Treatment-Free Remission in Chronic Myeloid Leukemia: Toward Precision and Personalized Approaches to Functional Cure

Treatment-free remission (TFR), defined as the maintenance of molecular remission without resumption of therapy after tyrosine kinase inhibitor (TKI) discontinuation, represents the clinical manifestation of functional cure in chronic-phase chronic myeloid leukemia (CML-CP), in which durable disease control is maintained without ongoing therapy despite the potential persistence of residual leukemic stem cells (LSCs). Emerging evidence supports a model in which outcomes after TKI discontinuation are determined by the balance between residual LSC persistence and coordinated host immune surveillance. Natural killer (NK)-cell abundance and maturation have shown the most consistent associations with TFR, while killer immunoglobulin-like receptor (KIR)-human leukocyte antigen (HLA) immunogenetics may further influence NK-cell education and antileukemic activity. Adaptive and regulatory mechanisms-including leukemia-associated antigen-specific cytotoxic T lymphocytes, T-cell receptor repertoire dynamics, T-cell exhaustion, plasmacytoid dendritic cells, and regulatory T cells-are increasingly implicated in residual disease control. Neutrophil abundance and maturation have also emerged as readily accessible candidate biomarkers. In parallel, persistent LSCs exploit BCR::ABL1-independent survival programs, immune-evasion mechanisms, and the protective bone marrow niche, providing a reservoir for molecular relapse. These observations argue against reliance on any single biomarker and instead support integrated models incorporating clinical variables, molecular residual disease, immune competence, immunogenetics, and LSC biology. Most candidate biomarkers remain exploratory and require independent prospective validation. Such multidimensional approaches may enable a transition from empiric TKI discontinuation toward precision, biomarker-guided TFR and extend durable functional cure to a broader population of patients with CML. Trail Registration: N/A.