Are We Moving Toward Curative Approaches in Chronic Lymphocytic Leukemia?

Over the past decade, chronic lymphocytic leukemia (CLL) management has undergone a fundamental transformation driven by the introduction of oral targeted inhibitors. Continuous Bruton tyrosine kinase (BTK) inhibition and time-limited BCL-2–based therapy has replaced chemoimmunotherapy as the standard of care, improving survival and quality of life. Ibrutinib and its next-generation analogues, acalabrutinib and zanubrutinib, provide durable disease control with improved safety. At the same time, venetoclax combined with anti-CD20 antibodies enables deep and measurable residual disease (MRD)-negative remissions within fixed-duration regimens. Recent trials have demonstrated the feasibility of MRD-guided treatment cessation and the potential benefit of combining BTK and BCL-2 inhibition to achieve durable, chemotherapy-free responses. Ongoing research focuses on optimizing treatment sequencing, overcoming acquired resistance through non-covalent BTK inhibitors, and integrating immunotherapeutic modalities such as bispecific antibodies and CAR-T cells. The current paradigm emphasizes individualized, biomarker- and comorbidity-driven therapy based primarily on TP53 and IGHV status, with treatment selection tailored to patient fitness, tolerance, and long-term safety. This review summarizes contemporary evidence, clinical practice recommendations, and future directions in the targeted management of CLL.