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

Area of Science:

• Hematology
• Oncology
• Immunology

Background:

• Treatment-free remission (TFR) is a key goal for chronic myeloid leukemia (CML) patients.
• Discontinuing tyrosine kinase inhibitors (TKIs) after deep molecular response (DMR) is a strategy explored for TFR.
• Understanding factors influencing TFR sustainability is crucial for optimizing treatment.

Purpose of the Study:

• To evaluate 5-year treatment-free survival (TFS) and immune profiles after discontinuing nilotinib (NIL) or dasatinib (DAS) in CML patients.
• To investigate the impact of immune modulation on TFR sustainability and molecular recurrence.
• To compare TFR outcomes and immune responses between NIL and DAS discontinuation cohorts.

Main Methods:

• Analysis of 5-year follow-up data from two independent phase 2 trials (JALSG N-STOP216 and D-STOP216).
• Patients discontinued frontline 2G-TKIs (NIL or DAS) after achieving DMR for ≥2 years.
• Exploratory immune profiling, including T cell and NK cell subsets, and cytokine analysis (IL-1β, IL-6).

Main Results:

• Both trials met primary endpoints with 12-month TFR rates of 76.5% (NIL) and 55.1% (DAS).
• Five-year TFS rates were 68.6% (NIL) and 50.9% (DAS); no disease progression observed.
• NIL cohort showed more gradual molecular recurrence; DAS cohort exhibited an 'immune paradox' with altered T and NK cell populations.
• Elevated pre-discontinuation IL-1β and IL-6 levels correlated with molecular relapse.

Conclusions:

• Discontinuation of 2G-TKIs (NIL, DAS) is a safe strategy for achieving long-term TFR in CML patients with DMR.
• Immune microenvironment modulation by 2G-TKIs may influence TFR sustainability.
• Specific immune profiles and cytokine levels (IL-1β, IL-6) are associated with molecular relapse risk after TKI discontinuation.