Pharmacokinetics of dasatinib for Philadelphia-positive acute lymphocytic leukemia with acquired T315I mutation

To determine whether plasma dasatinib pharmacokinetics influences the emergence of BCR-ABL mutations, we measured plasma dasatinib levels in 11 Ph？+？ALL patients undergoing dasatinib monotherapy.Bone marrow relapse occurred in 5 of the 11 Ph？+？ALL patients (45%). Importantly, a T315I mutation was detected in 4 of the 5 relapsed patients, despite the absence of BCR-ABL mutations in any patient at baseline. The median plasma concentration at 2 hours (C2h), the median plasma maximum concentration (Cmax), and the median area under the observed plasma concentration-time curve from 0 to 4 hours (AUC0-4) were all significantly lower in patients with T315I than those without the mutation (C2h, 22.3？ng/mL vs. 111.6？ng/mL, P？=？0.0242; Cmax, 43.8？ng/mL vs. 112.4？ng/mL, P？=？0.0242; AUC0-4, 108.3？ng·h/mL vs. 268.3？ng·h/mL, P？=？0.0061, respectively).These data indicate that the emergence of the T315I mutation among Ph？+？ALL patients treated with dasatinib is, in part, dependent on plasma dasatinib pharmacokinetics. Notably, these data also suggest that newly acquired BCR-ABL mutations may be inhibited by an increased exposure of dasatinib.