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https://www.readbyqxmd.com/read/28614781/cell-lines-generated-from-a-chronic-lymphocytic-leukemia-mouse-model-exhibit-constitutive-btk-and-akt-signaling
#1
Simar Pal Singh, Saravanan Y Pillai, Marjolein J W de Bruijn, Ralph Stadhouders, Odilia B J Corneth, Henk Jan van den Ham, Alice Muggen, Wilfred van IJcken, Erik Slinger, Annemieke Kuil, Marcel Spaargaren, Arnon P Kater, Anton W Langerak, Rudi W Hendriks
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature CD5+ B cells in blood. Spontaneous apoptosis of CLL cells in vitro has hampered in-depth investigation of CLL pathogenesis. Here we describe the generation of three monoclonal mouse cell lines, EMC2, EMC4 and EMC6, from the IgH.TEμ CLL mouse model based on sporadic expression of SV40 large T antigen. The cell lines exhibit a stable CD5+CD43+IgM+CD19+ CLL phenotype in culture and can be adoptively transferred into Rag1-/- mice...
May 26, 2017: Oncotarget
https://www.readbyqxmd.com/read/28605616/managing-patients-with-tp53-deficient-chronic-lymphocytic-leukemia
#2
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/28596280/extracellular-vesicles-of-bone-marrow-stromal-cells-rescue-chronic-lymphocytic-leukemia-b-cells-from-apoptosis-enhance-their-migration-and-induce-gene-expression-modifications
#3
Emerence Crompot, Michael Van Damme, Karlien Pieters, Marjorie Vermeersch, David Perez-Morga, Philippe Mineur, Marie Maerevoet, Nathalie Meuleman, Dominique Bron, Laurence Lagneaux, Basile Stamatopoulos
Interactions between chronic lymphocytic leukemia B-cells and the bone marrow microenvironment play a major function in the physiopathology of chronic lymphocytic leukemia. Extracellular vesicles, which are composed of exosomes and microparticles, play an important role in cell communication. However, little is known about their role in chronic lymphocytic leukemia/microenvironment interactions. In the present study, extracellular vesicles purified by ultracentrifugation from bone marrow mesenchymal stromal cell cultures were added to chronic lymphocytic leukemia B-cells...
June 8, 2017: Haematologica
https://www.readbyqxmd.com/read/28592762/chronic-lymphocytic-leukemia-pathophysiology-and-current-therapy
#4
Jun Takizawa
Chronic lymphocytic leukemia (CLL) is the most frequent adult leukemia in western countries, but it is rare in Japan. Several mutations have been identified in patients with CLL using next-generation sequencing, but disease-specific mutations were not found. Some mutations, such as those in TP53, NOTCH1, SF3B, and BIRC3 are useful for risk stratification and prognosis prediction in patients with CLL. Strategies for treating CLL are rapidly evolving, with targeted agents such as the B-cell receptor signaling pathway inhibitors (ibrutinib, idelalisib), novel anti-CD20 monoclonal antibody (obinutuzumab), and Bcl-2 inhibitor (venetoclax) being approved by the US Food and Drug Administration...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28589155/a-severe-case-of-cutaneous-adverse-drug-reaction-secondary-to-a-novice-drug-idelalisib
#5
Joseph Gabriel Gabriel, Aaysha Kapila, Alexei Gonzalez-Estrada
Phosphatidylinositol 3-kinase δ (PIK3δ) is a tyrosine kinase essential for B cell survival, making it an important target in the treatment of chronic lymphocytic leukemia. Idelalisib is an inhibitor of PIK3δ demonstrating initial success in disease response, but is now shown to have a decreased overall survival and life-threatening serious adverse events. The following is an unfortunate case of a grade III adverse skin reaction secondary to idelalisib with the likely complication of methicillin-resistant Staphylococcus aureus bacteremia...
April 2017: Journal of Investigative Medicine High Impact Case Reports
https://www.readbyqxmd.com/read/28579851/transformation-of-follicular-lymphoma-to-a-high-grade-b-cell-lymphoma-with-myc-and-bcl2-translocations-and-overlapping-features-of-burkitt-lymphoma-and-acute-lymphoblastic-leukemia-a-case-report-and-literature-review
#6
Alina M Bischin, Russell Dorer, David M Aboulafia
Most commonly, histologic transformation (HT) from follicular lymphoma (FL) manifests as a diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). Less frequently, HT may result in a high-grade B-cell lymphoma (HGBL) with MYC and B-cell lymphoma protein 2 (BCL2) and/or BCL6 gene rearrangements, also known as "double-hit" or "triple-hit" lymphomas. In the 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms, the category B-cell lymphoma, unclassifiable was eliminated due to its vague criteria and limiting diagnostic benefit...
