title: Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial.
abstract: BACKGROUND
  In many patients with chronic lymphocytic leukaemia requiring treatment, induction therapy with rituximab plus chemotherapy improves outcomes compared with chemotherapy alone. In this study we aimed to investigate the potential of rituximab maintenance therapy to prolong disease control in patients who respond to rituximab-containing induction regimens.
  
  
  METHODS
  In this randomised, international, multicentre, open-label, phase 3 clinical trial, we enrolled patients who had achieved a complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) to first-line or second-line rituximab-containing chemoimmunotherapy and randomly assigned them in a 1:1 ratio (central block randomisation in the electronic case report form system) to either intravenous rituximab 375 mg/m(2) every 3 months, or observation alone, for 2 years. Stratification was by country, line of treatment, type of chemotherapy added to the rituximab backbone, and degree of remission following induction. The primary endpoint was progression-free survival. Efficacy analysis was done in the intention-to-treat population. This is the final, event-triggered analysis. Final analysis was triggered by the occurrence of 92 events. This trial is registered with ClinicalTrials.gov, number NCT01118234.
  
  
  RESULTS
  Between April 1, 2010, and Dec 23, 2013, 134 patients were randomised to rituximab and 129 to observation alone. Median observation times were 33·4 months (IQR 25·7-42·8) for the rituximab group and 34·0 months (25·4-41·9) for the observation group. Progression-free survival was significantly longer in the rituximab maintenance group (47·0 months, IQR 28·5-incalculable) than with observation alone (35·5 months, 95% CI 25·7-46·3; hazard ratio [HR] 0·50, 95% CI 0·33-0·75, p=0·00077). The incidence of grade 3-4 haematological toxicities other than neutropenia was similar in the two treatment groups. Grade 3-4 neutropenia occurred in 28 (21%) patients in the rituximab group and 14 (11%) patients in the observation group. Apart from neutropenia, the most common grade 3-4 adverse events were upper (five vs one [1%] patient in the observation group) and lower (three [2%] vs one [1%]) respiratory tract infection, pneumonia (nine [7%] vs two [2%]), thrombopenia (four [3%] vs four [3%]), neoplasms (five [4%] vs four [3%]), and eye disorders (four [3%] vs two [2%]). The overall incidence of infections of all grades was higher among rituximab recipients (88 [66%] vs 65 [50%]).
  
  
  CONCLUSIONS
  Rituximab maintenance therapy prolongs progression-free survival in patients achieving at least a PR to induction with rituximab plus chemotherapy, and the treatment is well tolerated overall. Although it is associated with an increase in infections, there is no excess in infection mortality, suggesting that remission maintenance with rituximab is an effective and safe option in the management of chronic lymphocytic leukaemia in early treatment phases.
  
