Efficacy and safety of rituximab, high-dose methotrexate, and thiotepa (R-MT) as first-line induction therapy for primary central nervous system diffuse large B-cell lymphoma

Abstract Background and Objectives Primary central nervous system lymphoma (PCNSL) is a rare, centrally localized lymphoma with a poor prognosis, with a 5-year overall survival (OS) rate of only 30%. Currently, no standard treatment strategy has been established for this disease, and high-dose methotrexate-based combination regimens are the preferred clinical treatment option. The IELSG 32 study confirmed that a thiotepa-containing multi-drug combination regimen (rituximab + high-dose methotrexate + cytarabine + thiotepa, MATrix) achieves an overall objective response rate (ORR) of 87% when used as induction therapy for PCNSL. Patients who received whole-brain radiotherapy (WBRT) or autologous stem cell transplantation (ASCT) as consolidation therapy after induction therapy showed significantly improved long-term prognosis. However, the use of high-dose cytarabine in this regimen resulted in grade ≥3 adverse events (AEs) in more than 70% of patients. Based on this, our center proposes the use of rituximab combined with high-dose methotrexate and thiotepa (R-MT) as first-line induction therapy for primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) and aims to evaluate the efficacy and safety of this regimen through retrospective analysis. Methods This retrospective study included patients with PCNS-DLBCL who were treated in the Department of Hematology, The First Hospital of Jilin University, from 2022 to 2024. The inclusion criteria were as follows: patients received combined therapy with rituximab (375 mg/m²), high-dose methotrexate (3 g/m²), and thiotepa (30 mg/m²), with each treatment cycle lasting 21 days, and completed 4–6 cycles of treatment. The primary endpoint of the study was the complete response rate (CRR), and the secondary endpoints included the 2-year PFS rate and safety. Results A total of 36 newly diagnosed patients with PCNS-DLBCL were included in this study, all with cerebral parenchymal involvement. The median age at onset was 62.5 years (range: 31–75 years), and 61.1% (22/32) of patients were aged > 60 years. Baseline characteristics of patients showed: 69.4% had deep intracranial lesions, 72.2% had multiple lesions, and 77.8% had poor performance status (ECOG score ≥ 2). The median number of treatment cycles was 5 (range: 4–6 cycles). After 4 cycles of induction therapy, the ORR reached 97.2%, with a CRR of 80.6%. At a median follow-up of 19 months, the 2-year PFS rate and OS rate were 63.9% and 82.9%, respectively. Based on subsequent treatment strategies, patients were divided into three groups: 15 patients received induction therapy alone, 16 patients received sequential maintenance therapy (including Bruton tyrosine kinase inhibitors [BTKi: 7 with zanubrutinib, 4 with orelabrutinib] or immunomodulatory drugs [IMiD: 5 with lenalidomide, 1 with pomalidomide]), and 5 patients received ASCT as consolidation therapy. Subgroup analysis showed that the proportion of patients aged > 60 years in the sequential maintenance therapy group was 81.3%, which was significantly higher than that in the other two groups (81.3% vs. 53.3% vs. 0%, P=0.005). The median PFS of the three groups was 13.7 months, 27.4 months, and not reached, respectively (P=0.089), with 2-year PFS rates of 43.8%, 67.9%, and 100%, respectively. In terms of safety, no grade 5 AEs were observed. The most common grade 3–4 hematological AEs were neutropenia (33.3%), followed by leukopenia (22.7%) and anemia (11.1%); the most common non-hematological AE was pulmonary infection (3.8%). Among patients aged > 60 years, the common grade 3–4 hematological AEs were neutropenia (40.9%), followed by leukopenia (19.4%), anemia (9.1%), and thrombocytopenia (9.1%). All patients successfully completed the scheduled treatment courses after symptomatic supportive therapy, with no dose reduction or treatment discontinuation due to AEs. Conclusion The R-MT regimen, as first-line induction therapy for patients with PCNS-DLBCL, demonstrates excellent short-term efficacy and favorable safety. However, patients receiving induction therapy alone are prone to early disease progression. Therefore, it is recommended that patients receive sequential ASCT as consolidation therapy; for patients who are intolerant of or refuse consolidation therapy, BTKi/IMiD maintenance therapy can also provide favorable long-term efficacy.