慢性淋巴细胞白血病的诊断、预后与治疗-马军.ppt

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,*,慢性淋巴细胞白血病,CLL诊断,CLL预后,CLL治疗,慢性淋巴细胞白血病：诊断,定义：具有,特定免疫表型,的,成熟表,型,淋巴细胞在外周血、骨髓、淋巴,结及其他淋巴组织进行性积聚的一,种,克隆性B,淋巴增殖性疾病。,B淋巴细胞,5,10,9,/L,3月。,Hallek M,et al.Blood,2008,111:5446,lambda,成熟表型,形态学：小成熟淋巴细胞,CLL/PL：幼淋,10%,12m,Montserrat Br J Hematol 62:567,1986,b2-MG正常,22:4391996,Hallek M Leuk Lymph,sCD23正常,特殊的遗传学异常,单纯13q-,CD38 阴性,IgVH基因突变,Hamblin Blood 94:1848,1999,ZAP-70阴性,Crespo NEJM 348:1764,2003,淋巴细胞倍增时间 20%),CLL治疗策略,v.1.2010 NCCN,肿瘤抑制基因 p53,人类p53基因定位于l7号染色体短臂，含有,11个外显子，主要作用是诱导凋亡、抑制恶,性增殖,p53基因突变/失活可见于50%的人类肿瘤,集合多数信号通路控制细胞的生存和死亡,了解p53基因的功能和调节对于掌握肿瘤生,物学特性、探索新的治疗策略具有重要的意,义,6574 岁,SEER Cancer Statistics Review 19752007.,75岁,CLL主要发生于老年人群,20032007年，65岁人群中CLL发病率为23.9/10万,美国CLL初诊时的年龄分布(20032007),064 岁,31%,42%,27%,Thurmes P,et al.Leuk Lymphoma 2008;49:49,具有较少伴发疾病,具有较多伴发疾病,46%,43%,大多数患者具有伴发疾病,Mayo Clinic自1995年的CLL资料,无伴发疾病,11%,IWCLL的CLL治疗指征（初治/复治）,至少应该满足以下一个条件：,（,1,）进行性骨髓衰竭的证据，表现为贫血和,/,或血小板减少进展或恶化。,（,2,）巨脾（如左肋缘下,6 cm,）或进行性或有症状的脾肿,大。,（,3,）巨块型淋巴结肿大,(,如最长直径,10 cm),或进行性或有症状的淋巴结肿大。,（,4,）进行性淋巴细胞增多，如,2,个月内增多,50%,，或,LDT,6,个月。,（,5,）自身免疫性贫血和,/,或血小板减少对皮质类固,醇或其他标准治疗反应不佳。,（,6,）,至少存在下列一种疾病相关症状：,（,a,）在以前,6,月内无明显原因的体重下降,10%,。,（,b,）严重疲乏,如,ECOG PS,2,；不能工作或不能进行常规活动,。,（,c,）无其他感染证据，发热,38.0,，,2,周。,（,d,）无感染证据，夜间盗汗,1,个月,Hallek M,et al.Blood,2008,111:5446,淋巴细胞绝对数（ALC）不是治疗指证！,ALC25010,9,/L开始治疗？,1.Hallek M,et al.Guidelines for the diagnosis and treatment of chronic,lymphocytic leukemia:a report from the International Workshop on Chronic,Lymphocytic Leukemia updating the National Cancer Institute-Working,Group 1996 guidelines.Blood,2008,111:5446.,2.Gribben JG.How I treat CLL up front.Blood,2010,115:187.,3.v.1 2010 NCCN,4.Kaufman M,et al.Diagnosing and treating chronic lymphocytic leukemia in,2009.Oncology,2009,23:1,避免过度治疗！