CLL is the most prevalent adult leukemia in Western countries, characterized by the accumulation of monoclonal B lymphocytes. Over the past decade, the therapeutic landscape for CLL has undergone significant transformations, primarily due to the introduction of targeted small molecular therapies like BTK inhibitors and BCL-2 inhibitors, that have improved patient outcomes drastically. Despite significant advances, long-term disease management remains challenging for patients with double-refractory CLL, where responses with subsequent therapies are short-lived. Resistance to these therapies can arise through several mechanisms like kinase-altering BTK mutations, alterations in the BCL-2 pathway, and adaptations within the tumor microenvironment, necessitating the exploration of new therapeutic options. This review provides an in-depth overview of the promising novel treatment approaches under investigation in CLL, focusing on advanced cellular therapies (CAR T-cell therapy), T-cell engagers, new monoclonal antibodies, and various next-generation small molecule inhibitors including BTK degraders, PI3K inhibitors, MALT1 inhibitors, c-MYC inhibitors, CDK9 inhibitors, and agents targeting angiogenesis and DNA damage repair. In this review, we will discuss the novel therapeutic targets and agents as well as ongoing trials, emphasizing the potential of these treatments to overcome resistance and meet the unmet needs of patients, particularly those with double-refractory CLL.
慢性淋巴细胞白血病（CLL）是西方国家最常见的成人白血病，其特征为单克隆B淋巴细胞的积累。过去十年间，CLL的治疗格局发生了重大变革，主要得益于BTK抑制剂和BCL-2抑制剂等靶向小分子疗法的引入，这些疗法显著改善了患者预后。尽管取得了重大进展，但对于双重难治性CLL患者而言，长期疾病管理仍面临挑战，后续治疗的反应往往短暂。耐药性可能通过多种机制产生，如激酶结构改变的BTK突变、BCL-2通路变异以及肿瘤微环境适应性改变，这促使人们必须探索新的治疗选择。本综述深入探讨了当前CLL研究中具有前景的新型治疗策略，重点关注先进细胞疗法（CAR-T细胞疗法）、T细胞衔接器、新型单克隆抗体以及各类新一代小分子抑制剂（包括BTK降解剂、PI3K抑制剂、MALT1抑制剂、c-MYC抑制剂、CDK9抑制剂，以及靶向血管生成和DNA损伤修复的药物）。本文将系统阐述这些新型治疗靶点与药物及其相关临床试验，重点分析这些疗法在克服耐药性、满足患者（尤其是双重难治性CLL患者）未竟医疗需求方面的潜力。
Chronic Lymphocytic Leukemia: Novel Therapeutic Targets Under Investigation
肿瘤(癌症)患者之家