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

Abstract

Summary 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/m 2 , intravenous infusion, day 0; methotrexate 3·5 g/m 2 , the first 0·5 g/m 2 in 15 min followed by 3 g/m 2 in a 3 h intravenous infusion, day 1; cytarabine 2 g/m 2 every 12 h, in 1 h intravenous infusions, days 2 and 3; thiotepa 30 mg/m 2 , 30 min intravenous infusion, day 4) followed by three courses of RICE (rituximab 375 mg/m 2 , day 1; etoposide 100 mg/m 2 per day in 500–1000 mL over a 60 min intravenous infusion, days 1, 2, and 3; ifosfamide 5 g/m 2 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/m 2 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...

Outcome of a Real-World Patient Cohort with Secondary CNS Lymphoma Treated with High-Intensity Chemoimmunotherapy and Autologous Stem Cell Transplantation

“…With the inclusion of ifosfamide, they addressed concerns about the efficacy of cyclophosphamide, utilized in their previous study, to cross the blood-brain barrier. Although 2-year overall survival with 46% was not improved in comparison to previous studies, Ferreri et al [13] demonstrated a better survival for patients with CNS involvement at first diagnosis, with 71% alive after 2 years and an improvement in the overall safety of the new protocol. In order to add real-world evidence to the advances described [10], we report the outcome of 17 patients treated according to the published treatment protocol at two academic centers in Germany.…”

“…More recently, the results of the multicenter phase 2 MARIETTA trial by Ferreri et al [13] were published. This trial investigates a similar regimen including chemoimmunotherapy based on MTX and ifosfamide followed by consolidation with high-dose chemotherapy and ASCT.…”

Diagnosis and Individualized Treatment of Secondary Central Nervous System Lymphoma: A Case Report

“…Another prospective trial called MARIETTA study was published recently and was supported to be the largest trial for secondary CNS lymphoma until now. 6 , 22 Treatment consisted of a sequential combination of two standardized chemotherapy regimens, MATRix (methotrexate, cytarabine, thiotepa, and rituximab) and RICE (rituximab, etoposide, ifosfamide, and carboplatin), followed by carmustine-thiotepa and autologous HSCT as a consolidation therapy. Seventy-nine patients were enrolled, and 2-year progression-free survival was 71% in patients with CNS disease at initial lymphoma diagnosis.…”

“…Without any positive physical neurological examinations, a contrast-enhanced magnetic resonance imaging (MRI) scan of the brain suggested multiple enhancing masses in the corpus callosum and around the ventricles (Figure 1A-C). To make an accurate diagnosis, an 6 which was sponsored by International Extranodal Lymphoma Study Group (IELSG) and we decided to combine two standardized chemotherapy regimens, high dose methotrexate-based regimen (MT-R: methotrexate, temozolomide and rituximab) 7 for intracranial lesions and traditional R-CHOP (rituximab, vincristine, cyclophosphamide, prednisone and anthracycline) 8 immunochemotherapy regimen for extracranial lesions.…”

“…Considering the central nervous system (CNS) involvement of systemic DLBCL at the initial diagnosis and MGMT promoter methylation, we designed a methotrexate (MTX)-based immunochemotherapy regimen by referring to the MARIETTA trial (NCT02329080) 6 which was sponsored by International Extranodal Lymphoma Study Group (IELSG) and we decided to combine two standardized chemotherapy regimens, high dose methotrexate-based regimen (MT-R: methotrexate, temozolomide and rituximab) 7 for intracranial lesions and traditional R-CHOP (rituximab, vincristine, cyclophosphamide, prednisone and anthracycline) 8 immunochemotherapy regimen for extracranial lesions. Eventually, the details of the first cycle treatment for our patient were as follows: rituximab (375 mg/m 2 , day (d) 0); high-dose intravenous MTX (3.5 g/m 2 , d1) with leucovorin for rescue, as previously described; 9 vincristine (2 mg, d3); cyclophosphamide (0.75 g/m 2 once per day, d3–4); prednisone (60 mg, d3–7); and temozolomide (150 mg/m 2 once per day, d3–7) for the first chemotherapy cycle ( Figure 3 , chemotherapy regimen A).…”