Treatment-Free Remission and Immune Profiling after Frontline Second-Generation TKI Therapy in CML

Treatment-free remission (TFR) is a major therapeutic goal in chronic myeloid leukemia (CML). This study analyzed 5-year follow-up data and immune profiling from two independent phase 2 trials, JALSG N-STOP216 (nilotinib [NIL], n=51) and D-STOP216 (dasatinib [DAS], n=49), involving patients who discontinued frontline 2G-TKIs after sustaining deep molecular response (DMR) for ≥2 years. Both trials successfully met their primary endpoints, with 12-month TFR rates of 76.5% and 55.1% in the NIL and DAS trials, respectively. No disease progression was observed, confirming the safety of this strategy. The 5-year treatment-free survival (TFS) rates were 68.6% and 50.9% for NIL and DAS patients, respectively. While recurrent cases in both cohorts rapidly regained a molecular response, NIL-treated patients showed a more gradual molecular recurrence and a persistent gap between TFS and event-free survival, suggesting relatively stable immune surveillance. Comparative immune profiling, although exploratory, suggested an "immune paradox" in the DAS cohort, characterized by expansion of effector memory T cells and mature CD57+ CD56dim NK cells alongside depletion of the "immune reservoir" of naïve and central memory cells. In the D-STOP trial, the retreatment group showed higher levels effector Tregs and exhausted CD4+ T cells than the TFR group. Furthermore, elevated pre-discontinuation IL-1β and IL-6 levels were associated with molecular relapse. These findings suggest that 2G-TKI-specific off-target effects influence TFR sustainability by modulating the immune microenvironment and the CD4+ helper cell status. JALSG N-STOP216 (UMIN000024984); JALSG D-STOP216 (UMIN000024985).