title: Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial.
abstract: BACKGROUND
  Treatment for patients with chronic lymphocytic leukaemia who are elderly or who have comorbidities is challenging because fludarabine-based chemoimmunotherapies are mostly not suitable. Chlorambucil remains the standard of care in many countries. We aimed to investigate whether the addition of ofatumumab to chlorambucil could lead to better clinical outcomes than does treatment with chlorambucil alone, while also being tolerable for patients who have few treatment options.
  
  
  METHODS
  We carried out a randomised, open-label, phase 3 trial for treatment-naive patients with chronic lymphocytic leukaemia in 109 centres in 16 countries. We included patients who had active disease needing treatment, but in whom fludarabine-based treatment was not possible. We randomly assigned patients (1:1) to receive oral chlorambucil (10 mg/m(2)) on days 1-7 of a 28 day treatment course or to receive chlorambucil by this schedule plus intravenous ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg on day 8; subsequent cycles: 1000 mg on day 1) for three to 12 cycles. Assignment was done with a randomisation list that was computer generated at GlaxoSmithKline, and was stratified, in a block size of two, by age, disease stage, and performance status. The primary endpoint was progression-free survival in the intention-to-treat population and assessment was done by an independent review committee that was masked to group assignment. The study is registered with ClinicalTrials.gov, number NCT00748189.
  
  
  RESULTS
  We enrolled 447 patients, median age 69 years (range 35-92). Between Dec 22, 2008, and May 26, 2011, we randomly assigned 221 patients to chlorambucil plus ofatumumab and 226 patients to chlorambucil alone. Median progression-free survival was 22·4 months (95% CI 19·0-25·2) in the group assigned to chlorambucil plus ofatumumab compared with 13·1 months (10·6-13·8) in the group assigned to chlorambucil only (hazard ratio 0·57, 95% CI 0·45-0·72; p<0·0001). Grade 3 or greater adverse events were more common in the chlorambucil plus ofatumumab group (109 [50%] patients; vs 98 [43%] given chlorambucil alone), with neutropenia being the most common event (56 [26%] vs 32 [14%]). Grade 3 or greater infections had similar frequency in both groups. Grade 3 or greater infusion-related adverse events were reported in 22 (10%) patients given chlorambucil plus ofatumumab. Five (2%) patients died during treatment in each group.
  
  
  CONCLUSIONS
  Addition of ofatumumab to chlorambucil led to clinically important improvements with a manageable side-effect profile in treatment-naive patients with chronic lymphocytic leukaemia who were elderly or had comorbidities. Chlorambucil plus ofatumumab is therefore an important treatment option for these patients who cannot tolerate more intensive therapy.
  
  
  BACKGROUND
  GlaxoSmithKline, Genmab A/S.
authors.affiliation: Department of Haematology, St James's University Hospital, Leeds, UK. Electronic address: peter.hillmen@nhs.net.
authors.forename: Peter
authors.initials: P
authors.lastname: Hillmen
authors.affiliation: Department of Haematology, Medical University of Lodz, Lodz, Poland.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Robak
authors.affiliation: Universitaire Ziekenhuizen Leuven, Leuven, Belgium.
authors.forename: Ann
authors.initials: A
authors.lastname: Janssens
authors.affiliation: Kidwai Memorial Institute of Oncology, Bangalore, India.
authors.forename: K Govind
authors.initials: KG
authors.lastname: Babu
authors.affiliation: Medical University of Bialystok, Bialystok, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Kloczko
authors.affiliation: Medical University of Silesia, Katowice, Poland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Grosicki
authors.affiliation: Department of Haematology and Oncology, University Hospital Brno, Brno, Czech Republic.
authors.forename: Michael
authors.initials: M
authors.lastname: Doubek
authors.affiliation: University of Athens, Laikon General Hospital, Athens, Greece.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Panagiotidis
authors.affiliation: Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Kimby
authors.affiliation: Churchill Hospital, Oxford, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Schuh
authors.affiliation: Royal Liverpool and Broadgreen Hospitals NHS Trust, University of Liverpool, Liverpool, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Pettitt
authors.affiliation: Yakima Valley Memorial Hospital, Yakima, WA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Boyd
authors.affiliation: Department of Haematology, Ospedale Niguarda Ca'Granda, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Montillo
authors.affiliation: GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Ira V
authors.initials: IV
authors.lastname: Gupta
authors.affiliation: GlaxoSmithKline, Uxbridge, UK.
authors.forename: Oliver
authors.initials: O
authors.lastname: Wright
authors.affiliation: GlaxoSmithKline, Uxbridge, UK.
authors.forename: Iestyn
authors.initials: I
authors.lastname: Dixon
authors.affiliation: GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Jodi L
authors.initials: JL
authors.lastname: Carey
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Chai-Ni
authors.initials: CN
authors.lastname: Chang
authors.affiliation: Genmab, Copenhagen, Denmark.
authors.forename: Steen
authors.initials: S
authors.lastname: Lisby
authors.affiliation: GlaxoSmithKline, Uxbridge, UK.
authors.forename: Astrid
authors.initials: A
authors.lastname: McKeown
authors.affiliation: Universitair Ziekenhuis Gent, Gent, Belgium.
authors.forename: Fritz
authors.initials: F
authors.lastname: Offner
mesh_terms: D000328:Adult; D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002699:Chlorambucil / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D017678:Sex Distribution; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018906:Antineoplastic Agents, Alkylating; D002699:Chlorambucil; C527517:ofatumumab