  
  BACKGROUND
  Arbeitsgemeinschaft Medikamentöse Tumortherapie gemeinnützige GmbH (AGMT), Roche.
authors.affiliation: Third Medical Department at the Paracelsus Medical University Salzburg, Salzburg, Austria; Salzburg Cancer Research Institute (SCRI), Salzburg, Austria; Cancer Cluster Salzburg (CCS), Salzburg, Austria. Electronic address: r.greil@salk.at.
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
authors.affiliation: First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Obrtlíková
authors.affiliation: Fourth Department of Internal Medicine-Hematology, University Hospital and Charles University in Prague, Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic.
authors.forename: Lukáš
authors.initials: L
authors.lastname: Smolej
authors.affiliation: Department of Internal Medicine-Hematology, Univ Hospital Kralovske Vinohrady, Prague, Czech Republic.
authors.forename: Tomáš
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authors.lastname: Kozák
authors.affiliation: Department of Internal Medicine V, Medical University Innsbruck, Austria.
authors.forename: Michael
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authors.affiliation: Abteilung für Innere Medizin III, Landeskrankenhaus Steyr, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Andel
authors.affiliation: Abteilung für Innere Medizin IV, Klinikum Wels-Grieskirchen GmbH, Austria.
authors.forename: Sonja
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authors.lastname: Burgstaller
authors.affiliation: Department of Hematooncology 2, National Cancer Institute, Bratislava, Slovakia.
authors.forename: Eva
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authors.lastname: Mikušková
authors.affiliation: Clinic of Hematology, University Hospital St Marina, Varna, Bulgaria.
authors.forename: Liana
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authors.lastname: Gercheva
authors.affiliation: Third Medical Department for Hematology and Oncology, Hanusch Krankenhaus der Wiener Gebietskrankenkasse, Vienna, Austria.
authors.forename: Thomas
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authors.lastname: Nösslinger
authors.affiliation: Department of Hemato-oncology, University Hospital, Olomouc, Czech Republic.
authors.forename: Tomáš
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authors.lastname: Papajík
authors.affiliation: Department of Clinical Oncology 1, National Cancer Institute, Bratislava, Slovakia.
authors.forename: Miriam
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authors.lastname: Ladická
authors.affiliation: I Interne Abteilung, Elisabethinen Krankenhaus, Linz, Austria.
authors.forename: Michael
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authors.lastname: Girschikofsky
authors.affiliation: Clinic of Hematology and Transfusiology, Slovak Medical University, University Hospital Bratislava, Slovakia.
authors.forename: Mikuláš
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authors.lastname: Hrubiško
authors.affiliation: Department of Medicine I, Division of Hematology and Hemostaeology, Medical University Vienna, Austria.
authors.forename: Ulrich
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authors.lastname: Jäger
authors.affiliation: Department of Internal Medicine 3, Kepler Universitätsklinikum GmbH, Med Campus III, Linz, Austria.
authors.forename: Michael
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authors.lastname: Fridrik
authors.affiliation: University Hospital Krems, Karl Landsteiner Private University of Health Sciences, Department of Internal Medicine 2, Krems, Austria.
authors.forename: Martin
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authors.lastname: Pecherstorfer
authors.affiliation: Department of Hematology, FNsP F D Roosevelta, Banská Bystrica, Slovakia.
authors.forename: Eva
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authors.lastname: Králiková
authors.affiliation: Clinic of Haematology, Regional Institute of Oncology Iasi, Iasi, Romania.
authors.forename: Cristina
authors.initials: C
authors.lastname: Burcoveanu
authors.affiliation: Clinic of Hematology, UMHAT St George and Medical University, Plovdiv, Bulgaria.
authors.forename: Emil
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authors.lastname: Spasov
authors.affiliation: Innere Medizin I, Krankenhaus der Barmherzigen Schwestern Linz, Linz, Austria.
authors.forename: Andreas
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authors.lastname: Petzer
authors.affiliation: Hematological Clinic NSHATHD, Sofia, Bulgaria.
authors.forename: Georgi
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authors.lastname: Mihaylov
authors.affiliation: Clinic of Medical Hematology, Military Medical Academy, Sofia, Bulgaria.
authors.forename: Julian
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authors.lastname: Raynov
authors.affiliation: Innere Medizin, Landeskrankenhaus Hall, Austria.
authors.forename: Horst
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authors.lastname: Oexle
authors.affiliation: Innere Medizin II, Bezirkskrankenhaus Kufstein, Austria.
authors.forename: August
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authors.lastname: Zabernigg
authors.affiliation: Department of Hematology and Transfusion, University Hospital Martin, Martin, Slovakia.
authors.forename: Emília
authors.initials: E
authors.lastname: Flochová
authors.affiliation: Department of Clinical Hematology, FNsP, J A Reimana, Prešov, Slovakia.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Palášthy
authors.affiliation: University Hospital, Faculty of Medicine and CEITEC, Brno, Czech Republic.
authors.forename: Olga
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authors.lastname: Stehlíková
authors.affiliation: University Hospital, Faculty of Medicine and CEITEC, Brno, Czech Republic.
authors.forename: Michael
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authors.lastname: Doubek
authors.affiliation: Salzburg Cancer Research Institute (SCRI), Salzburg, Austria; Cancer Cluster Salzburg (CCS), Salzburg, Austria.
authors.forename: Petra
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authors.lastname: Altenhofer
authors.affiliation: Third Medical Department at the Paracelsus Medical University Salzburg, Salzburg, Austria; Salzburg Cancer Research Institute (SCRI), Salzburg, Austria; Cancer Cluster Salzburg (CCS), Salzburg, Austria.
authors.forename: Lisa
authors.initials: L
authors.lastname: Pleyer
authors.affiliation: Third Medical Department at the Paracelsus Medical University Salzburg, Salzburg, Austria; Salzburg Cancer Research Institute (SCRI), Salzburg, Austria; Cancer Cluster Salzburg (CCS), Salzburg, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Melchardt
authors.affiliation: Assign Data Management and Biostatistics GmbH, Innsbruck, Austria.
authors.forename: Anton
authors.initials: A
authors.lastname: Klingler
authors.affiliation: University Hospital, Faculty of Medicine and CEITEC, Brno, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Mayer
authors.affiliation: Third Medical Department at the Paracelsus Medical University Salzburg, Salzburg, Austria; Salzburg Cancer Research Institute (SCRI), Salzburg, Austria; Cancer Cluster Salzburg (CCS), Salzburg, Austria.
authors.forename: Alexander
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authors.lastname: Egle
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D000069461:Bendamustine Hydrochloride / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007167:Immunotherapy; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D012074:Remission Induction; D000069283:Rituximab / Q000008:administration & dosage*; D015996:Survival Rate; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000069283:Rituximab; D003520:Cyclophosphamide; D000069461:Bendamustine Hydrochloride; D014740:Vidarabine; C024352:fludarabine