title: Obinutuzumab in hematologic malignancies: lessons learned to date.
abstract: The routine use of anti-CD20 monoclonal antibodies (mAbs) has improved patient outcomes in CD20-positive non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Despite the clinical success achieved with rituximab, relapses are still common with further improvements in anti-CD20 mAb efficacy required. Many novel anti-CD20 antibodies are in development, but obinutuzumab is currently the only type II glycoengineered anti-CD20 mAb in clinical testing. Obinutuzumab has increased antibody-dependent cell-mediated cytotoxicity, reduced complement-dependent cytotoxicity and enhanced direct non-apoptotic cell death. In preclinical models, obinutuzumab induced superior tumor remission compared with rituximab at the equivalent dose levels, and was active in rituximab-refractory tumors. Obinutuzumab exhibits encouraging efficacy as monotherapy in NHL, and combined with chemotherapy in relapsed/refractory NHL and treatment-naïve symptomatic CLL. In a recent randomized, phase III trial in patients with untreated comorbid CLL, overall response rate was significantly greater (78% vs. 65%, P<0.0001) and median progression-free survival was significantly prolonged (26.7 vs. 15.2months, P<0.0001) for obinutuzumab plus chlorambucil vs. rituximab plus chlorambucil. Obinutuzumab is a type II anti-CD20 antibody that utilizes distinct mechanisms of action relative to type I antibodies like rituximab and has led to significant clinical improvement over rituximab in a phase III trial in CLL. Further trials are ongoing to determine whether such improvements in outcome will be seen in CD20-positive B-cell malignancies.
authors.affiliation: Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. Electronic address: tmi@manchester.ac.uk.
authors.forename: Tim
authors.initials: T
authors.lastname: Illidge
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland. Electronic address: christian.klein.ck1@roche.com.
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.affiliation: Centre for Lymphoid Cancer, BC Cancer Agency and the University of British Columbia, Vancouver, BC, Canada. Electronic address: lsehn@bccancer.bc.ca.
authors.forename: Laurie H
authors.initials: LH
authors.lastname: Sehn
authors.affiliation: Cancer Research UK Centre, Somers Cancer Research Building, Southampton General Hospital, Southampton, UK. Electronic address: a.davies@soton.ac.uk.
authors.forename: Andrew
authors.initials: A
authors.lastname: Davies
authors.affiliation: Hématologie, Hospices Civils de Lyon-Université de Lyon, Pierre-Bénite, France. Electronic address: gilles.salles@chu-lyon.fr.
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
authors.affiliation: Department of Hematology and UMR CNRS-5235, CHU Montpellier, France. Electronic address: g.carton@chu-montpellier.fr.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Cartron
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans
chemical_list: D061067:Antibodies, Monoclonal, Humanized; C543332:obinutuzumab
keywords: CD20; CLL; NHL; Obinutuzumab; Rituximab; Type II antibody