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

Lancet Haematol. 2016 May;3(5):e217-27. doi: 10.1016/S2352-3026(16)00036-3. Epub 2016 Apr 6.


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, number NCT01011920.

Findings: 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.

Interpretation: 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.

Funding: Associazione Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Foundation.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Acute Kidney Injury / chemically induced
  • Anemia / chemically induced
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Central Nervous System Neoplasms / diagnostic imaging
  • Central Nervous System Neoplasms / mortality
  • Central Nervous System Neoplasms / therapy*
  • Chemical and Drug Induced Liver Injury / epidemiology
  • Combined Modality Therapy / adverse effects*
  • Combined Modality Therapy / methods*
  • Comparative Effectiveness Research
  • Cytarabine / adverse effects*
  • Cytarabine / therapeutic use*
  • Death, Sudden / epidemiology
  • Denmark
  • Dexamethasone / therapeutic use
  • Disease-Free Survival
  • Female
  • Follow-Up Studies
  • Gastrointestinal Diseases / chemically induced
  • Germany
  • Heart Injuries / chemically induced
  • Hematopoietic Stem Cell Transplantation / adverse effects
  • Hematopoietic Stem Cell Transplantation / methods*
  • Humans
  • Hyperglycemia / chemically induced
  • Induction Chemotherapy / adverse effects
  • Induction Chemotherapy / methods*
  • Infections / chemically induced
  • Intraocular Lymphoma / diagnostic imaging
  • Intraocular Lymphoma / therapy
  • Italy
  • Kaplan-Meier Estimate
  • Lymphoma, B-Cell / diagnostic imaging
  • Lymphoma, B-Cell / mortality
  • Lymphoma, B-Cell / therapy*
  • Magnetic Resonance Imaging
  • Male
  • Methotrexate / adverse effects*
  • Methotrexate / therapeutic use*
  • Middle Aged
  • Mucositis / chemically induced
  • Neurotoxicity Syndromes / epidemiology
  • Neutropenia / chemically induced
  • Optic Nerve Neoplasms / diagnostic imaging
  • Optic Nerve Neoplasms / therapy
  • Poisoning / epidemiology
  • Radiotherapy, Adjuvant / adverse effects
  • Radiotherapy, Adjuvant / methods*
  • Remission Induction / methods
  • Rituximab / adverse effects*
  • Rituximab / therapeutic use*
  • Stroke / chemically induced
  • Switzerland
  • Thiotepa / adverse effects*
  • Thiotepa / therapeutic use*
  • Thrombocytopenia / chemically induced
  • Thrombosis / chemically induced
  • Transplantation Conditioning / adverse effects
  • Transplantation Conditioning / methods
  • Transplantation, Autologous / adverse effects
  • Treatment Outcome
  • United Kingdom


  • Cytarabine
  • Rituximab
  • Dexamethasone
  • Thiotepa
  • Methotrexate

Associated data