Impact of Body Weight Adjusted Dose on Efficacy and Safety of Radotinib in Chronic Myeloid Leukemia

Background: Radotinib is a BCR-ABL tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myeloid leukemia in chronic phase (CP-CML). It is typically administered as a fixed dose; however, a subanalysis of the Phase 2 study (Leuk Lymphoma. DOI 10.3109/10428194.2015.1113278) demonstrated that as the dose adjusted for body weight (Dose/BW) increased the risk of dose-limiting toxicity (DLT) significantly.

Aims: To assess the impact of Dose/BW of radotinib on the occurrence of DLT as well as on the achievement of major molecular response (MMR) using the clinical data obtained from the Phase 3 study

Methods: The Phase 3 study involved 160 CP-CML patients who were randomly assigned to a fixed dose of radotinib 300 mg BID or 400 mg BID regardless of BW. The authors performed a logistic regression analysis to evaluate the relationship between daily Dose/BW and the probability of achieving MMR at 12 months as well as experiencing DLT by 12 months. Chi-square test and Kaplan-Meier analysis (log-rank test) were utilized to compare the incidence of MMR and DLT, respectively, according to specific Dose/BW cut-offs.

Results:Efficacy. Dose/BW of radotinib was negatively associated with the rate of MMR when controlled for gender (p = 0.033). That is, increasing Dose/BW rather decreased the likelihood of achieving MMR. More specifically, patients who received ≥13 mg/kg/d showed a significantly lower rate of MMR at 12 months (35%) than those who received <13 mg/kg/d (56%) (p = 0.045). Safety. Dose/BW of radotinib was positively associated with the rate of DLT (p = 0.003). A Dose/BW cut-off 13 mg/kg/d yielded the largest difference in the rate of DLT, such that the patients who received ≥13 mg/kg/d had a substantially higher rate of DLT (91%) than those who received <13 mg/kg/d (57%) (p <0.001). The time at which 50% of patients experienced their first DLT was also much earlier in the ≥13 mg/kg/d group (83 days) than in the <13 mg/kg/d group (194 days) (p <0.001).

Conclusion: Dose adjustment of radotinib based on BW is warranted so as not to exceed 13 mg/kg/d. Therefore, a two-tier weight-based dosing regimen was developed: radotinib 300 mg BID for patients who weigh 60 kg or less, and 400 mg BID for patients who weigh more than 60 kg. A prospective clinical trial would be needed to confirm the efficacy and safety of this new dosing regimen.