Duque Adolfo E Diaz, Ferrari Pedro S S M, Ethiraj Purushoth, Jaafar Carine, Qiu Zhijun, Holder Kenneth, Butler Mathew J, Huelgas-Morales Gabriela, Karnad Anand, Dahia Patricia L M, Aguiar Ricardo C T
Division of Hematology and Medical Oncology, Mays Cancer Center, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA.
Department of Pathology, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA.
Cancers (Basel). 2024 Nov 18;16(22):3857. doi: 10.3390/cancers16223857.
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.
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.
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.
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.
弥漫性大B细胞淋巴瘤（DLBCL）是一种常见且往往致命的恶性肿瘤。标准的免疫化疗方案R-CHOP仅能治愈约60%的DLBCL患者。提高治愈率可能需要将基础生物学知识有效地转化为临床实践。我们之前确定环磷酸腺苷/磷酸二酯酶4（PDE4）轴是淋巴瘤发生过程的重要调节因子。我们还表明，美国食品药品监督管理局（FDA）批准的PDE4抑制剂罗氟司特可抑制B细胞受体（BCR）信号、磷酸肌醇3激酶（PI3K）活性和血管生成。这些数据表明，罗氟司特与R-CHOP联合使用可能对DLBCL有益。
我们对经病理证实、未经治疗的高危DLBCL患者进行了一项单中心、单臂、开放标签的1期研究，研究罗氟司特与标准治疗方案R-CHOP（Ro+R-CHOP）联合使用的情况。
Ro+R-CHOP是安全的，中位随访时间为44个月时，70%的患者存活且无疾病（中位总生存期未达到，无进展生存期为44%（95%CI，21-92））。在这个试点系列中，我们发现添加罗氟司特可抑制外周血单核细胞中的PI3K活性以及尿液中的血管内皮生长因子A（VEGF-A）分泌。我们还遇到了初步证据表明，Ro+R-CHOP联合方案可能对诊断为DLBCL高危基因亚型（即MCD和A53）的患者特别有益。
这些初步发现表明，罗氟司特可能是一种能够抑制DLBCL中BCR/PI3K活性和血管生成的替代药物，并且有必要在更多具有基因特征的肿瘤系列中对Ro+R-CHOP进行测试。本研究已在ClinicalTrials.gov注册，注册号为NCT03458546。
