Andrés J M Ferreri1, Jeanette K Doorduijn2, Alessandro Re3, Maria Giuseppina Cabras4, Jeffery Smith5, Fiorella Ilariucci6, Mario Luppi7, Teresa Calimeri8, Chiara Cattaneo3, Jahanzaib Khwaja9, Barbara Botto10, Claudia Cellini11, Luca Nassi12, Kim Linton13, Pam McKay14, Jacopo Olivieri15, Caterina Patti16, Francesca Re17, Alessandro Fanni4, Vikram Singh5, Jacoline E C Bromberg18, Kelly Cozens19, Elisabetta Gastaldi20, Massimo Bernardi8, Nicola Cascavilla21, Andrew Davies22, Christopher P Fox23, Maurizio Frezzato24, Wendy Osborne25, Anna Marina Liberati26, Urban Novak27, Renato Zambello28, Emanuele Zucca29, Kate Cwynarski9. 1. Lymphoma Unit, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: ferreri.andres@hsr.it. 2. Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands. 3. Spedali Civili, Brescia, Italy. 4. Ospedale Oncologico Businco, Cagliari, Italy. 5. Department of Haematology, Aintree Hospital, Liverpool, UK. 6. Division of Hematology, Azienda USL-IRCCS Reggio Emilia, Reggio Emilia, Italy. 7. Azienda Ospedaliera Universitaria, UNIMORE, Modena, Italy. 8. Lymphoma Unit, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy. 9. Department of Haematology, University College Hospital, London, UK. 10. AOU Città della salute e della Scienza, Turin, Italy. 11. Ospedale di Ravenna, IRST, Ravenna, Italy. 12. Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont and AOU Maggiore della Carità, Novara, Italy. 13. Department of Haemato-Oncology, The Christie Hospital, Manchester, UK. 14. Beatson Cancer Centre, Glasgow, UK. 15. AOU Santa Maria della Misericordia, Udine, Italy. 16. Division of Hematology, Azienda Villa Sofia-Cervello, Palermo, Italy. 17. AO Parma, Parma, Italy. 18. Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, Netherlands. 19. Southampton Clinical Trials Unit, University of Southampton, Southampton, UK. 20. International Extranodal Lymphoma Study Group Coordinating Center, Institute of Oncology Research, Università della Svizzera Italiana, Bellinzona, Switzerland. 21. Casa Sollievo della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy. 22. Cancer Research UK Centre, University of Southampton, Southampton, UK. 23. Department of Clinical Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK. 24. San Bortolo Hospital, Vicenza, Italy. 25. Department of Haematology, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK. 26. Università Degli Studi di Perugia-AO Santa Maria, Terni, Italy. 27. Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland; Swiss Group for Clinical Cancer Research, Bern, Switzerland. 28. Azienda Ospedaliera di Padova, Padua, Italy. 29. International Extranodal Lymphoma Study Group Coordinating Center, Institute of Oncology Research, Università della Svizzera Italiana, Bellinzona, Switzerland; Department of Medical Oncology, Inselspital, Bern University Hospital, Bern, Switzerland; Medical Oncology Clinic, Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland; Swiss Group for Clinical Cancer Research, Bern, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland.
Abstract
BACKGROUND: Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive, CNS-directed chemoimmunotherapy consolidated by autologous haematopoietic stem-cell transplantation (HSCT) in patients with secondary CNS lymphoma. METHODS: This international, single-arm, phase 2 trial was done in 24 hospitals in Italy, the UK, the Netherlands, and Switzerland. Adults (aged 18-70 years) with histologically diagnosed diffuse large B-cell lymphoma and CNS involvement at the time of primary diagnosis or at relapse and Eastern Cooperative Oncology Group Performance Status of 3 or less were enrolled and received three courses of MATRix (rituximab 375 mg/m2, intravenous infusion, day 0; methotrexate 3·5 g/m2, the first 0·5 g/m2 in 15 min followed by 3 g/m2 in a 3 h intravenous infusion, day 1; cytarabine 2 g/m2 every 12 h, in 1 h intravenous infusions, days 2 and 3; thiotepa 30 mg/m2, 30 min intravenous infusion, day 4) followed by three courses of RICE (rituximab 375 mg/m2, day 1; etoposide 100 mg/m2 per day in 500-1000 mL over a 60 min intravenous infusion, days 1, 2, and 3; ifosfamide 5 g/m2 in 1000 mL in a 24 h intravenous infusion with mesna support, day 2; carboplatin area under the curve of 5 in 500 mL in a 1 h intravenous infusion, day 2) and carmustine-thiotepa and autologous HSCT (carmustine 400 mg/m2 in 500 mL glucose 5% solution in a 1-2 h infusion, day -6; thiotepa 5 mg/kg in saline solution in a 2 h infusion every 12 h, days -5 and -4). The primary endpoint was progression-free survival at 1 year. Overall and complete response rates before autologous HSCT, duration of response, overall survival, and safety were the secondary endpoints. Analyses were in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02329080. The trial ended after accrual completion; the database lock was Dec 31, 2019. FINDINGS: Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. 