cml概述及格尼可经验分享.ppt

这张图表上面的线条越粗显示该药对该基因位点的作用越强 GIST,氟马替尼 * 152?Final Study Results of the Phase 3 Dasatinib Versus Imatinib in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Trial (DASISION, CA180-056) At 5 years, dasatinib 100 mg once daily has demonstrated superior outcome compared to imatinib 400 mg once daily as initial therapy for CML. This is manifested by a faster time to cytogenetic and molecular responses, with more pts achieving BCR-ABL ≤10% at 3 months, sustained higher cumulative rates of response, and a lower rate of transformation. The 5-year rates of PFS and OS were equal in both arms. After 5 years, no new safety signals have been reported. These consistent results suggest that dasatinib offers meaningful advantages for pts with newly diagnosed CML-CP and remains a standard of care in this setting. * 分子 学缓解 细胞遗传学缓解 血液学缓解 Ph染色体消失 疗效监测的意义 白细胞计数正常 BCR/ABL融合基因基本消失 监测精度和特异性增高 Ph 染色体消失 白细胞计数正常 * CML不同分期伊马替尼耐药的发生率 总耐药发生率随疾病进展而升高 伊马替尼耐药% Lahaye T, Riehm B, Berger U, et al. Cancer. 2005;103:1659-1669 慢性期（400mg） （n=139） 加速期 （400-600mg） （n=80） 髓样变期 （400-600mg） （n=76） 1. Branford S, Rudzki Z, Walsh S, et al. Blood. 2003;102:276-283. * 中国CML患者的伊马替尼耐药情况 中国15家医院慢性粒细胞白血病发病状况及目前诊断治疗模式调查分析，王建祥等，Chin J Hematol, 2009, vol.30,No.11 * 已知的伊马替尼耐药机理 Branford S, Rudzki Z, Walsh S, et al. Blood. 2003;102:276-283. Weisberg E, Griffin JD. Blood. 2000;95:3498-3505. Donato NJ, Wu JY, Stapley J, et al. Blood. 2003;101:690-698. 耐药机制 BCR-ABL激酶域突变 BCR-ABL过表达 其它癌性信号通路激活 获得/原发突变 P环 活化环 其它位点 SRC通路激活 Lyn和HCK激活 IM无法结合 * 伊马替尼耐药机制 BCR-ABL BCR-ABL无关的机制1 药物流入和流出转运体 α1酸性糖蛋白（AGP）结合 Src家族激酶成员Lyn的过表达和Hck的激活 1. Melo JV, et al. Cancer Lett 2007;249:121–132. 2. Baccarani M, et al. Blood 2006;108:1809–1820. 中国指南推荐二线选择 * CML二线治疗选择 * 0 2 4 6 8 10 12 14 16 18 M244V L248V G250A/E Q252E/H/R Y253F/H E255K/V D276G F311L T315I F317L G321E M351T E352G E355D/G F359A/C/V H396P/R Patients (%) 10% 2–10% 2% Reprinted from Experimental Hematology, Volume 35(4 Supplement 1), Deininger MWN, Optimizing therapy of