The Homocysteine Paradox: A Metabolic Biomarker for TKI Resistance in Chronic Myeloid Leukemia

Background: Tyrosine kinase inhibitors (TKIs) have significantly advanced Chronic Myeloid Leukemia (CML) treatment. However, TKI resistance remains problematic. Current monitoring measures BCR-ABL transcript levels, which indicate genetic burden but do not reflect metabolic stress caused by the oncogene. Homocysteine may serve as a novel metabolic biomarker.Objective: This study aimed to evaluate the utility of plasma homocysteine as a dynamic biomarker for monitoring responses to tyrosine kinase inhibitors (TKIs) and identifying resistance mechanisms.Patients and Methods: This retrospective cross-sectional study examined 120 patients with chronic-phase chronic myeloid leukemia (CML) undergoing at least 12 months of tyrosine kinase inhibitor (TKI) therapy at a Baghdad hospital from January to September 2025. Participants were classified as optimal (n=78) or suboptimal responders (n=42) based on clinical and metabolic parameters. Plasma homocysteine levels were measured using ELISA, and their correlations with lactate dehydrogenase (LDH), vitamin B12, and folate were analyzed. The diagnostic utility of these biomarkers was assessed through ROC analysis.Results: Homocysteine levels were significantly elevated in suboptimal responders (median: 21.4 µmol/L) compared to optimal responders (median: 9.8 µmol/L; p<0.001). A strong positive correlation was found between homocysteine and lactate dehydrogenase (LDH) (Spearman's ρ=0.83, p<0.001). ROC analysis demonstrated high diagnostic accuracy for homocysteine, with an AUC of 0.94, and an optimal cutoff of 15.2 µmol/L yielded 88.1% sensitivity and 89.7% specificity for resistance.Conclusion: Plasma homocysteine is a sensitive biomarker correlated with TKI resistance in CML, indicating metabolic dysregulation and aiding early detection of therapeutic failure.