Hallek Michael
Department I of Internal Medicine and Medical Faculty, University of Cologne, Köln, Germany.
Center for Integrated Oncology Aachen Bonn Köln Düsseldorf, Köln, Germany.
Am J Hematol. 2025 Mar;100(3):450-480. doi: 10.1002/ajh.27546. Epub 2025 Jan 28.
Chronic lymphocytic leukemia (CLL) is the most frequent type of leukemia. It typically occurs in older patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that interfere with the regulation of proliferation and apoptosis in clonal B-cells.
The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B-lymphocytes, which identify a clonal B-cell population carrying the CD5 antigen as well as typical B-cell markers.
Two clinical staging systems, Rai and Binet, provide prognostic information by using the results of physical examination and blood counts. Various biological and genetic markers provide additional prognostic information. Deletions of the short arm of chromosome 17 (del(17p)) and/or mutations of the TP53 gene predict a shorter time to progression with most targeted therapies. The CLL international prognostic index (CLL-IPI) integrates genetic, biological, and clinical variables to identify distinct risk groups of patients with CLL. The CLL-IPI retains its significance in the era of targeted agents, but the overall prognosis of CLL patients with high-risk stages has improved.
Only patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. When treatment is indicated, several therapeutic options exist: combinations of the BCL2 inhibitor venetoclax with obinutuzumab, or venetoclax with ibrutinib, or monotherapy with one of the inhibitors of Bruton tyrosine kinase (BTK). At relapse, the initial treatment may be repeated if the treatment-free interval exceeds 3 years. If the leukemia relapses earlier, therapy should be changed using an alternative regimen.
Combinations of targeted agents now provide efficient therapies with a fixed duration that generate deep and durable remissions. These fixed-duration therapies have gained territory in the management of CLL, as they are cost-effective, avoid the emergence of resistance, and offer treatment free time to the patient. The cure rate of these novel combination regimens is unknown. Moreover, the optimal sequencing of targeted therapies remains to be determined. A medical challenge is to treat patients who are double-refractory to both BTK and BCL2 inhibitors. These patients need to be treated within experimental protocols using novel drugs.
慢性淋巴细胞白血病（CLL）是最常见的白血病类型。它通常发生于老年患者，临床病程高度可变。白血病转化由特定的基因组改变引发，这些改变干扰了克隆性B细胞的增殖和凋亡调控。
通过血细胞计数、血涂片以及循环B淋巴细胞的免疫表型分析来确诊，这些检查可识别携带CD5抗原以及典型B细胞标志物的克隆性B细胞群体。
Rai和Binet这两种临床分期系统通过体格检查和血细胞计数结果提供预后信息。各种生物学和基因标志物可提供额外的预后信息。17号染色体短臂缺失（del(17p)）和/或TP53基因突变预示着大多数靶向治疗的疾病进展时间较短。慢性淋巴细胞白血病国际预后指数（CLL-IPI）整合了基因、生物学和临床变量，以识别慢性淋巴细胞白血病患者的不同风险组。CLL-IPI在靶向药物时代仍具有重要意义，但高危分期的慢性淋巴细胞白血病患者的总体预后有所改善。
仅患有活动性或有症状疾病或处于晚期Binet或Rai分期的患者需要治疗。当需要治疗时，有几种治疗选择：BCL2抑制剂维奈克拉与奥妥珠单抗联合使用，或维奈克拉与伊布替尼联合使用，或使用布鲁顿酪氨酸激酶（BTK）抑制剂之一进行单药治疗。复发时，如果无治疗间隔超过3年，可重复初始治疗。如果白血病复发较早，则应改用替代方案进行治疗。
靶向药物联合治疗目前可提供疗程固定的有效治疗方法，能产生深度且持久的缓解。这些疗程固定的治疗方法在慢性淋巴细胞白血病的管理中已占据一席之地，因为它们具有成本效益，可避免耐药性的出现，并为患者提供无治疗期。这些新型联合方案的治愈率尚不清楚。此外，靶向治疗的最佳顺序仍有待确定。一个医学挑战是治疗对BTK和BCL2抑制剂均双重耐药的患者。这些患者需要在使用新药的实验方案中接受治疗。
