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Chronic lymphocytic phase iii

Maria Winqvist, Fariba Mozaffari, Marzia Palma, Sandra Eketorp Sylvan, Lotta Hansson, Håkan Mellstedt, Anders Österborg, Jeanette Lundin
This phase I-II study explored safety, immunomodulatory and clinical effects of lenalidomide (weeks 1-16) and alemtuzumab (weeks 5-16) in 23 patients with refractory chronic lymphocytic leukemia. Most patients had Rai stage III/IV disease and were heavily pretreated (median 4 prior therapies), and 61% had del(17p)/del(11q). Eleven of 19 evaluable patients (58%) responded, with a median response duration of 12 months (1-29+); time to progression was short in non-responders. Lenalidomide had a narrow therapeutic dose range, 2...
November 4, 2016: Cancer Immunology, Immunotherapy: CII
Tadeusz Robak, Krzysztof Warzocha, K Govind Babu, Yaroslav Kulyaba, Kazimierz Kuliczkowski, Kudrat Abdulkadyrov, Javier Loscertales, Iryna Kryachok, Janusz Kłoczko, Grygoriy Rekhtman, Wojciech Homenda, Jerzy Z Błoński, Astrid McKeown, Michele M Gorczyca, Jodi L Carey, Chai-Ni Chang, Steen Lisby, Ira V Gupta, Sebastian Grosicki
: In this multicenter, open-label, phase III study, patients with relapsed chronic lymphocytic leukemia (CLL) were randomized (1:1) to receive ofatumumab plus fludarabine and cyclophosphamide (OFA + FC) or FC alone; the primary endpoint being progression-free survival (PFS) assessed by an independent review committee (IRC). Between March 2009 and January 2012, 365 patients were randomized (OFA + FC: n = 183; FC: n = 182). Median IRC-assessed PFS was 28.9 months with OFA + FC versus 18...
October 12, 2016: Leukemia & Lymphoma
Dena R Howard, Talha Munir, Anna Hockaday, Andy C Rawstron, Laura Collett, Jamie B Oughton, David Allsup, Adrian Bloor, David Phillips, Peter Hillmen
BACKGROUND: Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia. Combination immunochemotherapy such as fludarabine, cyclophosphamide and rituximab is the standard first line therapy in fit patients, but there is limited evidence regarding the optimal treatment of patients after relapse. Ofatumumab as monotherapy has been proven to be effective in the treatment of relapsed, refractory CLL, and as it is not myelotoxic, it is an ideal drug to combine with chemotherapy...
2016: Trials
Ann-Kathrin Uhde, Vanessa Herder, Muhammad Akram Khan, Malgorzata Ciurkiewicz, Dirk Schaudien, René Teich, Stefan Floess, Wolfgang Baumgärtner, Jochen Huehn, Andreas Beineke
Theiler´s murine encephalomyelitis virus (TMEV)-infection is a widely used animal model for studying demyelinating disorders, including multiple sclerosis (MS). The immunosuppressive cytokine Interleukin (IL)-10 counteracts hyperactive immune responses and critically controls immune homeostasis in infectious and autoimmune disorders. In order to investigate the effect of signaling via Interleukin-10 receptor (IL-10R) in infectious neurological diseases, TMEV-infected SJL mice were treated with IL-10R blocking antibody (Ab) in the acute and chronic phase of the disease...
2016: PloS One
Gabor Kovacs, Sandra Robrecht, Anna Maria Fink, Jasmin Bahlo, Paula Cramer, Julia von Tresckow, Christian Maurer, Petra Langerbeins, Günter Fingerle-Rowson, Matthias Ritgen, Michael Kneba, Hartmut Döhner, Stephan Stilgenbauer, Wolfram Klapper, Clemens-Martin Wendtner, Kirsten Fischer, Michael Hallek, Barbara Eichhorst, Sebastian Böttcher
PURPOSE: To determine the value of minimal residual disease (MRD) assessments, together with the evaluation of clinical response in chronic lymphocytic leukemia according to the 2008 International Workshop on Chronic Lymphocytic Leukemia criteria. PATIENTS AND METHODS: Progression-free survival (PFS) and overall survival of 554 patients from two randomized trials of the German CLL Study Group (CLL8: fludarabine and cyclophosphamide [FC] v FC plus rituximab; CLL10: FC plus rituximab v bendamustine plus rituximab) were analyzed according to MRD assessed in peripheral blood at a threshold of 10(-4) and clinical response...
