Overcoming Barriers to Treatment-Free Remission (TFR) in Chronic Myeloid Leukemia (CML): Predictive Factors, Patient Selection, and Emerging Strategies to Expand Eligibility

Treatment-free remission (TFR) has become an important therapeutic goal for patients with chronic myeloid leukemia (CML) who achieve a sustained deep molecular response (DMR) on tyrosine kinase inhibitor (TKI) therapy. However, only a subset of eligible patients maintain durable remission after discontinuation, and many patients never reach eligibility criteria for a TFR attempt. This review summarizes the evolution of TFR from early pilot studies to current international eligibility recommendations, and critically evaluates the clinical, molecular, and immunological factors that may predict molecular recurrence (MRec) after TKI discontinuation. We discuss possible strategies to improve patient selection for TFR attempts, such as multivariable prognostic scores and highly sensitive minimal residual disease (MRD) detection techniques, alongside outcomes in special CML subpopulations. We further review strategies aimed at expanding TFR eligibility, including the use of more potent TKIs, treatment switching, combination approaches, and dose de-escalation. Finally, we discuss possible future steps that may lead to a more individualized approach to TFR. Improving our knowledge of the clinical and biological determinants of successful treatment discontinuation is pivotal to developing strategies for patient selection and for expanding eligibility. This dual approach may lead to extending the benefits of TFR to a broader number of CML patients.