2017: Clinical Medicine Insights. Blood Disorders
https://www.readbyqxmd.com/read/28567239/bendamustine-and-its-role-in-the-treatment-of-unfit-patients-with-chronic-lymphocytic-leukaemia-a-perspective-review
#7
REVIEW
Othman Al-Sawaf, Paula Cramer, Valentin Goede, Michael Hallek, Natali Pflug
With a median age of 72 years at first diagnosis, chronic lymphocytic leukaemia (CLL) is a disease of the elderly. At this age, many patients cannot bear an intensive chemoimmunotherapy like fludarabine, cyclophosphamide and rituximab (FCR), and therapeutic decisions are commonly complicated by a high burden of accompanying comorbidities. Clinical trials, on the other hand, are mostly designed to include a far healthier and younger trial population, with a median age in most studies well below 70 years, leading to an insufficient reflection of clinical reality...
June 2017: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/28566383/drug-modulators-of-b-cell-signaling-pathways-and-epstein-barr-virus-lytic-activation
#8
John G Kosowicz, Jaeyeun Lee, Brandon Peiffer, Zufeng Guo, Jianmeng Chen, Gangling Liao, S Diane Hayward, Jun O Liu, Richard F Ambinder
Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that establishes a latency reservoir in B cells. In this work, we show that ibrutinib, idelalisib, and dasatinib, drugs that block BCR signaling and are used in the treatment of hematologic malignancies, block BCR-mediated lytic induction at clinically relevant doses. We confirm that the immunosuppressive drugs cyclosporine and tacrolimus also inhibit BCR-mediated lytic induction but find that rapamycin does not inhibit BCR-mediated lytic induction...
May 31, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28565930/current-perspectives-on-the-role-of-chemotherapy-in-chronic-lymphocytic-leukemia
#9
Clemens-Martin Wendtner, Michael Gregor
Chemotherapy has long been integral to the treatment of chronic lymphocytic leukemia (CLL). Fludarabine/cyclophosphamide, chlorambucil and bendamustine are commonly used as a backbone, depending on the patient's age and general health. The advent of the anti-CD20 monoclonal antibodies, such as rituximab and obinutuzumab, altered the face of treatment, and chemoimmunotherapy still forms the current standard first-line approach. However, the landscape is changing following the emergence of novel targeted agents, such as ibrutinib, idelalisib and venetoclax, which offer the chance for improved efficacy over standard therapy alone, with no substantial increase in toxicity...
June 1, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28523957/clinical-case-idelalisib-induced-immunoglobulin-flare
#10
Jan Novak, Martin Havrda, Lubica Gaherova, Jan Spicka, Tomas Kozak
IgM flare is a transient, treatment-induced, increase of monoclonal IgM levels in lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) patients. Until recently this phenomenon was observed in patients treated with Cladribine and Rituximab. Here we report a case of a heavily pretreated chronic lymphocytic leukemia patient with an atypically high immunoglobulin production who developed clinically significant immunoglobulin flare following Idelalisib treatment.
May 19, 2017: Immunopharmacology and Immunotoxicology
https://www.readbyqxmd.com/read/28462919/targeting-antigen-independent-proliferation-in-chronic-lymphocytic-leukemia-through-differential-kinase-inhibition
#11
E Slinger, R Thijssen, A P Kater, E Eldering
The clinical success of B cell receptor (BCR) signaling pathway inhibitors in chronic lymphocytic leukemia (CLL) is attributed to inhibition of adhesion in and migration towards the lymph node. Proliferation of CLL cells is restricted to this protective niche, but the underlying mechanism(s) is/are not known. Treatment with BCR pathway inhibitors results in rapid reductions of total clone size, while CLL cell survival is not affected, which points towards inhibition of proliferation. However, BCR stimulation does not induce proliferation of CLL in vitro, while triggering via TLR-, TNF- or cytokine- receptors does...
May 2, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28453705/optimal-sequencing-of-ibrutinib-idelalisib-and-venetoclax-in-chronic-lymphocytic-leukemia-results-from-a-multicenter-study-of-683-patients
#12
A R Mato, B T Hill, N Lamanna, P M Barr, C S Ujjani, D M Brander, C Howlett, A P Skarbnik, B D Cheson, C S Zent, J J Pu, P Kiselev, K Foon, J Lenhart, S Henick Bachow, A M Winter, A-L Cruz, D F Claxton, A Goy, C Daniel, K Isaac, K H Kennard, C Timlin, M Fanning, L Gashonia, M Yacur, J Svoboda, S J Schuster, C Nabhan
Background: Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence. Patients and methods: We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS)...
May 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28439761/small-molecule-inhibitors-in-chronic-lymphocytic-lymphoma-and-b-cell-non-hodgkin-lymphoma
#13
REVIEW
Allison Rosenthal
PURPOSE OF REVIEW: The purpose of this review is to summarize the available literature for the use of small molecule inhibitors in chronic lymphocytic leukemia and B cell non-Hodgkin lymphoma. RECENT FINDINGS: Ibrutinib, idelalisib, and venetoclax are small molecule inhibitors that have revolutionized therapeutic options for patients with CLL, particularly for those with high-risk disease including 17p deletion. These drugs are increasingly finding application in a variety of subtypes of B cell NHL...
April 24, 2017: Current Hematologic Malignancy Reports
https://www.readbyqxmd.com/read/28439132/idelalisib-and-rituximab-regimen
#14
A Kacee Barnett, J Aubrey Waddell, Dominic A Solimando
The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast...
