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), we aimed to identify the genetics of cHL in different clinical phases, as well as its modifications on treatment. The analysis was based on specimens collected from 80 newly diagnosed and 32 refractory patients with cHL, including longitudinal samples collected under ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) 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 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 positron emission tomography imaging for the early identification of chemorefractory patients with cHL. Collectively, our results provide the proof of concept that ctDNA may serve as a novel precision medicine biomarker in cHL.
sensitized an expanded panel of eight cHL cells towards the B-cell Non-Hodgkin's lymphoma-tailored small compound inhibitors of BCR signaling, ibrutinib and idelalisib, where dramatic death rates were observed after priming with two restore agents. Further investigations, including pre-clinical mouse trials, are currently in progress and will be reported at the meeting. Conclusions: In essence, we present here a novel "Restore & Target" strategy that builds on the re-expression of a lost tumor cell phenotype in the first place followed by it specific exploration as druggable vulnerability in a subsequent step. Such a strategy would expand the arsenal of treatment options for cHL by a "chemo-free" combination, and might not only be of interest for relapsed or refractory patients.
We recommend that each and every case observed be recorded, to enable the true extent of human dirofilariasis in Italy to be assessed, and that a reference centre be set up in the area to collate the data. The importance of the histopathologist's role in the diagnosis is stressed.
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