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We read with interest the article by Kim et al.1 in which the authors provided the efficacy and safety data of radotinib (IY5511HCL), an oral BCR-ABL1-specific 2nd generation tyrosine kinase inhibitor (TKI), in 77 patients with chronic phase-chronic myeloid leukemia (CP-CML) in a multinational phase II trial. After a median duration of radotinib exposure of approximately 12 months and a median follow up of 23.4 months, the complete cytogenetic response (CCyR) rate was 47% by 12 months, and the overall and progression-free survival rates at 12 months were 96.1% and 86.3%, respectively. Thrombocytopenia, hepatotoxicity, hyperbilirubinemia and hyperglycemia were the most common hematologic and non-hematologic adverse events (AEs). The authors implied that radotinib was effective and relatively well tolerated in patients with CP-CML, and CCyR rates were higher in patients without BCR-ABL1 mutations.1  Although most of the CP-CML patients do well under imatinib, some of them develop resistance, and BCR-ABL1 kinase domain mutations are detected in approximately 50% of patients with treatment failure and progression.2 Second generation TKIs (dasatinib and nilotinib) are used in patients who have intolerance and resistance to imatinib.3,4 In the study cohort, CCyR rate at 12 months was 47%, and the authors compared their results with dasatinib and nilotinib. They concluded that the efficacy of the study drug was comparable, and even favorable, to those observed with dasatinib3 and nilotinib.4 But these 2 studies which the authors mentioned have shorter followup durations than the present study, and when the other TKIs were used as a second-line treatment at longer followup periods the CCyR rates were similar to those of the present study: dasatinib 45%,5 nilotinib 44%,6 and bosutinib 41%7. As expected, the response rates were higher in imatinib intolerant cases than in those who were resistant,1 which has already been shown in the second-line dasatinib and nilotinib trials.5,6 The authors concluded that in 5 patients with a BCR-ABL1 mutation which was less sensitive to nilotinib or dasatinib, 2 had gained major CyR. But there seems to be a problem in terms of efficacy of radotinib in patients with a mutated clone (n=14) because only 3 of these patients have responded to the study drug. Moreover, during follow up, 6 additional patients were found to harbor new mutations, including T315I. This is a major challenge for clinicians given that nearly half the patients with imatinib resistance have BCR-ABL1 mutations.  Dasatinib and nilotinib are generally well tolerated but they do have AEs that appear in the short term or after a longer follow up.8 Their familiarity with these AEs allows physicians caring for CML patients to recognize and manage them.9 Radotinib was used at an initial dose of 2×400 mg/daily in the present study, and the most common grade 3–4 hematologic AE was thrombocytopenia, which was observed in 25% of the patients.1 Grade 1–2 hepatotoxicity was present in more than 70% of the patients, and the percentages of grade 3–4 hyperbilirubinemia and hyperglycemia were 23.4% and 19.5%, respectively. During follow up, 71.4% of the patients had a dose interruption, and a dose reduction was needed in 53 (68.8%). These numbers are quite high, which might suggest that the starting dose of radotinib should be lower. Furthermore, 42.9% of the patients discontinued treatment before 12 months, of which 18 patients (23.4%) stopped therapy due to AEs and abnormal laboratory results. This is also a high number after a relatively short duration of follow up, and although the authors concluded that the AEs were generally transient and manageable, nearly one-fourth of the patients stopped treatment with the study drug due to AEs within 12 months of treatment.  In conclusion, although radotinib seems to be a promising alternative treatment, more data should be collected regarding its efficacy and safety, and prospective randomized trials with longer follow-up periods are needed to strengthen the efficacy and safety data of this 2nd generation TKI.

Radotinib in the treatment of chronic phase chronic myeloid leukemia patients