,CLL治疗策略,1.,无del(17p)CLL治疗策略,2.,del(17p),(20%),CLL治疗策略,v.1.2010 NCCN,CLL的一线治疗,治疗方案,病例数,CR (%),PR(%),PFS(,月,),MS (,月,),欧洲协作,组,Flud,CAP,52,48,23,17,48,43,未达到,208,天,未达到,1580,天,美国,InterGro,up,Flud,CLB,Flud/CLB,170,181,123,20,4,20,44,33,41,25,14,NR,66,56,55,法国协作,组,Flud,CAP,CHOP,341,240,357,40,15,30,31,43,42,32,28,29,69,70,67,英国,LRF,CLL4,研究,Flud,CLB,181,366,15,7,65,65,5,年,10%,5,年,10%,52,59,氟达拉滨 vs 烷化剂治疗CLL的期临床试验,氟达拉滨(F),苯达莫司汀,vs 瘤可宁,Knauf WU,et al.J Clin Oncol,2009,27:4378,FC vc F治疗CLL的期临床试验,治疗方案,病例数 CR(%)PR(%)PFS,OS,德国CLL 研,究组,英国LRF,CLL4试验,美国,InterGroup,试验 E2997,Flud,FC,Flud,FC,Flud,FC,164,164,181,182,137,141,7,24,15,38,4.8,23.4,76,70,65,57,54.6,50.4,中位 20月,中位 48月,5年 10%,5年 36%,中位19.2月,中位31.6月,3年80.7%,3年80.3%,5年 59%,5年 54%,2年 80%,2年 79%,氟达拉滨+环磷酰胺(FC),FC vs F在非高危CLL可改善OS,(GCLLSG CLL4),FC median OS n.r.,F median OS 84.6,Months,P,=0.02,NR,84.6月,PFS,FR,F,FR,OS,F,FR(CALGB9712)vs F(CALGB9011),Byrd JC,et al.Blood,2005,105:49,ORR,CR,PR,FR,FR,90%,77%,47%,2843%,49%,氟达拉滨+美罗华(FR),59%,54%,77%,F,：,7,7,F+Pred,：,113,FC,：,10,7,FM,：,33,FCR,：,300,F vs FC/M vs FCR方案与生存(OS),(MD Anderson Cancer Center),Tam CS,et al.Blood,2008,112:975,氟达拉滨+环磷酰胺+美罗华(FCR),OR 95%,CR 72%,Patients(%),12,MabThera-FC,45,60,40,20,100,50,FC,p,0.01,23,0,CR,PR,CRu/CRi/nPR,9,与单用FC比较，,美罗华 500 mg/m,2,FC 使率加倍,ORR=93%,(n=408),ORR=85%,(n=409),80,40,Hallek M,et al.Blood,2008;112:Abstract 325.,CRu=unconfirmed CR,CRi=CR with incomplete bone marrow recovery,nPR=nodular partial remission,与单用FC比较，,美罗华 500 mg/m,2,FC显著改善 OS,随机化3年后 OS率:,FCR:87.2%,FC:82.5%,n=817,HR 0.664,p=0.012,不同基因亚组中的完全缓解率,(S.Stilgenbauer),n,CR(%),FC(%),FCR(%),p,所有患者,13q（单纯）,11q,+12,17p,无,IGHV,突变,IGHV,未突变,759,211,135,56,43,130,206,351,33.2,36.5,37.0,42.9,2.3,33.8,35.9,32.2,21.8,24.8,15.5,21.9,0,28.6,19.8,20.4,44.1,49.0,53.2,70.8,4.8,37.8,51.4,42.9,2.0 x,2.0 x,3.4x,3.2x,n.a.,1.3x,2.6x,2.1x,0.001,0.001,0.001,0.001,0.3,0.27,0.001,0.001,CLL的二线治疗,Primary endpoint:PFS,(N=552),PD off study,Fludarabine,25 mg/m,2,day 13,Cyclophosphamide,250 mg/m,2,day 13,Rituximab,Cycle 1:375 mg/m,2,day 0,Cycles 26:500 mg/m,2,day 1,A,N,D,O,M,I,S,E,R-FC q4wk,3,FC q4wk,3,R,E,S,T,A,G,E,R-FC q4wk,3,CR,PR,FC