City of Hope National Medical Center, Duarte, California, USA.
Curr Opin Oncol. 2022 Sep 1;34(5):540-545. doi: 10.1097/CCO.0000000000000871. Epub 2022 Jul 16.
Treatment of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) underwent paradigm shifts, with targeted agents rapidly displacing chemotherapy. Phosphoinotiside-3 kinase (PI3K) is essential for survival and proliferation of neoplastic B cells and has proven a tractable target in NHL, with four agents receiving FDA approval in the last decade. This review summarizes key data and challenges associated with use of PI3K inhibitors in routine practice.
Idelalisib and duvelisib are active in CLL and indolent NHL, including in patients with high-risk features. Despite differential targeting of PI3K isoforms, they exhibit comparable efficacy and adverse event profile including autoimmune events (transaminitis, colitis, pneumonitis), mediated by Treg/Th17 imbalance. Although copanlisib, a pan-PI3K inhibitor, is associated with a distinct safety profile (hyperglycemia, hypertension), preclinical studies indicate that umbralisib, a dual inhibitor of PI3Kδ and casein kinase 1ε, may have less effect on Tregs. However, both drugs may still cause immune-mediated toxicities.
With close monitoring and management of adverse events, PI3K inhibitors continue to have a role in therapy of R/R CLL and NHL. Strategies to mitigate adverse events and increase efficacy of PI3K inhibitors include time-limited combination approaches, intermittent dosing schedules.
非霍奇金淋巴瘤（NHL）和慢性淋巴细胞白血病（CLL）的治疗发生了重大转变，靶向药物迅速取代了化疗。磷酸肌醇 3 激酶（PI3K）是肿瘤 B 细胞存活和增殖所必需的，已被证明是 NHL 中一个可行的靶点，在过去十年中已有四种药物获得 FDA 批准。本综述总结了在常规实践中使用 PI3K 抑制剂的关键数据和挑战。
依鲁替尼和 duvelisib 在 CLL 和惰性 NHL 中均具有活性，包括高风险特征的患者。尽管 PI3K 同工型的靶向作用不同，但它们具有相似的疗效和不良事件谱，包括自身免疫事件（转氨酶升高、结肠炎、肺炎），这是由 Treg/Th17 失衡介导的。虽然 pan-PI3K 抑制剂 copanlisib 具有独特的安全性特征（高血糖、高血压），但临床前研究表明，PI3Kδ 和酪蛋白激酶 1ε 的双重抑制剂 umbralisib 可能对 Treg 的影响较小。然而，这两种药物仍可能引起免疫介导的毒性。
通过密切监测和管理不良反应，PI3K 抑制剂在 R/R CLL 和 NHL 的治疗中仍具有作用。减轻不良反应和提高 PI3K 抑制剂疗效的策略包括限时联合治疗方法、间歇性给药方案。
