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.
背景：弥漫性大B细胞淋巴瘤（DLBCL）是一种常见且常致命的恶性肿瘤。标准免疫化疗方案R-CHOP仅能治愈约60%的DLBCL患者。提高治愈率需要将基础生物学知识有效转化为临床实践。我们先前发现环磷酸腺苷/磷酸二酯酶4（PDE4）轴是淋巴瘤发生过程的重要调节因子，并证实美国食品药品监督管理局批准的PDE4抑制剂罗氟司特可抑制B细胞受体（BCR）信号传导、磷脂酰肌醇3-激酶（PI3K）活性及血管生成。这些数据提示罗氟司特联合R-CHOP方案可能对DLBCL患者具有临床获益。 方法：我们在经病理确诊、初治的高危DLBCL患者中开展了一项单中心、单臂、开放标签的I期临床研究，评估罗氟司特联合标准R-CHOP方案（Ro+R-CHOP）的疗效与安全性。 结果：Ro+R-CHOP方案安全性良好，中位随访44个月时，70%患者存活且无疾病进展（中位总生存期未达到，无进展生存率为44%（95% CI, 21–92））。本初步研究显示，加用罗氟司特可抑制外周血单个核细胞的PI3K活性，并降低尿液中血管内皮生长因子A（VEGF-A）的分泌水平。我们还发现初步证据表明，Ro+R-CHOP方案可能对高危遗传亚型（MCD与A53型）DLBCL患者具有特殊疗效。 结论：这些初步结果表明罗氟司特可能成为抑制DLBCL中BCR/PI3K通路活性及血管生成的新型药物，有必要在更大规模经遗传特征分析的肿瘤队列中验证Ro+R-CHOP方案的疗效。本研究已在ClinicalTrials.gov注册，注册号NCT03458546。
First-Line Combination of R-CHOP with the PDE4 Inhibitor Roflumilast for High-Risk DLBCL
肿瘤(癌症)患者之家