AI-Guided Repurposing of FDA-Approved Anti-Leukemic Molecularly Targeted Therapies for Fatal Blast Crisis Chronic Myeloid Leukemia: Integrative Genomics for Precision Medicine of Relapsed/Refractory Cancers in the Post-Pandemic Era

Background: The COVID-19 pandemic accelerated the paradigm of drug repurposing, leading to the rapid identification of new uses for existing therapeutics under urgent clinical need. This success story has ignited a broader movement towards leveraging repurposing strategies for relapsed, refractory, and traditionally difficult-to-treat diseases, specifically cancers. Chronic myeloid leukemia (CML), although treatable in the chronic phase (CP), is usually fatal in the blast crisis phase (BC-CML), exemplifying a pressing challenge to oncology, where standard tyrosine kinase inhibitor (TKI) therapies often fail, resulting in poor survival outcomes. Methods and Results: In a multi-institutional cohort of 141 CML patients, we performed WES across disease phases (123 CP-CML, 6 AP-CML, 12 BC-CML). Mutational landscapes were interrogated using the AI-driven PanDrugs2 platform to identify druggable targets and repurposable FDA-approved anti-leukemic therapies. A 54% surge in mutational burden was observed transitioning from AP-CML to BC-CM, revealing 67 recurrent pan-leukemic gene mutations. Notably, actionable alterations were found in NPM1, DNMT3A, PML, AKT1, CBL, JAK2, TET2, IDH1, and BCL2, with therapeutic opportunities using existing agents such as venetoclax, ivosidenib, decitabine, and azacitidine. Emerging vulnerabilities, including RPTOR and BCR mutations, suggest further avenues for mTOR and BTK inhibitor applications beyond traditional TKI paradigms. Conclusions: Our integrated genomic and AI-guided approach demonstrates the transformative potential of drug repurposing for BC-CML, highlighting immediate actionable options where conventional therapies fail. This strategy not only offers hope for patients with BC-CML but also paves a visionary path toward precision medicine frameworks for relapsed, refractory, and otherwise intractable cancers in the post-pandemic clinical era. Prospective multi-omics studies and tailored clinical trials are urgently warranted to expand these opportunities across the oncology landscape