title: Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions.
abstract: BACKGROUND
  The monoclonal anti-CD20 antibody rituximab, combined with chemotherapeutic agents, has been shown to prolong overall survival in physically fit patients with previously untreated chronic lymphocytic leukemia (CLL) but not in those with coexisting conditions. We investigated the benefit of the type 2, glycoengineered antibody obinutuzumab (also known as GA101) as compared with that of rituximab, each combined with chlorambucil, in patients with previously untreated CLL and coexisting conditions.
  
  
  METHODS
  We randomly assigned 781 patients with previously untreated CLL and a score higher than 6 on the Cumulative Illness Rating Scale (CIRS) (range, 0 to 56, with higher scores indicating worse health status) or an estimated creatinine clearance of 30 to 69 ml per minute to receive chlorambucil, obinutuzumab plus chlorambucil, or rituximab plus chlorambucil. The primary end point was investigator-assessed progression-free survival.
  
  
  RESULTS
  The patients had a median age of 73 years, creatinine clearance of 62 ml per minute, and CIRS score of 8 at baseline. Treatment with obinutuzumab-chlorambucil or rituximab-chlorambucil, as compared with chlorambucil monotherapy, increased response rates and prolonged progression-free survival (median progression-free survival, 26.7 months with obinutuzumab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio for progression or death, 0.18; 95% confidence interval [CI], 0.13 to 0.24; P<0.001; and 16.3 months with rituximab-chlorambucil vs. 11.1 months with chlorambucil alone; hazard ratio, 0.44; 95% CI, 0.34 to 0.57; P<0.001). Treatment with obinutuzumab-chlorambucil, as compared with chlorambucil alone, prolonged overall survival (hazard ratio for death, 0.41; 95% CI, 0.23 to 0.74; P=0.002). Treatment with obinutuzumab-chlorambucil, as compared with rituximab-chlorambucil, resulted in prolongation of progression-free survival (hazard ratio, 0.39; 95% CI, 0.31 to 0.49; P<0.001) and higher rates of complete response (20.7% vs. 7.0%) and molecular response. Infusion-related reactions and neutropenia were more common with obinutuzumab-chlorambucil than with rituximab-chlorambucil, but the risk of infection was not increased.
  
  
  CONCLUSIONS
  Combining an anti-CD20 antibody with chemotherapy improved outcomes in patients with CLL and coexisting conditions. In this patient population, obinutuzumab was superior to rituximab when each was combined with chlorambucil. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT01010061.).
authors.affiliation: From the German CLL Study Group, Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, Cologne (V.G., K.F., A.E., B.E., C.M.W., K.-A.K., M.H.), the Department for Geriatric Medicine and Research, St. Marien Hospital and University of Cologne, Cologne (V.G.), Institute of Medical Statistics and Epidemiology, Technical University Munich, Munich (R.B.), Klinikum Schwabing, Munich (C.M.W.), private oncology practice, Dresden (T.I.), Medical Department II, University of Schleswig-Holstein, City Hospital Kiel, Kiel (M.R., M.K.), the Department of Internal Medicine III, Ulm University, Ulm (S.S., H.D.), and Cluster of Excellence "Cellular Stress Responses in Aging-Associated Diseases" (CECAD), University of Cologne, Cologne (M.H.) - all in Germany; Penza Regional Oncology Dispensary, Penza (T.C.), and Regional Clinical Hospital N.A. Semashko, Nizhny Novgorod (O.S.) - both in Russia; Servicio De Hematologia, Hospital Universitario 12 De Octubre, Madrid (J.S.); Hôpital Haut Lévêque, Bordeaux, Pessac, France (M.-S.D.); the Department of Haematology, Monash Medical Centre, Clayton, Australia (S.O.); University of Calgary, Calgary, AB, Canada (C.J.O.); the Department of Immunology, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands (A.W.L.); F. Hoffmann-La Roche, Basel, Switzerland (E.A.); F. Hoffmann-La Roche, Welwyn, United Kingdom (K.H.); and Genentech, South San Francisco, CA (M.W.).
authors.forename: Valentin
authors.initials: V
authors.lastname: Goede
authors.forename: Kirsten
authors.initials: K
authors.lastname: Fischer
authors.forename: Raymonde
authors.initials: R
authors.lastname: Busch
authors.forename: Anja
authors.initials: A
authors.lastname: Engelke
authors.forename: Barbara
authors.initials: B
authors.lastname: Eichhorst
authors.forename: Clemens M
authors.initials: CM
authors.lastname: Wendtner
authors.forename: Tatiana
authors.initials: T
authors.lastname: Chagorova
authors.forename: Javier
authors.initials: J
authors.lastname: de la Serna
authors.forename: Marie-Sarah
authors.initials: MS
authors.lastname: Dilhuydy
authors.forename: Thomas
authors.initials: T
authors.lastname: Illmer
authors.forename: Stephen
authors.initials: S
authors.lastname: Opat
authors.forename: Carolyn J
authors.initials: CJ
authors.lastname: Owen
authors.forename: Olga
authors.initials: O
authors.lastname: Samoylova
authors.forename: Karl-Anton
authors.initials: KA
authors.lastname: Kreuzer
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Anton W
authors.initials: AW
authors.lastname: Langerak
authors.forename: Matthias
authors.initials: M
authors.lastname: Ritgen
authors.forename: Michael
authors.initials: M
authors.lastname: Kneba
authors.forename: Elina
authors.initials: E
authors.lastname: Asikanius
authors.forename: Kathryn
authors.initials: K
authors.lastname: Humphrey
authors.forename: Michael
authors.initials: M
authors.lastname: Wenger
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D018951:Antigens, CD20 / Q000276:immunology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002699:Chlorambucil / Q000008:administration & dosage* / Q000009:adverse effects; D015897:Comorbidity; D018572:Disease-Free Survival; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008875:Middle Aged; D012074:Remission Induction; D000069283:Rituximab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D002699:Chlorambucil; D000069283:Rituximab; C543332:obinutuzumab