title: Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial.
abstract: BACKGROUND
  Lenalidomide, an immunomodulatory drug with antineoplastic and antiproliferative effects, showed activity in many single-group studies in relapsed or refractory mantle cell lymphoma. The aim of this randomised study was to examine the efficacy and safety of lenalidomide versus best investigator's choice of single-agent therapy in relapsed or refractory mantle cell lymphoma.
  
  
  METHODS
  The MCL-002 (SPRINT) study was a randomised, phase 2 study of patients with mantle cell lymphoma aged 18 years or older at 67 clinics and academic centres in 12 countries who relapsed one to three times, had Eastern Cooperative Oncology Group performance status of 0-2, at least one measurable lesion to be eligible, and who were ineligible for intensive chemotherpy or stem-cell transplantation. Using a centralised interactive voice response system, we randomly assigned (2:1) patients in a permuted block size of six to receive lenalidomide (25 mg orally on days 1-21 every 28 days) until progressive disease or intolerability, or single-agent investigator's choice of either rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine. Randomisation was stratified by time from diagnosis, time from last anti-lymphoma therapy, and previous stem-cell transplantation. Individual treatment assignment between lenalidomide and investigator's choice was open label, but investigators had to register their choice of comparator drug before randomly assigning a patient. Patients who progressed on investigator's choice could cross over to lenalidomide treatment. We present the prespecified primary analysis results in the intention-to-treat population for the primary endpoint of progression-free survival, defined as the time from randomisation to progressive disease or death, whichever occurred first. Patient enrolment is complete, although treatment and collection of additional time-to-event data are ongoing. This study is registered with ClinicalTrials.gov, number NCT00875667.
  
  
  RESULTS
  Between April 30, 2009, and March 7, 2013, we enrolled 254 patients in the intention-to-treat population (170 [67%] were randomly assigned to receive lenalidomide, 84 [33%] to receive investigator's choice monotherapy). Patients had a median age of 68·5 years and received a median of two previous regimens. With a median follow-up of 15·9 months (IQR 7·6-31·7), lenalidomide significantly improved progression-free survival compared with investigator's choice (median 8·7 months [95% CI 5·5-12·1] vs 5·2 months [95% CI 3·7-6·9]) with a hazard ratio of 0·61 (95% CI 0·44-0·84; p=0·004). In the 167 patients in the lenalidomide group and 83 patients in the investigator's choice group who received at least one dose of treatment the most common grade 3-4 adverse events included neutropenia (73 [44%] of 167 vs 28 [34%] of 83) without increased risk of infection, thrombocytopenia (30 [18%] vs 23 [28%]), leucopenia (13 [8%] vs nine [11%]), and anaemia (14 [8%] vs six [7%]).
  
  
  CONCLUSIONS
  Patients with relapsed or refractory mantle cell lymphoma ineligible for intensive chemotherapy or stem-cell transplantation have longer progression-free survival, with a manageable safety profile when treated with lenalidomide compared with monotherapy investigator's choice options.
  
  
  BACKGROUND
  Celgene Corporation.
authors.affiliation: Department of Hematology, Charles University Hospital, Prague, Czech Republic. Electronic address: trneny@vfn.cz.
authors.forename: Marek
authors.initials: M
authors.lastname: Trněný
authors.affiliation: Department of Hematology, Rennes University Hospital, Rennes, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lamy
authors.affiliation: Department of Lymphoid Malignancies, Maria Sklodowska-Curie Memorial Institute and Oncology Centre, Warsaw, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Walewski
authors.affiliation: Fourth Department of Internal Medicine-Hematology, Charles University Hospital and Faculty of Medicine, Hradec Králové, Czech Republic.
authors.forename: David
authors.initials: D
authors.lastname: Belada
authors.affiliation: Department of Internal Medicine, Hematology and Oncology, Masaryk University Hospital, Brno, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Mayer
authors.affiliation: The University of Manchester and The Christie NHS Foundation Trust, Manchester, UK.
authors.forename: John
authors.initials: J
authors.lastname: Radford
authors.affiliation: Department of Haematology, Jagiellonian University, Krakow, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Jurczak
authors.affiliation: Centre Hospitalier Universitaire Régional de Lille, Unité GRITA, Lille, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Morschhauser
authors.affiliation: Federal Medical Research Center, St Petersburg, Russia.
authors.forename: Julia
authors.initials: J
authors.lastname: Alexeeva
authors.affiliation: Department of Hematology, Derriford Hospital, Plymouth, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Rule
authors.affiliation: First Pavlov State Medical University of St Petersburg, St Petersburg, Russia.
authors.forename: Boris
authors.initials: B
authors.lastname: Afanasyev
authors.affiliation: Volgograd Regional Clinical Oncology Dispensary Number 1, Department of Hematology, Volgograd, Russia.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kaplanov
authors.affiliation: Medical Oncology Department, Centre Antoine Lacassagne, Nice, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Thyss
authors.affiliation: Republican Clinical Oncology Dispensary, Kazan, Russia.
authors.forename: Alexej
authors.initials: A
authors.lastname: Kuzmin
authors.affiliation: Russian Research Institute of Hematology and Transfusion, St Petersburg, Russia.
authors.forename: Sergey
authors.initials: S
authors.lastname: Voloshin
authors.affiliation: Department of Hematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Kazimierz
authors.initials: K
authors.lastname: Kuliczkowski
authors.affiliation: Department of Haematology, Jagiellonian University, Krakow, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Giza
authors.affiliation: Service d'Hématologie et de Thérapie Cellulaire, CHU Haut-Lévêque, Bordeaux, France; University of Bordeaux, Bordeaux, France.
authors.forename: Noel
authors.initials: N
authors.lastname: Milpied
authors.affiliation: A.O. Bianchi Melacrino Morelli, Reggio Calabria, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Stelitano
authors.affiliation: Department of Hematology and Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Marks
authors.affiliation: Department of Hematology and Oncology, Universitätsmedizin Göttingen, Georg-August-Universität, Göttingen, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Trümper
authors.affiliation: Celgene Sarl, Boudry, Switzerland.
authors.forename: Tsvetan
authors.initials: T
authors.lastname: Biyukov
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: Meera
authors.initials: M
authors.lastname: Patturajan
authors.affiliation: Celgene Sarl, Boudry, Switzerland.
authors.forename: Marie-Laure Casadebaig
authors.initials: MC
authors.lastname: Bravo
authors.affiliation: Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo & Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Arcaini
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016001:Confidence Intervals; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077269:Lenalidomide; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D011446:Prospective Studies; D016019:Survival Analysis; D013792:Thalidomide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D013792:Thalidomide; D000077269:Lenalidomide