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Cll therapy

Ahmad Salimi, Mehryar Habibi Roudkenar, Leila Sadeghi, Alireza Mohseni, Enayatollah Seydi, Nahal Pirahmadi, Jalal Pourahmad
The present study investigates the in vitro and in vivo effect of acacetin (4'-methoxy-5,7-dihydroxyflavone) on chronic lymphocytic leukemia (CLL) B-lymphocytes and mitochondria. CLL B-lymphocytes and healthy B-lymphocytes were obtained from CLL patients and healthy donors, respectively. Mitochondria were isolated from B-lymphocytes of both groups. Xenografts in severe combined immune deficient mice were used to examine the toxicity and anti CLL activity of acacetin. We evaluated and compared the mechanism of action of acacetin on CLL and healthy B-lymphocytes and their mitochondria...
October 25, 2016: Nutrition and Cancer
G Lohmann, E Vasyutina, J Bloehdorn, N Reinart, J I Schneider, V Babu, G Knittel, G Crispatzu, P Mayer, C Prinz, J K Muenzner, B Biersack, D G Efremov, L Chessa, C D Herling, S Stilgenbauer, M Hallek, R Schobert, H C Reinhardt, B Schumacher, M Herling
Treatment resistance becomes a challenge at some point in the course of most patients with chronic lymphocytic leukemia (CLL). This applies to fludarabine-based regimens, but is also an increasing concern in the era of more targeted therapies. As cells with low replicative activity rely on repair that triggers checkpoint-independent non-canonical pathways, we reasoned that targeting the nucleotide excision repair (NER) reaction addresses a vulnerability of CLL and might even synergize with fludarabine, which blocks the NER gap-filling step...
October 24, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Maria Bozko, Monika Podhorecka, Arkadiusz Macheta, Andrzej Bozko, Nisar P Malek, Przemyslaw Bozko
No abstract text is available yet for this article.
2016: Current Cancer Drug Targets
(no author information available yet)
In 2014, ibrutinib was made available for relapsed/refractory chronic lymphocytic leukaemia (CLL) patients. The UK CLL Forum collected data from UK/Ireland patients with a minimum of 1 year follow-up with pre-planned primary endpoints; the number of patients still on therapy at 1 year (Discontinuation Free Survival; DFS) and 1 year overall survival (OS). With a median 16 months follow-up, data on 315 patients demonstrated 1 year DFS of 73.7% and 1 year OS of 83.8%. Patients with better pre-treatment performance status (PS 0/1 vs 2+) had superior DFS (77...
October 18, 2016: Haematologica
Arianna Bottoni, Lara Rizzotto, Tzung-Huei Lai, Chaomei Liu, Lisa L Smith, Rose Mantel, Sean Reiff, Dalia El-Gamal, Karilyn Larkin, Amy J Johnson, Rosa Lapalombella, Amy Lehman, William Plunkett, John C Byrd, James S Blachly, Jennifer A Woyach, Deepa Sampath
BTK is a critical mediator of survival in B cell neoplasms. While BTK inhibitors have transformed therapy in CLL, high genetic risk patients are at risk for relapse and have a poor prognosis. Identification of novel therapeutic strategies for this group of patients is an urgent unmet clinical need, and therapies that target BTK via alternative mechanisms may fill this niche. Herein, we identify a set of miRNAs that target BTK in primary CLL cells and show that the HDAC repressor complex is recruited to these miRNA promoters to silence their expression...
October 17, 2016: Blood
Yali Chen, Qianxiang Zhou, Lei Zhang, Ran Wang, Meihua Jin, Yuling Qiu, Dexin Kong
Increasing resistance of imatinib, a BCR-ABL tyrosine kinase inhibitor, hinders its use in the therapy of chronic myeloid leukemia (CML). The PI3K pathway is known to be closely involved in BCR-ABL transformation and the tumorigenesis of CML, suggesting that PI3K may be a potential target for CML therapy. Idelalisib, a specific inhibitor of PI3K p110δ, has been approved for the treatment of chronic lymphocytic leukemia (CLL). However, the antileukemia effect of idelalisib on CML remains unknown. In the present study, the antileukemia activity of idelalisib alone or in combination with imatinib was investigated by use of K562 cells...
October 17, 2016: Oncology Reports
Carlos I Amaya-Chanaga, Laura Z Rassenti
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course. The Rai and Binet staging systems are often used to predict survival. However, they do not take into account other biological characteristics of CLL cells that may influence the disease course and response to treatment. Prognostic factors such as chromosome abnormalities (trisomy 12, 11q deletions and 17p deletions), β2 microglobulin, thymidine kinase, CD38 and ZAP-70 expression, IGHV mutation status, and mutations in genes such as NOTCH1, MYD88, SF3B1, and ATM are also predictors of prognosis...
