慢性粒细胞白血病分子靶向治疗TKI的选择课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,#,慢性粒细胞白血病分子靶向治疗,TKI,的选择,CML,预后的相关因素,疗效评定标准提高，追求更好的治疗目标,一代,TKI,伊马替尼的优缺点,二代,TKI,的优势,CML,一线治疗方案的选择,CML,二线治疗,TKI,的选择,Sokal,评分,分期与预后,早慢性期、晚慢性期,初诊病人突变分析,PH,染色体以外的附加克隆异常,CML,的预后相关因素,通过,Sokal,预后积分公式评估：,Sokal,积分,=exp0.0116(,年龄,-43.4,岁,)+0.0345(,脾脏大小,-7.51)+0.188(,血小板,/7002-0.563)+0.0887(,原始细胞,-2.1),血小板计数（,10,9,L,），年龄为岁数，脾大小为肋下厘米数,Sokal,积分临床意义,低危,1.2,更高的突变频率,更快的增殖速度,更重的疾病负荷,BCR-ABL,突变率（,%,）,加速期,世界卫生组织（,WHO,）标准,外周血,WBCs,和,/,或骨髓细胞中原始细胞占,1019%,外周血中嗜碱性粒细胞,20%,与治疗不相关的持续血小板减少（,1000 10,9,/L,）,进行性脾增大，与治疗不相关的,WBC,计数增高,克隆演变,急变期,世界卫生组织（,WHO,）标准,外周血,WBCs,和,/,或骨髓细胞中原始细胞占,20%,髓外原始细胞增殖,骨髓活检显示原始细胞集聚,Swerdlow SH,et al.IARC Press:Lyon 2008.,Soverini S,et al.Clin Cancer Res.2006;12:7374-7379.,27%,52%,75%,83%,进展期,CML,的疾病特征,4,CML,预后的相关因素,疗效评定标准提高，追求更好的治疗目标,一代,TKI,伊马替尼的优缺点,二代,TKI,的优势,CML,一线治疗方案的选择,CML,二线治疗,TKI,的选择,无进展生存率,总生存率,3,个月时,BCR-ABL,转录水平,10%,10%,P,10%,10%,P,伊马替尼,ENESTnd,4,年,1,97%,84%,0.0001,99%,85%,0.0001,DASISION,2,3,年,96%,75%,0.0001,96%,88%,0.036,-GERMAN CML,STUDY IV,5,年,3,94%,87%,0.037,96%,87%,0.012,HAMMERSMITH,8,年,4,93%,57%,0.001,93%,57%,10%,或,10%,或,PCyR,12,个月,CCyR,PCyR,1,0%,-,无任何CyR,(Ph+95%),6,个月,至少获得,MCyR,（Ph+,90%,）,未获得任何,CyR,（Ph+,90%,）,-,至少达到,P,CyR,(Ph+,3,5%),-,BCR-ABL,IS,1,0%,-达到m,inor,CyR但未达到,P,CyR,(Ph+3,6,%-65%),-,BCR-ABL,IS,1,0%,-,未达到,minorCyR (Ph+,6,5%),12,个月,至少获得,PCyR,（Ph+,35%,）,未获得,PCyR,（Ph+,35%,）,-,达到CCyR（Ph+,0,%）,-,BCR-ABL,IS,1,%,-,BCR-ABL,IS,1,%,-,未达到,CCyR,(Ph+0),18,个月,至少获得,CCyR,（Ph+,0%,）,未获得,CCyR,（Ph+,0%,）,-,获得,MMR,-,未获得,MMR,-,未达到,CCyR,(Ph+0),任何时间,随访,-血液学复发,-丧失CyR,-,发生突变,-出现,Ph,染色体基础上其他克隆性染色体异常,-,稳定或达到,MMR,-丧失MMR,-无伊马替尼耐药性,BCR-ABL,激酶区突变,-丧失CHR,-丧失CCyR,-出现伊马替尼或其他,TKI,耐药性突变,-出现,Ph,染色体基础上其,他克隆性染色体异常,TKI/,伊马替尼用于,CML,慢性期一线治疗疗效评估“,最佳反应,”指标,2013,中国指南,1,ELN 2013,2,NCCN2014,3,ESMO 2012,4,3,个月,-,达到,CHR,基础上,-,至少达到,Minor,CyR,(Ph+,6,5%),-,BCR-ABL,IS,1,0%,BCR-ABL,IS,10%,和,/,或,Ph+,35%,-,至少达到,P,CyR(Ph+,3,5%),-,BCR-ABL,/ABL,1,0%,-,Ph+,9,5%,-,或,-,BCR-ABL,IS,10%,6,个月,-,至少达到,P,CyR (Ph+,3,5%),-,BCR-ABL,IS,1,0%,BCR-ABL 1%,和,/,或,Ph+0,-,至少达到,P,CyR(Ph+,3,5%),-BCR-ABL,/ABL,1,0%,-,Ph+,3,5%,-,或,-BCR-ABL10%,12,个月,-达到CCyR,-,BCR-ABL,IS,1,%,BCR-ABL 0.1%,（,MMR,）,-,达到CCyR（Ph+,0,%）,-,Ph+,0,%,-,或,BCR-ABL 1%,18,个月,获得,MMR,(,BCR,-,ABL,IS,0.1,%,),BCR-ABL,0.1%,-,达到CCyR（Ph+,0,%）,任何时间,-,稳定或达到,MMR,1.,中国慢性髓性白血病（,CML,）诊疗指南,(2013).2.Baccarani M,et al.,Blood.2013 June;26;doi:10.11821/blood-2013-05-501569,3,.NCCN Clinical Practice Guidelines in Oncology(NCCN Guidelines).Chronic Myelogenous Leukemia,（,Version 2.2014,）,4,.,Baccarani M,et al.,Ann Oncol.2012 