Radotinib in the treatment of chronic phase chronic myeloid leukemia patients

Abstract

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 2 nd 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. 1Although 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. 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 dasatinib 3 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 2x400 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 pe...

Chronic-phase chronic myeloid leukemia: Incidence of BCR/ABL transcript and its correlation with presenting features, response to treatment, and survival

“…Ghalesardi et al showed that the ratio of male to female was higher in the b2a2 group compared to b3a2 [19] . In a Mexican study, a higher leukocyte count in patients with the b2a2 transcript was reported [20] . However, in our patients, hyperleukocytosis ≥ 100 × 10⁹/L was found to be more associated with the b3a2 transcript type without statistically significant results, which is consistent with other studies [21] .…”

Current Treatment Options for Chronic Myeloid Leukemia Patients Failing Second-Generation Tyrosine Kinase Inhibitors

“…Overall survival (OS) and progression-free survival (PFS) rates at 12 months were 96% and 86%, respectively. However, radotinib has not been evaluated in patients failing 2GTKI [ 31 ].…”

Radotinib and its clinical potential in chronic-phase chronic myeloid leukemia patients: an update

“…Overall radotinib discontinuation rates both in the original study 8 and in the 24-month update 17 were also comparable to other studies as concluded by Kim and colleagues. 18 Relatively higher rates of AEs and biochemical abnormalities of radotinib in the salvage setting raised some concerns, 19 and the authors concluded that as a starting dose the current 800 mg daily dose may be appropriate in the second-line setting, but the dose for frontline administration should be reduced; studies were ongoing for further dose optimization. 18 Radotinib in newly diagnosed patients with CML-CP Prior to the utilization of radotinib in the context of first-line therapy, there were some 2GTKIs tested in the frontline treatment of patients with CML-CP.…”

“…Relatively higher rates of AEs and biochemical abnormalities of radotinib in the salvage setting raised some concerns, 19 and the authors concluded that as a starting dose the current 800 mg daily dose may be appropriate in the second-line setting, but the dose for frontline administration should be reduced; studies were ongoing for further dose optimization. 18…”