Third-line therapy for chronic myeloid leukemia: current status and future directions.
Third-line therapy for chronic myeloid leukemia: current status and future directions.
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DOI：
10.1186/s13045-021-01055-9
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发表时间：
2021-03-18
影响因子：
28.5
通讯作者：
Lang F
中科院分区：
文献类型：
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作者：
Cortes J;Lang F
慢性粒细胞白血病（CML）是由BCR-ABL 1融合蛋白驱动的，该融合蛋白是由9号和22号染色体之间的易位形成的，该易位产生了费城染色体。BCR-ABL 1融合蛋白是针对ABL 1的三磷酸腺苷（ATP）结合位点的酪氨酸激酶抑制剂（TKI）的最佳靶标。虽然这些药物大大改善了CML的预后，但许多患者最终治疗失败，一些患者需要多线TKI治疗。突变可能发生在ABL 1的ATP结合位点，通过阻止许多这些药物的结合导致耐药性，并使患者的治疗选择有限。获批的TKI也与可能导致某些患者停止治疗的不良反应相关。疗效随着每一治疗线的进展而降低;数据表明，在第一代TKI和2GTKI治疗失败后，三线（3L）、第二代酪氨酸激酶抑制剂（2GTKI）治疗的临床获益很小。需要在3L及以上环境中治疗的患者人群需要新的治疗选择。本综述强调了需要明确的指南和新的治疗方法的患者需要3L治疗及以上。
Chronic myeloid leukemia (CML) is driven by the BCR-ABL1 fusion protein, formed by a translocation between chromosomes 9 and 22 that creates the Philadelphia chromosome. The BCR-ABL1 fusion protein is an optimal target for tyrosine kinase inhibitors (TKIs) that aim for the adenosine triphosphate (ATP) binding site of ABL1. While these drugs have greatly improved the prognosis for CML, many patients ultimately fail treatment, some requiring multiple lines of TKI therapy. Mutations can occur in the ATP binding site of ABL1, causing resistance by preventing the binding of many of these drugs and leaving patients with limited treatment options. The approved TKIs are also associated with adverse effects that may lead to treatment discontinuation in some patients. Efficacy decreases with each progressive line of therapy; data suggest little clinical benefit of treatment with a third-line (3L), second-generation tyrosine kinase inhibitor (2GTKI) after failure of a first-generation TKI and a 2GTKI. Novel treatment options are needed for the patient population that requires treatment in the 3L setting and beyond. This review highlights the need for clear guidelines and new therapies for patients requiring 3L treatment and beyond.