March 2016: Best Practice & Research. Clinical Haematology
Mohamed A Kharfan-Dabaja, Jessica El-Asmar, Farrukh T Awan, Mehdi Hamadani, Ernesto Ayala
Novel therapies targeting various kinases downstream of the B-cell receptor have emerged along with monoclonal antibodies and BCL-2 antagonists, and are changing the therapeutic landscape of chronic lymphocytic leukemia. However, cure remains unattainable unless eligible patients are offered an allogeneic hematopoietic cell transplant. Access to allogeneic hematopoietic cell transplantation has expanded considerably with availability of reduced intensity conditioning regimens which is capable offering durable remissions even in poor-risk disease...
March 2016: Best Practice & Research. Clinical Haematology
Davide Rossi
Richter's syndrome (RS) is the development of an aggressive lymphoma in patients with a previous or concomitant diagnosis of chronic lymphocytic leukemia (CLL). The incidence rate for RS is ∼0.5% per year of observation. In the presence of clinical suspicious of RS, diagnosis of transformation and choice of the site of biopsy may take advantage of (18)FDG PET/CT. Molecular lesions of tumor suppression regulators (TP53), cell cycle (CDKN2A) and cell proliferation (NOTCH1, MYC) overall account for ∼90% of RS and may be responsible for its aggressive clinical phenotype...
March 2016: Best Practice & Research. Clinical Haematology
Deepa Jeyakumar, Susan O'Brien
Inhibitors of the B cell receptor (BCR) represent an attractive therapeutic option for patients with chronic lymphocytic leukemia. Recently approved inhibitors of Bruton's tyrosine kinase (ibrutinib) and phosphatidylinositol 3-kinase (idelalisib), are promising agents because they are generally well tolerated and highly effective. These agents may be particularly important in the treatment of older patients who are less able to tolerate the myelosuppression (and infections) associated with chemoimmunotherapy...
March 2016: Best Practice & Research. Clinical Haematology
Januario E Castro, Thomas J Kipps
Treatment of patients with chronic lymphocytic leukemia and other B cell malignancies is evolving very rapidly. We have observed the quick transition during the last couple of years, from chemo-immunotherapy based treatments to oral targeted therapies based on B cell receptor signaling and Bcl-2 inhibitors, as well as the increasing use of second generation glyco-engineered antibodies. The next wave of revolution in the treatment for this conditions is approaching and it will be based on strategies that harness the power of the immune system to fight cancer...
March 2016: Best Practice & Research. Clinical Haematology
Brian Koffman, Andrew Schorr
The 21st century has seen rapid, positive changes in the management of chronic lymphocytic leukaemia from the patient's perspective. New prognostic and predictive markers have ushered in the start of more precise and individualized therapy. For the first time, combined therapy [fludarabine, cyclophosphamide and rituximab] has been shown to prolong life significantly. Clinical trials have become more adaptive, faster and more patient friendly. Perhaps the greatest change of all is the development of novel oral agents (ibrutinib and idelalisib) and powerful monoclonal antibodies that offer robust and durable disease control...
March 2016: Best Practice & Research. Clinical Haematology
Paula Cramer, Barbara Eichhorst, Hans Christian Reinhardt, Michael Hallek
Given the current dynamics in the development of novel agents for CLL therapy, the task to find optimal, non-toxic combinations has become the primary goal. This article gives an update of the most interesting novel drugs. The strategy of the German CLL Study Group to use these agents in combinations is described in detail, highlighting the strategy and first results of a recently started series of phase II combination trials, the BXX series using agents such as bendamustine, idelalisib, ibrutinib, obinutuzumab, ofatumumab and venetoclax...
March 2016: Best Practice & Research. Clinical Haematology
Agata A Filip, Anna Grenda, Sylwia Popek, Dorota Koczkodaj, Małgorzata Michalak-Wojnowska, Michał Budzyński, Ewa Wąsik-Szczepanek, Szymon Zmorzyński, Agnieszka Karczmarczyk, Krzysztof Giannopoulos
Expression of microRNAs is altered in cancer. Circulating miRNA level assessed in body fluids commonly reflects their expression in tumor cells. In leukemias, however, both leukemic and nonleukemic cells compose circulating miRNA expression profile of peripheral blood. The latter contribution to extracellular miRNA pool may result in specific microenvironmental signaling, which promotes proliferation and survival. In our study, we used qT-PCR to assay peripheral blood serum of 22 chronic lymphocytic leukemia (CLL) patients for the expression of 84 miRNAs associated with activation and differentiation of B and T lymphocytes...
