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https://www.readbyqxmd.com/read/27872058/a-randomised-assessment-of-adding-the-kinase-inhibitor-lestaurtinib-to-1st-line-chemotherapy-for-flt3-mutated-aml
#1
Steven Knapper, Nigel Russell, Amanda Gilkes, Robert K Hills, Rosemary E Gale, James D Cavenagh, Gail Jones, Lars Kjeldsen, Michael R Grunwald, Ian Thomas, Heiko Konig, Mark J Levis, Alan K Burnett
The clinical benefit of adding FLT3-directed small molecule therapy to standard first-line treatment of acute myeloid leukemia (AML) has not yet been established. As part of the UK AML15 and 17 trials, patients with previously-untreated AML and confirmed FLT3-activating mutations, mostly aged <60 years, were randomised to receive oral Lestaurtinib (CEP701), or not, following each of four cycles of induction and consolidation chemotherapy. Lestaurtinib was commenced 2 days after completing chemotherapy and administered in cycles of up to 28 days...
November 21, 2016: Blood
https://www.readbyqxmd.com/read/27795558/expression-of-cd33-is-a-predictive-factor-for-effect-of-gemtuzumab-ozogamicin-at-different-doses-in-adult-acute-myeloid-leukemia
#2
N Khan, R K Hills, P Virgo, S Couzens, N Clark, A Gilkes, P Richardson, S Knapper, D Grimwade, N H Russell, A K Burnett, S D Freeman
It remains unclear in adult acute myeloid leukemia (AML) whether leukemic expression of CD33, the target antigen for Gemtuzumab Ozogamicin (GO), add prognostic information on GO effectiveness at different doses. CD33 expression quantified in 1583 patients recruited to UK-NCRI-AML17 (younger adults) and UK-NCRI-AML16 (older adults) trials was correlated with clinical outcomes and benefit from GO including a dose randomisation. CD33 expression associated with genetic subgroups, including lower levels in both adverse karyotype and core-binding factor (CBF)-AML, but was not independently prognostic...
October 31, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27699249/a-xenograft-model-of-macrophage-activation-syndrome-amenable-to-anti-cd33-and-anti-il-6r-treatment
#3
Mark Wunderlich, Courtney Stockman, Mahima Devarajan, Navin Ravishankar, Christina Sexton, Ashish R Kumar, Benjamin Mizukawa, James C Mulloy
Transgenic expression of key myelosupportive human cytokines in immune-deficient mice corrects for the lack of cross-species activities of stem cell factor (SCF), IL-3, and GM-CSF. When engrafted with human umbilical cord blood (UCB), these triple-transgenic mice produce BM and spleen grafts with much higher myeloid composition, relative to nontransgenic controls. Shortly after engraftment with UCB, these mice develop a severe, fatal macrophage activation syndrome (MAS) characterized by a progressive drop in rbc numbers, increased reticulocyte counts, decreased rbc half-life, progressive cytopenias, and evidence of chronic inflammation, including elevated human IL-6...
September 22, 2016: JCI Insight
https://www.readbyqxmd.com/read/27683177/liver-microvascular-injury-and-thrombocytopenia-of-antibody-calicheamicin-conjugates-in-cynomolgus-monkeys-mechanism-and-monitoring
#4
Magali Guffroy, Hadi Falahatpisheh, Kathleen Biddle, John Kreeger, Leslie Obert, Karen Walters, Richard Goldstein, Germaine Boucher, Tim Coskran, William Reagan, Danielle Sullivan, Chunli Huang, Sharon A Sokolowski, Richard Giovanelli, Hans-Peter Gerber, Martin B Finkelstein, Nasir K Khan
PURPOSE: Adverse reactions reported in patients treated with antibody-calicheamicin conjugates such as gemtuzumab ozogamicin (GO, Mylotarg®) and inotuzumab ozogamicin (IO) include thrombocytopenia and sinusoidal obstruction syndrome (SOS). The objective of this experimental work was to investigate the mechanism for thrombocytopenia, characterize the liver injury and identify potential safety biomarkers. EXPERIMENTAL DESIGN: Cynomolgus monkeys were dosed intravenously at 6 mg/m2/dose once every 3 weeks with a non-binding antibody-calicheamicin conjugate (PF-0259) containing the same linker-payload as GO and IO...