August 29, 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Paolo Strati, Mark Lanasa, Timothy G Call, Jose F Leis, Danielle M Brander, Betsy R LaPlant, Adam M Pettinger, Wei Ding, Sameer A Parikh, Curtis A Hanson, Asher A Chanan-Khan, Deborah A Bowen, Michael Conte, Neil E Kay, Tait D Shanafelt
BACKGROUND: Although several consolidation strategies to prolong treatment-free survival (TFS) in chronic lymphocytic leukaemia have been investigated, most have proven either ineffective or toxic. Ofatumumab is a human type I anti-CD20 antibody approved by the US Food and Drug Administration as maintenance treatment of patients with recurrent or progressive chronic lymphocytic leukaemia who are in complete or partial response after at least two lines of treatment; higher efficacy might be observed if used as consolidation strategy than without consolidation in previously untreated patients...
September 2016: Lancet Haematology
Peter Hillmen, Ann Janssens, K Govind Babu, Janusz Kloczko, Sebastian Grosicki, Stephanie Manson, Astrid McKeown, Ira Gupta, Chai-Ni Chang, Fritz Offner
BACKGROUND: Patients diagnosed with chronic lymphocytic leukemia (CLL) are usually elderly and frequently have a number of comorbidities. Health-related quality of life (HRQoL) for these patients is of utmost importance and should be taken into consideration when assessing new treatment options. The combination of ofatumumab with chlorambucil has shown longer progression-free survival compared with chlorambucil alone. In this study, we aim to assess how this treatment combination affects patients' health-related quality of life and patient-reported symptoms...
September 2016: Acta Oncologica
Emma D Deeks
Venetoclax (Venclexta™) is an oral selective inhibitor of the prosurvival protein BCL-2 and therefore restores the apoptotic ability of malignant cells. The drug arose from research by Abbott Laboratories (now AbbVie) during a collaboration with Genentech and is being co-developed by AbbVie and Genentech/Roche primarily for the treatment of haematological malignancies. Venetoclax is approved in the USA for use as monotherapy in patients with chronic lymphocytic leukaemia (CLL) with the 17p deletion (as detected by an approved FDA test) who have received at least one prior therapy, and is awaiting approval for similar indications in the EU and Canada...
June 2016: Drugs
Carmen Diana Herling, Marion Klaumünzer, Cristiano Krings Rocha, Janine Altmüller, Holger Thiele, Jasmin Bahlo, Sandra Kluth, Giuliano Crispatzu, Marco Herling, Joanna Schiller, Anja Engelke, Eugen Tausch, Hartmut Döhner, Kirsten Fischer, Valentin Goede, Peter Nürnberg, Hans Christian Reinhardt, Stephan Stilgenbauer, Michael Hallek, Karl-Anton Kreuzer
Genetic instability is a feature of chronic lymphocytic leukemia (CLL) with adverse prognosis. We hypothesized that chromosomal translocations or complex karyotypes and distinct somatic mutations may impact outcome after first-line chemoimmunotherapy of CLL patients. We performed metaphase karyotyping and next-generation sequencing (NGS) of 85 genes in pretreatment blood samples obtained from 161 patients registered for CLL11, a 3-arm phase 3 trial comparing frontline chlorambucil (Clb) vs Clb plus rituximab (Clb-R) or Clb plus obinutuzumab in CLL patients with significant comorbidity...
July 21, 2016: Blood
M A Alberelli, I Innocenti, S Sica, L Laurenti, E De Candia
INTRODUCTION: Ibrutinib treatment in patients with chronic lymphatic leukemia (LLC) is associated with bleeding-related adverse events. About 50% of treated patients display minor bleedings and about 5% major bleedings. A defect of platelet function has been hypothesized and inhibition of signaling by glycoprotein (GP) VI, which is the receptor for collagen, has been previously described. Ibrutinib-associated bleedings and platelet dysfunction may be relevant in the context of aged patients, who are often under antithrombotic treatments...
