The long-term results from key studies such as ENESTnd, DASISION, and BFORE have helped guide first-line treatment decisions in chronic myeloid leukemia (CML). These studies compare the efficacy of different TKIs, including imatinib, dasatinib, and nilotinib, showing the potential benefits of second-generation TKIs in achieving deeper and faster molecular responses. Early molecular response (EMR) is a crucial prognostic factor, as patients who achieve EMR are more likely to have better long-term outcomes. Risk scores such as Sokal, EUTOS, and ELTS play a role in determining the appropriate first-line TKI, with higher-risk patients potentially benefiting from second-generation TKIs due to their more aggressive nature.

Second-generation TKIs, including nilotinib, dasatinib, and bosutinib, offer enhanced potency over imatinib but come with distinct safety profiles. Nilotinib has demonstrated superior efficacy in terms of molecular response, but it is associated with cardiovascular risks, including QT prolongation. Dasatinib, while effective in achieving rapid molecular responses, can lead to pulmonary complications like pleural effusion. Bosutinib, which is less commonly used, has a more favorable gastrointestinal side effect profile but may have less activity in some resistant CML cases. Management of cardiovascular, pulmonary, and metabolic side effects is crucial in selecting the appropriate TKI for each patient, particularly for those at higher risk of cardiovascular or pulmonary issues.

TKI resistance, primarily due to BCR-ABL1 kinase domain mutations, presents a challenge in CML treatment. Mutations such as T315I are particularly problematic as they confer resistance to most TKIs. Ponatinib, a third-line treatment, is highly effective against T315I and other mutations, but it carries significant cardiovascular risks, necessitating careful monitoring. Asciminib, a newer drug that targets BCR-ABL1 through allosteric inhibition, offers a promising alternative for patients with resistance to other TKIs, as it bypasses common mutations like T315I and is associated with a different side-effect profile.

Off-target inhibition of kinases by TKIs is a significant contributor to their side-effect profiles. For instance, nilotinib has been linked to glucose metabolism disturbances, leading to hyperglycemia, whereas dasatinib may cause pulmonary hypertension due to PDGFR inhibition. Understanding these molecular mechanisms helps in managing side effects and improving patient outcomes. Monitoring for these adverse effects and adjusting treatment accordingly is essential to minimize long-term toxicity while maintaining treatment efficacy.

The concept of TFR, where patients discontinue TKI therapy after achieving sustained molecular remission, is gaining ground. Studies such as EURO-SKI, ENESTfreedom, and DASFREE have demonstrated that certain patients can safely stop treatment without relapse, provided they remain MRD-negative. Selecting the right candidates for TFR is critical, and patients must be closely monitored for minimal residual disease (MRD). Even after discontinuation, immunological changes and potential relapse mechanisms must be carefully tracked.

In special populations such as pregnant women, pediatric patients, and the elderly, TKI therapy requires careful consideration. TKIs are contraindicated in pregnancy due to potential teratogenic effects, and fertility preservation options should be discussed with male patients. In pediatric CML patients, concerns about growth and development arise, and TKI dosing must be adjusted for optimal treatment without affecting growth. Elderly patients or those with comorbidities may require lower doses and closer monitoring to minimize toxicity while ensuring adequate therapeutic effects.

This summary highlights key aspects of TKI therapy in CML, including treatment selection, resistance mechanisms, side effects, treatment discontinuation strategies, and considerations for special populations. Each of these factors plays a significant role in optimizing treatment and improving patient outcomes.