Abstract
Introduction Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma with a poor prognosis, mainly attributable to a high relapse risk. Median overall survival (OS) in relapsed/refractory (R/R) PCNSL is only 6.8 months (Houillier et al., Neurology 2020). Orelabrutinib is a novel, highly CNS-penetrant BTK inhibitor that has demonstrated efficacy in PCNSL with minimal off-target effects and an acceptable safety profile. According to previous studies, the combination of BTKi and anti-PD-1 monoclonal antibodies has been proven to have a synergistic therapeutic effect on B-cell lymphoma (Vincent-Fabert et al. Cell Commun Signal. 2019). This study evaluated the efficacy and safety of a triplet, chemo-free therapy regimen combining orelabrutinib, Sintilimab, and temozolomide (OST) in patients with R/R PCNSL.
Methods This was a prospective, multicenter, single-arm study (NCT04961515) in patients with clinically and histopathologically confirmed R/R PCNSL. Patients received OST therapy: orelabrutinib 150mg orally once daily, Sintilimab 200 mg intravenously on day 1, and temozolomide 150 mg/m² intravenously on day 1-5, in a 21-day cycle. After six cycles, maintenance therapy with Sintilimab 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 OS.
Results From July 2021 to March 2024, 19 patients with R/R PCNSL were enrolled. The median age was 59 years (range, 44–75), and 10 (52.6 %) were male. Most patients had an Eastern Cooperative Oncology Group performance-status score of 0–2 (68.4 %) and the non-germinal-center B-cell (non-GCB) subtype (78.9 %). Immunohistochemistry (IHC) showed double expression of BCL-2 and MYC in 42.1 % (8/19) of cases and Ki-67 >70 % in 73.7 % (14/19). Refractory disease was present in 52.6 % (10/19) and relapse in 47.4 % (9/19). According to the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score, patients were stratified as low-risk in 10.5 %, intermediate-risk in 47.4 %, and high-risk in 42.1 %. Using the International Extranodal Lymphoma Study Group (IELSG) prognostic system, the corresponding proportions were 26.3 % low-risk, 42.1 % intermediate-risk, and 31.6 % high-risk. Prior systemic therapy had comprised ≥2 lines in 31.6 % (6/19) of patients.
The median follow-up was 29.0 months (range, 1.0–32.0). After two cycles, the ORR was 78.9 % (15/19), with a CR rate of 42.1 % (8/19). At the end of induction treatment, the ORR rose to 84.2% and the CR rate to 78.9% (15/19). Median PFS was 9.0 months (range, 1–32 months), with 1- and 2-year PFS rates of 35.1% and 17.5%, respectively. Median OS was not reached, 1- and 2-year OS rates were 70.8% and 53.1%, respectively. Both univariate and multivariable analyses showed that gender, MSKCC prognostic score, IELSG prognostic score, GCB subtype, and double expression were not significantly associated with PFS or OS. However, disease status (relapsed vs. refractory) was strongly associated with PFS (p = 0.0014). In the relapsed cohort, median PFS was 15.0 months, with 1- and 2-year PFS rates of 64.8 % and 32.4 %, respectively. While in the refractory cohort, median PFS was 5.0 months, and both 1- and 2-year PFS rates were 0 %.
During the study, all patients experienced grade 1-2 adverse reactions, with grade 3-4 adverse reactions occurring in 26.3 % (5/19). The most common grade 3-4 adverse events were leukopenia (21.1%) and neutropenia (15.8%). Notably, BTK inhibitor–associated atrial fibrillation (0 %) and bradycardia (0 %) were absent, and no PD-1 immune checkpoint–related adverse events such as pneumonia or rash occurred.
Conclusion In patients with relapsed/refractory PCNSL, the OST regimen combining orelabrutinib, Sintilimab, and temozolomide elicited rapid, deep, and durable responses, achieving an ORR of 84.2% and a CR rate of 78.9%. Clinically meaningful survival benefit was observed (median PFS 9.0 months; 2-year OS 53.1%). Disease status was a key determinant of efficacy, with relapsed patients significantly outperforming those with refractory disease. The chemo-free regimen was generally well tolerated, supporting its further evaluation in prospective studies.
