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. 2025 May;39(5):1265-1268.
doi: 10.1038/s41375-025-02583-w. Epub 2025 Apr 9.

Guiding clinical management of patients with CNS lymphomas by minimal-invasive detection of ctDNA in cerebrospinal fluid

S Weinschenk  1 , U Philipp  1 , J C Kuehn  1   2 , K Mueller  3 , J Fauser  4 , D Boeckle  5 , I Gebhard  1 , M Hinz  1 , N Neidert  2   6 , S Bleul  1 , E M Lauer  1 , J A Mutter  7 , S K Alig  7   8 , D M Kurtz  7 , J Finke  1 , R Marks  1 , M Diehn  9 , A A Alizadeh  7 , P C Reinacher  10   11 , J Wehrle  1 , U Keller  5   12 , D Wolf  4 , F Kocher  4 , B Chapuy  5   12 , J Beck  6 , M Prinz  13   14 , L von Baumgarten  3   15   16 , E Schorb  1 , J Duyster  1 , F Scherer  17   18
Affiliations

Guiding clinical management of patients with CNS lymphomas by minimal-invasive detection of ctDNA in cerebrospinal fluid

S Weinschenk et al. Leukemia. 2025 May.
No abstract available

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Conflict of interest statement

Competing interests: FS receives research funding from Gilead Sciences, Roche Sequencing Solutions, and Takeda, and received honoraria from AstraZeneca and Servier. SKA reports consulting for Foresight Diagnostics. ES received honoraria from SERB Pharmaceuticals. NN serves on advisory board for Servier and is consultant for B. Braun. PCR received honoraria from Arcana and serves as consultant for Boston Scientific, Inomed, and Brainlab. All other authors did not report any conflicts of interest related to this work. This work was supported by the Advanced Clinician Scientist Program of the Deutsche Gesellschaft für Innere Medizin (DGIM, to FS), the Deutsche Forschungsgemeinschaft (DFG, to FS), the Mertelsmann Foundation (to FS), the German Cancer Research Center (Deutsches Konsortium für Translationale Krebsforschung, DKTK, to FS), the Else Kröner-Fresenius-Stiftung (to FS and PCR), and Fraunhofer Society Germany (to PCR). SW is supported by the José Carreras-DGHO fellowship. JCK and NN are supported by the Berta-Ottenstein Programm Förderlinie Clinician Scientist of the University Medical Center Freiburg. Ethics approval and consent to participate: All analyses in this manuscript have been performed in accordance with the relevant guidelines and regulations. All participants provided informed consent for sample collection and data analysis. Samples from the development and validation cohorts were collected from patients participating in research studies conducted at the University Medical Center Freiburg, Germany (DRKS15307), and University Hospital of the Ludwig-Maximilians-University (LMU) Munich, Germany (Nr. 22-0008) that were approved by the ethics committees in accordance with the Declaration of Helsinki. The observational study was a retrospective analysis conducted in accordance with the Declaration of Helsinki and approved by the ethics committee of the University Medical Center Freiburg, Germany (DRKS00034686).

Figures

Fig. 1
Fig. 1. MYD88 L265P ddPCR assay application in clinical practice.
A Number of CSF specimens submitted from internal (orange) and external (blue) sites for routine MYD88 L265P testing (grey: total submissions), shown by quarter from quarter 1 in 2022 until quarter 2 in 2024. B Scatter plot depicting submitted CSF volumes from all 205 samples in milliliters (mL). Lines highlight the median and range. C Pie chart showing the distribution of turnaround times in days for MYD88 L265P analyses. D Bar graph depicting the fraction of samples with positive (blue) and negative (gray) CSF-ctDNA results. E Scatter plot highlighting CSF-ctDNA allele frequencies for all CSF analyses. Lines show the median and range. CSF, cerebrospinal fluid; Q, quarter; mL, milliliters; ctDNA, circulating tumor DNA.
Fig. 2
Fig. 2. Implications of CSF-ctDNA analyses for clinical management of patients.
A Overview and graphical depiction of the reasons for CSF submissions for routine MYD88 L265P testing in CSF. Left [1]: Patients with unclear brain lesions and CNSL as differential diagnosis and either high-risk situation due to patient frailty or tumor lesions in eloquent brain regions [1a], delay of surgical intervention due to concomitant corticosteroid or antiplatelet treatment [1b], or unclear diagnosis after surgical intervention [1c]. Middle [2]: Patients with suspected secondary CNS involvement of systemic lymphomas either as occult [2a], synchronous [2b], or metachronous [2c] manifestation or suspected PCNSL relapse [2 d]. Right [3]: CSF submitted from patients with known CNSL for CSF-ctDNA monitoring. Bar plots and pie charts showing the fraction of patients with CSF-ctDNA positivity (red) and negativity (grey) among patients in categories [1a,b] (B) and [1c] (C) and the effects of CSF-ctDNA detection for surgical planning and treatment initiation. D Bar plot and pie chart showing the fraction of patients with CSF-ctDNA positivity (tourquoise) and negativity (grey) among patients in categories [2] and the effects of CSF-ctDNA detection for surgical planning and treatment initiation. E This panel highlights patients who received CNSL-specific treatment based on CSF-ctDNA positivity. The left bar plot shows the fraction of patients obtaining either curative-intent (dark blue) or palliative (light blue) CNS-directed therapies. Right: These two bar plots highlight the response to these therapies. Dark green: radiological CR, light green: radiological PR, lightest green: clinical response (radiologically LFU or no evaluable brain lesion), grey: no evaluable brain lesion by MRI due to occult involvement, red: radiological PD. F Kaplan-Meier analysis of PFS (black) and OS (grey) in patients undergoing curative-intent therapy based on positive CSF-ctDNA results. The dotted line marks the 1-year time point. G Bar charts revealing the proportion of CSF samples being ctDNA positive (blue) or negative (grey) in patients with no corticosteroids (left) or with corticosteroid treatment (right) prior to and during lumbar puncture. CNSL, central nervous system lymphoma; SCNSL, secondary CNSL; PCNSL, primary CNSL; CSF, cerebrospinal fluid; ctDNA, circulating tumor DNA; CR, complete response; PR, partial response; PD, progressive disease; LFU, last follow-up; PFS, progression-free survival; OS, overall survival.
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