Risk stratification of diffuse large B-cell lymphoma patients using plasma NMR-based metabolomics at diagnostic Open Access

• Plasma NMR-based metabolomics at diagnosis allows early detection of ultra-high risk DLBCL patients.

• NMR score based on a combination of three circulating metabolites linked to lipid metabolism is predictive of worse prognosis (OS and PFS).

Early detection of ultra-risk diffuse large B-cell lymphoma (DLBCL) is an unmet medical need to aid patient stratification for alternative treatment approaches. Metabolomics applied to cancer patient biofluids has emerged as a novel Omics that could provide important information to better stratify cancer patients. We performed a retrospective study by nuclear magnetic resonance (NMR)-based metabolomics using plasma samples at diagnosis from 154 randomized DLBCL patients treated by R-CHOP (from the phase 3 REMARC trial, #NCT01122472). Remarkably, we identified a combination of three circulating metabolites linked to lipid metabolism (named the "NMR score") that significantly impacted on overall survival (OS) (p < 0.0001) and progression-free survival (PFS) (p = 0.0003). The optimal cut off for each metabolite was determined using X-Tile and confirmed by a training validation method. Combining 2-amino-butyrate, 3-hydroxy-butyrate and LDL-1 lipoprotein yielded three risk groups with low (0-1), intermediate (2-3) and high risk (4-5) patients. GCB/non-GCB profile along with Bcl2 and Myc expression did not correlate with NMR score survival. In conclusion, we revealed that a combination of three circulating metabolites linked to lipid metabolism is a feature that capture DLBCL patient heterogeneity. This NMR score appeared promising for DLBCL risk stratification, even among responder patients after R-CHOP treatment.