title: Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial.
abstract: BACKGROUND
  Standard treatment for patients with primary CNS lymphoma remains to be defined. Active therapies are often associated with increased risk of haematological or neurological toxicity. In this trial, we addressed the tolerability and efficacy of adding rituximab with or without thiotepa to methotrexate-cytarabine combination therapy (the MATRix regimen), followed by a second randomisation comparing consolidation with whole-brain radiotherapy or autologous stem cell transplantation in patients with primary CNS lymphoma. We report the results of the first randomisation in this Article.
  
  
  METHODS
  For the international randomised phase 2 International Extranodal Lymphoma Study Group-32 (IELSG32) trial, HIV-negative patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and measurable disease were enrolled from 53 cancer centres in five European countries (Denmark, Germany, Italy, Switzerland, and the UK) and randomly assigned (1:1:1) to receive four courses of methotrexate 3·5 g/m(2) on day 1 plus cytarabine 2 g/m(2) twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m(2) on days -5 and 0 (group B); or the same methotrexate-cytarabine-rituximab combination plus thiotepa 30 mg/m(2) on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after the first stage were then randomly allocated between whole-brain radiotherapy and autologous stem cell transplantation. A permuted blocks randomised design (block size four) was used for both randomisations, and a computer-generated randomisation list was used within each stratum to preserve allocation concealment. Randomisation was stratified by IELSG risk score (low vs intermediate vs high). No masking after assignment to intervention was used. The primary endpoint of the first randomisation was the complete remission rate, analysed by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01011920.
  
  
  RESULTS
  Between Feb 19, 2010, and Aug 27, 2014, 227 eligible patients were recruited. 219 of these 227 enrolled patients were assessable. At median follow-up of 30 months (IQR 22-38), patients treated with rituximab and thiotepa had a complete remission rate of 49% (95% CI 38-60), compared with 23% (14-31) of those treated with methotrexate-cytarabine alone (hazard ratio 0·46, 95% CI 0·28-0·74) and 30% (21-42) of those treated with methotrexate-cytarabine plus rituximab (0·61, 0·40-0·94). Grade 4 haematological toxicity was more frequent in patients treated with methotrexate-cytarabine plus rituximab and thiotepa, but infective complications were similar in the three groups. The most common grade 3-4 adverse events in all three groups were neutropenia, thrombocytopenia, anaemia, and febrile neutropenia or infections. 13 (6%) patients died of toxicity.
  
  
  CONCLUSIONS
  With the limitations of a randomised phase 2 study design, the IELSG32 trial provides a high level of evidence supporting the use of MATRix combination as the new standard chemoimmunotherapy for patients aged up to 70 years with newly diagnosed primary CNS lymphoma and as the control group for future randomised trials.
  
