Integration of circulating tumor DNA profiling in the risk stratification of classical Hodgkin lymphoma in children, adolescents, and young adults.

This study aimed to define the potential role of circulating tumor DNA (ctDNA) in children, adolescents, and young adults (CAYA) with classical Hodgkin lymphoma (cHL). This prospective trial was conducted in France between 2019 and 2023 and recruited CAYA patients (≤25 years old) with a new diagnosis of cHL. Patients were treated according to the EuroNet-PHL-C2 trial (EudraCT: 2012-004053-88), and plasma ctDNA evaluations were performed at diagnosis, after two cycles of chemotherapy, and in case of relapse. Two hundred and seventy-five patients were included. Median age at diagnosis was 15 years (range 2-22), and 47% of the patients were treated as advanced stages (treatment level 3 [TL-3]). Using an 18-gene amplicon-based next-generation sequencing (NGS) targeted panel encompassing the most frequently mutated genes in cHL, at least one mutation was detected in 236/275 patients (86%). B-symptoms, erythrocyte sedimentation rate, and advanced stages were significantly associated with the level of ctDNA at diagnosis. TP53 mutations (19/275, 7%) were strongly associated with inadequate response at early response assessment. XPO1 and IGLL5 mutations were associated with a higher risk of relapse. The presence of detectable ctDNA after two cycles of chemotherapy (10%) was a strong and independent prognostic marker of relapse.