MOLECULAR HEMATOLOGY OF CHRONIC MYELOID LEUKEMIA: RECENT ADVANCES IN PATHOGENESIS, DIAGNOSIS AND TARGETED THERAPIES – AN UPDATED REVIEW

Gamal Abdul Hamid*, Samira A. Abdul Rahman

Background: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm driven by the BCR::ABL1 fusion oncogene, resulting from the reciprocal translocation t(9;22)(q34;q11.2). The development of tyrosine kinase inhibitors (TKIs) targeting BCR::ABL1 has revolutionized CML therapy, transforming a once-fatal disease into a manageable chronic condition with near-normal life expectancy. Objective: This comprehensive review synthesizes recent advances in the molecular pathogenesis, diagnostic approaches, therapeutic strategies, and emerging challenges in CML management, with a focus on developments from 2020-2025. Methods: We conducted a systematic review of peer-reviewed literature from PubMed, Scopus, and Web of Science databases, emphasizing clinical trials, consensus guidelines, and molecular studies published between 2000-2025. Results: Six TKIs are currently approved for CML treatment: imatinib (first-generation), dasatinib, nilotinib, bosutinib (second-generation), and ponatinib and asciminib (third-generation). Frontline therapy achieves 10-year overall survival rates of 82-87% and relative survival of 90-95%. Treatment-free remission (TFR) is achievable in 40-60% of patients with sustained deep molecular response (DMR) for ≥2 years, with TFR rates reaching 80-85% after ≥5 years of DMR. Resistance mechanisms include BCR::ABL1 kinase domain mutations (notably T315I), clonal evolution, and BCR::ABL1-independent pathways. The T315I "gatekeeper" mutation confers resistance to all first- and second-generation TKIs but is sensitive to ponatinib and asciminib. Cardiovascular toxicity remains a significant concern with second- and third-generation TKIs, particularly nilotinib and ponatinib. Emerging third-generation TKIs (olverembatinib, TGRX-678, TERN-701, ELVN-001) show promising efficacy in resistant disease. Conclusion: The molecular era has established precision medicine for CML, with ongoing research focused on overcoming resistance, increasing TFR rates, managing long-term toxicities, and ensuring global access to effective therapies.