Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Am J Hematol. 2020 Jun;95(6):691-709. doi: 10.1002/ajh.25792. Epub 2020 Apr 10.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100 000 adults. 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 gene (ABL1) 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-ABL oncoprotein.
Four tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, dasatinib, and bosutinib are approved by the United States Food and Drug Administration for first-line treatment of newly diagnosed CML in chronic phase (CML-CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses, but they had no impact on survival prolongation, likely because of the existence of highly effective salvage therapies for patients who have a cytogenetic relapse with frontline TKI.
For CML post failure on frontline therapy, second-line options include second and third generation TKIs. Although potent and selective, these exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients' comorbidities, disease stage, and BCR-ABL1 mutational status. Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP who have failed at least 2 TKIs, and for all patients in advanced phase disease. Even among older patients who have a cytogenetic relapse post failure on all TKIs, they can maintain long-term survival if they continue on a daily most effective/less toxic TKI, with or without the addition of non-TKI anti-CML agents (hydroxyurea, omacetaxine, azacitidine, decitabine, cytarabine, busulfan, others).
慢性髓性白血病（CML）是一种骨髓增生性肿瘤，成人发病率为每 10 万人中有 1-2 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 9q34 染色体上的 Abelson 基因（ABL1）与 22q11.2 染色体上的断裂簇区（BCR）基因融合。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-ABL 癌蛋白。
四种酪氨酸激酶抑制剂（TKI），伊马替尼、尼罗替尼、达沙替尼和博舒替尼已被美国食品和药物管理局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。第二代 TKI 的临床试验报告显示，其反应更深、更快，但对生存延长没有影响，这可能是因为对于用一线 TKI 发生细胞遗传学复发的患者，存在高度有效的挽救疗法。
对于一线治疗失败的 CML，二线选择包括第二代和第三代 TKI。尽管这些药物具有强大且选择性，但与不同的患者和疾病特征（如患者的合并症、疾病阶段和 BCR-ABL1 突变状态）相比，它们具有独特的药理学特征和反应模式。发生 T315I“守门员”突变的患者对除帕纳替尼以外的所有现有 TKI 均有耐药性。对于至少接受过 2 种 TKI 治疗失败的 CML-CP 患者，以及所有进展期疾病患者，同种异体干细胞移植仍然是一种重要的治疗选择。即使对于在所有 TKI 治疗失败后出现细胞遗传学复发的老年患者，如果他们继续使用每日最有效/毒性最小的 TKI，无论是否添加非 TKI 抗 CML 药物（羟基脲、奥马曲星、阿扎胞苷、地西他滨、阿糖胞苷、白消安等），也可以长期生存。
