With the improving knowledge of CML and its management, the goals of therapy need to be revisited to ensure an optimal use of the BCR::ABL1 TKIs in the frontline and later-line therapy of CML. In the frontline therapy of CML in the chronic phase (CML-CP), imatinib and the three second-generation TKIs (bosutinib, dasatinib and nilotinib) are associated with comparable survival results. The second-generation TKIs may produce earlier deep molecular responses, hence reducing the time to reaching a treatment-free remission (TFR). The choice of the second-generation TKI versus imatinib in frontline therapy is based on the treatment aims (survival, TFR), the CML risk, the drug cost, and the toxicity profile with respect to the patient’s comorbidities. The TKI dosing is more flexible than has been described in the registration trials, and dose adjustments can be considered both in the frontline and later-line settings (e.g., dasatinib 50 mg frontline therapy; dose adjusted schedules of bosutinib and ponatinib), as well as during an ongoing TKI therapy to manage toxicities, before considering changing the TKI. In patients who are not candidates for TFR, BCR::ABL1 (International Scale) transcripts levels <1% are acceptable, result in virtually similar survival as with deeper molecular remissions, and need not warrant a change of TKI. For patients with true resistance to second-generation TKIs or with the T315I gatekeeper mutation, the third-generation TKIs are preferred. Ponatinib should be considered first because of the cumulative experience and results in the CML subsets, including in T315I-mutated CML. A response-based dosing of ponatinib is safe and leads to high TKI compliance. Asciminib is a third-generation TKI with possibly a better toxicity profile, but lesser activity in T315I-mutated CML. Olverembatinib is another potent third-generation TKI with early promising results.
随着对慢性髓系白血病及其治疗认识的深入，有必要重新审视治疗目标，以确保在CML的一线和后线治疗中优化使用BCR::ABL1酪氨酸激酶抑制剂。在慢性期CML的一线治疗中，伊马替尼与三种第二代TKIs（博舒替尼、达沙替尼和尼洛替尼）的生存结果相当。第二代TKIs可能更早实现深度分子学反应，从而缩短达到无治疗缓解的时间。在一线治疗中选择第二代TKI还是伊马替尼，需基于治疗目标（生存期、无治疗缓解）、CML风险分层、药物费用以及患者合并症相关的毒性特征。TKI给药方案比注册试验中描述的更为灵活，在一线和后线治疗中均可考虑剂量调整（例如达沙替尼50毫克一线治疗；博舒替尼和普纳替尼的剂量调整方案），并在考虑更换TKI之前，可在持续治疗期间为控制毒性而调整剂量。对于不适合无治疗缓解的患者，BCR::ABL1（国际标准）转录本水平<1%是可接受的，其生存结果与更深层的分子学缓解几乎相同，且无需更换TKI。对于对第二代TKIs真正耐药或存在T315I看门基因突变的患者，应优先选择第三代TKIs。考虑到在CML亚群（包括T315I突变CML）中积累的经验和结果，应首先考虑普纳替尼。基于反应调整普纳替尼剂量是安全的，并能提高TKI治疗依从性。阿西米尼是第三代TKI，可能具有更好的毒性特征，但对T315I突变CML的活性较弱。奥雷巴替尼是另一种强效第三代TKI，早期研究结果显示出良好前景。
Management of chronic myeloid leukemia in 2023 – common ground and common sense
肿瘤(癌症)患者之家