Apeng Yang

Univariate and Multivariable Analysis of PFS in Overall

Kaplan–Meier survival curves comparing CR and non-CR patients by disease subtype

Univariate and Multivariate Logistic Regression Analysis of CR in Overall

Sites of CNS and other tissue involvement in SCNSL patients

Prior and Glofitamab Treatments

Characteristics and Response of patients with glofitamab monotherapy or combination therapy

Characteristics in CR and non-CR patients

Summary: Primary central nervous system lymphoma (PCNSL) exhibits marked clinical heterogeneity, while genomic risk stratification remains largely gene‐centric. The prognostic relevance of cumulative pathway‐level alterations remains unclear. Whole‐exome sequencing was performed in 76 newly diagnosed PCNSL patients treated with programmed cell death protein 1 (PD‐1) inhibitor–based immunochemotherapy. Somatic mutations were mapped to 10 canonical oncogenic pathways, and pathway disruption was quantified using the number of pathway alterations (NPAs). Associations with clinical, genomic and survival outcomes were evaluated. Frequent alterations were observed in the Notch, receptor tyrosine kinase–RAS (RTK–RAS), Hippo and Wingless‐related integration site (Wnt) pathways. NPA showed substantial interindividual variability and was strongly correlated with tumour mutational burden but only weakly associated with fraction of genome altered. Higher NPA was associated with distinct systemic inflammatory features and inferior overall and progression‐free survival. In multivariable analyses adjusting for International Extranodal Lymphoma Study Group (IELSG) score and LymphGen subtype, NPA remained independently associated with both overall survival (hazard ratio [HR] 1.26, p = 0.025) and progression‐free survival (HR 1.24, p = 0.029). Notch pathway alterations were associated with inferior survival and higher pathway activity scores. Pathway‐level mutational burden captures clinically relevant genomic heterogeneity and may serve as a prognostic biomarker in PCNSL.