Timing of tyrosine kinase inhibitor switching and long-term outcomes in chronic myeloid leukemia: A real-world comparative study

Abstract Background: In chronic myeloid leukemia (CML), switching tyrosine kinase inhibitors (TKIs) is often necessary due to intolerance, inadequate response, or resistance. However, the timing of such modifications—whether early after initiation or delayed—may significantly influence long-term clinical outcomes. This study evaluates the comparative safety and effectiveness of early switching (<3 months), late switching (≥6 months), and continued first-line TKI therapy across imatinib, dasatinib, and nilotinib. Methods: We conducted a retrospective cohort analysis using data from the TriNetX US Collaborative Network. Matched cohorts were constructed for each TKI: imatinib (early n=349, late n=1,309, non-switchers n=4,579), dasatinib (n=377/1,022/2,849), and nilotinib (n=114/370/1,308). Patients who returned to their original TKI or had outcomes of interest prior to switching were excluded. Outcomes—evaluated at 3 and 5 years—included all-cause mortality, cardiovascular events, diabetes, thromboembolism, hospitalizations, and ICU admissions. Logistic regression was used to calculate risk ratios (RRs) and 95% confidence intervals (CIs). Results: Across TKIs, early switching was consistently associated with worse outcomes. Imatinib early switchers had higher 5-year mortality compared to both late switchers (24.0% vs. 16.7%; RR=1.43, p=0.018) and non-switchers (24.0% vs. 11.9%; RR=2.03, p<0.001), as well as greater rates of heart failure, hospitalizations, and ICU admissions. Similar patterns were observed with dasatinib, where early switchers had increased 5-year mortality (21.1% vs. 14.0%; p=0.011), heart failure, and ICU use. Nilotinib early switchers showed a trend toward higher mortality and significantly more ICU admissions compared to non-switchers. In contrast, late switching revealed agent-specific effects. Imatinib late switchers had modestly increased 5-year mortality (18.8% vs. 15.5%; p=0.027) and cardiovascular risks, while dasatinib late switchers had outcomes comparable to non-switchers. Nilotinib late switchers experienced similar survival but significantly fewer hospitalizations at 3 years (13.7% vs. 22.1%; RR=0.62, p=0.044). Conclusions: Switch timing in CML has substantial prognostic implications. Early TKI switching, especially within the first 3 months, is associated with higher mortality and complications. Late switching may be better tolerated, particularly with second-generation agents. These findings underscore the need for careful, individualized decision-making in the management of TKI therapy.