling pathways. Understanding how this ancillary property of ibrutinib modifies the CLL microenvironment is crucial for further exploration of immune responses in this disease and devising future combination therapies. Here, we investigated the mechanisms underlying the immunomodulatory properties of ibrutinib...
October 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28972490/phagocytosis-and-expression-of-fcg-receptors-and-cd180-on-monocytes-in-chronic-lymphocytic-leukemia
#7
T Tsertsvadze, N Mitskevich, A Bilanishvili, D Girdaladze, N Porakishvili
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disease characterised by accumulation of monoclonal CD19+CD5+CD23+ lymphocytes in the peripheral blood and bone marrow. CLL is the most common type of the adult leukemia in the Western world. The disease is incurable, albeit there are new molecular and immunotherapy methods currently available in conjunction with chemotherapy, leading to the "precision therapy". The majority of immunotherapeutic approaches are based on the ability of therapeutic antibodies (Rituximab, Alemtuzumab) to mobilize anti-tumour potential of the Natural Killer cells and macrophages/monocytes through their Fcg-receptors (FcγR)...
September 2017: Georgian Medical News
https://www.readbyqxmd.com/read/28972395/venetoclax-for-the-treatment-of-chronic-lymphocytic-leukemia
#8
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/28945111/pi3k%C3%AE-selective-and-pi3k%C3%AE-%C3%AE-combinatorial-inhibitors-in-clinical-development-for-b-cell-non-hodgkin-lymphoma
#9
Benjamin L Lampson, Jennifer R Brown
The efficacy of the prototypical phosphatidylinositol-3-kinase (PI3K) inhibitor idelalisib for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL) has led to development of multiple compounds targeting this pathway. Areas Covered: We review the hypothesized therapeutic mechanisms of PI3K inhibitors, including abrogation of B cell receptor signaling, blockade of microenvironmental pro-survival signals, and enhancement of anti-tumor immunity. We examine toxicities of idelalisib, including bacterial infections (possibly secondary to drug-induced neutropenia), opportunistic infections (possibly attributable to on-target inhibition of T cell function), and organ toxicities such as transaminitis and enterocolitis (possibly autoimmune, secondary to on-target inhibition of p110δ in regulatory T cells)...
November 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28940587/liver-dysfunction-in-chronic-lymphocytic-leukemia-prevalence-outcomes-and-pathological-findings
#10
Paul J Hampel, Kari G Chaffee, Rebecca L King, Douglas Simonetto, Melissa C Larson, Sara Achenbach, Timothy G Call, Wei Ding, Saad S Kenderian, Jose F Leis, Asher A Chanan-Khan, Deborah A Bowen, Michael J Conte, Susan M Schwager, Curtis A Hanson, Susan L Slager, Neil E Kay, Tait D Shanafelt, Sameer A Parikh
The prevalence of liver dysfunction and its association with outcomes in patients with previously untreated chronic lymphocytic leukemia (CLL) is unknown. Newly diagnosed (<12 months) previously untreated CLL patients seen at Mayo Clinic, Rochester, MN between 9/1993 and 4/2016 who had baseline assessment of at least one liver function test (LFT) were included in this analysis. The prevalence of liver dysfunction at baseline, proportion of patients who acquired LFT abnormalities, time to first therapy (TTFT) and overall survival (OS) were assessed...
September 22, 2017: American Journal of Hematology
https://www.readbyqxmd.com/read/28938632/the-%C3%AE-secretase-inhibitors-enhance-the-anti-leukemic-activity-of-ibrutinib-in-b-cll-cells
#11
Paola Secchiero, Rebecca Voltan, Erika Rimondi, Elisabetta Melloni, Emmanouil Athanasakis, Veronica Tisato, Stefania Gallo, Gian Matteo Rigolin, Giorgio Zauli
Ibrutinib blocks B-cell receptor signaling and interferes with leukemic cell-to-microenvironment interactions. Ibrutinib plays a key role in the management of B-CLL and is recommended for first line treatment of high-risk CLL patients with 17p deletion. Therefore, elucidating the factors governing sensitivity/resistance to Ibrutinib represents a relevant issue. For this purpose, in 3 B-CLL patient samples harboring functional TP53 mutations, the frequency of the mutated clones was monitored during in vivo Ibrutinib therapy, revealing a progressive decline of the frequency of TP53(mut) clones during 12 months of treatment...
