Department of Pharmacy, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Expert Opin Pharmacother. 2022 Sep;23(13):1545-1557. doi: 10.1080/14656566.2022.2113384. Epub 2022 Aug 22.
The Bruton's tyrosine kinase (BTK) pathway has proven to be an effective and transformative therapeutic target in the treatment of chronic lymphocytic leukemia (CLL), fueling the growth of BTK inhibitors (BTKis) and landmark approval of first-generation BTKi, ibrutinib. However, ibrutinib's side effect profile left an unmet need for BTKis with improved tolerability, thus spurring the subsequent development of second-generation acalabrutinib and zanubrutinib. The treatment landscape continues to evolve with studies using BTKi combination therapies, notably with venetoclax, with and without an anti-CD20 monoclonal antibody as well as third-generation BTKis aimed to overcome BTKi resistance.
This article details the current literature highlighting the efficacy, toxicities, and potential therapeutic combinations of approved and preclinical BTKis.
BTKis have signaled the start of a new treatment paradigm in CLL and improved clinical outcomes, especially for patients with high-risk disease. However, drug resistance, low CR rates, and indefinite treatment necessitate the development of novel BTKis and fixed duration combination therapy. The results from recently completed and ongoing clinical trials are eagerly awaited with the potential promise of reduced treatment durations and financial burden while achieving durable remissions.
布鲁顿酪氨酸激酶（BTK）通路已被证明是治疗慢性淋巴细胞白血病（CLL）的有效且具有变革性的治疗靶点，推动了 BTK 抑制剂（BTKi）的发展，并首次批准了第一代 BTKi，伊布替尼。然而，伊布替尼的副作用谱仍存在未满足的需求，需要改善耐受性，从而推动了第二代阿卡替尼和泽布替尼的后续开发。随着使用 BTKi 联合疗法的研究不断发展，特别是与 venetoclax 联合使用，无论是否联合抗 CD20 单克隆抗体，以及旨在克服 BTKi 耐药性的第三代 BTKi，治疗领域仍在不断发展。
本文详细介绍了目前的文献，强调了已批准和临床前 BTKi 的疗效、毒性和潜在治疗组合。
BTKi 开创了 CLL 治疗的新模式，改善了临床结局，特别是对高危疾病患者。然而，耐药性、低完全缓解率和无限期治疗需要开发新型 BTKi 和固定疗程联合治疗。最近完成和正在进行的临床试验的结果备受期待，有可能减少治疗持续时间和经济负担，同时实现持久缓解。
