Starting with imatinib, tyrosine kinase inhibitors (TKIs) have turned chronic myeloid leukemia (CML) from a lethal blood cancer into a chronic condition. As patients with access to advanced CML care have an almost normal life expectancy, there is a perception that CML is a problem of the past, and one should direct research resources elsewhere. However, a closer look at the current CML landscape reveals a more nuanced picture. Most patients still require life-long TKI therapy to avoid recurrence of active CML. Chronic TKI toxicity and the high costs of the well-tolerated agents remain challenging. Progression to blast phase still occurs, particularly in socioeconomically disadvantaged parts of the world, where high risk CML at diagnosis is common. Here we will review the prospects of further improving TKIs to achieve optimal suppression of BCR::ABL1 kinase activity, the potential of combining different classes of TKIs, and the current state of BCR::ABL1 degraders. We will cover combination therapy approaches to address TKI resistance in the setting of residual leukemia and in advanced CML. Despite the unprecedented success of TKIs in CML, more work is needed to truly finish the job, and we hope to stimulate innovative research aiming to achieve this goal.

中文翻译：

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慢性粒细胞白血病的新治疗策略。


从伊马替尼开始，酪氨酸激酶抑制剂 （TKI） 已将慢性粒细胞白血病 （CML） 从致命的血癌转变为慢性疾病。由于获得高级 CML 护理的患者预期寿命几乎正常，因此人们认为 CML 已成为过去的问题，应该将研究资源引向其他地方。然而，仔细观察当前的 CML 形势会发现一个更微妙的画面。大多数患者仍需要终生 TKI 治疗，以避免活动性 CML 复发。慢性 TKI 毒性和耐受性良好的药物的高成本仍然具有挑战性。进展到急变期的情况仍然存在，尤其是在世界上社会经济落后地区，诊断时高危 CML 很常见。在这里，我们将回顾进一步改进 TKI 以实现 BCR：：ABL1 激酶活性最佳抑制的前景、组合不同类别 TKI 的潜力以及 BCR：：ABL1 降解剂的现状。我们将介绍联合治疗方法，以解决残余白血病和晚期 CML 中的 TKI 耐药问题。尽管 TKI 在 CML 中取得了前所未有的成功，但要真正完成这项工作还需要更多的工作，我们希望激发旨在实现这一目标的创新研究。