Circulating tumor DNA reveals genetics, clonal evolution and residual disease in classical Hodgkin lymphoma

Valeria Spina, Alessio Bruscaggin, Annarosa Cuccaro, Maurizio Martini, Martina Di Trani, Gabriela Forestieri, Martina Manzoni, Adalgisa Condoluci, Alberto Arribas, Lodovico Terzi-Di-Bergamo, Silvia Laura Locatelli, Elisa Cupelli, Luca Ceriani, Alden A. Moccia, Anastasios Stathis, Luca Nassi, Clara Deambrogi, Fary Diop, Francesca Guidetti, Alessandra Cocomazzi, Salvatore Annunziata, Vittoria Rufini, Alessandro Giordano, Antonino Neri, Renzo Boldorini, Bernhard Gerber, Francesco Bertoni, Michele Ghielmini, Georg Stüssi, Armando Santoro, Franco Cavalli, Emanuele Zucca, Luigi Maria Larocca, Gianluca Gaidano, Stefan Hohaus, Carmelo Carlo-Stella and Davide Rossi

Key points

  • ctDNA is as an easily accessible source of tumor DNA for cHL genotyping

  • ctDNA is a radiation-free tool to track residual disease in cHL


The rarity of neoplastic cells in the biopsy imposes major technical hurdles that have so far limited genomic studies in classical Hodgkin lymphoma (cHL). By using a highly sensitive and robust deep-next-generation-sequencing approach for circulating tumor DNA (ctDNA), here we aimed at tracking the genetics of cHL in different clinical phases, and its modifications upon treatment. The analysis was based on specimens collected from 80 newly diagnosed and 32 refractory cHL patients, including longitudinal samples collected under ABVD chemotherapy and longitudinal samples from relapsing patients treated with chemotherapy and immunotherapy. ctDNA mirrored Hodgkin and Reed-Sternberg cell genetics, thus establishing ctDNA as an easily accessible source of tumor DNA for cHL genotyping. By identifying STAT6 as the most frequently mutated gene in ~40% of cases, we refined the current knowledge of cHL genetics. Longitudinal ctDNA profiling identified treatment-dependent patterns of clonal evolution in patients relapsing after chemotherapy and patients maintained in partial remission under immunotherapy. By measuring ctDNA changes during therapy, we propose ctDNA as a radiation-free tool to track residual disease that may integrate PET imaging for the early identification of chemorefractory cHL patients. Collectively, our results provide the proof of concept that ctDNA may serve as novel precision medicine biomarker in cHL.

  • Submitted November 3, 2017.
  • Accepted February 11, 2018.