April 2016: Thrombosis Research
C Maurer, P Langerbeins, J Bahlo, P Cramer, A M Fink, N Pflug, A Engelke, J von Tresckow, G Kovacs, S Stilgenbauer, C-M Wendtner, L Müller, M Ritgen, T Seiler, K Fischer, M Hallek, B Eichhorst
This study aimed to assess the frequency of and the contributing factors for second primary malignancies (SPMs) and Richter's transformations (RTs) following first-line treatment of chronic lymphocytic leukemia within four phase II/III trials of the GCLLSG evaluating fludarabine (F) vs F+cyclophosphamide (FC), chlorambucil vs F, FC without or with rituximab, and bendamustine+R (BR). Among 1458 patients, 239 (16.4%) experienced either an SPM (N=191) or a RT (N=75). Solid tumors (N=115; 43.2% of all second neoplasias) appeared most frequently, followed by RTs (N=75; 28...
May 27, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Massimo Gentile, Katja Zirlik, Stefania Ciolli, Francesca R Mauro, Nicola Di Renzo, Lucia Mastrullo, Francesco Angrilli, Stefano Molica, Giovanni Tripepi, Annamaria Giordano, Francesco Di Raimondo, Carmine Selleri, Marta Coscia, Maurizio Musso, Lorella Orsucci, Donato Mannina, Angela Rago, Angela Giannotta, Felicetto Ferrara, Yair Herishanu, Lev Shvidel, Tamar Tadmor, Ilaria Scortechini, Fiorella Ilariucci, Roberta Murru, Attilio Guarini, Gerardo Musuraca, Giuseppe Mineo, Iolanda Vincelli, Annalisa Arcari, Giuseppe Tarantini, Giuseppe Caparrotti, Annalisa Chiarenza, Luciano Levato, Maria Rosaria Villa, Maria Rosaria De Paolis, Pier Luigi Zinzani, Aaron Polliack, Fortunato Morabito
Recently, encouraging results in terms of safety and efficacy have been obtained using bendamustine-rituximab (BR) in untreated chronic lymphocytic leukaemia (CLL) patients enrolled in a phase II study. Here, we report a retrospective international multicenter study of CLL patients treated with BR as front-line therapy. The cohort included 279 patients with progressive CLL from 33 centers (29 Italian, 3 Israeli and 1 German) who received at least 1 cycle of BR as first-line treatment during the 2008-2014 period...
June 2016: European Journal of Cancer
Tadeusz Robak, Jerzy Z Blonski, Pawel Robak
The development of non-chemotherapeutic agents, including monoclonal antibodies (mAbs) and other targeted drugs, makes chemotherapy-free treatment an attractive option for chronic lymphocytic leukemia (CLL). The classical mAb, rituximab, has been authorized for use in both first-line and second-line therapy for CLL. New mAbs directed against CD20, ofatumumab, and obinutuzumab (GA-101) have also been approved for the treatment of this disease. Recently, several new mAbs with potential benefits over the approved anti-CD20 antibodies have been developed for use in CLL...
April 2016: Seminars in Oncology
Peter H Wiernik
INTRODUCTION: Alvocidib, which has orphan drug designation in chronic lymphocytic leukemia (CLL) from the FDA and the EMA, is a plant-derived semisynthetic flavone that acts as a cyclin-dependent kinase inhibitor. It induces apoptosis in CLL cells in vitro and was introduced into clinical trials in CLL as an intravenous infusion in 1997, which proved disappointing. Since the drug avidly binds to plasma proteins, higher serum concentrations were required for clinical antileukemia activity than those suggested by in vitro studies...
June 2016: Expert Opinion on Investigational Drugs
Keith Dawson, Mollie Moran, Kathleen Guindon, Hui Wan
BACKGROUND: In patients with previously untreated chronic lymphocytic leukemia (CLL) and comorbidities, treatment with the glycoengineered, type II anti-CD20 monoclonal antibody obinutuzumab (Gazyva®) (GA101) plus chlorambucil (Leukeran®) was associated with superior outcomes to rituximab (Rituxan®) plus chlorambucil, with a similar safety profile. However, a higher occurrence of infusion-related reactions (IRRs) was reported with obinutuzumab. These reactions typically require additional management...
