Plasma metabolomics and ctDNA analysis in newly diagnosed diffuse large B-cell lymphoma: an exploratory study
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.
Authors
- Robin Foà (ORCID: https://orcid.org/0000-0002-5021-3026)
- Lodovico Terzi di Bergamo (ORCID: https://orcid.org/0000-0002-0843-9128)
- Enrica Antonia Martino (ORCID: https://orcid.org/0000-0002-8504-3231)
- Davide Rossi (ORCID: https://orcid.org/0000-0002-2837-1597)
- Massimo Gentile (ORCID: https://orcid.org/0000-0002-5256-0726)
- Renzo Luciano Boldorini (ORCID: https://orcid.org/0000-0003-1183-2737)
- Tamara Bittolo (ORCID: https://orcid.org/0000-0003-3674-4362)
- Riccardo Moia (ORCID: https://orcid.org/0000-0001-7393-1138)
- Nawar Maher (ORCID: https://orcid.org/0009-0007-9307-1965)
- Mohammad Almasri (ORCID: https://orcid.org/0000-0002-0048-3845)
- Mattia Schipani (ORCID: https://orcid.org/0009-0009-5710-2781)
- Gianluca Gaïdano (ORCID: https://orcid.org/0000-0002-4681-0151)
- Monica Leutner (ORCID: https://orcid.org/0000-0002-7042-3215)
- Alessandra Gennari (ORCID: https://orcid.org/0000-0002-0928-2281)
- Francesca Mercalli (ORCID: https://orcid.org/0000-0003-0818-4660)
- Silvia Rasi (ORCID: https://orcid.org/0000-0003-4935-3918)
- Matin Salehi
- Chiara Cosentino (ORCID: https://orcid.org/0000-0001-8199-4593)
- Angela Lorenzi
- Sreekar Kogila
- Giuseppe A. Palumbo (ORCID: https://orcid.org/0000-0003-1859-6319)
- Eleonora Secomandi
- Valter Gattei (ORCID: https://orcid.org/0000-0001-5933-9680)
- Riccardo Dondolin (ORCID: https://orcid.org/0009-0007-6842-3594)
- Clara Deambrogi
- Gian Mauro Sacchetti (ORCID: https://orcid.org/0000-0003-2690-4078)
- Elettra Barberis (ORCID: https://orcid.org/0000-0002-2296-9766)
- Samir Mouhssine (ORCID: https://orcid.org/0000-0002-0389-3268)
- Andrea Duminuco (ORCID: https://orcid.org/0000-0002-9510-4755)
- Riccardo Bruna (ORCID: https://orcid.org/0000-0002-8904-4098)
- Marcello Manfredi (ORCID: https://orcid.org/0000-0003-0632-5618)
- Joseph Ghanej (ORCID: https://orcid.org/0000-0002-9515-5827)
- Abdurraouf Mokhtar Mahmoud (ORCID: https://orcid.org/0000-0002-3969-0112)
- Riccardo Bomben (ORCID: https://orcid.org/0000-0002-8746-9404)
- Federico Garrou (ORCID: https://orcid.org/0009-0002-0873-4247)
- Shahzaib Khoso (ORCID: https://orcid.org/0000-0003-4181-6666)
- Jana Nabki (ORCID: https://orcid.org/0009-0008-6891-4825)
- Luca Cividini (ORCID: https://orcid.org/0009-0007-8096-7391)
- Bashar Al Deeban (ORCID: https://orcid.org/0000-0002-4218-1917)
- Francesca Maiellaro (ORCID: https://orcid.org/0009-0003-0725-2876)
- Denise Marradi
- Ndeye Marie Diop (ORCID: https://orcid.org/0009-0001-1551-8801)
- Andrea Carletti (ORCID: https://orcid.org/0009-0004-5214-1224)
- Annalisa Giovanna Andorno
Institutions
- Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT)
- University of Catania (IT)
- Institute of Oncology Research (CH)
- Azienda Ospedaliera di Cosenza (IT)
- Azienda Ospedaliero Universitaria Maggiore della Carita (IT)
- Centro di Riferimento Oncologico (IT)
- Sapienza University of Rome (IT)
Publication Details
- Journal
- Blood Advances
- Published
- 2026-10-30
- DOI
- https://doi.org/10.1182/bloodadvances.2026021464
- Primary Topic
- Lymphoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00