Combination of Phosphodiesterase 4 (PDE4) Inhibitor Roflumilast and R-CHOP As First-Line Therapy for High-Risk Diffuse Large B Cell Lymphoma Patients
Authors: Diaz Adolfo E , Butler Matthew James , Karnad Anand , Aguiar Ricardo 
Published: November 2019

R-CHOP remains the standard therapy for diffuse large B cell lymphoma (DLBCL), even though long-term disease free survival is achieved in only ~60-70% of the patients. One approach to improve on this cure rate is to implement rationally devised therapeutic strategies that capitalize on a better understanding of lymphoma biology, and on robust pre-clinical data. Still, in many instances clinical translation is limited by the difficulty in inhibiting key lymphomagenic proteins (e.g., MYC), or by subpar clinical responses and/or toxicity associated with the use of inhibitors to well-validated targets (e.g., SYK, BTK, PI3K, VEGF, etc.). Using genome-wide studies, we identified high expression of phosphodiesterase 4B (PDE4B) in fatal DLBCLs (Nat Med. PMID: 11786909). PDE4 hydroxylases cyclic adenosine monophosphate (cAMP) thus terminating its inhibitory signals and promoting B lymphocytes survival. Using in vitro and in vivo models, we showed that PDE4 inhibition augments cAMP signals and suppresses PI3K-AKT activity in DLBCL (Blood, PMID: 15331441). We mapped these events to SYK inhibition downstream of the B cell receptor (BCR) (Blood, PMID: 19369227). PDE4 inhibitors also suppress the pro-angiogenic lymphoma microenvironment by directly inhibiting the endothelium, and by decreasing VEGF production/secretion by the lymphoma cells, as we showed in a mouse engineered to develop lymphoma in a Pde4b KO background (Leukemia, PMID: 26503641). Earlier, we built on these pre-clinical data to test the safety and pharmacodynamics of the PDE4 inhibitor roflumilast (FDA-approved for COPD) in patients with relapsed/refractory mature B cell malignancies. In that first-in-cancer drug-repurposing study (NCT01888952), we found that roflumilast was well tolerated, clinically active, and that it suppressed PI3K activity, which correlated with the degree of clinical response (Clin. Cancer Res PMID: 27542768).
Aberrant BCR signaling and angiogenesis are integral to the pathogenesis of DLBCL. Yet, combination of either ibrutinib or bevacizumab with R-CHOP was not beneficial in this disease. Thus, considering the pleiotropic anti-lymphoma properties of PDE4 inhibitors (seeBloodPMID: 27756749), which includes BCR suppression and anti-angiogenesis, we opened a trial to test the combination of roflumilast with R-CHOP in treatment naïve DLBCLs (NCT03458546). This is a single center, phase Ib, open label, non-randomized single arm study of roflumilast + R-CHOP (RR-CHOP) aimed at untreated high-risk DLBCL patients. Key eligibility criteria include: non-GCB DLBCL (Han's algorithm), NCCN-IPI risk score of ≥ 2, Ann Arbor stage II-IV; key exclusion criteria include active CNS involvement and documented history of severe depression (a specific concern related to the use of roflumilast). Patients will receive R-CHOP every 21 days for 6 cycles, and roflumilast PO daily (500 mcg) throughout the 18-week treatment period. Given the anti-angiogenic properties of PDE4 inhibitors that we documented pre-clinically, and the prohibitive cardiotoxicity of bevacizumab + R-CHOP combination, we will monitor serum levels of troponin and B-type natriuretic peptide, as biomarkers for cardiac toxicity. In addition, PBMC, plasma and urine samples will be collected for measurement SYK/PI3K/AKT activity and VEGF levels at baseline and before cycles 3 and 6. Exome sequencing of germline and tumor DNA is to be performed too. Adverse events will be assessed and documented according to the CTCAE version 4.03 criteria. Eligible patients will be included in the intent-to-treat analysis. The primary objective of this study is to test safety and tolerability of RR-CHOP; the secondary objectives are to preliminarily assess anti-tumor efficacy of the combination and the biomarker potential of SYK/PI3K/AKT activity and VEGF levels. Given its exploratory nature, this study was designed for a cohort of 10 patients, in which no statistical assessment of response or sample size calculation was included. To date, we have met ~50% of the target accrual, with half of those patients being of Hispanics ethnicity. If RR-CHOP is proven safe, the next step will be to initiate a randomized trial that compares RR-CHOP to R-CHOP in untreated DLBCL patients, which should conclusively validate (or refute) our extensive, biologically-informed, pre-clinically data on the benefits of PDE4 inhibitors for the treatment of mature B cell malignancies.

Disclosures
No relevant conflicts of interest to declare.

OffLabel Disclosure:
roflumilast - PDE4 inhibitor, FDA-approved for COPD patients.