Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors

Abstract

Radotinib (IY5511HCL), a novel and selective BCR-ABL1 tyrosine kinase inhibitor, has shown pre-clinical and phase I activity and safety in chronic myeloid leukemia. This phase II study investigated the efficacy and safety of radotinib in Philadelphia chromosome-positive chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors. Patients received radotinib 400 mg twice daily for 12 cycles based on results from the phase I trial. The primary end point was rate of major cytogenetic response by 12 months. A total of 77 patients were enrolled. Major cytogenetic response was achieved in 50 (65%; cumulative 75%) patients, including 36 (47%) patients with complete cytogenetic response by 12 months. Median time to major cytogenetic response and complete cytogenetic response were 85 days and 256 days, respectively. Major cytogenetic response and complete cytogenetic response rates were similar between imatinib-resistant and imatinib-intolerant patients, but were higher in patients without BCR-ABL1 mutations. Overall and progression-free survival rates at 12 months were 96.1% and 86.3%, respectively. All newly-occurring or worsening grade 3/4 hematologic abnormalities included thrombocytopenia (24.7%) and anemia (5.2%); grade 3/4 drug-related non-hematologic adverse events included fatigue (3.9%), asthenia (3.9%), and nausea (2.6%). The most common biochemistry abnormality was hyperbilirubinemia (grade 3/4 23.4%), and 12 of 18 cases were managed with dose modification. Study findings suggest radotinib is effective and well tolerated in chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors and may represent a promising alternative for these patients. (clinicaltrials.gov identifier: 01602952).

Trial registration: ClinicalTrials.gov NCT01602952.

Figure 1.

Cumulative incidence of cytogenetic response. CCyR: complete cytogenetic response; MCyR: major cytogenetic response.

Figure 2.

Cytogenetic and molecular response in patients with and without base-line BCR-ABL1 kinase domain abnormality. CCyR: complete cytogenetic response; MCyR: major cytogenetic response; MMR: major molecular response. ^aAt baseline, 4 of 77 patients had PCyR, which was among the exclusion criteria for study entry. Therefore, patients with PCyR at baseline were only considered eligible for CCyR and were assessed as not responding if they remained in PCyR. According to these criteria, 3 patients achieving CCyR were assessed as responding. ^bType of mutation included 1 M244V, 1 M244V+H396R, 4 P-loop (1 G250E, 1 Y253F+E355G, 1 E255K, 1 E255V), 1 A-loop (1 L387M), and 7 other (1 F317L, 1 M351T, 1 E355G, 2 F359V, 1 35bp INS between exons 8 and 9, 1 del 363–386).

Figure 3.

Kaplan–Meier curves of OS and PFS. OS: overall survival; PFS: progression-free survival. ^aBy 12 months. ^bTwo patients died due to sepsis during treatment and 1 patient died after discontinuation due to disease progression.