Pophali Priyanka A, Patnaik Mrinal M
From the Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN.
Cancer J. 2016 Jan-Feb;22(1):40-50. doi: 10.1097/PPO.0000000000000165.
Imatinib mesylate was the first tyrosine kinase inhibitor (TKI) approved for the management of chronic myeloid leukemia. Imatinib produces acceptable responses in approximately 60% of patients, with approximately 20% discontinuing therapy because of intolerance and approximately 20% developing drug resistance. The advent of newer TKIs, such as nilotinib, dasatinib, bosutinib, and ponatinib, has provided multiple options for patients. These agents are more potent, have unique adverse effect profiles, and are more likely to achieve relevant milestones, such as early molecular responses (3-6 months) and optimal molecular responses (12 months). The acquisition of BCR-ABL kinase domain mutations is also reportedly lower with these drugs. Thus far, none of the randomized phase III clinical trials have shown a clinically significant survival difference between frontline imatinib versus newer TKIs. Cost and safety issues with the newer TKIs, such as vascular disease with nilotinib and ponatinib and pulmonary hypertension with dasatinib, have dampened the enthusiasm of using these drugs as frontline options. While the utility of new TKIs in the setting of imatinib failure or intolerance is clear, their use as frontline agents should factor in the age of the patient, additional comorbidities, risk stratification (Sokal score), and cost. Combination therapies and newer agents with potential to eradicate quiescent chronic myeloid leukemia stem cells offers future hope.
甲磺酸伊马替尼是首个被批准用于治疗慢性髓性白血病的酪氨酸激酶抑制剂（TKI）。伊马替尼在约60%的患者中产生可接受的反应，约20%的患者因不耐受而停药，约20%的患者产生耐药性。新型TKI如尼罗替尼、达沙替尼、博舒替尼和波纳替尼的出现为患者提供了多种选择。这些药物效力更强，具有独特的不良反应谱，更有可能达成相关的治疗目标，如早期分子反应（3 - 6个月）和最佳分子反应（12个月）。据报道，使用这些药物时BCR - ABL激酶域突变的发生率也较低。迄今为止，尚无随机III期临床试验表明一线使用伊马替尼与新型TKI之间存在具有临床意义的生存差异。新型TKI的成本和安全性问题，如尼罗替尼和波纳替尼导致的血管疾病以及达沙替尼导致的肺动脉高压，削弱了将这些药物作为一线选择的热情。虽然新型TKI在伊马替尼治疗失败或不耐受的情况下的效用是明确的，但将其作为一线药物使用时应考虑患者的年龄、其他合并症、风险分层（索卡尔评分）和成本。联合疗法以及有潜力根除静止期慢性髓性白血病干细胞的新型药物带来了未来的希望。
