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This shift has significantly improved survival rates, and for some patients, achieving deep molecular response (DMR) has made treatment\u2010free remission (TFR) a feasible goal. However, the ability to sustain TFR remains a challenge, primarily due to the persistence of leukemia stem cells (LSCs), which are inherently resistant to TKIs and contribute to relapse after treatment cessation. The barriers to TFR include not only the persistence of LSCs but also the complex biology of resistance mechanisms. Attempts to overcome these barriers through TKI rotation, second\u2010generation TKIs, or strategies targeting the tumor microenvironment have shown limited success. Third\u2010generation TKIs like ponatinib and novel agents such as asciminib and olverembatinib offer promising therapeutic alternatives, particularly for patients with the T315I mutation. However, their use is constrained by safety concerns and limited availability, especially in low\u2010resource settings. Patient selection remains a crucial aspect of achieving TFR, as not all patients with DMR sustain remission after discontinuation of therapy. Factors such as age, immune profile, and measurable residual disease levels significantly influence relapse risk. Identifying reliable clinical and molecular predictors of successful TFR is essential for optimizing treatment strategies and improving outcomes. The concept of the \u201cW\u201d questions\u2014who, when, why, what, and where\u2014frames the future of TFR in CML. Who should be selected for TFR? When should TFR be pursued? Why are some patients successful in achieving and sustaining TFR, while others relapse? What strategies can enhance the likelihood of TFR success, such as novel therapies, combination treatments, and patient\u2010specific approaches? Where should these strategies be implemented to ensure equitable access, particularly in resource\u2010limited settings? This review highlights the progress made in CML treatment, emphasizes the need for precision medicine to personalize TFR strategies, and stresses the importance of answering the fundamental \u201cW\u201d questions to advance the field. 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