ABSTRACT Chronic lymphocytic leukemia (CLL) is most frequently diagnosed at early, asymptomatic stages (Rai 0/Binet A), in which a watch‐and‐wait strategy remains the standard of care, based on historical trials demonstrating no overall survival benefit from early treatment. Over the past two decades, however, substantial advances in genomic profiling—including immunoglobulin heavy‐chain variable region (IGHV) mutational status, TP53 disruption, recurrent gene mutations, and complex karyotype—have uncovered marked biological heterogeneity among early‐stage patients and substantially improved prediction of disease progression. In parallel, targeted therapies such as Bruton tyrosine kinase (BTK) inhibitors and venetoclax‐based combinations have transformed the management of symptomatic CLL, raising renewed interest in whether early intervention might favorably alter the natural history of biologically high‐risk disease. In this review, we critically examine the evolution of prognostication in early‐stage CLL, integrate contemporary molecular and clinical risk models, and summarize evidence from both historical chemotherapy‐era studies and modern early‐intervention trials. We discuss key unresolved controversies, including reliance on surrogate endpoints, the risks of overtreatment, and the persistent absence of an overall survival benefit across all early‐treatment strategies. Finally, we outline future research priorities, including refined genomic stratification, minimal residual disease‐driven (MRD)‐driven approaches, and combination targeted therapies currently under investigation. Despite renewed interest in preemptive treatment, available evidence supports continued observation for asymptomatic patients outside clinical trials.
Martino et al. (Thu,) studied this question.