Background: Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin's lymphoma, predominantly diffuse large B-cell lymphomas. High-dose methotrexate (HD-MTX) is the cornerstone of chemotherapy for newly diagnosed PCNSL. Bruton kinase inhibitors (BTKi) can effectively inhibit the BCR pathway and block the NF-κB pathway to achieve therapeutic purposes. Orelabrutinib is a novel BTKi with high blood-brain barrier permeability and has demonstrated efficacy on PCNSL with minimal off-target effects and higher safety. Rituximab and thiotepa can also effectively inhibit PCNSL. We hypothesized that a combination of ORT, with or without HD-MTX, would be effective and safe for untreated PCNSL.
Method: This prospective, multicenter, single-arm, study enrolled untreated PCNSL patients (≥18 years) who received ORT therapy: orelabrutinib 150mg/day orally, rituximab 375 mg/m² intravenously on day 0, and thiotepa 40mg/m² intravenously on day 1, in a 21-day cycle. HD-MTX (3.5g/m² IV) was administered every 3 weeks to patients ≤60 years with normal renal function. After 4 cycles, patients with a response continued the same dose for up to 4 more cycles, with autologous stem cell transplantation (ASCT) recommended for those ≤60 years. Maintenance therapy with orelabrutinib continued until 2 years of treatment. A combination of PET/CT and MRI was used to evaluate tumors according to the Lugano classification. Adverse events (AEs) were graded according to Standard 5.0 Common Terminology for Adverse Events. The primary endpoint was the objective response rate (ORR) with secondary endpoints including disease-free survival (DFS) and overall survival (OS).
Results: From August 2022 to July 2024, 17 untreated PCNSL patients were enrolled, with a median age of 58 years (range: 49-78 years). Among them, 29.4% were older than 65 years, and 64.7% had deep lesions. Next-generation sequencing in 14 patients revealed 71.4% (12/17) MCD subtypes, 21.3% (3/17) TP53, and 1 BN2. MYC was positive in 85.71%, P53 positive in all 6 patients, and Ki67 in 46.7%, greater than 75%. Elevated serum lactate dehydrogenase was noted in 20%.
35.3% (6/17) received ORT and 64.7% (11/17) received ORT+HD-MTX. The median follow-up was 8.27 months. The best CR rate was 85.71% (12/14), and the longest CR duration was 22.53 months. The ORR rate was 85.71%. PD occurred in 14.3 % (2/14). Since all 14 patients survived, OS has not been assessed and the estimated 12-month PFS rate is 85.7%. Subgroup analysis showed a 77.8% response rate in MCD subtypes, with no significant differences among efficacy groups based on age, lesion site, genotyping, LDH level, or Ki67 greater than 75%.
The CR rate and ORR were 83.3% (5/6) and the 12-month PFS rate was 83.3% in patients treated with ORT. The CR rate and ORR of patients treated with ORT+HD-MTX were both 87.5% (7/8) and the 12-month PFS rate was 87.5%. None of the patients who achieved CR experienced disease recurrence. 33.3% (4/10) of CR patients who finished chemotherapy received ASCT. Ninety percent (9/10) of CR patients received subsequent orelabrutinib maintenance therapy, with a median maintenance time of 9.5 months.
Among the 17 patients, 14 (82.3%) had adverse events, most grade 1 and 2, including leukopenia, anemia, pneumonia, thrombocytopenia, and hematuria. Grade 3 and above adverse events were 11.8% (2/17), manifested as leukopenia.
Conclusion: The ORT regimen, with or without HD-MTX, has shown initial efficacy and a manageable safety profile in treating PCNSL, particularly in elderly patients with MCD subtypes. ASCT following ORT with or without HD-MTX induction therapy further improves patient response. Patients with CR did not relapse and were well-tolerated on orelabrutinib maintenance therapy. These findings will be updated as more data is accrued.
No relevant conflicts of interest to declare.
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