Tyrosine kinase inhibitors and secondary malignancies in chronic myeloid leukemia: A protocol for systematic review

Background: Chronic myeloid leukemia (CML) is a hematologic malignancy characterized by the BCR-ABL1 fusion oncogene and effectively treated with tyrosine kinase inhibitors (TKIs). While TKIs have significantly improved survival, their long-term use has raised concerns regarding adverse events, particularly the development of secondary malignancies (SMs). Reports from the FDA Adverse Events Reporting System and conflicting evidence from observational studies highlight the need for a comprehensive synthesis of data. The aims of this planned systematic review are therefore: to assess the incidence and types of SMs reported in CML patients receiving TKIs; and to compare the risk of SMs across different TKI agents used in chronic-phase CML. Methods: This systematic review will follow the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols. We will search multiple databases, including PubMed, EMBASE, Scopus, Web of Science, and Web of Conferences from inception to May 2025. Eligible studies will include randomized controlled trials, cohort studies, case series, and conference abstracts reporting on SMs in CML patients treated with TKIs (imatinib, dasatinib, nilotinib, bosutinib, ponatinib, or asciminib). Study selection, data extraction, and quality assessment will be carried out independently by multiple reviewers using standardized tools. Results: This systematic review will be among the first to comprehensively evaluate the risk of SMs associated with long-term TKI therapy in chronic-phase CML. The conflicting results in the current literature call for a systematic methodology to thoroughly answer the concerns of long-term safety of TKIs in this population. Conclusion: The protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD420251067085).