September 28, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27624670/a-comparison-of-clofarabine-with-ara-c-each-in-combination-with-daunorubicin-as-induction-treatment-in-older-patients-with-acute-myeloid-leukaemia
#5
A K Burnett, N H Russell, R K Hills, J Kell, O J Nielsen, M Dennis, P Cahalin, C Pocock, S Ali, S Burns, S Freeman, D Milligan, R E Clark
The study was designed to compare clofarabine plus daunorubicin versus daunorubicin/ara-C in older patients with acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS). Eight hundred and six untreated patients in the UK NCRI AML16 trial with AML/high-risk MDS (median age, 67yrs; range 56-84) and normal serum creatinine were randomised to two courses of induction chemotherapy with either daunorubicin/ara-C (DA) or daunorubicin/clofarabine (DClo). Patients were also included in additional randomisations; +/- one dose of gemtuzumab ozogamicin in course 1; 2v3 courses and +/- azacitidine maintenance...
September 2, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/27460485/relapsed-childhood-acute-myeloid-leukemia-patient-with-inversion-of-chromosome-16-harboring-a-low-flt3-internal-tandem-duplication-allelic-burden-and-kit-mutations
#6
Ai Yamada, Hiroshi Moritake, Mariko Kinoshita, Daisuke Sawa, Sachiyo Kamimura, Shotaro Iwamoto, Yuka Yamashita, Jiro Inagaki, Takahide Takahashi, Akira Shimada, Megumi Obara, Hiroyuki Nunoi
Inversion of chromosome 16 [inv(16)] has a good prognosis in acute myeloid leukemia (AML), but additional genetic aberrations influence the outcome. We herein describe the case of a 15-year-old Japanese boy with inv(16) harboring a low-allelic burden internal tandem duplication of FLT3 (FLT3-ITD) and KIT mutations. Conventional chemotherapy eradicated a clone with a low-allelic burden FLT3-ITD mutation, although another clone with a KIT mutation occurred 17 months later. Further investigation is necessary to identify AML with inv(16) conferring poor prognosis, to facilitate appropriate treatment with additional drugs, such as dasatinib or gemtuzumab ozogamicin...
September 2016: Pediatrics International: Official Journal of the Japan Pediatric Society
https://www.readbyqxmd.com/read/27330760/disseminated-intravascular-coagulation-observed-following-treatment-with-gemtuzumab-ozogamicin-for-relapsed-refractory-acute-promyelocytic-leukemia
#7
Yoshiko Azuma, Aya Nakaya, Masaaki Hotta, Shinya Fujita, Yukie Tsubokura, Hideaki Yoshimura, Atsushi Satake, Kazuyoshi Ishii, Tomoki Ito, Shosaku Nomura
Gemtuzumab ozogamicin (GO) is a recombinant humanized immunoglobulin G4 anti-cluster of differentiation (CD)33 monoclonal antibody conjugated to N-acetyl-γ calicheamicin dimethylhydrazide, a naturally potent antibiotic. It has been introduced for the treatment of acute promyelocytic leukemia (APL), since large quantities of CD33 are commonly expressed on the surface of APL cells. The present study reported two cases with prominent disseminated intravascular coagulation (DIC), which was transiently observed following treatment with GO with relapsed/refractory APL...
July 2016: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/27268298/lineage-switch-with-t-6-11-q27-q23-from-t-cell-lymphoblastic-lymphoma-to-acute-monoblastic-leukemia-at-relapse
#8
Yusuke Higuchi, Kenji Tokunaga, Yuko Watanabe, Toshiro Kawakita, Naoko Harada, Shunichiro Yamaguchi, Kisato Nosaka, Hiroaki Mitsuya, Norio Asou
We present a patient with T-cell lymphoblastic lymphoma (T-LBL) harboring t(6;11)(q27;q23) that converted to acute monoblastic leukemia at relapse. A 27-year-old man developed T-LBL with a mediastinal mass. He exhibited several recurrences in the central nervous system and marrow. A fifth relapse occurred in the marrow, with 42.8% blasts with CD4, CD5, CD7, CD10, CD33, CD34, HLA-DR and cytoplasmic (cy) CD3. While achieving complete remission with nelarabine, sixth relapse occurred in the marrow with 6.8% blasts, which had characteristics of monoblastic features, 2 months later...
