primary efficacy and safety of first-line R-MTO regimen (rituximab, methotrexate, thiotepa, and orelabrutinib) followed by autologous hematopoietic stem cell transplantation in PCNSL

Abstract Background: Primary central nervous system lymphoma (PCNSL) is a rare and aggressive B-cell malignancy with poor long-term survival. The MATRix regimen (high-dose methotrexate, cytarabine, thiotepa, and rituximab combination therapy) was considered as an effective therapy for the younger patients with PCNSL. However, due to severe hematologic toxicity, mainly caused by high-dose cytarabine, the regimen's application is limited in elderly patients with PCNSL. Therefore, a safe and effective regimen is essential for PCNSL patients across a broader age range. Orelabrutinib, a novel Bruton tyrosine kinase inhibitor with high positive cerebrospinal fluid concentration and fewer off-target effects, has demonstrated impressive efficacy and manageable safety in PCNSL. We aimed to evaluate the efficacy and safety of R-MTO regimen (rituximab, methotrexate, thiotepa, and orelabrutinib) followed by autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with PCNSL. Methods This was a prospective, open-label, single-center, single-arm study. Patients with newly diagnosed PCNSL received 6-8 cycles of R-MTO regimen as induction therapy, consisting of rituximab 375 mg/m2 intravenously on day 0, methotrexate 3.5 g/m2 intravenously on day 1, thiotepa 30 mg/m2 intravenously on day 4, and oral orelabrutinib 150 mg once daily every 3 weeks. The treatment response was assessed by magnetic resonance imaging or positron emission tomography-computed tomography according to the International PCNSL Collaborative Group (IPCG) criteria. Patients without disease progression underwent consolidation treatment with high-dose chemotherapy (HCT) followed by auto-HSCT. The HCT regimen involved thiotepa 250 mg/m2 on days -7 and -6, busulfan 3.2 mg/kg on days -5 and -4, cytarabine 2 g/m2 every 12 hours on days -3 and -2. Hematopoietic stem cells were reinfused on day 0. The primary endpoint was 24-month progression-free survival (PFS) rate, evaluated by intention-to-treat. Secondary endpoints included complete Response (CR) rate, overall response rate (ORR), overall survival (OS), and safety. Results Between April 2022 and June 2025, 35 patients were enrolled, with a median age of 59 years (range, 28-75), and 19 (54.29%) were male. At the data cutoff, all patients had completed induction therapy, and the CR rate and ORR were 91.43% (32/35) and 97.14% (34/35) after 4 cycles of induction therapy, respectively. One patient with a P53 mutation did not respond to induction treatment and died 3.8 months after diagnosis. Fifteen (42.86%) patients underwent auto-HSCT, all achieving CR beforehand. One patient died from COVID-19 infection, and another relapsed and died after 6 cycles of R-MTO and auto-HSCT. The 18-month PFS and OS rates were 80.68% (95% CI 61.69-90.90) and 82.98% (95% CI 63.55-92.61), respectively. The most common adverse events associated with the R-MTO regimen were hematological toxicity, with grade 3-4 observed in 25.71% (9/35) of patients and grade 4 hematological toxicity in only 8.57% (3/35) of patients. Conclusion The R-MTO induction treatment has demonstrated notable efficacy in achieving higher response rate among patients with newly diagnosed PCNSL, with a manageable safety profile. Further related data will be presented at a later date.