Therapy-driven clonal dynamics in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a paradigmatic malignancy driven by intraclonal diversity and dynamic evolutionary processes. High-resolution genomic profiling has demonstrated that CLL progression rarely follows a linear trajectory; rather, it is characterized by a complex and evolving (sub)clonal architecture shaped by intrinsic biological features and extrinsic factors, including therapeutic pressure. Recurrent genetic alterations affect key signaling pathways and cellular processes, including B-cell receptor and NF-αB signaling, DNA damage response, RNA processing, and apoptosis. Many of these lesions arise as subclonal events and subsequently expand, thereby influencing disease progression, therapeutic resistance, and transformation. Over the past decade, the treatment paradigm in CLL has shifted from chemoimmunotherapy to targeted agents, resulting in substantial clinical benefit. Nevertheless, the emergence of therapeutic resistance remains a major challenge. In this review, we summarize current knowledge of clonal evolution and resistance mechanisms in CLL. Resistance to chemoimmunotherapy is frequently driven by genetic lesions, such as TP53 aberrations, and by expansion of resistant microclones. In contrast, targeted therapies select for distinct resistance mechanisms, such as BTK and PLCG2 mutations in patients treated with BTK inhibitors, as well as activation of alternative survival pathways. We further discuss emerging technologies, including single-cell sequencing and integrative multi-omics approaches. Finally, we highlight the need for future studies addressing resistance in evolving clinical contexts, such as combination targeted therapies, bispecific antibodies, and CAR T-cell therapy. Taken together, a deeper understanding of clonal evolution is central to the development of personalized therapeutic strategies and to improving long-term outcomes for patients with CLL.