MRD-2 in the GHSG HD21 trial assessed by a validated circulating tumor DNA sequencing assay

Beyond cure, major goals in patients with Hodgkin lymphoma (HL) are tailoring treatment to a patient's individual risk for relapse to reduce acute and late toxicities, identifying candidates for early incorporation of novel agents, and making treatment affordable on a global level. Minimal residual disease (MRD) assessment by circulating tumor (ct)DNA sequencing emerged as a promising strategy to achieve these goals; however, previous studies differed in sampling timepoints, assay validation, and definitions for MRD negativity. Here, we applied LymphoVista - a validated ctDNA sequencing assay for genotyping and MRD monitoring in lymphoma - to samples obtained from the GHSG HD21 trial following two cycles of treatment (MRD-2) using a case-cohort-design. Patients with positive MRD-2 were at higher risk for relapse, progression or death compared with MRD-2 negative patients (4-year progression-free survival (PFS): 36.7% vs. 82.2%; HR 5.3, 95%CI 2.0-13.8; p = 0.0008). Following inverse probability weighting accounting for the number of events in the full reference set, patients with positive and negative MRD-2 had 4-year PFS rates of 72.2% vs. 95.3%. By combining MRD-2 with PET-2, patients were stratified into three distinct groups regarding risk of relapse: low (MRD-2 negative and PET-2 negative), intermediate (MRD-2 positive or PET-2 positive), and high (MRD-2 positive and PET-2 positive). In summary, these results suggest that assessment of MRD-2 by LymphoVista allows for early outcome prognostication in patients with HL and could be used as a tool to improve treatment guidance on its own or in conjunction with PET-2.