June 2016: Cancer Genetics
https://www.readbyqxmd.com/read/27248327/expression-and-functional-characterization-of-cd33-transcript-variants-in-human-acute-myeloid-leukemia
#9
George S Laszlo, Kimberly H Harrington, Chelsea J Gudgeon, Mary E Beddoe, Matthew P Fitzgibbon, Rhonda E Ries, Jatinder K Lamba, Martin W McIntosh, Soheil Meshinchi, Roland B Walter
With the demonstration of improved survival of some acute myeloid leukemia (AML) patients with the CD33 antibody-drug conjugate, gemtuzumab ozogamicin (GO), CD33 has been validated as a target for antigen-specific immunotherapy. Since previous studies identified a CD33 splice variant missing exon 2 (CD33∆E2) and, consequently, the immune-dominant membrane-distal V-set domain, we investigated the expression and functional characteristics of CD33 transcript variants in AML. In primary AML specimens, we not only found full-length CD33 (CD33FL) and CD33∆E2 but also corresponding variants containing an alternate exon 7 predicted to encode a CD33 protein lacking most of the intracellular domain (CD33E7a and, not previously described, CD33∆E2,E7a) in almost all cases...
May 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27189165/characterization-of-cd33-cd3-tetravalent-bispecific-tandem-diabodies-tandabs-for-the-treatment-of-acute-myeloid-leukemia
#10
Uwe Reusch, Kimberly H Harrington, Chelsea J Gudgeon, Ivica Fucek, Kristina Ellwanger, Michael Weichel, Stefan H J Knackmuss, Eugene A Zhukovsky, Judith A Fox, Lori A Kunkel, Jeanmarie Guenot, Roland B Walter
PURPOSE: Randomized studies with gemtuzumab ozogamicin have validated CD33 as a target for antigen-specific immunotherapy of acute myelogenous leukemia (AML). Here, we investigated the potential of CD33/CD3-directed tandem diabodies (TandAbs) as novel treatment approach for AML. These tetravalent bispecific antibodies provide two binding sites for each antigen to maintain the avidity of a bivalent antibody and have a molecular weight exceeding the renal clearance threshold, thus offering a longer half-life compared to smaller antibody constructs...
December 1, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27176800/the-blind-men-and-the-aml-elephant-can-we-feel-the-progress
#11
REVIEW
S Tauro
The pharmacological therapy of non-promyelocytic acute myeloid leukemia (AML) has remained unchanged for over 40 years with an anthracycline-cytarabine combination forming the backbone of induction treatments. Nevertheless, the survival of younger patients has increased due to improved management of the toxicity of therapies including stem cell transplantation. Older patients and those with infirmity that precludes treatment-intensification have, however, not benefited from improvements in supportive care and continue to experience poor outcomes...
2016: Blood Cancer Journal
https://www.readbyqxmd.com/read/27118319/a-prognostic-model-for-survival-after-salvage-treatment-with-flag-ida-gemtuzumab-ozogamicine-in-adult-patients-with-refractory-relapsed-acute-myeloid-leukaemia
#12
Juan M Bergua, Pau Montesinos, David Martinez-Cuadrón, Pascual Fernández-Abellán, Josefina Serrano, María J Sayas, Julio Prieto-Fernandez, Raimundo García, Ana J García-Huerta, Manuel Barrios, Celina Benavente, Manuel Pérez-Encinas, Adriana Simiele, Gabriela Rodríguez-Macias, Pilar Herrera-Puente, Rebeca Rodríguez-Veiga, María P Martínez-Sánchez, María L Amador-Barciela, Rosalía Riaza-Grau, Miguel A Sanz
The combination of fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor (FLAG-Ida) is widely used in relapsed/refractory acute myeloid leukaemia (AML). We retrospectively analysed the results of 259 adult AML patients treated as first salvage with FLAG-Ida or FLAG-Ida plus Gentuzumab-Ozogamicin (FLAGO-Ida) of the Programa Español de Tratamientos en Hematología (PETHEMA) database, developing a prognostic score system of survival in this setting (SALFLAGE score). Overall, 221 patients received FLAG-Ida and 38 FLAGO-Ida; 92 were older than 60 years...
