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CLL, chronic lymphocytic leukemia

Riccardo Moia, Fary Diop, Chiara Favini, Ahad Ahmed Kodipad, Gianluca Gaidano
Chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease. Deregulation of apoptosis is a major pathogenetic feature, and represents a therapeutic target. TP53 disrupted patients are categorized as high risk patients and are treated with novel target therapies. Among these new drugs, venetoclax, an orally bioavailable BCL2 inhibitor, has shown high efficacy also in relapsed/refractory CLL with TP53 disruption. Venetoclax has also been tested in combination with other drugs without compromising venetoclax dose and with a good safety profile...
March 21, 2018: Expert Review of Hematology
Marc Sorigue, Elisa Orna, Juan-Manuel Sancho
Lenalidomide has been associated with an increased risk of venous thromboembolism (VTE) in multiple myeloma. It is unclear whether patients with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) are also at such risk. We conducted a systematic review of the incidence of VTE in prospective trials of lenalidomide-treated patients with NHL or CLL. Sixty-eight unique reports were assessed for inclusion. For grade ≥3 VTE, 98 events were reported in 3043 patients (60 studies) (crude incidence: 3...
March 21, 2018: Leukemia & Lymphoma
John C Byrd, Stephen Smith, Nina Wagner-Johnston, Jeff Sharman, Andy I Chen, Ranjana Advani, Bradley Augustson, Paula Marlton, S Renee Commerford, Kwame Okrah, Lichuan Liu, Elaine Murray, Elicia Penuel, Ashley F Ward, Ian W Flinn
GDC-0853 is a selective, reversible, and non-covalent inhibitor of Bruton's tyrosine kinase (BTK) that does not require interaction with the Cys481 residue for activity. In this first-in-human phase 1 study we evaluated safety, tolerability, pharmacokinetics, and activity of GDC-0853 in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL). Twenty-four patients, enrolled into 3 cohorts, including 6 patients who were positive for the C481S mutation, received GDC-0853 at 100, 200, or 400 mg once daily, orally...
February 27, 2018: Oncotarget
Kristina Busygina, Janina Jamasbi, Till Seiler, Hans Deckmyn, Christian Weber, Richard Brandl, Reinhard Lorenz, Wolfgang Siess
Interaction of Von Willebrand factor (VWF) with platelet glycoprotein (GP) Ib and of collagen with GPVI is essential for thrombus formation on ruptured or eroded atherosclerotic plaques (atherothrombosis). GPIb and GPVI signal through Bruton tyrosine kinase (Btk) which can irreversibly be blocked by oral application of ibrutinib, an established therapy for chronic lymphocytic leukemia (CLL) with long term safety. We found that ibrutinib and the novel Btk-inhibitors acalabrutinib and ONO/GS-4059 block GPVI-dependent static platelet aggregation in blood exposed to human plaque homogenate and collagen but not to ADP or arachidonic acid...
March 20, 2018: Blood
Xu Chen, Stefan Gustafsson, Thomas Whitington, Yan Borné, Erik Lorentzen, Jitong Sun, Peter Almgren, Jun Su, Robert Karlsson, Jie Song, Yi Lu, Yiqiang Zhan, Sara Hägg, Per Svensson, Karin E Smedby, Susan L Slager, Erik Ingelsson, Cecilia M Lindgren, Andrew P Morris, Olle Melander, Thomas Karlsson, Ulf de Faire, Kenneth Caidahl, Gunnar Engström, Lars Lind, Mikael C I Karlsson, Nancy L Pedersen, Johan Frostegård, Patrik K E Magnusson
Phosphorylcholine (PC) is an epitope on oxidized low-density lipoprotein (oxLDL), apoptotic cells and several pathogens like Streptococcus pneumoniae. Immunoglobulin M against PC (IgM anti-PC) has the ability to inhibit uptake of oxLDL by macrophages and increase clearance of apoptotic cells. From our genome-wide association studies (GWAS) in four European-ancestry cohorts, six SNPs in 11q24.1 were discovered (in 3002 individuals) and replicated (in 646 individuals) to be associated with serum level of IgM anti-PC (the leading SNP rs35923643-G, combined beta=0...
