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https://www.readbyqxmd.com/read/27903679/the-bruton-s-tyrosine-kinase-btk-inhibitor-acalabrutinib-demonstrates-potent-on-target-effects-and-efficacy-in-two-mouse-models-of-chronic-lymphocytic-leukemia
#1
Sarah E M Herman, Arnau Montraveta, Carsten U Niemann, Helena Mora-Jensen, Michael Gulrajani, Fanny Krantz, Rose Mantel, Lisa L Smith, Fabienne McClanahan, Bonnie Harrington, Dolors Colomer, Todd Covey, John C Byrd, Raquel Izumi, Allard Kaptein, Roger Ulrich, Amy Johnson, Brian J Lannutti, Adrian Wiestner, Jennifer A Woyach
PURPOSE: Acalabrutinib (ACP-196) is a novel, potent, and highly selective BTK inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the anti-tumor effects of acalabrutinib treatment in two established mouse models of chronic lymphocytic leukemia (CLL). EXPERIMENTAL DESIGN: Two distinct mouse models were used, the TCL1 adoptive transfer model where leukemic cells from Eμ-TCL1 transgenic mice are transplanted into C57BL/6 mice, and the human NSG primary CLL xenograft model...
November 30, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27862308/alemtuzumab-consolidation-in-chronic-lymphocytic-leukaemia-a-phase-i-ii-multicentre-trial
#2
Othman Al-Sawaf, Kirsten Fischer, Carmen D Herling, Matthias Ritgen, Sebastian Böttcher, Jasmin Bahlo, Thomas Elter, Stephan Stilgenbauer, Barbara F Eichhorst, Raymonde Busch, Ute Elberskirch, Wolfgang Abenhardt, Michael Kneba, Michael Hallek, Clemens-Martin Wendtner
OBJECTIVE: Despite high rates of long-lasting remissions in patients with chronic lymphocytic leukaemia (CLL) treated with chemoimmunotherapy, none of the current therapeutic approaches is curative with the exception of allogeneic transplantation. One strategy to extend progression-free survival and long-term survival might be the establishment of consolidation therapies. METHODS: In this trial, patients with complete or partial second remission after fludarabine-based treatment received consolidation therapy with alemtuzumab...
November 9, 2016: European Journal of Haematology
https://www.readbyqxmd.com/read/27822100/the-danish-national-chronic-lymphocytic-leukemia-registry
#3
REVIEW
Caspar da Cunha-Bang, Christian Hartmann Geisler, Lisbeth Enggaard, Christian Bjørn Poulsen, Peter de Nully Brown, Henrik Frederiksen, Olav Jonas Bergmann, Elisa Jacobsen Pulczynski, Robert Schou Pedersen, Linda Højberg Nielsen, Ilse Christiansen, Carsten Utoft Niemann
AIM: In 2008, the Danish National Chronic Lymphocytic Leukemia Registry was founded within the Danish National Hematology Database. The primary aim of the registry is to assure quality of diagnosis and care of patients with chronic lymphocytic leukemia (CLL) in Denmark. Secondarily, to evaluate adherence to national guidelines and to provide source data for research purposes. STUDY POPULATION: All patients diagnosed with CLL in Denmark from 2008 onward are included in the registry...
2016: Clinical Epidemiology
https://www.readbyqxmd.com/read/27819687/impact-of-drug-development-on-the-use-of-stem-cell-transplantation-a-report-by-the-european-society-for-blood-and-marrow-transplantation-ebmt
#4
J R Passweg, H Baldomero, P Bader, C Bonini, S Cesaro, P Dreger, R F Duarte, C Dufour, J Kuball, D Farge-Bancel, A Gennery, N Kröger, F Lanza, A Nagler, A Sureda, M Mohty
Hematopoietic stem cell transplantation (HSCT) is used with increasing frequency in Europe with 40 000 transplants reported in 2014. Transplant-related mortality remains high in allogeneic HSCT (10-20%); high-dose chemotherapy is toxic and demanding for patients. Drug development is accelerating and with limited toxicity of some targeted drugs may replace HSCT, whereas others may function as a 'bridge to transplant'. We analyzed HSCT reported to the activity survey for selected diseases in which major advances in drug development have been made...
November 7, 2016: Bone Marrow Transplantation
https://www.readbyqxmd.com/read/27802969/ibrutinib-efficacy-and-tolerability-in-patients-with-relapsed-chronic-lymphocytic-leukemia-following-allogeneic-hct
#5
Christine E Ryan, Bita Sahaf, Aaron C Logan, Susan O'Brien, John C Byrd, Peter Hillmen, Jennifer R Brown, Martin J S Dyer, Anthony R Mato, Michael J Keating, Samantha Jaglowski, Fong Clow, Andrew R Rezvani, Lori Styles, Steven E Coutre, David B Miklos
Ibrutinib, a potent and irreversible small molecule inhibitor of both Bruton's tyrosine kinase (BTK) and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplantation who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87...
