Clonal hematopoiesis and cell-free DNA characteristics in patients with high-risk large B-cell lymphomas

Clonal hematopoiesis (CH) can predict treatment outcomes in solid cancers, but the prevalence and clinical impact of CH in previously untreated, aggressive large B-cell lymphomas (LBCL) remains poorly characterized. Moreover, CH may be detected in cell-free DNA (cfDNA)-based biomarker assays, but the longitudinal dynamics of CH mutations during and after immunochemotherapy in LBCL remain unknown. Hence, we characterized the spectrum of CH mutations in 247 patients with high-risk primary LBCL from three phase II clinical trials. We identified CH mutations in 23% of patients. Compared with healthy controls, TET2 mutations were enriched in peripheral blood (PB) samples of LBCL patients (P=0.01). CH clone size showed high concordance between PB and cfDNA (R2=0.59, P<0.0001) but was not associated with circulating tumor DNA (ctDNA) concentration (P-values 0.25-0.86). In contrast with prior reports in the context of recurrent lymphoma, CH mutation status was not associated with overall survival (OS) (P=0.78) or progression-free survival (PFS) (P=0.89) in our primary LBCL cohort. CH clones showed variable longitudinal dynamics during immunochemotherapy, with 18% of evaluable patients developing mutant CH clones, mostly with TP53/PPM1D mutations. Together, CH mutations can be readily detected in cfDNA of lymphoma patients, but they do not predict survival in primary high-risk LBCL.