Chronic lymphocytic leukemia (CLL) predominantly affects older adults, characterized by a relapsing and remitting pattern with sequential treatments available for many patients. Identification of progressive/relapsed CLL should prompt close monitoring and early discussion about the next therapies when treatment indications are present. The intervening period represents an opportunity to optimize patient health, including establishing adequate vaccination and surveillance for second primary malignancies, and treating non-CLL-related comorbidities which may impact well-being and CLL therapy. We now see patients with relapsed/refractory (RR) CLL in the clinic who have been previously treated with chemoimmunotherapy (CIT) and/or one or more novel therapies. Continuous covalent inhibitors of Bruton’s tyrosine kinase (cBTKi) and fixed-duration venetoclax (Ven)-anti-CD20 monoclonal antibody (mAb) are preferred over CIT given the survival advantages associated with these therapies, although have never been evaluated head-to-head. While both classes are effective for RR CLL, potential side effects and the logistics of administration differ. Few randomized data demonstrate the sequential use of cBTKi and fixed-duration Ven-anti-CD20 mAb; however, they may be used in either sequence. Newer non-covalent BTKi, active against BTK C481 resistance mutations emerging with continuous cBTKi exposure, and novel approaches such as BTK degraders, bispecific antibodies, and chimeric antigen receptor T-cell therapies demonstrate impressive efficacy. In this review of RR CLL we explore relevant investigations, consideration of broader CLL- and non-CLL-related health needs, and evidence for efficacy and safety of B-cell receptor inhibitors and Ven, including available data to support drug sequencing or switching. We describe novel approaches to RR CLL, including rechallenging with fixed-duration therapies, allogeneic stem cell transplant indications in the novel therapy era, and highlight early data supporting the use of T-cell directing therapies and novel drug targets.
慢性淋巴细胞白血病（CLL）主要影响老年人，其特征为复发缓解型病程，多数患者可接受序贯治疗。一旦发现疾病进展/复发，应在符合治疗指征时立即启动密切监测并尽早讨论后续治疗方案。治疗间歇期为优化患者健康状况提供了机会，包括完成充分疫苗接种、监测第二原发恶性肿瘤，以及治疗可能影响生活质量和CLL治疗的合并症。目前在临床中，复发/难治性（RR）CLL患者往往曾接受过化学免疫治疗（CIT）和/或一种及以上新型疗法。相较于CIT，布鲁顿酪氨酸激酶持续共价抑制剂（cBTKi）与固定疗程维奈托克（Ven）联合抗CD20单克隆抗体（mAb）方案因生存优势更受青睐，尽管二者尚未进行头对头比较。这两类疗法虽对RR CLL均有效，但其潜在副作用和给药方式存在差异。目前关于cBTKi与固定疗程Ven-抗CD20 mAb序贯应用的随机数据有限，但二者可按任意顺序使用。新型非共价BTKi能靶向持续cBTKi暴露后出现的BTK C481耐药突变，而BTK降解剂、双特异性抗体及嵌合抗原受体T细胞疗法等新策略也展现出显著疗效。本文通过综述RR CLL相关研究，探讨更广泛的CLL及非CLL相关健康需求，分析B细胞受体抑制剂与Ven的疗效及安全性证据，包括支持药物序贯或转换的现有数据。我们阐述RR CLL的新型治疗策略，涵盖固定疗程疗法再挑战、新型药物时代的异基因干细胞移植指征，并重点介绍支持T细胞导向疗法及新药物靶点的早期数据。
Update on the management of relapsed/refractory chronic lymphocytic leukemia
肿瘤(癌症)患者之家