Improving Targeted Therapies in Primary CNS Lymphoma: Real-World Use of Cerebrospinal Fluid Circulating Tumor DNA for Monitoring
Authors: Jiang Ming , Zou Liqun , Liang Lijie , Liu Yingze , Li Na , Feng You 
Published: December 2024

Background

Primary Central Nervous System Lymphoma (PCNSL) often has a bleak prognosis. Current standard treatments with high-dose methotrexate (HD-MTX) and chemotherapy are suboptimal. Novel targeted drug combinations are under investigation. Cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) technology offers the potential for better diagnostics and monitoring. This study evaluates the effectiveness of novel targeted therapies and the utility of ctDNA in PCNSL patients.

Methods

We enrolled 96 newly diagnosed PCNSL patients at West China Hospital, Sichuan University, with a median follow-up of 22.0 months (range: 17.32-26.47) by July 2024. Patients received one of four treatment regimens: Group A (R2-MTX: rituximab, HD-MTX, lenalidomide), Group B (R-MTX+BTKi: rituximab, HD-MTX, orelabrutinib), Group C (MEDZ-R: rituximab, HD-MTX, zanubrutinib, liposomal doxorubicin, etoposide), and Group D (MTX + chemotherapy without targeted drugs). CSF (166 samples) and tissue (20 samples) were collected from 70 patients for next-generation sequencing (NGS) at various treatment stages.

Results

Out of 96 PCNSL patients, 88 were evaluable for treatment efficacy, while 8 were excluded due to toxicity or personal choice. Among these 88, 73 opted for regimens with novel targeted drugs, with overall 1-year progression-free survival (PFS) and overall survival (OS) rates of 70.5% and 92.0%, respectively. Complete response (CR) rates were 63.9% for Group A (36 patients), 63.6% for Group B (22 patients), and 86.7% for Group C (15 patients), with overall response rates (ORR) of 72.2%, 68.2%, and 86.7%, respectively. Group D, which lacked novel targeted drugs, had a 40% CR rate, 60% ORR, and 1-year PFS and OS rates of 48.2% and 70.7%, respectively. Although differences in efficacy between groups were not statistically significant, Groups A, B, and C tended to have better prognoses than Group D.

Among 63 patients with pre-treatment CSF ctDNA, 49 (77.8%) tested positive, correlating with higher tumor loads (6.0 cm² vs. 1.9 cm², P=0.047). Common mutations in baseline CSF samples were MYD88 (65.30%), PIM1 (61.22%), CD79B (51.02%), and BTG1 (28.57%). Additionally, 85.1% (74/87) of high-frequency mutated genes detected in CSF were validated in matched baseline tissue samples. Baseline CSF ctDNA levels demonstrated prognostic predictive value. Patients with high-level CSF ctDNA (&gt;1.96 log10 hGE/ml, n=18) had significantly worse survival than those with low-level CSF ctDNA (n=31). The 24-month PFS rate was 40.6% for the high-level group versus 83.33% for the low-level group (HR=2.72; 95% CI, 0.795-9.29; P=0.005), and 2-year OS rates were 61.0% and 100%, respectively (HR=4.30E+07; 95% CI 0-Inf; P=0.012).

Lymphgen typing of CSF mutations identified MCD type in 25 patients (51.02%), TP53 inactivation type in 8 patients (16.32%), BN2 type in 2 patients (4.08%), BN2/MCD type in 2 patients (4.08%), and unclassified in 12 patients (24.49%). The CR rate for MCD type patients was significantly higher with BTKi treatment (73.33% [11/15] vs. 40% [4/10], P=0.039). Mutations in B2M, CDKN2B, and TP53 in baseline CSF ctDNA were associated with worse PFS and OS (P &lt; 0.01).

During treatment and follow-up, 53 patients underwent at least one CSF ctDNA monitoring, with 19 patients showing positive ctDNA results. Median PFS was 16 months in positive ctDNA patients versus not reached in negative ctDNA patients during monitoring (HR=2.51; 95% CI 1.02-6.16; P=0.04); median OS was 40 months versus not reached (HR=7.97; 95% CI 0.96-66.45; P=0.02). Notably, different novel drug induction treatments showed varying CSF ctDNA clearance rates: 48% (12/25) for Group A, 100% (9/9) for Group B, and 90.9% (10/11) for Group C (P&lt;0.01). Group D had only one patient who did not achieve CSF ctDNA clearance.

C onclusion

PCNSL patients treated with HD-MTX and novel drugs (BTKi or lenalidomide) demonstrated higher response rates and better survival trends. High baseline CSF ctDNA levels and mutations in B2M, CDKN2B, and TP53 indicate a poor prognosis. BTKi regimens are more effective in MCD patients and improve CSF ctDNA clearance rates. Monitoring CSF ctDNA is crucial for predicting treatment efficacy and prognosis, underscoring its importance in PCNSL management.