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)

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.

Citation

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. https://doi.org/10.1016/S2352-3026%2820%2930366-5

• 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
• DOI: https://doi.org/10.1016/S2352-3026%2820%2930366-5
• Keywords: Hematology
• Public URL: https://nottingham-repository.worktribe.com/output/17084389
• Publisher URL: https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(20)30366-5/fulltext
• Additional Information: Authors on behalf of the International Extranodal Lymphoma Study Group (IELSG)