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

Year: 2024

Type: article

Abstract: 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.

Source: Cancers

DOI: 10.3390/cancers16223857

Authors: Adolfo E. Diaz Duque, Pedro S. S. M. Ferrari, Purushoth Ethiraj, Carine Jaafar, Zhijun Qiu, Kenneth Holder, Mathew J. Butler, Gabriela Huelgas-Morales, Anand Karnad, Patricia L. M. Dahia, Ricardo C. T. Aguiar

Institutions: The University of Texas at San Antonio Health Science Center, Mays Cancer Center at UT Health San Antonio, Audie L. Murphy Memorial VA Hospital, South Texas Veterans Health Care System

Language: English

Topic: Lymphoma Diagnosis and Treatment

Subfield: Pathology and Forensic Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,296

Funders: U.S. Department of Veterans Affairs, Cancer Prevention and Research Institute of Texas, Leukemia and Lymphoma Society, Neuroendocrine Tumor Research Foundation, VHL Alliance, National Institutes of Health, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Environmental Health Sciences

OpenAlex ID: W4404500380