慢性髓性白血病培训课件

1、第52届ASH会议慢性髓性白血病相关文献AbstractsLate breaking AbstractsOral and Poster AbstractsChronic Myeloid Leukemia - Therapy Chronic Myeloid Leukemia - Biology and Pathophysiology Education ProgramCML 2010: Where Are We Now and Where Can We Go?第52届ASH会议慢性髓性白血病相关文献第一部分 CML治疗-TKI伊马替尼比较大剂量与标准剂量伊马替尼治疗的有效性及安全性 （the G

2、erman CML-Study IV）分析伊马替尼治疗的分子反应程度与生存的关系评估伊马替尼治疗老年患者的疗效及安全性评价伊马替尼治疗青少年患者的临床疗效尼洛替尼评估尼洛替尼治疗的有效性和安全性（ENESTnd Trial）达沙替尼评价达沙替尼治疗的有效性和安全性（DASISION Trial）比较达沙替尼和伊马替尼治疗的有效性和安全性 （The S0325 Intergroup Trial）分析BCR-ABL激酶区突变与治疗反应的关系Oral and Poster Abstracts Late-breaking Abstracts第一部分 CML治疗-TKI伊马替尼Oral and PoSe

3、ven-Year Follow-up Data on Sequential Prospective Trials of Imatinib 400mg Vs 800mg Daily Schedule for Front-Line Treatment of Chronic Myeloid Leukemia (CML)Naveen Pemmaraju, MD Poster Session: Chronic Myeloid Leukemia - Therapy: Poster III 3438目的-比较使用伊马替尼800mg与400mg作为CML一线治疗的长期临床疗效结果IM800mg（n=208）I

4、M400mg （n=73）P值中位随访时间mos（范围）79 (3-107)110 (2-116)-累积CCyR率91%87%0.49累积MMR 率87%78%0.0612 个月CCyR90%66%0.001*18个月MMR82%68%0.04*7年EFS 86% 76%0.049*7年TFS-0.467年OS-0.27因毒性中止治疗16 (8%) 6 (8%) -Seven-Year Follow-up Data on SSeven-Year Follow-up Data on Sequential Prospective Trials of Imatinib 400mg Vs 800mg

5、Daily Schedule for Front-Line Treatment of Chronic Myeloid Leukemia (CML)Naveen Pemmaraju, MD Poster Session: Chronic Myeloid Leukemia - Therapy: Poster III 3438结论-7年跟踪调查显示：与伊马替尼400mg相比，伊马替尼800mg 12 个月CCyR 、18个月MMR、7年PFS明显改善,但OS无差异-大剂量伊马替尼治疗CML有一定益处Seven-Year Follow-up Data on SSuperior CMR-Rates wi

6、th Tolerability-Adapted Imatinib 800 Mg Vs. 400 Mg Vs. 400 Mg + IFN In CML: The Randomized German CML-Study IV Rdiger Hehlmann, MD Oral Session: Chronic Myeloid Leukemia - Therapy: Optimizing Front-Line Therapy in CML 357目的-评价大剂量伊马替尼治疗初诊Ph+ CML-CP患者的疗效研究设计-完全分子学缓解CMR被定义为BCR-ABL/ABLIS 0.01%-1012例CML患

7、者入组（338例IM 800mg；324例IM 400mg；350例IM联合干扰素）-IM 800mg组，平均每日伊马替尼剂量628mg；IM 400mg组，平均每日伊马替尼剂量400mgSuperior CMR-Rates with ToleraRdiger Hehlmann, MD Oral Session: Chronic Myeloid Leukemia - Therapy: Optimizing Front-Line Therapy in CML 357结果-IM 800mg组12个月缓解率显著提高12个月累积CCyR:IM 800mg组为63%；IM 400mg及联合组为50%12

8、个月累积MMR:IM 800mg组为54.8%；IM 400mg组为30.8%; 联合组为34.7% 36个月内IM 800mg组均有较高的CMR，且比IM 400mg组更快获得CMR初始治疗时间 (月) 累积发病率MMR (%) CMR (%) IM400 n=306 IM800 n=328 IM400 +IFN n=336 IM400 n=306 IM800 n=328 IM400 +IFN n=336 6 8.6 18.1 8.4 3 3.7 2.4 12 30.8 54.8 34.7 7.5 19.8 12.4 18 50.3 68.4 54.1 21.2 33.4 23.6 24 6