August 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28935694/cellular-kinetics-of-ctl019-in-relapsed-refractory-b-cell-acute-lymphoblastic-leukemia-and-chronic-lymphocytic-leukemia
#12
Karen Thudium Mueller, Shannon L Maude, David L Porter, Noelle Frey, Patricia Wood, Xia Han, Edward Waldron, Abhijit Chakraborty, Rakesh Awasthi, Bruce L Levine, J Joseph Melenhorst, Stephan A Grupp, Carl H June, Simon F Lacey
Tisagenlecleucel (CTL019) is an investigational immunotherapy that involves reprogramming a patient's own T cells with a transgene encoding a chimeric antigen receptor to identify and eliminate CD19-expressing cells. We previously reported that CTL019 achieved impressive clinical efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), including the expansion and persistence of CTL019 cells, which correlates with response to therapy. Here, we performed formal cellular kinetic analyses of CTL019 in a larger cohort of 103 patients treated with CTL019 in 2 different diseases (ALL and CLL)...
September 21, 2017: Blood
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
#13
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/28919818/standard-of-care-and-direct-medical-costs-of-the-treatment-of-chronic-lymphocytic-leukemia-among-the-adult-population-in-ukraine-russia-and-kazakhstan-data-from-the-leukospect-study
#14
Averyan Vasylyev, Valentina Molostvova, Boris A Rebrov, Janina Makarova, Andrey Zaritskey, Vadim Ptushkin, Raigul Ramazanova, Yuriy Popovych, Orest Tsyapka, Evgeny Pashanov
PURPOSE: The LEUKOSPECT study aimed to describe health service utilization and to estimate the direct medical costs (DMCs) of chronic lymphocytic leukemia (CLL) in 2013 in the adult population of three post-Soviet countries - Russia, Ukraine, and Kazakhstan. As oncologic medical care is provided by federal state-owned, specialized medical institutions, the cost estimation in this study primarily informs from a state budget perspective. Patients' contributions to medical costs were not included in the cost evaluation...
2017: Cancer Management and Research
https://www.readbyqxmd.com/read/28916311/lenalidomide-maintenance-after-first-line-therapy-for-high-risk-chronic-lymphocytic-leukaemia-cllm1-final-results-from-a-randomised-double-blind-phase-3-study
#15
Anna Maria Fink, Jasmin Bahlo, Sandra Robrecht, Othman Al-Sawaf, Ali Aldaoud, Holger Hebart, Kathleen Jentsch-Ullrich, Steffen Dörfel, Kirsten Fischer, Clemens-Martin Wendtner, Thomas Nösslinger, Paolo Ghia, Francesc Bosch, Arnon P Kater, Hartmut Döhner, Michael Kneba, Karl-Anton Kreuzer, Eugen Tausch, Stephan Stilgenbauer, Matthias Ritgen, Sebastian Böttcher, Barbara Eichhorst, Michael Hallek
BACKGROUND: The combined use of genetic markers and detectable minimal residual disease identifies patients with chronic lymphocytic leukaemia with poor outcome after first-line chemoimmunotherapy. We aimed to assess lenalidomide maintenance therapy in these high-risk patients. METHODS: In this randomised, double-blind, phase 3 study (CLLM1; CLL Maintenance 1 of the German CLL Study Group), patients older than 18 years and diagnosed with immunophenotypically confirmed chronic lymphocytic leukaemia with active disease, who responded to chemoimmunotherapy 2-5 months after completion of first-line therapy and who were assessed as having a high risk for an early progression with at least a partial response after four or more cycles of first-line chemoimmunotherapy, were eligible if they had high minimal residual disease levels or intermediate levels combined with an unmutated IGHV gene status or TP53 alterations...
