Background: Primary central nervous system lymphoma (PCNSL) is a rare and poor-prognosis disease, predominantly of B-cell origin. Orelabrutinib, a novel highly selective Bruton's tyrosine kinase (BTK) inhibitor, has demonstrated significant promise in retrospective studies when combined with rituximab and high-dose methotrexate (MTX) for the initial treatment of PCNSL patients. It achieves a complete response(CR) rate exceeding 60%, with high drug concentrations in cerebrospinal fluid and effective penetration of the blood-brain barrier. Additionally, the dynamic monitoring of circulating tumor DNA (ctDNA) in cerebrospinal fluid(CSF) to assess treatment response and recurrence status in PCNSL patients may serve as a novel surrogate endpoint for evaluating the efficacy of new drugs.

Methods: This prospective, single-arm, single-center study included 22 newly diagnosed PCNSL patients. The study aimed to evaluate the efficacy and safety of Orelabrutinib with rituximab and methotrexate (ORM regimen) as first-line therapy for PCNSL and investigate the predictive and prognostic value of ctDNA testing in CSF. The ORM induction therapy (Orelabrutinib 150 mg qd , rituximab 375 mg/m2 on day 1 and methotrexate 3g/m2 on days 2 and every 21 days per cycle) consisted of 6 cycles. Patients eligible for autologous stem cell transplantation (ASCT) were administered ASCT as consolidation therapy, while those ineligibles underwent whole-brain radiotherapy. All patients maintained with Orelabrutinib 150 mg qd for 1 year. Primary endpoints included objective response rate (ORR), while secondary endpoints including CR, duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS). Safety and tolerability of the treatment regimen were assessed. Tissue and CSF samples collected at baseline, mid-treatment (C5D1), and at the end of induction therapy (EOT) underwent next-generation sequencing.

Results:

Among 22 patients, the median age was 64 years (range 41-79) , with 45.5% being male; Cell of Origin classification showed non-GCB subtype in 14 cases (63.6%) and GCB subtype in 8 cases (36.4%); 40.9% of patients expressed MYC/BCL-2, 90.1% had deep lesions, and 45.5% had elevated CSF protein levels; MSKCC score categorized 59.1% as intermediate risk and 27.3% as high risk.

During treatment the best response evaluation showed an ORR of 86.4% and a DCR of 100%; Among the 21 patients who completed all induction therapies, the ORR was 85.71% (18/21) with a CR rate of 76.19% (16/21). 5 patients underwent ASCT after induction therapy, while 9 received radiotherapy as consolidation treatment. Among the 18 patients who achieved PR or better at EOT, maintenance treatment with Orelabrutinib was administered with a median duration of 176.5 days (13-365). The median follow-up time was 11.3 months, with 3 patient deaths reported, 1 from disease progression and 2 from infections. The median DOR for patients achieving CR was 381 days (24-1147 days). Median OS and PFS have not been reached yet, with estimated 1-year OS at 86.1% and 1-year PFS at 65.6%.

All patients experienced treatment-related adverse events. Common grade 1-2 AEs included fatigue, decreased hemoglobin, and fever; while common grade 3-4 AEs included neutropenia, lymphopenia, and leukopenia.

Among 20 patients before treatment, the mutation detection rate in tissue samples was 100%, with 95% (19/20) in CSF samples. High-frequency mutations were similar in tissue and CSF, including MYD88, PIM1, KMT2D, CD79B and CARD11. Patients with baseline DTX1 mutations had significantly shorter OS compared to wild-type patients. Lower baseline CSF ctDNA abundance suggested better efficacy of ORM treatment, elevated baseline CSF protein levels and higher baseline ctDNA maximum mutation abundance had shorter PFS.

Among 19 patients with detectable ctDNA in baseline CSF, 13 patients had undetectable ctDNA in C5D1 CSF, of which 12 patients achieved CR (92.3%). Patients with undetectable CSF ctDNA at C5D1 showed longer PFS, indicating that early clearance of CSF ctDNA can predict favorable prognosis.

Conclusion: The ORM regimen demonstrates high ORR and CR in the treatment of PCNSL, with acceptable safety. Our results suggest that dynamic monitoring of cerebrospinal fluid ctDNA is of significant importance for the early evaluation of therapeutic efficacy and prognosis prediction in PCNSL.

Disclosures

No relevant conflicts of interest to declare.

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