November 1, 2016: Blood
https://www.readbyqxmd.com/read/27797975/long-term-follow-up-of-treatment-with-ibrutinib-and-rituximab-ir-in-patients-with-high-risk-chronic-lymphocytic-leukemia-cll
#6
Preetesh Jain, Michael J Keating, William Wierda, Mariela Sivina, Philip A Thompson, Alessandra Ferrajoli, Zeev Estrov, Hagop Kantarjian, Susan O'Brien, Jan Burger
BACKGROUND: Ibrutinib is an active therapy with acceptable safety profile for patients with CLL, including high-risk patients with del17p or with TP53 mutations. Ibrutinib is broadly indicated for the treatment of patients with chronic lymphocytic leukemia and specifically including those with 17p deletion. The optimal use of ibrutinib in combination with other agents, remains controversial. METHODS: We report the long term outcome [median follow up of 47 months (range 36-51 months)] of 40 patients with high risk CLL, treated on the first ibrutinib combination trial with rituximab (IR)...
October 19, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27757305/mono-and-dual-targeting-triplebodies-activate-natural-killer-cells-and-have-anti-tumor-activity-in-vitro-and-in-vivo-against-chronic-lymphocytic-leukemia
#7
Maulik Vyas, Ann-Charlott Schneider, Olga Shatnyeva, Katrin S Reiners, Samir Tawadros, Stephan Kloess, Ulrike Köhl, Michael Hallek, Hinrich P Hansen, Elke Pogge von Strandmann
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia that affects B lymphocytes in adults. Natural killer (NK) cells in CLL patients are intrinsically potent but display poor in situ effector functions. NKG2D is an activating receptor found on NK and CD8(+) T cells and plays a role in immunosurveillance of CLL. In this study, we developed mono- and dual-targeting triplebodies utilizing a natural ligand for human NKG2D receptor (ULBP2) to retarget NK cells against tumor cells. Triplebodies in both formats showed better ability to induce NK-cell-dependent killing of target cells compared to bispecific counterparts...
2016: Oncoimmunology
https://www.readbyqxmd.com/read/27742075/tp53-dysfunction-in-cll-implications-for-prognosis-and-treatment
#8
Gera D Te Raa, Arnon P Kater
Despite the availability of novel targeted agents, TP53 defects remain the most important adverse prognostic factor in chronic lymphocytic leukemia (CLL). Detection of deletion of TP53 locus (17p deletion) by fluorescent in situ hybridization (FISH) has become standard and performed prior to every line of treatment as the incidence dramatically increases as relapses occur. As monoallelic mutations of TP53 equally affect outcome, novel methods are being developed to improve detection of TP53 defects and include next-generation sequencing (NGS) and functional assays...
March 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27742072/current-state-of-hematopoietic-cell-transplantation-in-cll-as-smart-therapies-emerge
#9
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
https://www.readbyqxmd.com/read/27742070/richter-s-syndrome-novel-and-promising-therapeutic-alternatives
#10
REVIEW
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
https://www.readbyqxmd.com/read/27728807/lyn-kinase-in-the-tumor-microenvironment-is-essential-for-the-progression-of-chronic-lymphocytic-leukemia
#11
Phuong-Hien Nguyen, Oleg Fedorchenko, Natascha Rosen, Maximilian Koch, Romy Barthel, Tomasz Winarski, Alexandra Florin, F Thomas Wunderlich, Nina Reinart, Michael Hallek
Survival of chronic lymphocytic leukemia (CLL) cells strictly depends on the support of an appropriate tumor microenvironment. Here, we demonstrate that LYN kinase is essential for CLL progression. Lyn deficiency results in a significantly reduced CLL burden in vivo. Loss of Lyn within leukemic cells reduces B cell receptor (BCR) signaling including BTK phosphorylation, but surprisingly does not affect leukemic cell expansion. Instead, syngeneic CLL transplantation of CLL cells into Lyn- or Btk-deficient recipients results in a strongly delayed leukemic progression and prolonged survival...
