Clonal haematopoiesis in chronic lymphocytic leukaemia: Biology, inflammaging and clinical implications in the era of targeted therapy.

[BACKGROUND] Clonal haematopoiesis (CH) is an age-related condition increasingly recognised for its relevance in haematologic malignancies. In chronic lymphocytic leukaemia (CLL), its prevalence and clinical implications are gaining attention, particularly in the context of prolonged patient survival and the widespread adoption of targeted therapies. A comprehensive understanding of the biological and clinical significance of CH in CLL is therefore essential.

[METHODS] This review synthesises current evidence on the biological basis, epidemiology and clinical impact of CH in CLL. Data from prospective clinical trials, real-world cohorts and translational studies were analysed to explore the associations between CH, genomic instability, immune dysregulation and inflammaging. Particular attention was given to the interaction between CH and contemporary therapeutic strategies, including Bruton tyrosine kinase (BTK) inhibitors and BCL2 inhibitors, and their potential influence on long-term outcomes.

[RESULTS] Available evidence indicates that CH is relatively frequent in patients with CLL and may contribute to disease biology through mechanisms involving genomic instability, chronic inflammation and immune system alterations. Emerging data suggest that CH can influence prognosis, treatment-related toxicities and cardiovascular risk, as well as predispose to therapy-related myeloid neoplasms. The interplay between CH and targeted agents may further modulate long-term outcomes, although the impact of CH on Richter transformation remains incompletely defined.

[CONCLUSIONS] CH represents a clinically relevant factor in the management of CLL in the era of targeted therapies. Its detection may have important implications for risk stratification, toxicity monitoring and survivorship care. Further prospective studies are needed to clarify its prognostic value and to integrate CH assessment into routine clinical practice and personalised treatment algorithms.

[KEY POINTS] Clonal haematopoiesis (CH) is common in patients with chronic lymphocytic leukaemia (CLL) and reflects age-related genomic and inflammatory remodeling of haematopoiesis. CH may influence prognosis, treatment-related toxicities, cardiovascular risk, and the development of therapy-related myeloid neoplasms. Targeted therapies, including BTK and BCL2 inhibitors, interact differently with CH compared with chemoimmunotherapy, potentially mitigating some adverse effects. Integrating CH assessment into CLL management may improve risk stratification and long-term survivorship strategies.