Hematology, Department of Translational and Precision Medicine, Az. Policlinico Umberto I-Sapienza University, Via Benevento 6, 00161, Rome, Italy.
Curr Hematol Malig Rep. 2022 Dec;17(6):198-205. doi: 10.1007/s11899-022-00683-3. Epub 2022 Oct 20.
The clinical scenario for chronic myeloid leukemia patients rapidly changed after the introduction of tyrosine kinase inhibitors (TKIs). Second-generation TKIs as frontline treatment increased the rate of deep molecular responses without increasing the rate of overall survival. About 20% of patients experience resistance to these agents, needing alternative treatments. Here, we reviewed the possible mechanisms of resistance, available treatment, and new drugs developed to counteract and overcome resistance.
Results of novel TKIs have been recently reported, especially for the setting of T315I mutated patients, such as olverembatinib and asciminib, or for patients who developed resistance due to other mutations, such as vodobatinib. Most of new TKIs are selected among compounds tested selective on ABL, therefore without possible off-target effects in the long term. New potential treatments are on the horizon in the field of CML, able to rescue patients treated firstly with one or more second-generation TKIs. Results of ongoing trials and real-world evidence dataset will help us to identify the appropriate timing of intervention and to select appropriate candidate to these drugs.
酪氨酸激酶抑制剂（TKI）问世后，慢性髓系白血病患者的临床情况迅速发生变化。作为一线治疗的第二代 TKI 增加了深度分子反应率，而不增加总生存率。约 20%的患者对这些药物产生耐药性，需要替代治疗。在这里，我们综述了耐药的可能机制、可用的治疗方法以及为对抗和克服耐药性而开发的新药。
新型 TKI 的研究结果最近已公布，特别是针对 T315I 突变患者，如 olverembatinib 和 asciminib，或针对因其他突变而产生耐药性的患者，如 vodobatinib。大多数新型 TKI 是从对 ABL 具有选择性的化合物中筛选出来的，因此在长期内不会产生潜在的脱靶效应。在 CML 领域，新的潜在治疗方法即将出现，能够挽救最初使用一种或多种第二代 TKI 治疗的患者。正在进行的试验和真实世界证据数据集的结果将帮助我们确定干预的适当时机，并为这些药物选择合适的候选药物。
