CtDNA sequencing was applied to plasma and CSF samples using a targeted gene panel. Peripheral residual disease (PRD) was developed as a novel biomarker in CNSL and shown to be predictive of outcomes. Integration of dynamically assessed clinical and molecular features resulted in development and validation of MOP-C—a tool with high predictive value in CNSL. ECOG PS, Eastern Cooperative Oncology Group performance status; IELSG, International Extranodal Lymphoma Study Group. Created with BioRender.com. See Figure 1 in the article by Heger et al that begins on page 522.