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MATRix–RICE therapy and autologous haematopoietic stem-cell transplantation in diffuse large B-cell lymphoma with secondary CNS involvement (MARIETTA): an international, single-arm, phase 2 trial

Ferreri, Andrés J. M.; Doorduijn, Jeanette K.; Re, Alessandro; Cabras, Maria Giuseppina; Smith, Jeffery; Ilariucci, Fiorella; Luppi, Mario; Calimeri, Teresa; Cattaneo, Chiara; Khwaja, Jahanzaib; Botto, Barbara; Cellini, Claudia; Nassi, Luca; Linton, Kim; McKay, Pam; Olivieri, Jacopo; Patti, Caterina; Re, Francesca; Fanni, Alessandro; Singh, Vikram; Bromberg, Jacoline E. C.; Cozens, Kelly; Gastaldi, Elisabetta; Bernardi, Massimo; Cascavilla, Nicola; Davies, Andrew; Fox, Christopher P.; Frezzato, Maurizio; Osborne, Wendy; Liberati, Anna Marina; Novak, Urban; Zambello, Renato; Zucca, Emanuele; Cwynarski, Kate; International Extranodal Lymphoma Study Group (IELSG), International Extranodal Lymphoma Study Group (IELSG)


Andrés J. M. Ferreri

Jeanette K. Doorduijn

Alessandro Re

Maria Giuseppina Cabras

Jeffery Smith

Fiorella Ilariucci

Mario Luppi

Teresa Calimeri

Chiara Cattaneo

Jahanzaib Khwaja

Barbara Botto

Claudia Cellini

Luca Nassi

Kim Linton

Pam McKay

Jacopo Olivieri

Caterina Patti

Francesca Re

Alessandro Fanni

Vikram Singh

Jacoline E. C. Bromberg

Kelly Cozens

Elisabetta Gastaldi

Massimo Bernardi

Nicola Cascavilla

Andrew Davies

Clinical Professor in Haematology

Maurizio Frezzato

Wendy Osborne

Anna Marina Liberati

Urban Novak

Renato Zambello

Emanuele Zucca

Kate Cwynarski

International Extranodal Lymphoma Study Group (IELSG) International Extranodal Lymphoma Study Group (IELSG)


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, 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.


Ferreri, A. J. M., Doorduijn, J. K., Re, A., Cabras, M. G., Smith, J., Ilariucci, F., …International Extranodal Lymphoma Study Group (IELSG), I. E. L. S. G. (. (2021). MATRix–RICE therapy and autologous haematopoietic stem-cell transplantation in diffuse large B-cell lymphoma with secondary CNS involvement (MARIETTA): an international, single-arm, phase 2 trial. Lancet Haematology, 8(2), e110-e121.

Journal Article Type Article
Acceptance Date Feb 1, 2021
Online Publication Date Feb 1, 2021
Publication Date 2021-02
Deposit Date Feb 10, 2023
Publicly Available Date Feb 10, 2023
Journal The Lancet Haematology
Print ISSN 2352-3026
Electronic ISSN 2352-3026
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 8
Issue 2
Pages e110-e121
Keywords Hematology
Public URL
Publisher URL
Additional Information Authors on behalf of the International Extranodal Lymphoma Study Group (IELSG)


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