Snead Jennifer L, O'Hare Thomas, Eide Christopher A, Deininger Michael W
Oregon Health & Science University Cancer Institute, Portland, OR, USA.
Clin Lymphoma Myeloma. 2008 Mar;8 Suppl 3:S107-17. doi: 10.3816/CLM.2008.s.006.
Imatinib is well established as a safe, effective therapy for patients with chronic myeloid leukemia (CML). However, point mutations in the kinase domain of Bcr-Abl can lead to imatinib resistance and reactivation of kinase activity. The second-generation Abl kinase inhibitors nilotinib and dasatinib were developed to reestablish disease control. A rising clinical challenge is using imatinib and novel Abl kinase inhibitors with the aim of completely preempting resistance. Fortunately, relapse on imatinib therapy so far has affected a minority of patients commencing treatment in the chronic phase of CML, and relapse rates continue to decline with treatment duration. In contrast, nearly all patients with CML have molecularly detectable disease. Thus, even among the best responders to imatinib, disease eradication is not achieved within a timeframe of years. Herein, we review current and emerging paradigms for using Abl kinase inhibitors to achieve maximal disease control and strategies to eradicate disease by targeting leukemic stem cells.
伊马替尼已被公认为是治疗慢性粒细胞白血病（CML）患者的一种安全、有效的疗法。然而，Bcr-Abl激酶结构域中的点突变可导致伊马替尼耐药并使激酶活性重新激活。第二代Abl激酶抑制剂尼罗替尼和达沙替尼就是为重新控制疾病而研发的。目前临床上面临的一个日益严峻的挑战是，使用伊马替尼和新型Abl激酶抑制剂以期完全预防耐药。幸运的是，迄今为止，接受伊马替尼治疗的复发情况仅影响了少数开始在CML慢性期接受治疗的患者，并且复发率随着治疗时间的延长而持续下降。相比之下，几乎所有CML患者都有分子可检测的疾病。因此，即使在对伊马替尼反应最佳的患者中，也无法在数年的时间内实现疾病根除。在此，我们综述了使用Abl激酶抑制剂实现最大程度疾病控制的当前和新兴模式，以及通过靶向白血病干细胞根除疾病的策略。
