Potential utility of PPARγ agonists in targeting chronic myeloid leukemia stem cells

Tyrosine kinase inhibitors (TKIs) have transformed the treatment of chronic myeloid leukemia (CML), yet persistent leukemia stem cells (LSCs) remain a barrier to cure. PPARγ agonists like pioglitazone have been proposed to enhance eradication of LSCs when used alongside TKIs. This study investigated the impact of adding pioglitazone to imatinib therapy in 26 newly diagnosed chronic-phase CML patients. Patients received imatinib (400 mg) plus pioglitazone (15 mg) daily for six months, with follow-up extending to 60 months. Treatment responses and adverse events were recorded, and expression levels of CITED2 and HIF2α genes were measured before and after therapy, compared to a control group of 52 matched patients treated with imatinib alone. The combination therapy showed improved early cytogenetic and molecular responses, though long-term outcomes were not significantly different. Significant reductions in median CITED2 (from 276.3 to 2.6; P = 0.005) and HIF2α (from 2.7 to 1; P = 0.026) expression were observed post-treatment. These results suggest that pioglitazone may enhance early molecular response and suppress LSC-associated genes, but further research is needed to confirm its long-term benefit and clarify the role of PPARγ modulation in CML management. Clinical Trial Number: NCT04883125.