Effective available treatment options for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who relapse after becoming refractory to both a covalent Bruton Tyrosine Kinase inhibitor (cBTKi) and a B cell leukemia/lymphoma 2 inhibitor (BCL2i) remain limited, and prognosis is very poor. Emerging areas of drug development include cellular therapies such as chimeric antigen receptor T-cell therapy and bispecific antibodies. However, cost, accessibility, toxicity, and the need for either prolonged or repeated hospitalization prevent universal application of these therapies. Given this area of unmet clinical need, we present this review article on Bruton Tyrosine Kinase (BTK) degraders in patients with CLL/SLL. We focus on their development as a drug class, the up-to-date clinical data available, as well as future directions. BTK protein degraders are a novel drug class with an alternate mechanism of action (MOA), compared to cBTKis and non-covalent BTKis (ncBTKis), causing ubiquitination of BTK, thereby leading to its degradation through the proteasome. Encouraging pre-clinical data show that this MOA allows BTK protein degraders to overcome common BTK mutations. We focus on four agents which are under investigation in B-cell malignancies in early clinical trials: BGB-16673, NX-2127, NX-5948, and AC676. Preliminary data suggest a comparable safety and toxicity profile between agents across this drug class with many patients on phase 1 trials deriving durable clinical benefit. Optimal sequencing of BTK degraders in the therapeutic landscape of CLL/SLL treatment is yet to be established. Further trials investigating these agents in combination with other targeted CLL agents may help to further understand their applicability. An effective, tolerable oral class of drugs would be invaluable in the treatment of patients with multiply relapsed CLL/SLL.
对于慢性淋巴细胞白血病/小淋巴细胞淋巴瘤（CLL/SLL）患者，在同时对共价布鲁顿酪氨酸激酶抑制剂（cBTKi）和B细胞白血病/淋巴瘤2抑制剂（BCL2i）产生耐药后复发，目前有效的治疗选择仍然有限，且预后极差。药物研发的新兴领域包括细胞疗法，如嵌合抗原受体T细胞疗法和双特异性抗体。然而，成本、可及性、毒性以及需要长期或反复住院治疗等因素，限制了这些疗法的普遍应用。鉴于这一临床需求尚未得到满足，本文综述了布鲁顿酪氨酸激酶（BTK）降解剂在CLL/SLL患者中的应用。我们重点关注其作为一类药物的研发进展、最新的临床数据以及未来的发展方向。与cBTKis和非共价BTKis（ncBTKis）相比，BTK蛋白降解剂是一类具有全新作用机制（MOA）的药物，通过泛素化BTK蛋白，进而通过蛋白酶体使其降解。令人鼓舞的临床前数据显示，这种作用机制使BTK蛋白降解剂能够克服常见的BTK突变。我们重点介绍了四种正在早期临床试验中用于B细胞恶性肿瘤研究的药物：BGB-16673、NX-2127、NX-5948和AC676。初步数据表明，这类药物在安全性和毒性方面具有可比性，许多参与一期试验的患者获得了持久的临床获益。在CLL/SLL治疗领域中，BTK降解剂的最佳用药顺序尚未确定。进一步研究这些药物与其他靶向CLL药物联合使用的试验，可能有助于更好地理解其适用性。对于多次复发的CLL/SLL患者而言，一类有效且耐受性良好的口服药物将具有不可估量的价值。
肿瘤(癌症)患者之家