Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the BCR-ABL1 fusion gene, which activates tyrosine kinase activity. Tyrosine kinase inhibitors (TKIs) have revolutionized CML treatment, enabling long-term disease control in most patients. However, a subset of individuals—particularly those classified as high-risk—develop resistance to TKIs, often associated with BCR-ABL1 kinase domain mutations, cytogenetic abnormalities, or progression to advanced phases. This resistance presents a major challenge, requiring tailored strategies and close molecular monitoring.

To identify the key mechanisms driving TKI resistance in high-risk CML; to review current and emerging therapeutic strategies, including second- and third- generation TKIs and allogeneic hematopoietic cell transplantation (allo-HCT); and to assess the role of predictive models in guiding personalized treatment and anticipating therapeutic failure.

This systematic review was conducted following PRISMA guidelines. A comprehensive PubMed search was performed using the terms “chronic myeloid leukemia,” “TKI resistance,” “high-risk CML,” “BCR-ABL1 mutations,” and related MeSH terms. Articles published between 2009 and 2025 were considered. Inclusion criteria comprised studies addressing TKI resistance mechanisms, therapeutic strategies in high-risk CML, and predictive modeling. After screening titles, abstracts, and full texts, 28 studies were included. These encompassed clinical trials (including Phase 1/2), reviews, retrospective analyses, population- based data, registry studies, and research on predictive tools.

The review confirms that BCR-ABL1 kinase domain mutations—particularly T315I—are central to TKI resistance, significantly limiting the efficacy of first- and second-generation TKIs. Additionally, baseline or emerging cytogenetic abnormalities (e.g., +8, i(17q), or complex karyotypes) are predictive of poor prognosis and disease progression. Second-generation TKIs (dasatinib, nilotinib, bosutinib) improve responses in patients with suboptimal outcomes on imatinib, while third-generation agents such as ponatinib and olverembatinib (HQP1351) demonstrate efficacy against T315I-mutated disease. Olverembatinib, in particular, shows high rates of major molecular response in Phase 1/2 trials with manageable toxicity. Allo-HCT remains the only curative option for patients with multiple TKI failures or advanced disease, with improved transplant outcomes observed in the TKI era. Patients in blast phase benefit from intensive regimens combining TKIs with chemotherapy. Finally, emerging predictive models—such as molecular response kinetics, BCR-ABL1 halving time, and artificial intelligence–based algorithms—offer promise in anticipating resistance and enabling early therapeutic intervention. TKI resistance in high-risk CML is multifactorial and continues to present a major clinical challenge. Mutational burden, cytogenetic complexity, and suboptimal molecular responses remain key determinants of poor outcome. Newer TKIs like olverembatinib and tailored use of allo-HCT have expanded the therapeutic arsenal. Incorporating predictive tools and risk stratification models into clinical practice may allow for earlier intervention and truly personalized therapy. Improving outcomes in this population demands a dynamic, molecularly guided approach.