Hematology and Stem Cell Transplantation Department, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.
Cancer J. 2011 Nov-Dec;17(6):465-76. doi: 10.1097/PPO.0b013e31823dec8d.
The clinical outcome for patients with chronic myelogenous leukemia (CML) has changed dramatically in the past 15 years. This has been due to the development of tyrosine kinase inhibitors (TKIs), compounds that inhibit the activity of the oncogenic BCR-ABL1 protein. Imatinib was the first TKI developed for CML, and it led to high rates of complete cytogenetic responses and improved survival for patients with this disease. However, approximately 35% of patients in chronic phase treated with imatinib will develop resistance or intolerance to this drug. The recognition of the problem of imatinib failure led to the design of second-generation TKI (dasatinib, nilotinib, and bosutinib). These drugs are highly active in the scenario of imatinib resistance or intolerance. More recently, both nilotinib and dasatinib were approved for frontline use in patients with chronic phase CML. Ponatinib represents the last generation of TKI, and this drug has been developed with the aim of targeting a specific BCR-ABL1 mutation (T315I), which arises in the setting of prolonged TKI therapy and leads to resistance to all commercially available TKI. Parallel to the development of specific drugs for treating CML, major advances were made in the field of disease monitoring and standardization of response criteria. In this review, we summarize how therapy with TKI for CML has evolved during the last decade.
在过去的 15 年中，慢性髓性白血病（CML）患者的临床结局发生了巨大变化。这主要归功于酪氨酸激酶抑制剂（TKI）的发展，这些化合物可抑制致癌 BCR-ABL1 蛋白的活性。伊马替尼是第一种用于 CML 的 TKI，它可使患者获得高完全细胞遗传学缓解率和改善生存。然而，接受伊马替尼治疗的慢性期患者中约有 35%会对该药物产生耐药或不耐受。人们认识到伊马替尼耐药的问题，导致了第二代 TKI（达沙替尼、尼洛替尼和博舒替尼）的设计。这些药物在伊马替尼耐药或不耐受的情况下具有高度活性。最近，尼洛替尼和达沙替尼均被批准用于慢性期 CML 患者的一线治疗。帕纳替尼代表了最后一代 TKI，该药的开发旨在靶向特定的 BCR-ABL1 突变（T315I），该突变出现在 TKI 治疗延长的情况下，导致对所有市售 TKI 的耐药。在针对 CML 治疗的特定药物发展的同时，在疾病监测和反应标准的标准化领域也取得了重大进展。在本篇综述中，我们总结了过去十年中 CML 用 TKI 治疗的演变情况。
