title: Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study.
abstract: BACKGROUND
  Ofatumumab is a human anti-CD20 monoclonal antibody that has proven efficacy as monotherapy in refractory chronic lymphocytic leukaemia. We assessed the efficacy and safety of ofatumumab maintenance treatment versus observation for patients in remission after re-induction treatment for relapsed chronic lymphocytic leukaemia.
  
  
  METHODS
  This open-label, multicentre, randomised phase 3 study enrolled patients aged 18 years or older from 130 centres in 24 countries who had chronic lymphocytic leukaemia in complete or partial remission after second-line or third-line treatment. Eligible patients had a WHO performance status of 0-2, had a response assessment within the previous 3 months, did not have refractory disease, autoimmune haemolytic anaemia requiring treatment, chronic or active infection requiring treatment, and had not previously received maintenance treatment or autologous or allogeneic stem-cell transplant. Using a randomisation list generated by a central computerised system and an interactive voice recognition system, we randomly assigned (1:1) patients to receive ofatumumab (300 mg followed by 1000 mg 1 week later and every 8 weeks for up to 2 years) or undergo observation. Randomisation was stratified by number and type of previous treatment and remission status after induction treatment (block size of four). Treatment assignment was open label. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. We report the results of a prespecified interim analysis after two-thirds of the planned study events (disease progression or death) had happened. This trial is closed to accrual but follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00802737.
  
  
  RESULTS
  Between May 6, 2010, and June 19, 2014, we enrolled 474 patients: 238 patients were randomly assigned to receive ofatumumab maintenance treatment and 236 to undergo observation. One (<1%) patient in the ofatumumab group did not receive the allocated intervention (withdrawal of consent). The median follow-up was 19·1 months (IQR 10·3-28·8). Progression-free survival was improved in patients assigned to the ofatumumab group (29·4 months, 95% CI 26·2-34·2) compared with those assigned to observation (15·2 months, 11·8-18·8; hazard ratio 0·50, 95% CI 0·38-0·66; p<0·0001). The most common grade 3 or higher adverse events up to 60 days after last treatment were neutropenia (56 [24%] of 237 patients in the ofatumumab group vs 23 [10%] of 237 in the observation group) and infections (31 [13%] vs 20 [8%]). 20 (8%) of 237 patients in the ofatumumab group and three (1%) of 237 patients in the observation group had adverse events that led to permanent discontinuation of treatment. Up to 60 days after last treatment, two deaths related to adverse events occurred in the ofatumumab treatment group and five deaths related to adverse events occurred in the observation group; no deaths were attributed to the study drug.
  
  
  CONCLUSIONS
  These data are important for the development of optimum maintenance strategies in patients with relapsed chronic lymphocytic leukaemia, notably in the present era of targeted drugs, many of which are to be used until progression.
authors.affiliation: Department of Hematology, Academisch Medisch Centrum, Amsterdam, Netherlands; The Haemato Oncology Foundation for Adults in the Netherlands (HOVON), Amsterdam, Netherlands. Electronic address: m.h.vanoers@amc.uva.nl.
authors.forename: Marinus H J
authors.initials: MH
authors.lastname: van Oers
authors.affiliation: Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wrocławiu, Wrocławiu, Poland.
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Kuliczkowski
authors.affiliation: 4th Department of Internal Medicine-Hematology, Faculty of Medicine in Hradec Králové, University Hospital and Charles University, Prague, Czech Republic.
authors.forename: Lukáš
authors.initials: L
authors.lastname: Smolej
authors.affiliation: Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Petrini
authors.affiliation: Universitair Ziekenhuis Gent, Gent, Belgium.
authors.forename: Fritz
authors.initials: F
authors.lastname: Offner
authors.affiliation: Department of Cancer Prevention, Faculty of Public Health, Silesian Medical University, Katowice, Poland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Grosicki
authors.affiliation: The Haemato Oncology Foundation for Adults in the Netherlands (HOVON), Amsterdam, Netherlands; Albert Schweitzer Ziekenhuis, Dordrecht, Netherlands.
authors.forename: Mark-David
authors.initials: MD
authors.lastname: Levin
authors.affiliation: GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Ira
authors.initials: I
authors.lastname: Gupta
authors.affiliation: GlaxoSmithKline, Collegeville, PA, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Phillips
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Williams
authors.affiliation: Novartis, Stockley Park, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Manson
authors.affiliation: Genmab, Copenhagen, Denmark.
authors.forename: Steen
authors.initials: S
authors.lastname: Lisby
authors.affiliation: Department of Haematology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Geisler
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000401:mortality / Q000628:therapy*; D060046:Maintenance Chemotherapy / Q000009:adverse effects / Q000379:methods*; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D057832:Watchful Waiting
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C527517:ofatumumab