In conclusion, we showed that the Ro+R-CHOP combination is safe in treatment-naïve DLBCL patients, that the addition of roflumilast inhibited VEGF-A secretion in the urine and PI3K activity in the PBMCs, and that this new therapeutic scheme may be particularly active in specific genetic subsets of DLBCL. Here, PIK3CG is linked to diffuse large B-cell lymphoma.