Oct;23 Suppl 7:vii72-7.4,四大指南一致推荐最早在,3,个月时根据,BCR-ABL10%,确定最佳疗效,TKI/,伊马替尼用于,CML,慢性期一线治疗疗效评估“,最佳反应,”指标,2013,中国指南,1,ELN 2013,2,NCCN2014,3,ESMO 2012,4,3,个月,-,达到,CHR,基础上,-,至少达到,Minor,CyR,(Ph+,6,5%),-BCR-ABL,IS,1,0%,BCR-ABL,IS,10%,和,/,或,Ph+,35%,-,至少达到,P,CyR(Ph+,3,5%),-BCR-ABL,/ABL,1,0%,-,Ph+,9,5%,-,或,-,BCR-ABL,IS,10%,6,个月,-,至少达到,P,CyR (Ph+,3,5%),-,BCR-ABL,IS,1,0%,BCR-ABL 1%to 10%,10%,Censored Observations,Pts Evt Cen,145 6 139,89287,24519,100,90,80,70,60,50,40,30,20,10,0,0,1,2,3,4,5,6,Patients Alive,%,Time Since Randomization,Calendar Years,100,90,80,70,60,50,40,30,20,10,0,0,1,2,3,4,5,6,Time Since Randomization,Calendar Years,OS by 5 Years,a,P,1%to 10%,10%,Censored,Observations,Pts Evt Cen,432 41,133 1132,88 1672,Cen,censored;EMR,early molecular response;Evt,events;Pts,patients.,a,OS rates reported consider each year to consist of twelve 28-day cycles.,丧失早期分子学反应,(BCR-ABL 10%,，,3,个月时,),患者，,5,年,OS,明显更差,与伊马替尼相比，尼洛替尼,300 mg BID,组患者早期分子学反应失败率更低,79.5%,95.7%,97.6%,81.9%,Patients Alive,%,EMR Failure:9%of pts,EMR Failure:33%of pts,15,Saglio G,et al.,Blood,.2013:abstract 92.,基于,3,个月时不同,BCR-ABL,水平,患者获得,MR,4.5,的比例,58%,28%,4%,P,=.0001,P,=.0135,70%,52%,8%,P,=.0046,P,=.0001,MR,4.5,by 4 Years,a,MR,4.5,by 5 Years,a,BCR-ABL Level,1%,1%to 10%,10%,Pts,144,89,24,100,90,80,70,60,50,40,30,20,10,0,0,1,2,3,4,5,6,Patients With MR,4.5,%,Time Since Randomization,Calendar Years,MR,4.5,by 4 Years,a,MR,4.5,by 5 Years,a,65%,24%,5%,P,1%to 10%,10%,Pts,43,133,88,100,90,80,70,60,50,40,30,20,10,0,0,1,2,3,4,5,6,Patients With MR,4.5,%,Time Since Randomization,Calendar Years,a,Cumulative response rates reported consider each year to consist of twelve 28-day cycles.,BCR-ABL,IS,1%:,16%of pts,BCR-ABL,IS,1%:,56%of pts,Nilotinib 300 mg BID,Imatinib 400 mg QD,3,个月时,BCR-ABL 1%,的患者在治疗第,5,年获得,MR,4.5,几率明显更高,与伊马替尼相比，尼洛替尼,300 mg BID,组患者更易获得,MR,4.5,16,Saglio G,et al.,Blood,.2013:abstract,92,.,ENESTnd,：,3,个月,BCR-ABL,水平,*Calculated from total number of evaluable patients with PCR assessments at 3 months.,BCR-ABL 10%,Patients,%,BCR-ABL Level at 3 Months,n 176 234 88 24,BCR-ABL 10%,91,67,9,33,1-10%,Nilotinib 300 mg BID(n=258),Imatinib(n=264),1-10%,1%,17,Saglio G,et al.,Blood,.2013:abstract 92.,1%,Adelaide,：根据三个月,BCR-ABL,值获得稳定的,UMRD,4.5,开始伊马替尼治疗后的时间（年）,累积发生率,%,P0.001,P0.1-1.0%IS,n=147,1-10%IS,n=144,10%IS,n=82,0,20,40,60,80,100,10,30,50,70,90,0,1,2,3,4,5,6,7,8,Branfords,et al.Blood,2012;120:165oral.,ENESTnd,不同,Sokal,评分患者,3,个月,BCR-ABL,10%,的比例,n,=,102,97,92,91,70,70,ENESTnd 4-year:Landmark Analysis,Hughes TP,et al.Blood,Feb 2014;123:13