March 14, 2018: Human Molecular Genetics
Abdullateef Abdulkareem, Ryan S D'Souza, Joshua Mundorff, Pragya Shrestha, Oluwaseun Shogbesan, Anthony Donato
Acquired angioedema due to C1 inhibitor deficiency (C1INH-AAE) is a rare and potentially fatal syndrome of bradykinin-mediated angioedema characterized by episodes of angioedema without urticaria. It typically manifests with nonpitting edema of the skin and edema in the gastrointestinal (GI) tract mucosa or upper airway. Edema of the upper airway and tongue may lead to life-threatening asphyxiation. C1INH-AAE is typically under-diagnosed because of its rarity and its propensity to mimic more common abdominal conditions and allergic reactions...
2018: Case Reports in Hematology
Michael Hallek, Bruce D Cheson, Daniel Catovsky, Federico Caligaris-Cappio, Guillermo Dighiero, Hartmut Döhner, Peter Hillmen, Michael Keating, Emili Montserrat, Nicholas Chiorazzi, Stephan Stilgenbauer, Kanti R Rai, John C Byrd, Barbara Eichhorst, Susan O'Brien, Tadeusz Robak, John F Seymour, Thomas J Kipps
In 2008, International Workshop on CLL (iwCLL) published consensus guidelines for the design and conduct of clinical trials for patients with chronic lymphocytic leukemia (CLL) that were revised from those previously published by the National Cancer Institute-sponsored Working Group. These guidelines provided definitions intended to standardize the assessment of patients that were adopted by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the evaluation of new drugs. Since the publication of these guidelines there have been major advances in the biology and treatment of patients with CLL, prompting the iwCLL to evaluate and revise the 2008 criteria...
March 14, 2018: Blood
Xiaojun Huang, Lugui Qiu, Jie Jin, Daobin Zhou, Xiequn Chen, Ming Hou, Jianda Hu, Yu Hu, Xiaoyan Ke, Junmin Li, Yingmin Liang, Ting Liu, Yue Lv, Hanyun Ren, Aining Sun, Jianmin Wang, Chunting Zhao, Mariya Salman, Steven Sun, Angela Howes, Jingzhao Wang, Peng Wu, Jianyong Li
In the Asia-Pacific region, treatment options are limited for patients with relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Rituximab is widely used in this setting when purine analog-based therapies are not appropriate. We evaluated the efficacy and safety of ibrutinib compared with rituximab in a randomized, open-label phase 3 study in predominantly Asian patients with relapsed/refractory CLL/SLL. Patients (N = 160) were randomly assigned 2:1 to receive 420 mg ibrutinib (n = 106) until disease progression (PD) or unacceptable toxicity or up to six cycles of rituximab (n = 54)...
March 13, 2018: Cancer Medicine
Mengge Li, Yu Gan, Chunsun Fan, Hui Yuan, Xianjing Zhang, Yuling Shen, Qing Wang, Zihong Meng, Dengfei Xu, Hong Tu
Previous studies have focused on the relationship between hepatitis B virus (HBV) infection and non-Hodgkin lymphoma (NHL). However, the results remain inconsistent and somehow conflicting in different sub-groups. The aim of this study was to combine the findings of independent studies to comprehensively assess the association between HBV and NHL using a meta-analysis. Relevant studies were identified through structured keyword searches in PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) database and 58 studies with a total of 53,714 NHL cases and 1,778,591 controls were finally included...
March 13, 2018: Journal of Viral Hepatitis
Yuta Ito, Shinichi Makita, Akiko Miyagi Maeshima, Shunsuke Hatta, Tomotaka Suzuki, Sayako Yuda, Suguru Fukuhara, Wataru Munakata, Tatsuya Suzuki, Dai Maruyama, Koji Izutsu
Paraneoplastic pemphigus (PNP) is a severe autoimmune blistering disease associated with an underlying malignancy, and its prognosis is poor. We herein report the first patient with B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL)-associated PNP successfully treated with the Bruton's tyrosine kinase inhibitor ibrutinib and rituximab. Although his PNP lesions did not improve with ibrutinib monotherapy, the combination of ibrutinib and rituximab was effective against B-CLL/SLL-associated PNP...
