Andrés J M Ferreri1, Kate Cwynarski2, Elisa Pulczynski3, Maurilio Ponzoni4, Martina Deckert5, Letterio S Politi6, Valter Torri7, Christopher P Fox8, Paul La Rosée9, Elisabeth Schorb10, Achille Ambrosetti11, Alexander Roth12, Claire Hemmaway13, Angela Ferrari14, Kim M Linton15, Roberta Rudà16, Mascha Binder17, Tobias Pukrop18, Monica Balzarotti19, Alberto Fabbri20, Peter Johnson21, Jette Sønderskov Gørløv22, Georg Hess23, Jens Panse24, Francesco Pisani25, Alessandra Tucci26, Stephan Stilgenbauer27, Bernd Hertenstein28, Ulrich Keller29, Stefan W Krause30, Alessandro Levis31, Hans J Schmoll32, Franco Cavalli33, Jürgen Finke10, Michele Reni34, Emanuele Zucca33, Gerald Illerhaus10. 1. Unit of Lymphoid Malignancies, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: ferreri.andres@hsr.it. 2. Royal Free Hospital/University College London Hospital, London, UK. 3. Aarhus University Hospital, Aarhus, Denmark. 4. Ateneo Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy; Pathology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. 5. Institute of Neuropathology, University Hospital of Cologne, Cologne, Germany. 6. Unit of Neuroradiology, IRCCS San Raffaele Scientific Institute, Milan, Italy. 7. IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. 8. University Hospitals NHS Trust, Nottingham, UK. 9. Universitätsklinikum Jena, Jena, Germany. 10. Uniklinik Freiburg, Freiburg, Germany. 11. Dipartimento di Medicina, Sezione di Ematologia, Università di Verona, Verona, Italy. 12. Universitatsklinikum Essen, Essen, Germany. 13. Queen's Hospital, Romford, UK. 14. Azienda Ospedaliera Arcispedale Santa Maria Nuova IRCCS, Reggio Emilia, Italy. 15. The Christie Hospital NHS Foundation Trust, Manchester, UK. 16. AOU Città Della Salute e Della Scienza di Torino, Turin, Italy. 17. Uke Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany. 18. Georg-August-Universität, Göttingen, Germany. 19. Istituto Clinico Humanitas, Milano Rozzano, Italy. 20. Azienda Ospedaliera Università Senese, Siena, Italy. 21. Medical Oncology Unit, Southampton General Hospital, Southampton, UK. 22. Rigshospitalet, Copenhagen, Denmark. 23. J Gutenberg Universität, Mainz, Germany. 24. Department of Oncology, Hematology, Hemostaseology and Stem Cell Transplantation, University Hospital Aachen, Medical Faculty, RWTH Aachen University, Aachen, Germany. 25. Hematology and Stem Cell Transplantation Unit, Istituto Nazionale dei Tumori Regina Elena, Rome, Italy. 26. Spedali Civili, Brescia, Italy. 27. Department of Internal Medicine III, Ulm University, Ulm, Germany. 28. Klinikum Bremen-Mitte, Bremen, Germany. 29. Technische Universität München, Munich, Germany. 30. Universitätsklinikum Erlangen, Erlangen, Germany. 31. A.O. Santi Antonio e Biagio e Cesare Arrigo, Alessandria, Italy. 32. Martin-Luther Universität, Halle (Saale), Germany. 33. Istituto Oncologico Della Svizzera Italiana, Bellinzona, Switzerland. 34. Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
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. 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.
RCT Entities:
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. 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.
Authors: Heiner Zimmermann; Mirko Nitsche; Christiane Pott; Petra Reinke; Nina Babel; Robert M Hermann; Ingeborg A Hauser; Dennis Hahn; Matthias Ritgen; Claudia Pietschmann; Wolfram Klapper; Ioannis Anagnostopoulos; Ralf U Trappe Journal: Ann Hematol Date: 2021-05-11 Impact factor: 3.673
Authors: E Schorb; C P Fox; K Fritsch; L Isbell; A Neubauer; A Tzalavras; R Witherall; S Choquet; O Kuittinen; D De-Silva; K Cwynarski; C Houillier; K Hoang-Xuan; V Touitou; N Cassoux; J-P Marolleau; J Tamburini; R Houot; V Delwail; G Illerhaus; C Soussain; B Kasenda Journal: Bone Marrow Transplant Date: 2017-04-24 Impact factor: 5.483
Authors: S Kassam; E Chernucha; A O'Neill; C Hemmaway; T Cummins; S Montoto; A Lennard; G Adams; K Linton; P McKay; D Davies; C Rowntree; S Easdale; T A Eyre; R Marcus; K Cwynarski; C P Fox Journal: Bone Marrow Transplant Date: 2017-06-05 Impact factor: 5.483
Authors: Christian Grommes; James L Rubenstein; Lisa M DeAngelis; Andres J M Ferreri; Tracy T Batchelor Journal: Neuro Oncol Date: 2019-02-19 Impact factor: 12.300