March 2017: Hospital Pharmacy
https://www.readbyqxmd.com/read/28424165/suppression-of-b-cell-development-genes-is-key-to-glucocorticoid-efficacy-in-treatment-of-acute-lymphoblastic-leukemia
#15
Karina A Kruth, Mimi Fang, Dawne N Shelton, Ossama Abu-Halawa, Ryan Mahling, Hongxing Yang, Jonathan S Weissman, Mignon L Loh, Markus Müschen, Sarah K Tasian, Michael C Bassik, Martin Kampmann, Miles A Pufall
Glucocorticoids (GCs), including dexamethasone (dex), are a central component of combination chemotherapy for childhood B-cell precursor acute lymphoblastic leukemia (B-ALL). GCs work by activating the GC receptor (GR), a ligand-induced transcription factor, which in turn regulates genes that induce leukemic cell death. Which GR-regulated genes are required for GC cytotoxicity, which pathways affect their regulation, and how resistance arises are not well understood. Here, we systematically integrate the transcriptional response of B-ALL to GCs with a next-generation short hairpin RNA screen to identify GC-regulated "effector" genes that contribute to cell death, as well as genes that affect the sensitivity of B-ALL cells to dex...
June 1, 2017: Blood
https://www.readbyqxmd.com/read/28389687/advances-in-the-treatment-of-relapsed-refractory-chronic-lymphocytic-leukemia
#16
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...
July 2017: Annals of Hematology
https://www.readbyqxmd.com/read/28348046/b-cell-lymphoma-patient-derived-xenograft-models-enable-drug-discovery-and-are-a-platform-for-personalized-therapy
#17
Leo Zhang, Krystle Nomie, Hui Zhang, Taylor Bell, Lan Pham, Sabah Kadri, Jeremy Segal, Shaoying Li, Shouhao Zhou, David Santos, Shawana Richard, Shruti Sharma, Wendy Chen, Onyekachukwu Oriabure, Yang Liu, Shengjian Huang, Hui Guo, Zhihong Chen, Wenjing Tao, Carrie Li, Jack Wang, Bingliang Fang, Jacqueline Wang, Lei Li, Maria Badillo, Makhdum Ahmed, Selvi Thirumurthi, Steven Y Huang, Yiping Shao, Laura Lam, Qing Yi, Y Lynn Wang, Michael Wang
Purpose: Patients with B-cell lymphomas often relapse after frontline therapy, and novel therapies are urgently needed to provide long-term remission. We established B-cell lymphoma patient-derived xenograft (PDX) models to assess their ability to mimic tumor biology and to identify B-cell lymphoma patient treatment options.Experimental Design: We established the PDX models from 16 patients with diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, or Burkitt lymphoma by inoculating the patient tumor cells into a human bone chip implanted into mice...
March 27, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28343293/pharmacokinetic-and-pharmacodynamic-considerations-in-the-treatment-of-chronic-lymphocytic-leukemia-ibrutinib-idelalisib-and-venetoclax
#18
REVIEW
Madeline Waldron, Allison Winter, Brian T Hill
Management of chronic lymphocytic leukemia has changed markedly over the last several years with the emergence of several novel oral agents targeting B-cell receptor and Bcl-2 signaling pathways. For patients requiring treatment, ibrutinib, idelalisib, and venetoclax offer unique clinical benefits with a different set of therapeutic considerations compared with traditional parenteral therapy. Despite the conveniences afforded by oral therapy, these agents also carry unique logistical obstacles. Drug interactions with agents that are metabolized via the cytochrome P450 3A4 pathway are possible with all three agents...
March 25, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28331288/development-of-venetoclax-for-therapy-of-lymphoid-malignancies
#19
REVIEW
Huayuan Zhu, Alexandru Almasan
B-cell lymphoma-2 (BCL-2) family dysfunction and impairment of apoptosis are common in most B-cell lymphoid malignancies. Venetoclax (Venclexta™, formerly ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor, which mimics its BCL-2 homology 3-domain to induce apoptosis. It was approved for treatment of previously treated chronic lymphocytic leukemia (CLL) patients with 17p deletion early in 2016. It has also been in clinical trials for other B-cell lymphoid malignancies. Unlike the other recently approved targeted agents idelalisib and ibrutinib, so far there has been no relapse reported in some patients...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28327905/phase-ii-study-of-idelalisib-a-selective-inhibitor-of-pi3k%C3%AE-for-relapsed-refractory-classical-hodgkin-lymphoma
#20
A K Gopal, M A Fanale, C H Moskowitz, A R Shustov, S Mitra, W Ye, A Younes, A J Moskowitz
Background: The phosphatidylinositol-3-kinase delta (PI3Kδ) inhibitor idelalisib has been shown to block downstream intracellular signaling, reduce the production of prosurvival chemokines and induce apoptosis in classical Hodgkin lymphoma (HL) cell lines. It has also been shown to inhibit regulatory T cells and myeloid-derived suppressor cells in other tumor models. We hypothesized that inhibiting PI3Kδ would have both direct and indirect antitumor effects by directly targeting the malignant cells as well as modulating the inflammatory microenvironment...
May 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
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