March 9, 2018: Internal Medicine
Fang Zhu, Ismat Khatri, David Spaner, Reginald M Gorczynski
Chronic Lymphocytic Leukemia B cells (CLL) are malignant cells which retain at least some functions of normal B cells. Paramount amongst the latter is that when such cells are appropriately stimulated, they are able to present antigens, including any potential tumor antigens, making them excellent choices as a candidate tumor vaccine. We show that following stimulation of CLL cells with Phorbol myristic acetate, IL-2, the TLR7 agonist imiquimod (P2I) and ionomycin (P2Iio), markedly increased expression of CD54 and CD83 was seen, indicative of B cell activation and a transition to antigen-presenting cells...
March 2, 2018: Leukemia Research
Nadia Khan, Brad Kahl
Resistance to apoptosis is one of the hallmarks of cancer and members of the B-cell lymphoma 2 (BCL-2) family of proteins are central regulators of apoptosis. Many cancers become resistant to chemotherapy and apoptosis by up-regulating BCL-2 and other family members, making these proteins attractive targets for cancer therapy. Venetoclax is an orally administered, small-molecule apoptosis stimulant that targets BCL-2 proteins by acting as a BCL-2 homology domain 3 (BH3) mimetic. The drug is approved in the USA and EU as a monotherapy for the for the treatment of certain patients with chronic lymphocytic leukemia (CLL) and is in phase III clinical development for multiple myeloma (MM), and in phase II or I/II clinical trials for acute myeloid leukemia, and several B-cell malignancies, including diffuse large B-cell lymphoma, Waldenstrom's macroglobulinaemia, follicular lymphoma, and mantle-cell lymphoma...
March 8, 2018: Targeted Oncology
Caroline Holm Nørgaard, Lasse Hjort Jakobsen, Andrew J Gentles, Karen Dybkær, Tarec Christoffer El-Galaly, Julie Støve Bødker, Alexander Schmitz, Preben Johansen, Tobias Herold, Karsten Spiekermann, Jennifer R Brown, Josephine L Klitgaard, Hans Erik Johnsen, Martin Bøgsted
Diagnostic and prognostic evaluation of chronic lymphocytic leukemia (CLL) involves blood cell counts, immunophenotyping, IgVH mutation status, and cytogenetic analyses. We generated B-cell associated gene-signatures (BAGS) based on six naturally occurring B-cell subsets within normal bone marrow. Our hypothesis is that by segregating CLL according to BAGS, we can identify subtypes with prognostic implications in support of pathogenetic value of BAGS. Microarray-based gene-expression samples from eight independent CLL cohorts (1,024 untreated patients) were BAGS-stratified into pre-BI, pre-BII, immature, naïve, memory, or plasma cell subtypes; the majority falling within the memory (24...
2018: PloS One
Tilly Varughese, Ying Taur, Nina Cohen, M Lia Palomba, Susan K Seo, Tobias M Hohl, Gil Redelman-Sidi
Background: Ibrutinib is a Bruton's tyrosine kinase inhibitor that is used for the treatment of lymphoid malignancies, including chronic lymphocytic leukemia (CLL), Waldenström's macroglobulinemia and mantle cell lymphoma (MCL). Several case series have described opportunistic infections among ibrutinib recipients, but the full extent of these infections is unknown. We sought to determine the spectrum of serious infections associated with ibrutinib treatment. Methods: We reviewed the electronic medical records of patients with lymphoid malignancies at Memorial Sloan Kettering Cancer Center who received ibrutinib during a five-year period from January 1, 2012 to December 31, 2016...