September 2016: British Journal of Haematology
https://www.readbyqxmd.com/read/27084986/high-feasibility-and-antileukemic-efficacy-of-fludarabine-cytarabine-and-idarubicin-flai-induction-followed-by-risk-oriented-consolidation-a-critical-review-of-a-10-year-single-center-experience-in-younger-non-m3-aml-patients
#13
Fabio Guolo, Paola Minetto, Marino Clavio, Maurizio Miglino, Carmen Di Grazia, Filippo Ballerini, Giordana Pastori, Daniela Guardo, Nicoletta Colombo, Annalisa Kunkl, Giuseppina Fugazza, Barbara Rebesco, Mario Sessarego, Roberto Massimo Lemoli, Andrea Bacigalupo, Marco Gobbi
About 105 consecutive acute myeloid leukemia (AML) patients treated with the same induction-consolidation program between 2004 and 2013 were retrospectively analyzed. Median age was 47 years. The first induction course included fludarabine (Flu) and high-dose cytarabine (Ara-C) plus idarubicin (Ida), with or without gemtuzumab-ozogamicin (GO) 3 mg/m(2) (FLAI-5). Patients achieving complete remission (CR) received a second course without fludarabine but with higher dose of idarubicin. Patients not achieving CR received an intensified second course...
August 2016: American Journal of Hematology
https://www.readbyqxmd.com/read/27036160/salvage-therapy-with-high-dose-cytarabine-and-mitoxantrone-in-combination-with-all-trans-retinoic-acid-and-gemtuzumab-ozogamicin-in-acute-myeloid-leukemia-refractory-to-first-induction-therapy
#14
Marie-Luise Hütter-Krönke, Axel Benner, Konstanze Döhner, Jürgen Krauter, Daniela Weber, Margit Moessner, Claus-Henning Köhne, Heinz A Horst, Ingo G H Schmidt-Wolf, Mathias Rummel, Katharina Götze, Elisabeth Koller, Andreas L Petzer, Hans Salwender, Walter Fiedler, Heinz Kirchen, Detlef Haase, Stephan Kremers, Matthias Theobald, Axel C Matzdorff, Arnold Ganser, Hartmut Döhner, Richard F Schlenk
Outcome of patients with primary refractory acute myeloid leukemia remains unsatisfactory. We conducted a prospective phase II clinical trial with gemtuzumab ozogamicin (3 mg/m(2) intravenously on day 1), all-trans retinoic acid (45 mg/m(2) orally on days 4-6 and 15 mg/m(2) orally on days 7-28), high-dose cytarabine (3 g/m(2)/12 h intravenously on days 1-3) and mitoxantrone (12 mg/m(2) intravenously on days 2-3) in 93 patients aged 18-60 years refractory to one cycle of induction therapy. Primary end point of the study was response to therapy; secondary end points included evaluation of toxicities, in particular, rate of sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation...
July 2016: Haematologica
https://www.readbyqxmd.com/read/27030962/evaluation-of-gemtuzumab-ozogamycin-associated-sinusoidal-obstructive-syndrome-findings-from-an-academic-pharmacovigilance-program-review-and-a-pharmaceutical-sponsored-registry
#15
Jametta S Magwood-Golston, Samuel Kessler, Charles L Bennett
BACKGROUND: In 2000, the Food and Drug Administration (FDA) approved gemtuzumab ozogamycin for monotherapy for older patients with relapsed AML. A 0.9% rate of hepatic sinusoidal obstructive syndrome (SOS) was noted in licensing trials. In 2001, FDA received reports of 14 GO-associated SOS cases from MD Anderson Cancer Center. A State of South Carolina/National Cancer Institute funded pharmacovigilance program and a manufacturer sponsored registry independently evaluated this concern...
