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，其特点是复发和缓解模式，许多患者可以进行序贯治疗。进展性/复发性 CLL 的识别应促使密切监测，并在出现治疗指征时及早讨论下一步的治疗方法。干预期间是优化患者健康的机会，包括对第二原发恶性肿瘤进行充分的疫苗接种和监测，以及治疗可能影响健康和 CLL 治疗的非 CLL 相关合并症。我们现在在诊所看到先前接受过化学免疫疗法 (CIT) 和/或一种或多种新疗法治疗的复发/难治性 (RR) CLL 患者。布鲁顿酪氨酸激酶 (cBTKi) 的连续共价抑制剂和固定持续时间的维奈托克 (Ven)-抗 CD20 单克隆抗体 (mAb) 优于 CIT，因为这些疗法具有生存优势，尽管从未进行过面对面的评估。虽然这两种药物均对 RR CLL 有效，但潜在的副作用和给药流程有所不同。很少有随机数据证明 cBTKi 和固定持续时间的 Ven-anti-CD20 mAb 的顺序使用；然而，它们可以按任一顺序使用。新型非共价 BTKi，可有效对抗因连续 cBTKi 暴露而出现的BTK C481 耐药突变，以及 BTK 降解剂、双特异性抗体和嵌合抗原受体 T 细胞疗法等新方法，显示出令人印象深刻的疗效。在本次 RR CLL 综述中，我们探讨了相关调查，考虑了更广泛的 CLL 和非 CLL 相关健康需求，以及 B 细胞受体抑制剂和 Ven 的功效和安全性证据，包括支持药物测序或转换的可用数据。我们描述了治疗 RR CLL 的新方法，包括用固定时间疗法进行再挑战、新疗法时代的同种异体干细胞移植适应症，并重点介绍了支持使用 T 细胞定向疗法和新药物靶点的早期数据。