Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Am J Hematol. 2024 Nov;99(11):2191-2212. doi: 10.1002/ajh.27443. Epub 2024 Aug 2.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an annual incidence of two cases/100 000. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults.
CML is characterized by a balanced genetic translocation, t(9;22) (q34;q11.2), involving a fusion of the Abelson murine leukemia (ABL1) gene from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR::ABL1 fusion oncogene, which in turn translates into a BCR::ABL1 oncoprotein.
Four tyrosine kinase inhibitors (TKIs), imatinib, dasatinib, bosutinib, and nilotinib, are approved by the United States Food and Drug Administration (FDA) for first-line treatment of newly diagnosed CML in the chronic phase (CML-CP). Clinical trials with second and third-generation TKIs in frontline CML-CP therapy reported significantly deeper and faster responses but had no impact on survival prolongation, likely because of their potent efficacy and the availability of effective TKIs salvage therapies for patients who have a cytogenetic relapse with frontline TKI therapy. All four TKIs are equivalent if the aim of therapy is to improve survival. In younger patients with high-risk disease and in whom the aim of therapy is to induce a treatment-free remission status, second-generation TKIs may be favored.
For CML post-failure on frontline therapy, second-line options include second and third-generation TKIs. Although potent and selective, these TKIs exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients' comorbidities and financial status, disease stage, and BCR::ABL1 mutational status. Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs except ponatinib, asciminib, and olverembatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP and failure (due to resistance) of at least two TKIs and for all patients in advanced-phase disease. Older patients who have a cytogenetic relapse post-failure on all TKIs can maintain long-term survival if they continue a daily most effective/least toxic TKI, with or without the addition of non-TKI anti-CML agents (hydroxyurea, omacetaxine, azacitidine, decitabine, cytarabine, and others).
慢性髓性白血病（CML）是一种骨髓增生性肿瘤，年发病率为每 10 万人 2 例。它约占成人新发白血病病例的 15%。
CML 的特征是一种平衡的遗传易位，t（9；22）（q34；q11.2），涉及来自 9q34 染色体的 Abelson 鼠白血病（ABL1）基因与 22q11.2 染色体上的断裂簇区（BCR）基因的融合。这种重排被称为费城染色体。这种易位的分子后果是产生 BCR::ABL1 融合癌基因，进而转化为 BCR::ABL1 癌蛋白。
四种酪氨酸激酶抑制剂（TKIs），伊马替尼、达沙替尼、博舒替尼和尼罗替尼，已被美国食品和药物管理局（FDA）批准用于治疗新诊断的慢性期（CML-CP）慢性髓性白血病的一线治疗。在一线 CML-CP 治疗中进行的第二代和第三代 TKI 临床试验报告了更深和更快的反应，但对生存延长没有影响，这可能是由于其强大的疗效和有效的 TKI 挽救治疗可用于因一线 TKI 治疗而出现细胞遗传学复发的患者。如果治疗的目的是提高生存率，那么这四种 TKI 是等效的。对于高危疾病的年轻患者，以及那些旨在诱导无治疗缓解状态的患者，第二代 TKI 可能更有利。
对于一线治疗失败的 CML，二线选择包括第二代和第三代 TKI。尽管这些 TKI 具有强大的选择性，但它们相对于不同的患者和疾病特征（如患者的合并症和经济状况、疾病阶段和 BCR::ABL1 突变状态）表现出独特的药理学特征和反应模式。发生 T315I“守门员”突变的患者对除 ponatinib、asciminib 和 olverembatinib 以外的所有现有 TKI 均有耐药性。同种异体干细胞移植仍然是 CML-CP 失败（由于耐药）的患者和所有晚期疾病患者的重要治疗选择。对于所有 TKI 治疗失败（由于耐药）且至少两种 TKI 治疗后出现细胞遗传学复发的老年患者，如果继续使用每日最有效/毒性最低的 TKI，并辅以非 TKI 抗 CML 药物（羟基脲、奥卡替尼、阿扎胞苷、地西他滨、阿糖胞苷等），则可长期生存。
