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

Simple Summary: 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. Background: Diffuse large B-cell lymphoma (DLBCL) is a common and often fatal malignancy. The standard-of-care immunochemotherapy, R-CHOP, cures only about 60% of DLBCL patients. Improving this cure rate will likely require the effective translation of basic biology knowledge into clinical activities. We previously identified the cyclic-AMP/phosphodiesterase 4 (PDE4) axis as an important modulator of lymphomagenic processes. We also showed that the FDA-approved PDE4 inhibitor roflumilast can suppress B-cell receptor (BCR) signals, phosphoinositide 3-kinase (PI3K) activity and angiogenesis. These data suggested that combining roflumilast with R-CHOP may be beneficial in DLBCL. Methods: We conducted a single-center, single-arm, open-label, phase 1 study of roflumilast in combination with the standard of care, R-CHOP (Ro+R-CHOP), in pathologically proven, treatment-naïve, high-risk DLBCL patients. Results: Ro+R-CHOP was safe, and at a median follow-up time of 44 months, 70% of patients were alive and disease free (median OS not reached, PFS 44% (95% CI, 21–92). In this pilot series, we found that the addition of roflumilast suppressed PI3K activity in peripheral blood mononuclear cells, and VEGF-A secretion in the urine. We also encountered preliminary evidence to suggest that the Ro+R-CHOP combination may be particularly beneficial to patients diagnosed with high-risk genetic subtypes of DLBCL, namely MCD and A53. Conclusions: These initial findings suggest that roflumilast may be an alternative agent able to inhibit BCR/PI3K activity and angiogenesis in DLBCL, and that the testing of Ro+R-CHOP in a larger series of genetically characterized tumors is warranted. This study was registered at ClinicalTrials.gov, number NCT03458546. [ABSTRACT FROM AUTHOR]