S. Fernández-Castillejo, J. Badia, L. de la Cruz-Merino, A. Martín Garcia-Sáncho, F. Carnicero-González, N. Palazón-Carrión, E. Ríos-Herranz, F. de la Cruz-Vicente, A. Rueda-Domínguez, N. Martínez-Banaclocha, J. Gómez-Codina, J. Labrador, F. Martínez-Madueño, N. Amigó, A. Salar-Silvestre, D. Rodríguez-Abreu, L. Gálvez-Carvajal, M. Sánchez-Beato, M. Provencio-Pulla, M. Guirado-Risueño, E. Nogales, V. Sánchez-Margalet, C. Jiménez-Cortegana, G. Rodríguez-García, R. Cumeras, J. Gumà, et al. (2025). Ketone Bodies Are Potential Prognostic Biomarkers in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Results from the R2-GDP-GOTEL Trial. Cancers, 17(3). https://doi.org/10.3390/cancers17030532

PubMed 39941898

[Abstract]
Background: Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who are ineligible for high-dose chemotherapy have limited treatment options and poor life expectancy. The purpose of this study is to identify a serum metabolomic profile that may be predictive of outcome in patients with R/R-DLBCL. Methods: This study included 69 R/R DLBCL patients from the R2-GDP-GOTEL trial (EudraCT 2014-001620-299). Serum samples were collected at baseline, and the mean length of follow-up was 41 months. Serum metabolites were analyzed by nuclear magnetic resonance (NMR). Metabolites were correlated with treatment response, progression-free survival (PFS), and overall survival (OS). Results: Serum levels of 3-hydroxybutyrate (3OHB) and acetone were significantly (p < 0.001) associated with PFS (3OHB: hazard ratio [HR] 7.7, 95% confidence interval [CI] 2.5-24.1; acetone: HR 9.32, 95% CI 2.75-31.6) and OS (3OHB: HR 9.32, 95% CI 2.75-31.6; acetone: HR 1.92, 95% CI 1.36-2.69). Serum values of 141 µM for 3OHB and 40 µM for acetone were the optimal cutoffs associated with the survival outcomes. Elevated 3OHB levels (>141 μM) were specific to the ABC subtype of DLBCL, while acetone levels were elevated in both types of DLCBL but more pronounced in ABC cases. In a multivariate survival analysis, including the International Prognostic Index (IPI) score and refractoriness status (R/R), 3OHB and acetone remained significant. To aid oncologists employing the R2-GDP regime, we constructed PFS and OS nomograms for R/R-DLBCL risk stratification, incorporating 3OHB levels or acetone levels, IPI score, and refractoriness status. The nomogram with 3OHB and refractoriness status showed a time-dependent AUC of 0.86 for 6-month PFS and 0.84 for 12-month OS. These nomograms provide a comprehensive tool for individualized risk assessment and treatment optimization. Conclusions: The ketone bodies 3OHB and acetone are potential prognostic biomarkers of poor outcome in R/R DLBCL patients treated with the R2-GDP regimen, independently of IPI score and chemorefractoriness status.