9、3 76.0 62.8 30.7 43 30.0 36 79.3 81.6 70.7 45.5 56.8 40.5 Superior CMR-Rates with Tolerability-Adapted Imatinib 800 Mg Vs. 400 Mg Vs. 400 Mg + IFN In CML: The Randomized German CML-Study IV Rdiger Hehlmann, MD 结果-IM 80Superior CMR-Rates with Tolerability-Adapted Imatinib 800 Mg Vs. 400 Mg Vs. 400 Mg

10、 + IFN In CML: The Randomized German CML-Study IV Rdiger Hehlmann, MD Oral Session: Chronic Myeloid Leukemia - Therapy: Optimizing Front-Line Therapy in CML 357结论-大剂量伊马替尼治疗耐受性良好-伊马替尼800mg组比400mg组获得更高CMR-伊马替尼800mg组比400mg组有更多患者获得稳定CMR Superior CMR-Rates with ToleraMolecular Response 1% BCR-ABL IS at 1

11、2 Months Is Associated with Improved Overall and Progression-Free Survival: the Randomized German CML-Study IV Martin C. Mller, MD Oral Session: Chronic Myeloid Leukemia - Therapy: Rethinking Therapy Targets and Prognostic Factors 669目的-评估分子反应程度与生存的关系研究设计-848例CML患者入组-3个分子反应组 (1% BCR-ABL/ABLIS) -12个月

12、PFS和OS结果-12个月时，341例患者获得MMR(BCR-ABL/ABLIS1%-与BCR-ABL/ABLIS 1%组相比， BCR-ABL/ABLIS 0.1%-1%和MMR组3年PFS和OS更高Molecular Response 1% BCR-ABLMartin C. Mller, MD Oral Session: Chronic Myeloid Leukemia - Therapy: Rethinking Therapy Targets and Prognostic Factors 669结论-更快、更深的分子反应与PFS和OS的提高有关-关键临界值似乎是1% BCR-ABL/AB

13、LIS水平（与CCyR密切相关）Molecular Response 65years): Results of the German CML-Study IVSusanne Saussele, MD Poster Session: Chronic Myeloid Leukemia - Therapy: Poster III 3411目的-评估伊马替尼治疗年龄大于65岁CML患者的疗效及安全性研究设计-以65岁为年龄分界，分为IM 400mg和800mg组-观测血液学、细胞遗传学、分子学缓解时间，总生存率和不良反应年龄65 (n=150）65years): Results of the Germ

14、an CML-Study IVSusanne Saussele, MD Poster Session: Chronic Myeloid Leukemia - Therapy: Poster III 3411结果有效性-年老与年轻患者间细胞遗传学和分子学缓解率无显著差异-IM 400mg组中，年老比年轻患者更慢获得CCyR和MMR(CCvR: 14.2 月 vs 12.1 月,p=.019; MMR: 18.7 月 vs 17.5 月,p=.006）-IM 800mg组中，两组间无差异 (CCvR : 7.7 月 vs 8.9 月, MMR: 9.9 月 vs 10.0 月)-3年总生存率两组分

15、别为94.7% 和96.1% 安全性-血液学不良反应：年老比年轻患者稍重-3、4级非血液学不良反应：无差异Therapy with Imatinib In ElderTherapy with Imatinib In Elderly CML Patients (65years): Results of the German CML-Study IVSusanne Saussele, MD Poster Session: Chronic Myeloid Leukemia - Therapy: Poster III 3411结论-年老患者使用伊马替尼400mg和800mg均耐受性良好-应用伊马替尼8

16、00mg治疗，年老与年轻患者获得CCyR和MMR的中位时间无差异-应用伊马替尼400mg治疗，年老患者比年轻患者更慢获得CCyR和MMRTherapy with Imatinib In ElderAnalysis of Outcomes In Adolescents and Young Adults (AYA) with Chronic Myeloid Leukemia (CML) Treated with Upfront Tyrosine Kinase Inhibitors (TKI) Naveen Pemmaraju, MD Poster Session: Chronic Myeloid

17、Leukemia - Therapy: Poster 1234目的-评价酪氨酸激酶抑制剂治疗青少年CML患者的临床疗效研究对象-年龄15至21岁的CML患者；移植患者排除结果年龄21 (n=422) P 值 总数Sokal 危险度, n (%)低危 中危 高危 12 (92) 1 (8) 0 288 (68) 105 (25) 29 (7) 0.24 300 (69) 106 (24) 29 (7) CCyR, n (%) 7 (64) 384 (93) 0.008 391 / 425中位达CCyR时间 (月) 3 3 3 (2-64) MMR, n (%) 7 (64) 359 (87) 0

