Single-center phase 1 trial of first-line R-CHOP plus the PDE4 inhibitor roflumilast for high-risk diffuse large B-cell lymphoma

Despite recent progress in the understanding of the biology of diffuse large B-cell lymphoma (DLBCL), R-CHOP has been the first-line treatment for more than 20 years. Preclinical work has shown a role of the PDE4 axis in B-cell receptors signals and PI3K4 activity in DLBCL. A phase 1 study at University of Texas Health Science Center San Antonio evaluated the combination of the PDE4 inhibitor roflumilast and R-CHOP for previously untreated high-risk DLBCL. Patients received 6 cycles of standard R-CHOP plus roflumilast 500 μg once daily. The combination was safe, with adverse events not different from AEs in a historical cohort receiving R-CHOP alone. At a median follow-up of 44 months, 70% of patients were alive and disease-free (median overall survival not reached, median progression-free survival rate 44%; 95% CI 21-92). There was evidence that addition of roflumilast to R-CHOP suppressed PI3K activity in peripheral blood mononuclear cells and VEGF-A secretion in the urine. The authors conclude that the combination of roflumilast and R-CHOP was safe and active in patients with previously untreated high-risk DLBCL.