  
  BACKGROUND
  Associazione Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Foundation.
authors.affiliation: Unit of Lymphoid Malignancies, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: ferreri.andres@hsr.it.
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authors.forename: Elisa
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authors.affiliation: Ateneo Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy; Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
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authors.affiliation: Institute of Neuropathology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Martina
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authors.affiliation: Unit of Neuroradiology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
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authors.affiliation: IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
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authors.affiliation: University Hospitals NHS Trust, Nottingham, UK.
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authors.affiliation: Universitätsklinikum Jena, Jena, Germany.
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authors.affiliation: Uniklinik Freiburg, Freiburg, Germany.
authors.forename: Elisabeth
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authors.affiliation: Dipartimento di Medicina, Sezione di Ematologia, Università di Verona, Verona, Italy.
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authors.lastname: Ambrosetti
authors.affiliation: Universitatsklinikum Essen, Essen, Germany.
authors.forename: Alexander
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authors.affiliation: Queen's Hospital, Romford, UK.
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authors.affiliation: Azienda Ospedaliera Arcispedale Santa Maria Nuova IRCCS, Reggio Emilia, Italy.
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authors.affiliation: The Christie Hospital NHS Foundation Trust, Manchester, UK.
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authors.affiliation: Uke Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
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authors.lastname: Binder
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authors.forename: Tobias
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authors.affiliation: Istituto Clinico Humanitas, Milano Rozzano, Italy.
authors.forename: Monica
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authors.lastname: Balzarotti
authors.affiliation: Azienda Ospedaliera Università Senese, Siena, Italy.
authors.forename: Alberto
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authors.affiliation: Medical Oncology Unit, Southampton General Hospital, Southampton, UK.
authors.forename: Peter
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authors.forename: Jette Sønderskov
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authors.lastname: Gørløv
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authors.forename: Georg
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authors.affiliation: Department of Oncology, Hematology, Hemostaseology and Stem Cell Transplantation, University Hospital Aachen, Medical Faculty, RWTH Aachen University, Aachen, Germany.
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authors.lastname: Panse
authors.affiliation: Hematology and Stem Cell Transplantation Unit, Istituto Nazionale dei Tumori Regina Elena, Rome, Italy.
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authors.lastname: Pisani
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authors.forename: Alessandra
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authors.lastname: Tucci
authors.affiliation: Department of Internal Medicine III, Ulm University, Ulm, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Stilgenbauer
authors.affiliation: Klinikum Bremen-Mitte, Bremen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Hertenstein
authors.affiliation: Technische Universität München, Munich, Germany.
authors.forename: Ulrich
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authors.lastname: Keller
authors.affiliation: Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: Stefan W
authors.initials: SW
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authors.forename: Alessandro
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authors.lastname: Levis
authors.affiliation: Martin-Luther Universität, Halle (Saale), Germany.
authors.forename: Hans J
authors.initials: HJ
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authors.affiliation: Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
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authors.affiliation: Istituto Oncologico Della Svizzera Italiana, Bellinzona, Switzerland.
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mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D016543:Central Nervous System Neoplasms / Q000000981:diagnostic imaging / Q000401:mortality / Q000628:therapy*; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology; D003131:Combined Modality Therapy / Q000009:adverse effects* / Q000379:methods*; D057186:Comparative Effectiveness Research; D003561:Cytarabine / Q000009:adverse effects* / Q000627:therapeutic use*; D003645:Death, Sudden / Q000453:epidemiology; D003718:Denmark; D003907:Dexamethasone / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D005858:Germany; D006335:Heart Injuries / Q000139:chemically induced; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced; D060828:Induction Chemotherapy / Q000009:adverse effects / Q000379:methods*; D007239:Infections / Q000139:chemically induced; D064090:Intraocular Lymphoma / Q000000981:diagnostic imaging / Q000628:therapy; D007558:Italy; D053208:Kaplan-Meier Estimate; D016393:Lymphoma, B-Cell / Q000000981:diagnostic imaging / Q000401:mortality / Q000628:therapy*; D008279:Magnetic Resonance Imaging; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000627:therapeutic use*; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced; D020258:Neurotoxicity Syndromes / Q000453:epidemiology; D009503:Neutropenia / Q000139:chemically induced; D019574:Optic Nerve Neoplasms / Q000000981:diagnostic imaging / Q000628:therapy; D011041:Poisoning / Q000453:epidemiology; D018714:Radiotherapy, Adjuvant / Q000009:adverse effects / Q000379:methods*; D012074:Remission Induction / Q000379:methods; D000069283:Rituximab / Q000009:adverse effects* / Q000627:therapeutic use*; D020521:Stroke / Q000139:chemically induced; D013557:Switzerland; D013852:Thiotepa / Q000009:adverse effects* / Q000627:therapeutic use*; D013921:Thrombocytopenia / Q000139:chemically induced; D013927:Thrombosis / Q000139:chemically induced; D019172:Transplantation Conditioning / Q000009:adverse effects / Q000379:methods; D014182:Transplantation, Autologous / Q000009:adverse effects; D016896:Treatment Outcome; D006113:United Kingdom
chemical_list: D003561:Cytarabine; D000069283:Rituximab; D003907:Dexamethasone; D013852:Thiotepa; D008727:Methotrexate