18、.0497 366 /424中位达 MMR时间 (月) 9 6 6 (2-78) CMR, n (%) 1 (9) 160 (39) 0.06 161/424中位达 CMR时间 (月) 1224 24 (3-84) 5年无事件生存79 90 0.26 5年无进展生存 (%) 100 94 0.51 5年总生存 (%) 88 93 0.9 Analysis of Outcomes In AdolesAnalysis of Outcomes In Adolescents and Young Adults (AYA) with Chronic Myeloid Leukemia (CML) Treat

19、ed with Upfront Tyrosine Kinase Inhibitors (TKI) Naveen Pemmaraju, MD Poster Session: Chronic Myeloid Leukemia - Therapy: Poster 1234结论-与青少年CML患者相比，年长患者CCyR明显提高；MMR和CMR也有升高趋势-青少年与年长CML患者EFS，TFS和OS无差别Analysis of Outcomes In AdolesENESTnd Update: Continued Superiority of Nilotinib Versus Imatinib In P

20、atients with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) Timothy P. Hughes, MD, MBBS Oral Session: Chronic Myeloid Leukemia - Therapy: Optimizing Treatment Outcome207目的-评价尼洛替尼治疗初诊Ph+ CML-CP患者的疗效和安全性(中位随访18个月的ENESTnd研究结果更新) 研究设计-随机开放的多中心的3期临床研究 -846例初诊CML-CP患者入组-主要终点：12个月MMR (

21、0.1% BCR-ABLIS) -次要终点：24个月持续MMR-其他： 24 个月加速/急变率、EFS、PFS和OSENESTnd Update: Continued SupeTimothy P. Hughes, MD, MBBS Oral Session: Chronic Myeloid Leukemia - Therapy: Optimizing Treatment Outcome207 中位随访18个月的总体有效性Nilotinib 300 mg bid (n = 282) Nilotinib 400 mg bid (n = 281) Imatinib 400 mg qd (n = 28

22、3) MMR, % 66 P .0001* 62 P .0001* 40 Sokal危险度, % 低危(n = 103, n = 103, n = 104) 70 69 51 中危 (n = 101, n = 100, n = 101) 67 63 39 高危 (n = 78, n = 78, n = 78) 59 51 28 BCR-ABLIS 0.0032% , % 21 P .0001* 17 P .0001* 6 CCyR, % 85 P .001* 82 P = .017* 74 向加速/急变进展 不包括克隆演进, n (%) 2 (0.7) P = .006* 1 (0.4) P

23、= .003* 12 (4.2) 包括克隆演进, n (%) 2 (0.7) P 4log A Randomized Phase II Trial ofA Randomized Phase II Trial of Dasatinib 100 Mg Vs Imatinib 400 Mg In Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP): The S0325 Intergroup Trial 结果-达沙替尼组12个月分子反应更深，BCRABL IS 中位下降3.3log；伊马替尼组中位下降2.8log （P=

24、0.048）-两组获得HemCR和CCyR无显著差异-死亡、复发及进展均极少，OS和PFS相似-均无致命的不良反应，达沙替尼最常见的3、4级血液学不良反应是血小板减少IM 400mg (n=123) DAS (N=123) 2-sided P* HemCR 111 (90%) 104 (86%) 0.25 CCyR 40/58 (69%) 55/67 (82%) 0.097 3 log 39/90 (43%) 58/99 (59%) 0.042 4 log 18/90 (20%) 27/99 (27%) 0.31 4.5 log 13/90 (14%) 21/99 (21%) 0.26 12个

25、月OS 99% 100% 0.60 12个月PFS 96% 99% 0.19 A Randomized Phase II Trial ofA Randomized Phase II Trial of Dasatinib 100 Mg Vs Imatinib 400 Mg In Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP): The S0325 Intergroup TrialJerald P. Radich, MD Session: Late-Breaking Abstracts Session LBA-6

26、 结论 达沙替尼和伊马替尼400mg治疗初诊Ph+ CML-CP均有效，且耐受性好与伊马替尼相比，达沙替尼12个月时获得更深的分子反应达沙替尼和伊马替尼OS和PFS相似达沙替尼有更多的3、4级血液学不良反应A Randomized Phase II Trial ofPatients with Chronic Myeloid Leukemia In Chronic Phase Carrying More Than One BCR-ABL Kinase Domain Mutation Exhibit Poorer Response Rates and Outcomes to Second-Line

