Timing of Tyrosine Kinase Inhibitor Switching in Chronic Myeloid Leukemia: A Comparative Analysis of Early Versus Late Strategies

Optimal timing for switching tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) remains uncertain. While early molecular milestones inform treatment decisions, real-world evidence evaluating how the timing of TKI switch influences survival and toxicity is limited.

Using the TriNetX US Collaborative Network, we identified adults with CML treated with first-line imatinib, dasatinib, or nilotinib between 2000 and 2022. Patients were categorized as early switchers (≤3 months), late switchers (>12 months), or monotherapy continuers. Propensity score matching (1:1) was performed for three comparisons per TKI: early switching versus monotherapy, late switching versus monotherapy, and early versus late switching. The primary outcome was overall survival; secondary outcomes included hematologic toxicity, cardiovascular events, metabolic complications, and healthcare utilization.

Among 15,967 patients, 3309 (20.7%) underwent TKI switching (776 early, 2,533 late). Early switching was associated with numerically higher mortality without statistical significance (imatinib HR: 1.34; dasatinib HR: 1.15), but significantly higher mortality than late switching in imatinib-treated patients (HR: 2.38). Late switching showed no consistent survival difference across any TKI; imatinib late switchers had increased stroke (HR: 2.09) and pleural effusion (HR: 1.72). Agent-specific complications included heart failure and pleural effusion with imatinib early switching, and anemia, diabetes, and hyperlipidemia with dasatinib early switching.

Timing of TKI switching was associated with outcome differences in CML without consistent survival effects. Early switching in imatinib-treated patients carried higher mortality than late switching, suggesting timing reflects underlying disease risk rather than a direct treatment effect. These findings support individualized decision-making incorporating response trajectory, comorbidities, and cumulative toxicity over fixed timepoint thresholds.