Introduction 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. 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. This study aimed to evaluate the efficacy and safety of a combination regimen consisting of ORT, with or without HD-MTX, in untreated PCNSL patients (pts).

Methods This prospective, multicenter, single-arm, study enrolled untreated PCNSL pts (≥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 pts ≤60 years with normal renal function. After 4 cycles, pts 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. 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 progression-free survival (PFS) and overall survival (OS).

Results From August 2022 to June 2025, 31 untreated PCNSL pts were enrolled, with a median age of 61 years (range, 31-88 years). Among them, 38.7% were older than 65 years, and 61.3% were male. Next-generation sequencing (NGS) was performed on 22 pts, revealing that 81.8% (18/22) had MCD subtypes, 13.6% (3/22) had TP53 mutations, and 1 patient had the BN2 subtype. Immunohistochemistry (IHC) assessed protein expression in 25 pts, showing MYC positivity in 96.0% (24/25), double expression of BCL-2 and MYC in 28.0 % (7/25), and Ki67 greater than 75% in 68.0 % (17/25).

32.3 % (10/31) received ORT and 67.7 % (21/31) received ORT+HD-MTX. The median follow-up was 12 months (range, 3-34 months). Among the 29 pts who completed all induction therapies, the ORR was 86.2 % (25/29) with a CR rate of 82.6 % (24/29). Stable disease (SD) was observed in 3.4 % (1/29) of pts. Subgroup analysis showed an 83.3% (15/18) response rate in MCD subtypes. The median PFS was not reached, with the estimated 1- and 2-year PFS rates of 84.9 % and 74.3 %, respectively. The median OS was not reached, with the estimated 1- and 2-year OS rates were both 95.2%.

In the patient cohort treated with ORT, the ORR and CR rate were both 88.9% (8/9). The median PFS was not reached, and the 1- and 2-year PFS rates of 88.9 % and 66.7%. In the group receiving ORT+HD - MTX, the ORR were 85.0% (17/20) with a CR rate of 80.0% (16/20). The median PFS was not reached, and the 1- and 2-year PFS rates were both 84.0 %. Statistical analysis revealed no significant differences between the two treatment groups (p=0.5362). 45.8 % (11/24) of CR pts who finished chemotherapy received ASCT. 15 pts (15/24) of CR pts received subsequent orelabrutinib maintenance therapy, with a median maintenance time of 11 months. Among the 31 pts, 64.5 % (20/31) pts experienced grade 1-2 adverse reactions, with grade 3-4 adverse reactions occurring in 19.4 % (6/31). The most common grade 3-4 adverse events were leukopenia and thrombocytopenia.

ConclusionThe ORT regimen, with or without HD-MTX, demonstrated initial efficacy and a manageable safety profile in treating PCNSL, particularly in elderly pts with MCD subtypes.

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2025
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