Next-generation sequencing-based monitoring of circulating tumor DNA reveals clonotypic heterogeneity in untreated PTCL

Peripheral T-cell lymphomas (PTCLs) have marked biologic and clinical heterogeneity, which confounds treatment decisions. Advances in circulating tumor DNA (ctDNA) assays using next-generation sequencing (NGS) have improved the detection of molecular relapse and driver mutations in diffuse large B-cell lymphoma and show the potential utility of ctDNA across lymphomas. We investigated NGS-based monitoring of T-cell receptor (TCR) sequences in patients with PTCL undergoing frontline treatment. Of 45 patients, 34 (76%) had tumor-specific clonotypes of the TCRO or TCRy genes identified, which included 18 (86%) from baseline tissue and 16 (67%) from baseline serum. Twenty-five (74%) patients had both TCRO and TCRy clonotypes, 23 (68%) had more than 1 TCRy clonotype, and 4 (9%) had multiple TCRO or TCRy clonotypes, demonstrating significant intrapatient clonotypic heterogeneity. Among 24 patients with available serial serum samples during treatment, 9 (38%) cleared ctDNA after 2 cycles of therapy, and 11 (46%) had detectable ctDNA at the end of treatment. Patients with detectable ctDNA after therapy showed a trend toward worse survival. Notably, 2 patients with persistently detectable ctDNA after therapy remained in remission with 10 years of follow-up. Clonotypic heterogeneity in tumors and persistence, despite long-term remission, suggests variability in oncological potential. This trial was registered at www.clinicaltrials.gov as #NCT00001337.

Automated summary

Peripheral T-cell lymphomas (PTCLs) exhibit significant heterogeneity in terms of biology and clinical presentation, making treatment decisions challenging. This study showed that monitoring T-cell receptor (TCR) sequences using next-generation sequencing (NGS) identified tumor-specific clonotypes in PTCL patients undergoing frontline treatment. Patients with detectable ctDNA after therapy tended to have worse survival outcomes, indicating the potential utility of ctDNA as a prognostic marker in PTCL.