March 2, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Stefano Baldoni, Beatrice Del Papa, Erica Dorillo, Patrizia Aureli, Filomena De Falco, Chiara Rompietti, Daniele Sorcini, Emanuela Varasano, Debora Cecchini, Tiziana Zei, Ambra Di Tommaso, Emanuela Rosati, Gabriela Alexe, Giovanni Roti, Kimberly Stegmaier, Mauro Di Ianni, Franca Falzetti, Paolo Sportoletti
Dysregulated NOTCH1 signaling, either by gene mutations or microenvironment interactions, has been increasingly linked to chronic lymphocytic leukemia (CLL). Thus, inhibiting NOTCH1 activity represents a potential therapeutic opportunity for this disease. Using gene expression-based screening, we identified the calcium channel modulator bepridil as a new NOTCH1 pathway inhibitor. In primary CLL cells, bepridil induced selective apoptosis even in the presence of the protective stroma. Cytotoxic effects of bepridil were independent of NOTCH1 mutation and other prognostic markers...
March 6, 2018: International Journal of Cancer. Journal International du Cancer
Ida K Myhrvold, Andrea Cremaschi, Johanne U Hermansen, Geir E Tjønnfjord, Ludvig A Munthe, Kjetil Taskén, Sigrid S Skånland
Chronic lymphocytic leukemia (CLL) has a high incidence and a steeply growing prevalence in the Western world. The heterogeneity of the disease necessitates individual mapping of biology and predicted drug response in each patient as basis for administration of tailored treatments. Cell signaling aberrations may serve as biological indicators for suitable therapy. By applying phospho-specific flow cytometry, we mapped basal and induced phosphorylation levels of 20 phospho-epitopes on proteins relevant to B-cell signaling in B cells from 22 CLL patients and 25 normal controls...
February 6, 2018: Oncotarget
E C Church, R Banks, B Wilson, L Arfons, F Perez, R Jump
Through a "virtual clinic," we used the electronic medical record to identify and intervene upon patients with chronic lymphocytic leukemia (cll) who were not current for pneumococcal vaccines. Within 180 days, 100/160 patients (62%) received the recommended pneumococcal vaccine. A virtual clinic may improve vaccination rates among high-risk patient populations.
February 2018: Current Oncology
Eric Sanchez, Edward J Tanenbaum, Saurabh Patil, Mingjie Li, Camilia M Soof, Aleksandra Vidisheva, Gabriel N Waterman, Tara Hekmati, George Tang, Cathy S Wang, Haiming Chen, James Berenson
B-cell maturation antigen (BCMA) is a cell membrane bound tumor necrosis factor receptor family member that is expressed exclusively on late stage normal and malignant B-cells and plasma cells. Addition of two of its ligands, B-cell activating factor and a proliferation inducting ligand, to normal B-cells cause B-cell proliferation and antibody production. Serum BCMA is elevated among patients with multiple myeloma (MM) and chronic lymphocytic leukemia (CLL), and is a prognostic and monitoring tool for these patients...
March 7, 2018: Expert Review of Molecular Diagnostics
Hamid Rashtbari, Mazdak Razi, Hassan Hassani-Bafrani, Hamed Najaran
BACKGROUND: Varicocele is present in 10-20% of the male infertile population. PURPOSE: Present study was done to demonstrate the reinforcing effect of berberine (BBR), as an antioxidant and anti-inflammatory agent, on Sertoli cells-related niche and spermatogonial stem cells (SSCs) self-renewal in experimentally-induced VCL condition. STUDY DESIGN: 50 mature male Wistar rats were divided into control, control-sham, non-treated VCL-induced, 50 mg kg-1 and 100 mg kg-1 BBR-treated VCL-induced groups...
February 1, 2018: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
Sam Vander Meeren, Bert Heyrman, Wim Renmans, Marleen Bakkus, Brigitte Maes, Hendrik De Raeve, Rik Schots, Kristin Jochmans
High-count monoclonal B cell lymphocytosis (MBL) with a chronic lymphocytic leukemia (CLL) phenotype is a well-known entity, featuring 1-4% annual risk of progression towards CLL requiring treatment. Lymphoma-like MBL (L-MBL), on the other hand, remains poorly defined and data regarding outcome are lacking. We retrospectively evaluated 33 L-MBL cases within our hospital population and compared them to 95 subjects with CLL-like MBL (C-MBL). Diagnoses of L-MBL were based on asymptomatic B cell clones with Matutes score < 3, B cells < 5...
February 28, 2018: Annals of Hematology
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