Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors
Efficacy and safety of radotinib in chronic phase chronic myeloid leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase inhibitors
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DOI：
10.3324/haematol.2013.096776
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发表时间：
2014-07-01
期刊：
影响因子：
10.1
通讯作者：
Kim, Dong-Wook
中科院分区：
文献类型：
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作者：
Kim, Sung-Hyun;Menon, Hari;Kim, Dong-Wook
Radotinib （IY5511HCL）是一种新型的选择性BCR-ABL1酪氨酸激酶抑制剂，在慢性髓性白血病中显示出临床前和I期活性和安全性。这项II期研究调查了拉多替尼在对BCR-ABL1酪氨酸激酶抑制剂耐药和/或不耐受的费城染色体阳性慢性期慢性髓系白血病患者中的疗效和安全性。根据I期试验的结果，患者接受拉多替尼400mg，每日两次，共12个周期。主要终点为12个月的主要细胞遗传学反应率。共有77名患者入组。50例（65%；累计75%）患者获得主要细胞遗传学缓解，其中36例（47%）患者在12个月前获得完全细胞遗传学缓解。达到主要细胞遗传学反应和完全细胞遗传学反应的中位时间分别为85天和256天。伊马替尼耐药患者和伊马替尼不耐受患者的主要细胞遗传学反应率和完全细胞遗传学反应率相似，但无BCR-ABL1突变患者的细胞遗传学反应率更高。12个月的总生存率和无进展生存率分别为96.1%和86.3%。所有新发生或恶化的3/4级血液学异常包括血小板减少（24.7%）和贫血（5.2%）；3/4级药物相关非血液学不良事件包括疲劳（3.9%）、乏力（3.9%）和恶心（2.6%）。最常见的生化异常是高胆红素血症（3/4级，占23.4%），18例患者中有12例接受了剂量调整。研究结果表明，拉多替尼对BCR-ABL1酪氨酸激酶抑制剂耐药和/或不耐受的慢慢性髓系白血病患者有效且耐受性良好，可能是这些患者的一种有希望的替代方案。
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.