Steven Wang, Parisa Mapar, Norbert Moldovan, Ymke van der Pol, Aram Safrastyan, Erik van Werkhoven, Normastuti Adhini Tantyo, Bart Snieder, André F Do Brito Valente, A Vera de Jonge, Avinash Dinmohamed, Esther E E Drees, Margaretha G M Roemer, Bauke Ylstra, Clara P W Klerk, Leonie Strobbe, Yorick Sandberg, Rinske S Boersma, Harry Koene, Hans Pruijt, Koen de Heer, Rozemarijn van Rijn, Yavuz M Bilgin, Eva de Jongh, Marcel Nijland, Marjolein van der Poel, Ad Koster, Laurens Nieuwenhuizen, Rob Fijnheer, Aart Beeker, Rogier Mous, Vibeke K J Vergote, Joost S P Vermaat, D Michiel Pegtel, Martine E D Chamuleau, Florent Mouliere
Curative-intent immunochemotherapy fails in ∼30% of patients with large B cell lymphoma (LBCL), yet no validated molecular tool enables early identification of high-risk individuals to guide treatment intensification. Using shallow whole-genome sequencing (sWGS) of plasma cell-free DNA from 190 LBCL patients, we develop and validate the ACT score (aberrations, composition of fragments, and terminal motif analyses), a composite classifier integrating genomic and fragmentomic features from a single post-cycle-1 sample. ACT-positive patients have worse 2-year outcomes versus ACT-negative patients: time-to-progression 29% vs. 83% (hazard ratio [HR]: 4.4, 95% confidence interval [CI]: 1.9-10.0; p = 1.5 × 10-4) and overall survival 47% vs. 93% (HR: 8.7, 95% CI: 3.0-25.4; p = 1.8 × 10-6). The ACT score is independently prognostic of the International Prognostic Index, and their combination identifies the highest risk patients. Unlike mutation-based approaches, this assay requires neither tumor tissue, germline control, nor a baseline plasma sample. Built on open-source tools and sWGS, the ACT score offers a feasible, scalable strategy for early risk stratification in aggressive LBCL.