Quantitative and mutational properties in the ctDNA uncovered by systemic inflammation in large B-cell lymphoma

Risk assessment of large B-cell lymphomas (LBCLs) using liquid biopsy (LB) has so far focused primarily on the genomic properties of circulating tumor DNA (ctDNA), overlooking the host response. We previously identified an inflamed serum protein signature that reflects systemic host response and correlates with survival. Here, we integrated the inflammation signature and ctDNA to connect inflammation to genomic alterations and defined how this crosstalk informs treatment outcomes in two independent LBCL cohorts from Nordic phase II trials. We identify initiation of immune evasion at multiple genomic levels in patients with an inflammatory serum profile and uncover distinct mutational signatures that reflect diagnostic subtypes and inflammatory host response. We describe the added prognostic value of multimodal LB assessment, where patients with high levels of both ctDNA and inflammatory serum proteins have the worst overall survival (hazard ratio 7.93, p < 0.001) and progression free survival (hazard ratio 5.35, p < 0.001), thereby improving the risk estimate compared to either of the markers alone. This advanced multimodal LB employs clinically critical information on lymphoma and the host, both of which are essential for accurate treatment decision-making.