Plasma metabolomics and ctDNA analysis in newly diagnosed diffuse large B-cell lymphoma: an exploratory study
Year: 2026
Type: article
Study design: Observational Study
Abstract: Despite the development of robust prognostic biomarkers for risk stratification in newly diagnosed diffuse large B-cell lymphoma (DLBCL), namely international prognostic index (IPI), cell-of-origin (COO), circulating tumor DNA (ctDNA) and molecular clusters, none of these capture potential host-related features. In this study, untargeted plasma metabolomics was performed in a discovery cohort of 96 newly diagnosed R-CHOP-treated DLBCL patients. The key finding was validated in an independent cohort of 42 DLBCL with comparable clinical characteristics and outcomes. None of the 280 identified plasma metabolites was associated with COO classification subtypes. Conversely, the metabolomic profile appeared to show variations across ctDNA-defined molecular clusters. After an elastic net regression-based survival analysis, 2-hydroxybutyric acid (2HB) was selected as the only endogenous metabolite to be associated with worse progression-free survival (PFS) in the discovery cohort. The impact of 2HB levels on PFS was confirmed in the validation cohort. Also, 2HB levels (HR 2.09, 95% CI 1.04-4.19, p=0.04) maintained an independent association with shorter PFS when adjusted for higher ctDNA levels (HR 2.08, 95% CI 1.06-4.08, p=0.03). Therefore, 2HB and ctDNA levels were included in a two-factor prognostic score based entirely on minimally invasive plasma-derived biomarkers. This hypothesis-generating score improved outcome prediction compared with ctDNA assessment alone and enabled the identification of high-risk patients who might benefit from early restaging and potential treatment intensification (24-month PFS 28.8%). In conclusion, plasma metabolomics revealed a prognostically relevant role and 2HB sorted out as a potential host-related biomarker able to refine risk stratification in newly diagnosed DLBCL.
Source: Blood Advances
Authors: Riccardo Dondolin, Mohammad Almasri, Denise Marradi, Elettra Barberis, Shahzaib Khoso, Nawar Maher, Samir Mouhssine, Federico Garrou, Tamara Bittolo, Andrea Duminuco, Enrica Antonia Martino, Lodovico Terzi di Bergamo, Matin Salehi, Luca Cividini, Chiara Cosentino, Jana Nabki, Bashar Al Deeban, Joseph Ghanej, Francesca Maiellaro, Annalisa Giovanna Andorno, Francesca Mercalli, Andrea Carletti, Monica Leutner, Angela Lorenzi, Abdurraouf Mokhtar Mahmoud, Ndeye Marie Diop, Sreekar Kogila, Eleonora Secomandi, Clara Deambrogi, Silvia Rasi, Renzo Boldorini, Massimo Gentile, Giuseppe A Palumbo, Mattia Schipani, Riccardo Bruna, Riccardo Bomben, Valter Gattei, Robin Foa, Davide Rossi, Alessandra Gennari, Gian Mauro Sacchetti, Gianluca Gaidano, Marcello Manfredi, Riccardo Moia
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
OpenAlex ID: W7224768656