April 2016: Clinical Journal of Oncology Nursing
Candida Vitale, Jan A Burger
INTRODUCTION: The critical role of the tissue microenvironment and B-cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) pathogenesis, and the clinical success of targeted agents that disrupt BCR signaling are currently changing the CLL landscape. Three new drugs were recently approved for CLL therapy, and other agents are in late development. AREAS COVERED: In this review, we summarize data on promising new targeted drugs for CLL. The heterogeneous mechanisms of actions of these molecules are described, such as the inhibition of BCR signaling, direct targeting of CD20 molecules on the CLL cell surface, and BCL-2 inhibition...
June 2016: Expert Opinion on Pharmacotherapy
Cory M Vela, Ali McBride, Samantha M Jaglowski, Leslie A Andritsos
PURPOSE: The pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of ibrutinib are described. SUMMARY: Ibrutinib is a first-in-class oral inhibitor of Bruton tyrosine kinase (BTK) approved for treatment of relapsed chronic lymphocytic leukemia (CLL). Ibrutinib blocks downstream signaling of the B-cell receptor, disrupting stromal microenvironment interactions and B-cell cytokine signaling. BTK inhibition has been shown to be effective in relapsed or refractory CLL...
March 15, 2016: American Journal of Health-system Pharmacy: AJHP
Anders Österborg, Miklós Udvardy, Andrey Zaritskey, Per-Ola Andersson, Sebastian Grosicki, Grzegorz Mazur, Polina Kaplan, Michael Steurer, Anna Schuh, Marco Montillo, Iryna Kryachok, Jan Moritz Middeke, Yaroslav Kulyaba, Grygoriy Rekhtman, Michele Gorczyca, Siobhan Daly, Chai-Ni Chang, Steen Lisby, Ira Gupta
We report results of a randomized, phase III study of ofatumumab versus physicians' choice treatment in patients with bulky fludarabine-refractory chronic lymphocytic leukemia and explore extended versus standard-length ofatumumab treatment. Patients (79 ofatumumab, 43 physicians' choice) completed a median 6 (ofatumumab) or 3 (physicians' choice) months' therapy. Ofatumumab-treated patients with stable disease or better were randomized (2:1) to 6 months' extended ofatumumab treatment or observation. Although the study did not meet the primary endpoint of progression-free survival (PFS) by independent review committee (ofatumumab: 5...
September 2016: Leukemia & Lymphoma
Kirsten Fischer, Jasmin Bahlo, Anna Maria Fink, Valentin Goede, Carmen Diana Herling, Paula Cramer, Petra Langerbeins, Julia von Tresckow, Anja Engelke, Christian Maurer, Gabor Kovacs, Marco Herling, Eugen Tausch, Karl-Anton Kreuzer, Barbara Eichhorst, Sebastian Böttcher, John F Seymour, Paolo Ghia, Paula Marlton, Michael Kneba, Clemens-Martin Wendtner, Hartmut Döhner, Stephan Stilgenbauer, Michael Hallek
Despite promising results with targeted drugs, chemoimmunotherapy with fludarabine, cyclophosphamide (FC), and rituximab (R) remains the standard therapy for fit patients with untreated chronic lymphocytic leukemia (CLL). Herein, we present the long-term follow-up of the randomized CLL8 trial reporting safety and efficacy of FC and FCR treatment of 817 treatment-naïve patients with CLL. The primary end point was progression-free survival (PFS). With a median follow-up of 5.9 years, median PFS were 56.8 and 32...
January 14, 2016: Blood
G Palermo, D Maisel, M Barrett, H Smith, G Duchateau-Nguyen, T Nguyen, R-F Yeh, A Dufour, T Robak, D Dornan, M Weisser
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease. Various disease-related and patient-related factors have been shown to influence the course of the disease. The aim of this study was to identify novel biomarkers of significant clinical relevance. Pretreatment CD19-separated lymphocytes (n=237; discovery set) and peripheral blood mononuclear cells (n=92; validation set) from the REACH trial, a randomized phase III trial in relapsed CLL comparing rituximab plus fludarabine plus cyclophosphamide with fludarabine plus cyclophosphamide alone, underwent gene expression profiling...
October 2, 2015: Blood Cancer Journal
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