Risk stratification of patients with diffuse large B-cell lymphoma using plasma NMR-based metabolomics at diagnosis.

ABSTRACT: Early detection of ultrahigh-risk diffuse large B-cell lymphoma (DLBCL) is an unmet medical need to aid patient stratification for alternative treatment approaches. Metabolomics applied to biofluids of patients with cancer has emerged as a novel omics that could provide important information to better stratify these patients. In this work, the authors performed a retrospective study by nuclear magnetic resonance (NMR)-based metabolomics using plasma samples at diagnosis from 154 randomized patients with DLBCL treated by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) (from the phase 3 REMARC [Reduced-intensity Maintenance therapy with Rituximab After R-CHOP in elderly patients with DLBCL] trial). Remarkably, a combination of 3 circulating metabolites was linked to lipid metabolism (named the "NMR score") that significantly affected overall survival (OS) (P< .0001) and progression-free survival (PFS) (P = .0003). The optimal cutoff 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 3 risk groups with low- (0-1), intermediate- (2-3), and high-risk (4-5) patients. Germinal center B-cell (GCB)/non-GCB profile along with Bcl2 and Myc expression did not correlate with NMR score survival. In conclusion, the combination of 3 circulating metabolites linked to lipid metabolism is revealed as a feature that captures heterogeneity among patients with DLBCL. This NMR score seemed promising for DLBCL risk stratification, even among responder patients after R-CHOP treatment. This trial was registered at www.ClinicalTrials.gov as #NCT01122472.