May 2016: Leukemia Research
https://www.readbyqxmd.com/read/27013443/decitabine-enhances-anti-cd33-monoclonal-antibody-bi-836858-mediated-natural-killer-adcc-against-aml-blasts
#16
Sumithira Vasu, Shun He, Carolyn Cheney, Bhavani Gopalakrishnan, Rajeswaran Mani, Gerard Lozanski, Xiaokui Mo, Veronica Groh, Susan P Whitman, Renate Konopitzky, Christian Kössl, Donna Bucci, David M Lucas, Jianhua Yu, Michael A Caligiuri, William Blum, Paul J Adam, Eric Borges, Bjoern Rueter, Karl-Heinz Heider, Guido Marcucci, Natarajan Muthusamy
Acute myeloid leukemia (AML) is the most common type of acute leukemia, affecting older individuals at a median age of 67 years. Resistance to intensive induction chemotherapy is the major cause of death in elderly AML; hence, novel treatment strategies are warranted. CD33-directed antibody-drug conjugates (gemtuzumab ozogamicin) have been shown to improve overall survival, validating CD33 as a target for antibody-based therapy of AML. Here, we report the in vitro efficacy of BI 836858, a fully human, Fc-engineered, anti-CD33 antibody using AML cell lines and primary AML blasts as targets...
June 9, 2016: Blood
https://www.readbyqxmd.com/read/26942450/the-addition-of-gemtuzumab-ozogamicin-to-chemotherapy-in-adult-patients-with-acute-myeloid-leukemia
#17
Jonathan Kell
The treatment of acute myeloid leukaemia has remained largely unchanged for the last 30 years since the advent of combination chemotherapy with cytarabine arabinoside and daunorubicin with remission rates around 70% but with long term survival still only around 40% in young adults. Doses of chemotherapy have been pushed to the limit of toxicity. Gemtuzumab ozogamicin allows additional chemotherapy to be delivered to the leukaemic cells without significantly adding to toxicity since the active agent is coupled to a monoclonal anti-CD33 antibody...
2016: Expert Review of Anticancer Therapy
https://www.readbyqxmd.com/read/26929274/the-level-of-blast-cd33-expression-positively-impacts-the-effect-of-gemtuzumab-ozogamicin-in-patients-with-acute-myeloid-leukemia
#18
LETTER
Guillaume Olombel, Estelle Guerin, Julien Guy, Jean-Yves Perrot, Florent Dumezy, Adrienne de Labarthe, Jean-Noël Bastie, Ollivier Legrand, Emmanuel Raffoux, Adriana Plesa, Orianne Wagner-Ballon, Edouard Cornet, Véronique Salaun, Claude Preudhomme, Xavier Thomas, Cécile Pautas, Sylvain Chantepie, Pascal Turlure, Sylvie Castaigne, Hervé Dombret, Jean Feuillard
No abstract text is available yet for this article.
April 28, 2016: Blood
https://www.readbyqxmd.com/read/26921360/defining-the-dose-of-gemtuzumab-ozogamicin-in-combination-with-induction-chemotherapy-in-acute-myeloid-leukemia-a-comparison-of-3-mg-m2-with-6-mg-m2-in-the-ncri-aml17-trial
#19
Alan Burnett, Jamie Cavenagh, Nigel Russell, Robert Hills, Jonathan Kell, Gail Jones, Ove Juul Nielsen, Asim Khwaja, Ian Thomas, Richard Clark
Arecent source data meta-analysis of randomized trials in adults assessing the immunoconjugate gemtuzumab ozogamicin combined with standard chemotherapy in acute myeloid leukemia showed a significant survival benefit in patients without an adverse karyotype. It is not clear whether the optimal dose should be 3 mg/m(2) or 6 mg/m(2) In this study, we randomized 788 patients to a single dose of gemtuzumab ozogamicin 3 mg/m(2) or 6 mg/m(2) with the first course of induction therapy. We found that the rate of complete remission was higher with 3 mg/m(2) [82% vs 76%; odds ratio 1...
June 2016: Haematologica
https://www.readbyqxmd.com/read/26876592/complete-response-to-gemtuzumab-ozogamicin-in-a-patient-with-refractory-mast-cell-leukemia
#20
I Alvarez-Twose, P Martínez-Barranco, J Gotlib, A García-Montero, J M Morgado, M Jara-Acevedo, J D Merker, F J Peñalver, A Matito, Y Hou, L Sánchez-Muñoz, A Mayado, M Mollejo, L Escribano, A Orfao
No abstract text is available yet for this article.
August 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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