October 2017: Lancet Haematology
https://www.readbyqxmd.com/read/28905668/the-impact-of-agent-orange-exposure-on-prognosis-and-management-in-patients-with-chronic-lymphocytic-leukemia-a-national-veteran-affairs-tumor-registry-study
#16
Craig Mescher, David Gilbertson, Nicole M Randall, Gobind Tarchand, Julie Tomaska, Lisa Baumann Kreuziger, Vicki A Morrison
Exposure to Agent Orange (AO) has been associated with the development of chronic lymphocytic leukemia (CLL). We performed a retrospective study of 2052 Vietnam veterans identified in the National VA Tumor Registry to assess the impact of AO exposure on CLL prognosis, treatment and survival. Prognostic factors did not differ based on exposure. Veterans exposed to AO were diagnosed younger (63.2 vs. 70.5 years, p < .0001) and had longer overall survival (median not reached vs. 91 months, p < .001)...
September 14, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28891959/the-pi3k%C3%AE-inhibitor-idelalisib-inhibits-homing-in-an-in-vitro-and-in-vivo-model-of-b-all
#17
Etai Adam, Hye Na Kim, Eun Ji Gang, Caitlin Schnair, Solomon Lee, Solah Lee, Sajad Khazal, Osanna Kosoyan, Marina Konopleva, Chintan Parekh, Deepa Bhojwani, Alan S Wayne, Hisham Abdel-Azim, Nora Heisterkamp, Yong-Mi Kim
The quest continues for targeted therapies to reduce the morbidity of chemotherapy and to improve the response of resistant leukemia. Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stromal cells triggers intracellular signals that promote cell-adhesion-mediated drug resistance (CAM-DR). Idelalisib, an U.S. Food and Drug Administration (FDA)-approved PI3Kδ-specific inhibitor has been shown to be effective in CLL in down-regulating p-Akt and prolonging survival in combination with Rituximab; herein we explore the possibility of its use in B ALL and probe the mechanism of action...
September 10, 2017: Cancers
https://www.readbyqxmd.com/read/28864095/minimal-residual-disease-in-chronic-lymphocytic-leukaemia
#18
REVIEW
José Antonio García Vela, José Antonio García Marco
Minimal residual disease (MRD) assessment is an important endpoint in the treatment of chronic lymphocytic leukaemia (CLL). It is highly predictive of prolonged progression-free survival (PFS) and overall survival and could be considered a surrogate for PFS in the context of chemoimmunotherapy based treatment. Evaluation of MRD level by flow cytometry or molecular techniques in the era of the new BCR and Bcl-2 targeted inhibitors could identify the most cost-effective and durable treatment sequencing. A therapeutic approach guided by the level of MRD might also determine which patients would benefit from an early stop or consolidation therapy...
August 29, 2017: Medicina Clínica
https://www.readbyqxmd.com/read/28851760/tumor-lysis-syndrome-in-chronic-lymphocytic-leukemia-with-novel-targeted-agents
#19
Bruce D Cheson, Sari Heitner Enschede, Elisa Cerri, Monali Desai, Jalaja Potluri, Nicole Lamanna, Constantine Tam
Tumor lysis syndrome (TLS) is an uncommon but potentially life-threatening complication associated with the treatment of some cancers. If left untreated, TLS may result in acute renal failure, cardiac dysrhythmia, neurologic complications, seizures, or death. Tumor lysis syndrome is most commonly observed in patients with hematologic malignancies with a high proliferation rate undergoing treatment with very effective therapies. In chronic lymphocytic leukemia (CLL), historically, TLS has been observed less often, owing to a low proliferation rate and slow response to chemotherapy...
August 29, 2017: Oncologist
https://www.readbyqxmd.com/read/28845710/combination-therapy-with-the-type-ii-anti-cd20-antibody-obinutuzumab
#20
REVIEW
Christian Klein, Marina Bacac, Pablo Umana, Günter Fingerle-Rowson
Obinutuzumab is a novel humanized type II glycoengineered anti-CD20 antibody approved for first-line treatment of chronic lymphocytic leukemia (CLL) in combination with chlorambucil and for treatment of rituximab-refractory follicular lymphoma (FL). Areas covered: We describe current preclinical and clinical evidence supporting the combination of obinutuzumab with not only chemotherapy but also novel targeted therapies for B-cell hematologic malignancies, and its application in chemoimmunotherapy. We also provide an overview of the current clinical trial landscape investigating novel combination therapies based on obinutuzumab...
October 2017: Expert Opinion on Investigational Drugs
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