Hochhaus A, La Rosée P
III Medizinische Klinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany.
Leukemia. 2004 Aug;18(8):1321-31. doi: 10.1038/sj.leu.2403426.
Imatinib is a molecularly targeted therapy that inhibits the oncogenic fusion protein BCR-ABL, the tyrosine kinase involved in the pathogenesis of chronic myelogenous leukemia (CML). Selective inhibition of BCR-ABL activity by imatinib has demonstrated efficacy in the treatment of CML, particularly in chronic phase. Some patients, however, primarily those with advanced disease, are either refractory to imatinib or eventually relapse. Relapse with imatinib frequently depends not only on re-emergence of BCR-ABL kinase activity but may also indicate BCR-ABL-independent disease progression not amenable to imatinib inhibition. Results from phase 2/3 trials suggest that rates of resistance and relapse correlate with the stage of disease and with the monitoring parameters--hematologic, cytogenetic and molecular response. These observations and more recent trials with imatinib, combined with insights provided by an increased understanding of the molecular mechanisms of resistance, have established the rationale for strategies to avoid and overcome imatinib resistance in the management of CML patients. To prevent resistance, early diagnosis and prompt treatment with appropriate initial dosing is essential. Management of resistance may include therapeutic strategies such as dose escalation to achieve individual optimal levels, combination therapy, as well as treatment interruption.
伊马替尼是一种分子靶向治疗药物，可抑制致癌融合蛋白BCR-ABL，即参与慢性粒细胞白血病（CML）发病机制的酪氨酸激酶。伊马替尼对BCR-ABL活性的选择性抑制已证明对CML治疗有效，尤其是在慢性期。然而，一些患者，主要是那些患有晚期疾病的患者，要么对伊马替尼耐药，要么最终复发。伊马替尼治疗后的复发不仅常常取决于BCR-ABL激酶活性的重新出现，还可能表明疾病进展不依赖于BCR-ABL，对伊马替尼抑制不敏感。2/3期试验结果表明，耐药率和复发率与疾病分期以及监测参数（血液学、细胞遗传学和分子反应）相关。这些观察结果以及最近关于伊马替尼的试验，再加上对耐药分子机制认识的加深所提供的见解，为在CML患者管理中避免和克服伊马替尼耐药的策略奠定了理论基础。为预防耐药，早期诊断并采用适当的初始剂量进行及时治疗至关重要。耐药的管理可能包括如剂量递增以达到个体最佳水平、联合治疗以及治疗中断等治疗策略。