q4wk,3,Relapsed/refractory,CLL,One previous therapy,All Binet stages,ECOG PS 01,Prior FC or Rituximab,excluded,Phase III trial of R-FC versus FC,in relapsed CLL(REACH),R,Robak T,et al.J Clin Oncol,2010:28;1756,Response,CR,PR/nPR,ORR,SD,PD,n=276,13.0,44.9,58.0,22.1,5.4,p-,value,0.001,0.8642,0.0034,ND,ND,14.5,ND,*Mainly patients with response that was not confirmed through a second,assessment;ND=not done,Robak T,et al.J Clin Oncol,2010:28;17561765.,REACH:Efficacy,R-FC(%)FC(%),n=276,24.3,45.7,69.9,17.0,2.5,Not evaluable*10.5,PFS,REACH:Primary endpoint,investigator-assessed PFS,FC,(n=276),R-FC,(n=276),HR,p-v,alue,Median OS,51.9 months,Not reached,0.83,0.2874,Years,0.5,0.0,2.0,2.5,3.0,3.5,4.0,4.5,5.0,0.2,0.0,1.0,0.8,0.6,0.4,p,20%)CLL治疗策略,v.1.2010 NCCN,无del(17p)CLL治疗策略,(按先后顺序选择治疗方案),v.1.2010 NCCN,虚弱患者，严重合并症,（不能耐受嘌呤类似物）,瘤可宁泼尼松,美罗华（单用）,冲击剂量皮质类固醇,瘤可宁泼尼松,苯达莫司汀,烷化剂为基础的化疗,CVP（环磷酰胺+长春新碱+泼尼松）美罗华(RTX),阿仑单抗,美罗华(RTX),氟达拉滨美罗华(RTX),年龄3年,重复一线治疗,短期反应2年，年龄,70岁,化学免疫治疗,减量FCR,减量PCR,苯达莫司汀美罗华(RTX),HDMP+美罗华(RTX),瘤可宁泼尼松,Ofatumumab,剂量密集美罗华(RTX),短期反应2年，年龄70岁或超过70岁但无严重合并症,化学免疫治疗,FCR（氟达拉滨，环磷酰胺，美罗华）,PCR（喷司他叮，环磷酰胺，美罗华）,苯达莫司汀美罗华(RTX),氟达拉滨+阿仑单抗,CHOP+美罗华(RTX),HyperCVAD+美罗华(RTX),EPOCH+美罗华(RTX),OFAR,Ofatumumab,阿仑单抗+美罗华(RTX),v.1.2010 NCCN,del(17p)难治/复发CLL的治疗策略,(按先后顺序选择治疗方案),v.1.2010 NCCN,CHOP+美罗华（RTX）,CFAR（CTX、氟达拉滨、阿仑单抗、RTX）,HyperCVAD+美罗华（RTX）,OFAR,Ofatumumab,阿仑单抗+美罗华（RTX）,大剂量地塞米松,苯达莫司汀（Bendamustine）,一线、二线治疗建议,Foon KA,Hallek MJ.Leukemia,2010,24:500,Gribben JG.Blood,2010,115:187,How I treat CLL,Diagnosis,Symptomatic,Good performance status?,Yes,P53,del/mutation?,Yes,Alemtuzumab,RIC allo-SCT,No,Clinical trial,or R-FC,Asymptomatic,Watch and wait,No,Chlorambucil or,clinical trail,How I treat AIHA in CLL,symptomatic CLL?,Yes,R-Fc,Rituximab 375,mg/m2 weekly x 4,No,Add CSA,5 mg/kg/day,Maintain dose,and taper at 3 m,No response,Splenectomy,No response,R-Fc or Alemtuzumab,Gribben JG.Blood,2010,115:187,No,No,Prednisone 1 mg/kg/day,Response,Yes,谢 谢 大 家,END,