75 patients were assessable. 319 (71%) of the 450 planned courses were delivered. At 1 year from enrolment the primary endpoint was met, 42 patients were progression free (progression-free survival 58%; 95% CI 55-61). 49 patients (65%; 95% CI 54-76) had an objective response after MATRix-RICE, 29 (39%) of whom had a complete response. 37 patients who responded had autologous HSCT. At the end of the programme, 46 patients (61%; 95% CI 51-71) had an objective response, with a median duration of objective response of 26 months (IQR 16-37). At a median follow-up of 29 months (IQR 20-40), 35 patients were progression-free and 33 were alive, with a 2-year overall survival of 46% (95% CI 39-53). Grade 3-4 toxicity was most commonly haematological: neutropenia in 46 (61%) of 75 patients, thrombocytopenia in 45 (60%), and anaemia in 26 (35%). 79 serious adverse events were recorded in 42 (56%) patients; four (5%) of those 79 were lethal due to sepsis caused by Gram-negative bacteria (treatment-related mortality 5%; 95% CI 0·07-9·93). INTERPRETATION: MATRix-RICE plus autologous HSCT was active in this population of patients with very poor prognosis, and had an acceptable toxicity profile. FUNDING: Stand Up To Cancer Campaign for Cancer Research UK, the Swiss Cancer Research foundation, and the Swiss Cancer League.
BACKGROUND:Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive, CNS-directed chemoimmunotherapy consolidated by autologous haematopoietic stem-cell transplantation (HSCT) in patients with secondary CNS lymphoma. METHODS: This international, single-arm, phase 2 trial was done in 24 hospitals in Italy, the UK, the Netherlands, and Switzerland. Adults (aged 18-70 years) with histologically diagnosed diffuse large B-cell lymphoma and CNS involvement at the time of primary diagnosis or at relapse and Eastern Cooperative Oncology Group Performance Status of 3 or less were enrolled and received three courses of MATRix (rituximab 375 mg/m2, intravenous infusion, day 0; methotrexate 3·5 g/m2, the first 0·5 g/m2 in 15 min followed by 3 g/m2 in a 3 h intravenous infusion, day 1; cytarabine 2 g/m2 every 12 h, in 1 h intravenous infusions, days 2 and 3; thiotepa 30 mg/m2, 30 min intravenous infusion, day 4) followed by three courses of RICE (rituximab 375 mg/m2, day 1; etoposide 100 mg/m2 per day in 500-1000 mL over a 60 min intravenous infusion, days 1, 2, and 3; ifosfamide 5 g/m2 in 1000 mL in a 24 h intravenous infusion with mesna support, day 2; carboplatin area under the curve of 5 in 500 mL in a 1 h intravenous infusion, day 2) and carmustine-thiotepa and autologous HSCT (carmustine 400 mg/m2 in 500 mL glucose 5% solution in a 1-2 h infusion, day -6; thiotepa 5 mg/kg in saline solution in a 2 h infusion every 12 h, days -5 and -4). The primary endpoint was progression-free survival at 1 year. Overall and complete response rates before autologous HSCT, duration of response, overall survival, and safety were the secondary endpoints. Analyses were in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02329080. The trial ended after accrual completion; the database lock was Dec 31, 2019. FINDINGS: Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. 75 patients were assessable. 319 (71%) of the 450 planned courses were delivered. At 1 year from enrolment the primary endpoint was met, 42 patients were progression free (progression-free survival 58%; 95% CI 55-61). 49 patients (65%; 95% CI 54-76) had an objective response after MATRix-RICE, 29 (39%) of whom had a complete response. 37 patients who responded had autologous HSCT. At the end of the programme, 46 patients (61%; 95% CI 51-71) had an objective response, with a median duration of objective response of 26 months (IQR 16-37). At a median follow-up of 29 months (IQR 20-40), 35 patients were progression-free and 33 were alive, with a 2-year overall survival of 46% (95% CI 39-53). Grade 3-4 toxicity was most commonly haematological: neutropenia in 46 (61%) of 75 patients, thrombocytopenia in 45 (60%), and anaemia in 26 (35%). 79 serious adverse events were recorded in 42 (56%) patients; four (5%) of those 79 were lethal due to sepsis caused by Gram-negative bacteria (treatment-related mortality 5%; 95% CI 0·07-9·93). INTERPRETATION: MATRix-RICE plus autologous HSCT was active in this population of patients with very poor prognosis, and had an acceptable toxicity profile. FUNDING: Stand Up To Cancer Campaign for Cancer Research UK, the Swiss Cancer Research foundation, and the Swiss Cancer League.
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