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 Cmax_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 Cmax_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 Cmax_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 Cmax_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 Cmin (trough concentration)>49 ng/mL, as well as between nausea and vomiting and a Cmax_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.