October 10, 2016: Cancer Cell
https://www.readbyqxmd.com/read/27660167/clinical-practice-recommendations-for-use-of-allogeneic-hematopoietic-cell-transplantation-in-chronic-lymphocytic-leukemia-on-behalf-of-the-guidelines-committee-of-the-american-society-for-blood-and-marrow-transplantation
#12
REVIEW
Mohamed A Kharfan-Dabaja, Ambuj Kumar, Mehdi Hamadani, Stephan Stilgenbauer, Paolo Ghia, Claudio Anasetti, Peter Dreger, Emili Montserrat, Miguel-Angel Perales, Edwin P Alyea, Farrukh T Awan, Ernesto Ayala, Jacqueline C Barrientos, Jennifer R Brown, Januario E Castro, Richard R Furman, John Gribben, Brian T Hill, Mohamad Mohty, Carol Moreno, Susan O'Brien, Steven Z Pavletic, Javier Pinilla-Ibarz, Nishitha M Reddy, Mohamed Sorror, Christopher Bredeson, Paul Carpenter, Bipin N Savani
We sought to establish clinical practice recommendations to redefine the role of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with chronic lymphocytic leukemia (CLL) in an era of highly active targeted therapies. We performed a systematic review to identify prospective randomized controlled trials comparing allo-HCT against novel therapies for treatment of CLL at various disease stages. In the absence of such data, we invited physicians with expertise in allo-HCT and/or CLL to participate in developing these recommendations...
December 2016: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/27595282/bendamustine-added-to-allogeneic-conditioning-improves-long-term-outcomes-in-patients-with-cll
#13
I F Khouri, D Sui, E J Jabbour, B I Samuels, F Turturro, G Alatrash, P Anderlini, S Ahmed, B Oran, S O Ciurea, D Marin, A Olson, K K Patel, U R Popat, C Ledesma, T M Kadia, A Ferrajoli, J A Burger, J L Jorgensen, L J Medeiros, R L Bassett, A M Gulbis
Bendamustine has shown a favorable safety profile when included in chemotherapy regimens for several types of lymphoma, including CLL. This study investigated the long-term effect of adding bendamustine to a conditioning regimen on survival, rate of engraftment, immune recovery and GvHD after allogeneic stem cell transplantation (alloSCT) in CLL patients. These outcomes were compared with the fludarabine, cyclophosphamide and rituximab (FCR) conditioning regimen. We reviewed the data for 89 CLL patients treated on three trials at our institution...
September 5, 2016: Bone Marrow Transplantation
https://www.readbyqxmd.com/read/27521330/treatment-of-chronic-lymphocytic-leukemia-with-del-17p-tp53-mutation-allogeneic-hematopoietic-stem-cell-transplantation-or-bcr-signaling-inhibitors
#14
REVIEW
Emili Montserrat, Peter Dreger
The treatment of patients with chronic lymphocytic leukemia (CLL) whose tumor presents the del(17p)/TP53 mutation is a major challenge. Treatment with chemo(immuno)therapy, immunomodulators, or the anti-CD52 monoclonal antibody alemtuzumab produces transient, unsatisfactory responses. Reduced-intensity-conditioning allotransplantation produces sustained progression-free survival and overall survival (40%-60% at 5 years), equivalent to the cure of the disease, even in cases with adverse biomarkers. Unfortunately, despite improvements in this procedure, the non-relapse mortality continues to be high (15%-30%), and only highly selected patients (young, physically fit, with treatment-sensitive disease, not heavily pretreated, and with a fully matched donor) may benefit from the intervention without incurring unacceptable treatment-related risks...
August 2016: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/27479233/chimeric-antigen-receptor-car-t-cell-therapy-targeting-cd19-positive-leukemia-and-lymphoma-in-the-context-of-stem-cell-transplantation
#15
Maria-Luisa Schubert, Angela Gabriele Hückelhoven, Jean-Marc Hoffmann, Anita Schmitt, Patrick Wuchter, Leopold Sellner, Susanne Hofmann, Anthony D Ho, Peter Dreger, Michael Schmitt
Novel therapies with chimeric antigen receptor (CAR) transduced T cells (TCs) sparked new hope for patients with relapsed or refractory CD19-positive leukemia or lymphoma even after stem cell therapies. This review focuses on CARs recognizing the B cell antigen CD19. Both retro- and lentiviral vectors are used encoding the different anti-CD19 CAR constructs comprising costimulatory molecules like CD28, CD137/4-1BB and OX40 either alone (2nd generation CARs) or in combination (3rd generation CARs). Current up-to-date published studies on anti-CD19 CAR therapy for acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) and Non-Hodgkin lymphoma (NHL) with observed side effects are discussed and an outlook on 59 ongoing trials is given...
August 1, 2016: Human Gene Therapy
https://www.readbyqxmd.com/read/27473564/longitudinal-analyses-of-leukemia-associated-antigen-specific-cd8-t%C3%A2-cells-in-patients-after-allogeneic-stem-cell-transplantation
#16
Elke Rücker-Braun, Cornelia S Link, Maria Schmiedgen, Antje Tunger, Petra Vizjak, Raphael Teipel, Rebekka Wehner, Denise Kühn, Yannik F Fuchs, Uta Oelschlägel, Lothar Germeroth, Marc Schmitz, Martin Bornhäuser, Johannes Schetelig, Falk Heidenreich
Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment approach for patients with acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). Graft versus leukemia (GVL) effects, which are exerted by donor T cells directed against leukemic-associated antigens (LAAs), are considered to play a crucial role in disease eradication. Although the expansion of cytotoxic T lymphocytes (CTLs) specific for cytomegalovirus (CMV) in response to an infection has been shown in multiple studies, data on CTLs mediating GVL effects are limited...
