The Primary Results of R-MTO Regimen (Rituximab, Methotrexate, Thiotepa, and Orelabrutinib) As the First-Line Induction Therapy Followed By Autologous Stem Cell Transplantation in Newly Diagnosed Primary Central Nervous System Lymphoma

Background: Primary central nervous system lymphoma (PCNSL) is a rare, aggressive B-cell malignancy with poor long-term survival. The MATRix regimen (High-dose methotrexate, cytarabine, thiotepa, and rituximab combination therapy) was considered an effective therapy for the young PCNSL patients, but more frequent serious haematological toxicity was found. The SAE dued mainly to the high-dose cytarabine. A safe and effective regimen is required for PCNSL patients who are usually in elderly age. Orelabrutinib, a novel Bruton tyrosine kinase (BTK) inhibitor with high cerebrospinal fluid concentrations³, may be a good choice. We aimed to investigate the efficacy and safety of R-MTO regimen followed by autologous hematopoietic stem cell transplantation (ASCT) in treatment of the patients with PCNSL.

Methods: This is a prospective designed, ongoing, single-center, single-arm, open-label study. The patients received 4-6 cycles of R-MTO regimen as induction therapy, consisting of rituximab 375 mg/m ² iv on day 0, MTX 3.5 g/m ² iv on day1, thiotepa 30 mg/m ² on day 4 and orelabrutinib 150 mg qd po for 3 weeks per cycle. The efficacy was assessed by MRI/PET-CT according to the International PCNSL Collaborative Group (IPCG) criteria.

Patients who achieved partial response (PR) or complete remission (CR) underwent consolidation treatment with high-dose chemotherapy (HCT) plus ASCT. The HCT regimen involved thiotepa 250 mg/m ² on days -7 and -6, busulfan 3.2 mg/kg on days -5, -4, cytarabine 2g/m ² q12h on days -3 and -2, followed by reinfusion of stem cells on day 0. The primary endpoint of the study was progression-free survival (PFS) at 2 years, evaluated by intention-to-treat (ITT). Secondary endpoints included CR rate, overall response rate (ORR), overall survival (OS) and toxicities.

Results:

Between April 2022 and July 2024, a total of 26 patients with newly diagnosed PCNSL were enrolled in this study. The median age of the patients was 61years, ranging from 36 to 70, 13 patients were male. By the data cutoff, all the patients had completed 4 cycles of treatment. The ORR was 96.15% (25/26), and the CR rate was 92.30% (24/26) after 4 cycles of treatment. However, one patient with a P53 mutation had no response after 4 cycles of treatment and unfortunately died 3.8 months after diagnosis. Among ten patients who underwent autologous HSCT, all of them (100%) remained in CR. One patient died due to a COVID-19 infection and other to a relapse after 6 cycles of R-MTO and ASCT. The PFS and OS rate at 12month were 82.24% (95% CI 58.45-93.13), and 87.00 %（95% CI 64.72-97.77）respectively.

The most common adverse events associated with the R-MTO regimen were hematological toxicity, grade 3 hematologic toxicity were observed in 30.77% patients, three patients with grade 4 hematologic toxicity.

Conclusions:

The R-MTO induction treatment has demonstrated notable efficacy in achieving higher response rates among patients with newly diagnosed PCNSL, and a tolerable safety profile.