Cell-Free DNA Genomic and Fragmentomic Features for Early Outcome Prediction in Large B-Cell Lymphoma.
Wang, S.; Mapar, P.; Moldovan, N.; van der Pol, Y.; Safrastyan, A.; van Werkhoven, E.; Tantyo, N. A.; Snieder, B.; Do Brito Valente, A. F.; de Jong, A. V.; Dinmohamed, A.; Drees, E. E. E.; Roemer, M. G. M.; Ylstra, B.; Klerk, C. P. W.; Strobbe, L.; Sandberg, Y.; Boersma, R. S.; Koene, H.; Pruijt, H.; de Heer, K.; van Rijn, R.; Bilgin, Y. M.; de Jongh, E.; Nijland, M.; van der Poel, M.; Koster, A.; Nieuwenhuizen, L.; Fijnheer, R.; Beeker, A.; Mous, R.; Vergote, V. K. J.; Vermaat, J. S. P.; Pegtel, D. M.; Chamuleau, M. E. D.; Mouliere, F.
Show abstract
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 developed and validated the ACT score (Aberrations, fragment Composition, Terminal motifs), a composite classifier integrating genomic and fragmentomic features from a single post-cycle-1 sample. ACT-positive patients had worse 2-year outcomes versus ACT-negative patients: time-to-progression 29% vs. 83% (HR 4.4, 95% CI 1.9 - 10.0; P = 1.5 x 10 - 4) and overall survival 47% vs. 93% (HR 8.7, 95% CI 3.0 - 25.4; P = 1.8 x 10-6). ACT score was independently prognostic of the International Prognostic Index, and their combination identified 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.
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