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Over the past two decades, however, substantial advances in genomic profiling\u2014including immunoglobulin heavy\u2010chain variable region (IGHV) mutational status, TP53 disruption, recurrent gene mutations, and complex karyotype\u2014have uncovered marked biological heterogeneity among early\u2010stage patients and substantially improved prediction of disease progression. In parallel, targeted therapies such as Bruton tyrosine kinase (BTK) inhibitors and venetoclax\u2010based combinations have transformed the management of symptomatic CLL, raising renewed interest in whether early intervention might favorably alter the natural history of biologically high\u2010risk disease. In this review, we critically examine the evolution of prognostication in early\u2010stage CLL, integrate contemporary molecular and clinical risk models, and summarize evidence from both historical chemotherapy\u2010era studies and modern early\u2010intervention 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\u2010treatment strategies. Finally, we outline future research priorities, including refined genomic stratification, minimal residual disease\u2010driven (MRD)\u2010driven 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.<\/jats:p>","DOI":"10.1111\/ejh.70219","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T01:16:02Z","timestamp":1778807762000},"page":"750-766","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["To Treat or Not to Treat: Navigating Early\u2010Stage\n                    <scp>CLL<\/scp>\n                    in the Era of Targeted Therapy"],"prefix":"10.1111","volume":"117","author":[{"given":"Enrica Antonia","family":"Martino","sequence":"first","affiliation":[{"name":"Hematology Unit, Department of Onco\u2010Hematology  Cosenza Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santino","family":"Caserta","sequence":"additional","affiliation":[{"name":"Hematology Unit, Department of Onco\u2010Hematology  Cosenza 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