Treatment-free Remission in Chronic Myeloid Leukaemia: A Critical Appraisal of the Evidence, Persistent Uncertainties and Research Priorities

Abstract

Chronic myeloid leukaemia (CML) has been transformed by BCR::ABL1 tyrosine kinase inhibitors (TKIs), and for many patients life expectancy now approaches that of the general population. Against this background, treatment-free remission (TFR), defined as the maintenance of molecular response after planned TKI discontinuation, has become a central therapeutic objective. This critical narrative review examines the evidence underpinning TFR, appraises the methodological strengths and weaknesses of the supporting studies, and identifies questions that remain unresolved. Across more than a dozen prospective discontinuation studies, roughly half of carefully selected patients in sustained deep molecular response maintain remission after stopping treatment, with most recurrences occurring within the first six to eight months and with rapid restoration of response once treatment is resumed. The evidence is strongest for the association between the duration of TKI therapy, the duration of deep molecular response and the probability of sustained TFR, whereas the predictive value of individual immunological and molecular biomarkers is inconsistent. Heterogeneity in eligibility thresholds, molecular relapse definitions, monitoring intervals and follow-up duration constrains direct comparison between studies and exaggerates the apparent variability in reported success. Persistence of leukaemic stem cells in most patients who maintain remission indicates that discontinuation achieves operational rather than biological cure, and the mechanisms sustaining durable control are only partly understood. The TKI withdrawal syndrome, the possibility of late recurrence and the burden of intensive monitoring temper the quality-of-life and economic gains attributed to discontinuation. Approaches intended to widen eligibility, including dose de-escalation, repeat discontinuation attempts and immunomodulatory combinations, appear promising but rest on limited or preliminary evidence. Confidence in present conclusions is limited by the predominance of single-arm designs, the concentration of data in high-income settings and the scarcity of very long-term follow-up. TFR is a legitimate and attainable goal for a defined subgroup, yet reliable individual prediction, equitable access and validated interventions to raise success rates remain the principal outstanding challenges.