October 12, 2016: Annals of Hematology
Isabel González-Gascón Y Marín, Ana África Martín, María Hernández-Sanchez, Cristina Robledo, María Lourdes Hermosín, Natalia de Las Heras, Laura Lacalle, Josefina Galende, Felipe de Arriba, Ana Eugenia Rodríguez-Vicente, José-Ángel Hernández, Jesús María Hernández-Rivas
: The presence of chromosomal gains other than trisomy 12 in chronic lymphocytic leukaemia (CLL) is unusual. However, some patients may show gains on several chromosomes simultaneously suggesting a hyperdiploid karyotype. OBJECTIVE: The objective of this study was to analyse by FISH the frequency and prognostic impact of hyperdiploidy in CLL. METHOD: A review of 1359 consecutive cases diagnosed with CLL referred for FISH analysis to a unique institution was carried out...
September 26, 2016: European Journal of Haematology
Emily C Ayers, Anthony R Mato
Richter's transformation (RT) is the transformation of chronic lymphocytic leukemia (CLL) into rapidly progressive B-cell lymphoma. This disease has long been recognized as a difficult-to-treat illness with poor survival outcomes. Although the incidence of RT has been well documented in previous studies, less is understood in the era of novel therapeutics, such as kinase inhibitors (KIs). The present review discusses the current risk factors, incidence, and outcomes of patients with RT in the modern era of KI therapy...
September 8, 2016: Clinical Lymphoma, Myeloma & Leukemia
Luis Felipe Casado, Amparo Burgos, Eva González-Haba, Javier Loscertales, Tania Krivasi, Javier Orofino, Carlos Rubio-Terres, Darío Rubio-Rodríguez
OBJECTIVE: To evaluate the cost-effectiveness of obinutuzumab in combination with chlorambucil (GClb) versus rituximab plus chlorambucil (RClb) in the treatment of adults with previously untreated chronic lymphocytic leukemia (CLL) and with comorbidities that make them unsuitable for full-dose fludarabine-based therapy, from the perspective of the Spanish National Health System. METHODS: A Markov model was developed with three mutually exclusive health states: progression-free survival (with or without treatment), progression, and death...
2016: ClinicoEconomics and Outcomes Research: CEOR
Marwan Kwok, Andy C Rawstron, Abraham Varghese, Paul A S Evans, Sheila J M O'Connor, Chi Doughty, Darren J Newton, Paul Moreton, Peter Hillmen
Minimal residual disease (MRD) negativity, defined as <1 chronic lymphocytic leukemic (CLL) cell detectable per 10,000 leukocytes, has been shown to independently predict for clinical outcome in patients receiving combination chemoimmunotherapy in the frontline setting. However, the long-term prognostic value of MRD status in other therapeutic settings remains unclear. Here, we retrospectively analyzed, with up to 18 years follow up, all patients at our institution who achieved at least a partial response (PR) with various therapies between 1996 and 2007, and received a bone marrow MRD assessment at the end of treatment according to the international harmonized approach...
October 3, 2016: Blood
Rachael J M Bashford-Rogers, Anne L Palser, Clare Hodkinson, Joanna Baxter, George A Follows, George S Vassiliou, Paul Kellam
Chronic lymphocytic leukaemia (CLL) is characterised by the accumulation of clonally-derived mature CD5(high) B-cells, however the cellular origin of CLL is still unknown. Patients with CLL also harbour variable numbers of CD5(low) B-cells, but the clonal relationship of these cells to the bulk disease is unknown and can have important implications for monitoring, treating and understanding the biology of CLL. Here we use B-cell receptors (BCRs) as molecular barcodes to first show that the great majority of CD5(low) B-cells in the blood of CLL patients are clonally related to CD5(high) CLL B-cells by single-cell BCR sequencing...
September 27, 2016: Experimental Hematology
Supriya V Vartak, Mahesh Hegde, Divyaanka Iyer, Snehal Gaikwad, Vidya Gopalakrishnan, Mrinal Srivastava, Subhas S Karki, Bibha Choudhary, Pritha Ray, T R Santhoshkumar, Sathees C Raghavan
Antiapoptotic protein BCL2, serves as an excellent target for anticancer therapy owing to its increased level in cancers. Previously, we have described characterization of a novel BCL2 inhibitor, Disarib, which showed selective cytotoxicity in BCL2 'high' cancer cells and CLL patient cells. Here, we have investigated the mechanism of Disarib-induced cytotoxicity, and compared its efficacy with a well-established BCL2 inhibitor, ABT199. We show that Disarib administration caused tumor regression in mouse allograft and xenograft models, exhibited platelet sparing property and did not exhibit significant side effects...
September 29, 2016: Biochemical Pharmacology
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