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1、Differentiation,TAS141124204,目 录,作用机理ENESTnd & DASISION安全性和合并症区隔,TAS141124204,作用机理区隔,TAS141124204,达希纳优先精准抑制Bcr-Abl,目前公认 Ph+ CML是一种“单一靶点疾病”Bcr-Abl是Ph+ CML的确切病因和关键驱动因素在伊马替尼治疗耐药的CP或AP CML患者中，90%是由于Bcr-Abl重新激活所致与多靶点抑制相比，优先靶向作用于Bcr-Abl，能减少不需要的非靶向不良事件,Deininger MWN, Druker BJ. Pharmacol Rev. 2003; 55: 401
2、-423.,TAS141124204,多靶点抑制与相关不良事件的发生,Giles FJ, ODwyer M, Swords R. Leukemia. 2009; 23(10):1698-1707Alfonso Quintas-Cardama, et al, J Clin Oncol 25:3908-3914.Eur J Clin Invest 2009; 39 (12): 10981109.,TAS141124204,ENESTnd & DASISION 各5年的数据解读,TAS141124204,ENESTnd 研究终点MMR符合CML发展方向,TAS141124204,Habucky K,
3、 Megyeri A. Tasigna (nilotinib) 150 mg and 200 mg hard capsules core data sheet version 1.3. West Sussex, United Kingdom: Novartis Europharm Limited; 2014:1-61.,Rates of MMR by 5 years remained higher in both Tasigna arms than in the imatinib arm,达希纳12个月获得MMR患者更多，且5年结果两组仍然维持显著差异, 27%, 20%, 20%,TAS14
4、1124204,DASISION :达沙组累积MMR高于伊马替尼组,MMR = major molecular response, BCR-ABL (IS) 0.1%; IS = International Scale.,P = .0022,18,TAS141124204,MR4.5, molecular response of BCR-ABLIS 0.0032%.,Habucky K, Megyeri A. Tasigna (nilotinib) 150 mg and 200 mg hard capsules core data sheet version 1.3. West Sussex,
5、 United Kingdom: Novartis Europharm Limited; 2014:1-61.Larson RA, et al. JCO. 2013;31(18s):abstract 7052.,达希纳MR4.5 结果组间差异随时间延长逐年增高，有统计学差异,达希纳和伊马替尼MR4.5 差异随时间延长逐年增高获得MR4.5 无一例患者发生疾病进展AP/BC,100,90,80,70,60,50,40,60,54,48,42,35,30,By 5 Years,54% P .0001,31%,By 4 Years,40% P .0001,23%,By 3 Years,32% P .
6、0001,15%,By 2 Years,25% P .0001,Time Since Randomization, months,Patients With MR4.5, %,30,By 1 Year,0,24,18,12,6,0,9%,20,10,1%,11% P .0001, 10%, 23%,n, 17%, 17%, 16%,TAS141124204,DASISION :累积MR4.5 两组差异有缩小趋势,MR4.5 = BCR-ABL (IS) 0.0032%; IS = International Scale.,P = .0251,11,11,11,9,TAS141124204,a
7、Progression to AP/BC events included progressions to AP/BC (excluding clonal evolution) or CML-related deaths occurring on core treatment or on study (on core or extension treatment or during follow-up after treatment discontinuation).,Habucky K, Megyeri A. Tasigna (nilotinib) 150 mg and 200 mg hard
8、 capsules core data sheet version 1.3. West Sussex, United Kingdom: Novartis Europharm Limited; 2014:1-61,CML 治疗的基本目标是防止疾病进展达希纳是唯一被证明可以降低疾病进展风险的2nd TKI,2组达希纳降低疾病进展的发生均低于伊马替尼，且300mg组99%患者维持在慢性期核心治疗组自从2年分析后无一例发生新的疾病进展病例,ENESTnd核心治疗中进展到 AP/BC5年结果,AP, accelerated phase; BC, blast crisis; BID, twice dail
9、y; QD, once daily.,DASISION 5years,Dasatinib 100 mg QD (n = 259),Imatinib 400 mg QD(n = 260),进展 AP/BP, n,12 (4.6%),19 (7.3%),差异无统计学意义,TAS141124204,进展 AP/BP, n,安全性和合并症区隔,TAS141124204,Dasatinib胸膜腔积液仍为最主要安全性问题(发生率 30%),DASISION 5-Year Final Study Results,Diarrhea,Headache,Musculoskeletal pain,Skin rash
10、,Fatigue,Abdominal pain,Nausea,Face edema,Peripheral edema,Myalgia,Muscle spasms,Vomiting,Pleural Effusion,0,5,10,15,20,25,30,35,Grade 1-2Grade 3-4Grade 1-2Grade 3-4,Dasatinib100 mg QD,Imatinib400 mg QD,Patients, %,TAS141124204,胸腔积液持续新发，且复发率高（63%),DASISION 5-Year Final Study Results,cCCyR = confirme
11、d complete cytogenetic response; MMR = major molecular response, BCR-ABL (IS) 0.1%; MR4.5 = BCR-ABL (IS) 0.0032%; IS = international scale,患者, %,随访第五年，仍有胸膜腔积液发生报道复发率63%（46 / 73 )发生胸膜腔积液患者, 96% 获得CCyR, 82% 获得 MMR, 50%获得 MR4.5,TAS141124204,尼洛替尼（达希纳 ）400mg BID 二线治疗胆红素水平升高,Kantarjian HM, et al.Blood.200
12、7；10(10)：3540-3546.Hochhaus et al. Blood 2007; 109: 2303-2309.,NR：未报告。,这些数据来自非头对头的研究，不可进行显著性差异比较,TAS141124204,胆红素水平升高的解析,Leukeamia Research 33(2009). 159-161.Kantarjian.Blood,2007,110:3540-3546.,胆红素代谢过程中的关键酶是尿嘧啶二磷酸葡萄糖醛酸基转移酶（UGT1A1）尼洛替尼（达希纳）会降低UGT1A1活性，从而导致高胆红素血症。并非肝细胞损伤导致在A2101研究中，尼洛替尼（达希纳）导致的高胆红素多表
13、现为自限性，绝大多数患者无需停药，继续以相同剂量治疗可自发降低或恢复至正常范围。无1例患者因为胆红素水平升高而中断治疗，严重者仅需要减少尼洛替尼（达希纳）的治疗剂量,TAS141124204,尼洛替尼（ 达希纳 ）与达沙替尼需要谨慎使用的临床情况,Sprycel (dasatinib) package insert. Princeton, NJ: Bristol-Myers Squibb Company; 2007.Tasigna (nilotinib) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2007.Leukenia 48(12):2461-2464,TAS141124204,总 结,达希纳更强效精准靶向BCR/ABL,减少非靶点相关不良反应发生Nilotinib 是唯一一个降低疾病风险的二代TKIDASISON 5年MR4.5 组间差异越来越小，而ENESTnd中组间差异越来越大，且有显著统计学意义Dastinib胸腔积液仍是最常见AE，发生率约30%，且复发率高Nilotinib 胆红素增高非肝损伤引起，多具有自限性,TAS141124204,
