First-Line Combination of R-CHOP with the PDE4 Inhibitor Roflumilast for High-Risk DLBCL

Diffuse large B-cell lymphoma (DLBCL) is a common and often fatal cancer type. Despite recent progress in our understanding of DLBCL biology, the translation of this knowledge into clinical initiatives has lagged, and the first-line treatment for this tumor type, the immunochemotherapy R-CHOP, has been the same for more than two decades. We previously identified the cyclic-AMP/phosphodiesterase 4 (PDE4) axis as a critical modulator of B-cell receptor (BCR) signals and PI3K activity in DLBCL. Pre-clinically and clinically, we confirmed that PDE4 inhibition suppressed PI3K activity, and downstream to it, angiogenesis in the lymphoma microenvironment. Here, we report on a phase 1 clinical trial that combines the PDE4 inhibitor roflumilast with R-CHOP in treatment-naïve DLBCL patients. We show that this combination is safe, active, and inhibits PI3K activity and VEGF-A levels. Further, we preliminarily identified the genetic subtypes of DLBCL that may be especially vulnerable to this new drug combination.