Genomic features of clonal hematopoiesis associated genes in primary and CAR T-cell related secondary T-cell malignancies

• Secondary TCLs after CAR T-cell therapy are enriched in genomic alterations in CH associated genes, particularly TET2 and DNMT3A. • Primary and secondary TCLs have shared genomic alterations, including in genes associated with CH and JAK-STAT signaling. Secondary T-cell leukemias and lymphomas (TCLs) following chimeric antigen receptor (CAR) T-cell therapy represent an emerging concern, but the pathogenesis remains poorly understood. Risk factors are multifactorial and potentially include exposure to prior anticancer treatments, insertional mutagenesis, and latent oncogenic mutations. In this study, the molecular features of CAR T-cell associated secondary TCLs are analyzed and contrasted with primary TCLs. Our study examines the role of clonal hematopoiesis and its interplay with somatic mutations that are associated with TCL pathogenesis, with implications for patient risk stratification, monitoring, and treatment.