Optimizing Flumatinib Therapy in Chinese Chronic-Phase Chronic Myeloid Leukemia Based on Therapeutic Drug Monitoring

Background: The quantitative exposure-response-toxicity relationships for flumatinib have yet to be established in chronic-phase chronic myeloid leukemia (CML-CP) patients. Methods: We investigated associations between steady-state flumatinib plasma concentrations and clinical efficacy/adverse events in CML-CP patients. Results: Flumatinib exposure exhibited dose-dependent pharmacokinetics. In first-line patients, responders achieving major molecular response (MMR) exhibited significantly higher C max _2h (2-hour post-dose concentration) than non-responders (Non-MMR) (127.75± 60.40 vs. 58.29± 30.47 ng/mL; p< 0.001). Similarly, deep molecular response (DMR) responders showed higher C max _2h than Non-DMR patients (134.63± 66.45 vs. 88.87± 47.89 ng/mL; p< 0.001). Receiver operating characteristic analysis identified an optimal C max _2h threshold of > 87.75 ng/mL for MMR (AUC=0.87, 95% CI: 0.78– 0.96) and > 132.0 ng/mL for DMR (AUC=0.79, 95% CI: 0.68– 0.89). In the later-line, the effective treatment group also achieved substantially higher mean C max _2h than the failure group (133.75± 39.02 vs 88.69± 65.07 ng/mL; p< 0.01). Furthermore, the results identified an association between diarrhea and a C min (trough concentration)> 49 ng/mL, as well as between nausea and vomiting and a C max _2h> 126.5 ng/mL. Conclusion: Flumatinib demonstrates exposure-efficacy-toxicity relationships in Chinese patients with CML-CP. These exploratory findings suggest potential concentration thresholds that may inform future therapeutic drug monitoring strategies, pending prospective validation.