November 2016: Experimental Hematology
https://www.readbyqxmd.com/read/27467957/targeting-b-cell-neoplasia-with-t-cell-receptors-recognizing-a-cd20-derived-peptide-on-patient-specific-hla
#17
Nadia Mensali, Fan Ying, Vincent Oei Yi Sheng, Weiwen Yang, Even Walseng, Shraddha Kumari, Lars-Egil Fallang, Arne Kolstad, Wolfgang Uckert, Karl Johan Malmberg, Sébastien Wälchli, Johanna Olweus
T cells engineered to express chimeric antigen receptors (CARs) targeted to CD19 are effective in treatment of B-lymphoid malignancies. However, CARs recognize all CD19 positive (pos) cells, and durable responses are linked to profound depletion of normal B cells. Here, we designed a strategy to specifically target patient B cells by utilizing the fact that T-cell receptors (TCRs), in contrast to CARs, are restricted by HLA. Two TCRs recognizing a peptide from CD20 (SLFLGILSV) in the context of foreign HLA-A*02:01 (CD20p/HLA-A2) were expressed as 2A-bicistronic constructs...
May 2016: Oncoimmunology
https://www.readbyqxmd.com/read/27431272/protection-of-rat-liver-against-hepatic-ischemia-reperfusion-injury-by-a-novel-selenocysteine-containing-7-mer-peptide
#18
Qianqian Jiang, Yu Pan, Yupeng Cheng, Huiling Li, Hui Li
Hepatic ischemia-reperfusion (I-R) injury causes acute organ damage or dysfunction, and remains a problem for liver transplantation. In the I-R phase, the generation of reactive oxygen species aggravates the injury. In the current study, a novel selenocysteine-containing 7‑mer peptide (H-Arg-Sec-Gly-Arg-Asn-Ala-Gln-OH) was constructed to imitate the active site of an antioxidant enzyme, glutathione peroxidase (GPX). The 7‑mer peptide which has a lower molecular weight, and improved water‑solubility, higher stability and improved cell membrane permeability compared with other GPX mimics...
September 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27378086/ncri-phase-ii-study-of-chop-in-combination-with-ofatumumab-in-induction-and-maintenance-in-newly-diagnosed-richter-syndrome
#19
Toby A Eyre, Ruth Clifford, Adrian Bloor, Lucy Boyle, Corran Roberts, Maite Cabes, Graham P Collins, Stephen Devereux, George Follows, Christopher P Fox, John Gribben, Peter Hillmen, Chris S Hatton, Tim J Littlewood, Helen McCarthy, Jim Murray, Andrew R Pettitt, Elizabeth Soilleux, Basile Stamatopoulos, Sharon B Love, Andrew Wotherspoon, Anna Schuh
Richter syndrome (RS) is associated with chemotherapy resistance and a poor historical median overall survival (OS) of 8-10 months. We conducted a phase II trial of standard CHOP-21 (cyclophosphamide, doxorubicin, vincristine, prednisolone every 21 d) with ofatumumab induction (Cycle 1: 300 mg day 1, 1000 mg day 8, 1000 mg day 15; Cycles 2-6: 1000 mg day 1) (CHOP-O) followed by 12 months ofatumumab maintenance (1000 mg given 8-weekly for up to six cycles). Forty-three patients were recruited of whom 37 were evaluable...
October 2016: British Journal of Haematology
https://www.readbyqxmd.com/read/27375124/t-cell-replete-hla-haploidentical-donor-transplantation-with-post-transplant-cyclophosphamide-is-an-effective-salvage-for-patients-relapsing-after-an-hla-matched-related-or-matched-unrelated-donor-transplantation
#20
Jessica Gorgeis, Xu Zhang, Katelin Connor, Stacey Brown, Scott R Solomon, Lawrence E Morris, H Kent Holland, Asad Bashey, Melhem Solh
A second allogeneic hematopoietic stem cell transplantation (HSCT) using the same donor or another fully matched donor is an effective treatment approach for a subset of patients relapsing after a matched related (MRDT) or matched unrelated donor transplant (MUDT). There are limited data on the use of haploidentical transplantation (HIDT) with post-transplant cyclophosphamide in the setting of a second HSCT after an MRDT or MUDT. We analyzed the outcomes of 20 patients who received HIDT with post-transplant cyclophosphamide as a second HSCT after an MRDT (n = 10) or MUDT (n = 10)...
October 2016: Biology of Blood and Marrow Transplantation
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