Purpose of Review

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.

Recent Findings

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.

Summary

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.

中文翻译：

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对第二代 TKI 耐药的 CML：机制、后续步骤和新方向

审查目的

引入酪氨酸激酶抑制剂 (TKI) 后，慢性粒细胞白血病患者的临床情况迅速改变。作为一线治疗的第二代 TKI 增加了深度分子反应的速度，但没有增加总生存率。大约 20% 的患者对这些药物产生耐药性，需要替代疗法。在这里，我们回顾了耐药性的可能机制、可用的治疗方法以及为抵消和克服耐药性而开发的新药。

最近的发现

最近报道了新型 TKI 的结果，特别是对于 T315I 突变患者的设置，例如 olverembatinib 和 asciminib，或者对于由于其他突变而产生耐药性的患者，例如 vodobatinib。大多数新的 TKI 是从对 ABL 选择性测试的化合物中选择的，因此从长远来看没有可能的脱靶效应。

概括

CML 领域即将出现新的潜在治疗方法，能够挽救首先接受一种或多种第二代 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适当的干预时机，并为这些药物选择合适的候选药物。