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. This study analyzed 5-year follow-up data and immune profiling from 2 independent phase 2 trials conducted by the Japan Adult Leukemia Study Group (JALSG), N-STOP216 (nilotinib [NIL], n = 51) and D-STOP216 (dasatinib [DAS], n = 49), involving patients who discontinued frontline second-generation (2G)-tyrosine kinase inhibitors (TKIs) after sustaining deep molecular response for ≥2 years. Both trials successfully met their primary end points, 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-treated patients, respectively. Although 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 natural killer cells alongside depletion of the "immune reservoir" of naïve and central memory cells. In the D-STOP trial, the retreatment group showed higher levels of effector regulatory T cells and exhausted CD4+ T cells compared with the TFR group. Furthermore, elevated prediscontinuation interleukin-1β (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. The trials were registered at www.umin.ac.jp as UMIN000024984 (JALSG N-STOP216) and UMIN000024985 (JALSG D-STOP216).