The proliferation and survival of chronic lymphocytic leukemia (CLL) cells are heavily dependent on B-cell receptor (BCR) signaling and resistance to apoptosis. Approvals of multiple covalent Bruton’s tyrosine kinas inhibitors (cBTKis) as well as the B-cell lymphoma-2 inhibitor (BCL2i) venetoclax targeting these pathways have revolutionized the treatment of CLL and small lymphocytic lymphoma (SLL). The superiority of these treatments over chemoimmunotherapy has been proven in phase III studies in both treatment-naïve and relapsed refractory settings, leading to the majority of patients with CLL being treated sequentially with cBTKis and the BCL2i venetoclax as their first- and second-line therapies. While most patients with CLL respond for many years to these sequenced treatments, they are unfortunately not curative. There remains an unmet need for effective treatment options for patients who progressed after treatment with both cBTKis and BCL2i, also referred to as double refractory patients. Treatment options for double refractory CLL has improved recently with the approval of the non-covalent BTK inhibitor (ncBTKi) pirtobrutinib as well as the CD19 targeted chimeric antigen receptor T-cell (CAR T-cell) therapy lisocabtagene maraleucel (liso-cel). These recently approved treatment options for patients with CLL with at least two prior lines of therapy have fortunately demonstrated efficacy for double refractory CLL. Additionally, there are several novel treatment options in clinical development, including bi-specific antibodies, second-generation BCL2is, new ncBTKis, and BTK degraders. Understanding resistance mechanisms to existing cBTKis and venetoclax can potentially inform us of the best utilization of available treatment options for double refractory CLL and provide a personalized approach for these patients. In this review, a challenging example of a double refractory patient with CLL will serve as the basis for a review of available literature on the treatment of double refractory CLL/SLL.
慢性淋巴细胞白血病（CLL）细胞的增殖与存活高度依赖于B细胞受体（BCR）信号通路及其抗凋亡特性。针对这些通路开发的共价布鲁顿酪氨酸激酶抑制剂（cBTKis）及B细胞淋巴瘤-2抑制剂（BCL2i）维奈托克相继获批，彻底改变了CLL和小淋巴细胞淋巴瘤（SLL）的治疗格局。多项III期研究证实，在初治及复发难治性患者中，这些疗法均优于化学免疫疗法，使得多数CLL患者相继接受cBTKis和BCL2i维奈托克作为一线及二线治疗。尽管大多数患者对这些序贯治疗可维持多年应答，但遗憾的是这些疗法仍无法实现疾病根治。对于cBTKis和BCL2i治疗后仍出现疾病进展（即双重难治性）的患者，目前仍缺乏有效的治疗选择。 近期随着非共价BTK抑制剂（ncBTKi）吡托布鲁替尼以及靶向CD19的嵌合抗原受体T细胞（CAR-T）疗法利索基仑赛（liso-cel）获批，双重难治性CLL的治疗选择得以拓展。值得庆幸的是，这些针对至少接受过二线治疗CLL患者的新疗法，已在双重难治性CLL中展现出疗效。此外，目前尚有多种创新疗法处于临床研发阶段，包括双特异性抗体、第二代BCL2is、新型ncBTKis及BTK降解剂等。深入理解现有cBTKis和维奈托克的耐药机制，将有助于优化双重难治性CLL的现有治疗策略，并为这类患者提供个体化治疗方案。本综述将以一例具有挑战性的双重难治性CLL患者为例，系统回顾当前关于双重难治性CLL/SLL治疗的现有文献。
Improving Treatment Options for Patients with Double Refractory CLL
肿瘤(癌症)患者之家