Tumor-infiltrating clonal hematopoiesis is associated with adverse clinical outcomes in diffuse large B-cell lymphoma

Tumor-infiltrating clonal hematopoiesis (TI-CH) contributes to progression of non-hematologic cancers. CH is prevalent in peripheral blood of patients with diffuse large B-cell lymphoma (DLBCL), but TI-CH prevalence and clinical relevance remain largely unexplored. Here, through genome- and exome-wide sequencing of DLBCL biopsies and blood samples from 304 treatment-naïve patients, we identified TI-CH in 13.5% of cases, which emerged as an independent risk indicator for disease progression and death. TI-CH cases had enrichment of inflammatory myeloid signature revealed by gene expression profiling of tumor biopsies. In addition, we developed a TI-CH-associated prognostic signature (CAPS) based on 24 differentially expressed genes. High CAPS score correlated with poor survival across four patient cohorts, and remained significant in three cohorts after adjustment for patient age, sex, International Prognostic Index score, and cell-of-origin classification. Collectively, these findings establish a link between TI-CH and clinical outcomes and implicate inflammatory signature as the potential underlying basis.