Real-World Use and Outcomes of Tyrosine Kinase Inhibitor Treatment in Patients with Chronic Myeloid Leukaemia

Tyrosine kinase inhibitors (TKIs) have changed survival outcomes in many cancers. Despite their targeted action, TKIs exhibit large inter-individual variability in exposure (pharmacokinetics, PK) and effects (pharmacodynamics, PD). Understanding factors that contribute to variability in PK and PD of TKIs can guide precision medicine. In this research, a retrospective study investigated the real-world use and outcomes of the BCR-ABL1 TKIs imatinib, dasatinib and nilotinib in patients with chronic myeloid leukemia (CML) at two Australian hospitals. Results confirm the real-world effectiveness of imatinib, nilotinib and dasatinib in patients with CML, inducing rapid and deep molecular responses (DMR). However, many patients relapsed or failed to achieve sustained DMR (sDMR). TKI-related adverse drug reactions (ADRs) were common, with over 50% of patients experiencing grade ≥3 ADRs by 2 years of treatment. Multivariable regression identified a range of baseline biological (age, sex, comorbidities, geographic ancestry), clinical (disease risk scores, concomitant medicines) and treatment-related factors (starting dose, line of treatment) that predicted TKI treatment cessation, molecular response, survival and ADRs in this real-world cohort. To investigate whether predicted systemic exposure could explain the occurrence of grade ≥3 ADRs or failure to achieve early molecular response (EMR) with imatinib, a simulation study was conducted using physiologically-based pharmacokinetic modelling. Patients who experienced a grade ≥ 3 ADR and who achieved EMR at 3 months had a significantly higher predicted imatinib AUCss, Css,max and Css,min compared to patients who did not. Sensitivity analyses identified a range of patient and medicine-related factors that could contribute to the inter-individual variability in imatinib systemic exposure. This research supports the rationale for TKI dose individualisation in CML, to increase the likelihood of sDMR and to reduce ADRs