27、 Dasatinib Compared to Those with No or Only One BCR-ABL Mutation Alfonso Quints-Cardama Poster Session: Chronic Myeloid Leukemia - Therapy: Poster II 2297目的-分析CML-CP患者BCR-ABL激酶区突变与治疗反应的关系研究设计-回顾性分析-1150例对伊马替尼耐药或不耐受、使用达沙替尼治疗的CML-CP患者入组-2期START-C (-013)、START-R (-017）、3期剂量优化试验(-034) Patients with Chr

28、onic Myeloid Patients with Chronic Myeloid Leukemia In Chronic Phase Carrying More Than One BCR-ABL Kinase Domain Mutation Exhibit Poorer Response Rates and Outcomes to Second-Line Dasatinib Compared to Those with No or Only One BCR-ABL Mutation Alfonso Quints-Cardama Poster Session: Chronic Myeloid

29、 Leukemia - Therapy: Poster II 2297总数 (N=1150) 24个月最佳反应24个月无进展生存12个月获得的治疗反应与相应的24个月无进展生存24个月总生存MCyRa CCyRa 无基线突变, N=641 410/633 (64.8) 354/633 (55.9) 83.2% CCyR 96.5% 93.5 % PCyR 94.3% Other 75.1% 有基线突变, N=402 222/399 (55.6) 172/399 (43.1) 70.2% CCyR 93.4% 88.6% PCyR 86.6% Other 72.6% 一个基线突变, N=332

30、186/330 (56.4) 147/330 (44.6) 72.9% CCyR 92.3% 88.6% PCyR 88.1% Other 79.5% 大于一个基线突变, N=70 36/69 (52.2) 25/69 (36.2) 57.4% CCyR 100% 88.9% PCyR 75% Other 41.7% 结果Patients with Chronic Myeloid Patients with Chronic Myeloid Leukemia In Chronic Phase Carrying More Than One BCR-ABL Kinase Domain Mutatio

31、n Exhibit Poorer Response Rates and Outcomes to Second-Line Dasatinib Compared to Those with No or Only One BCR-ABL Mutation Alfonso Quints-Cardama Poster Session: Chronic Myeloid Leukemia - Therapy: Poster II 2297结论无论有、无BCR-ABL激酶区基线突变，达沙替尼疗效显著存在基线突变的CML-CP患者治疗反应率和PFS较低存在大于一个基线突变的CML-CP患者治疗反应率和PFS最低

32、Patients with Chronic Myeloid 第二部分：TKI耐药的机制研究-相关信号通路JAK2信号STAT5信号Hedgehog信号通路NF-B信号Syk-Lyn-Axl信号通路Oral and Poster Abstracts 第二部分：TKI耐药的机制研究-相关信号通路Oral anJAK2信号Jak2 Regulates Bcr-Abl In CD34+ Cells From Imatinib Mesylate-Resistant CML Patients-Bastianella Perazzona, Ph.D. JAK2-Mediated Extrinsic Surv

33、ival of CML Stem Cells: Exploring the Potential Combination of BCR-ABL and JAK2 Inhibitors In Vivo-Elie Traer, MD, PhD Combined Targeting of BCR-ABL and JAK2 with ABL and JAK2 Inhibitors Is Effective Against CML Patients Leukemic Stem/Progenitor Cells-Donna DeGeer, MSc Poster Session: Chronic Myeloi

34、d Leukemia - Biology and Pathophysiology, excluding Therapy: Poster I 1220 Oral Session: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Therapy: CML Stem Cell/Progenitor Biology 199 Poster Session: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Therapy: Poster I

35、I 3404JAK2信号Poster Session: Chronic JAK2信号JAK2抑制剂明显降低BCR-ABL蛋白表达和磷酸酪氨酸177水平JAK2抑制剂有效诱导伊马替尼耐药的CD34+干、祖细胞死亡体内同时抑制BCR-ABL和JAK2表达，显著降低BCR-ABL表达的细胞数量,但骨髓毒性较大BCR-ABL和JAK2抑制剂联用可有效杀伤TKI耐受的CML干、祖细胞Poster Session: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Therapy: Poster I 1220 Oral Se

36、ssion: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Therapy: CML Stem Cell/Progenitor Biology 199 Poster Session: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Therapy: Poster II 3404JAK2信号Poster Session: Chronic STAT5信号Distinct Functions of Stat5A and Stat5B

37、 in Chronic Myeloid Leukemia (CML): Stat5B Is Implicated in Survival and Self-Renewal and Stat5A in Imatinib Resistance-Ali G. Turhan, MD, PhD Bcr-Abl Directly Activates Stat5 Independent of Jak2-Oliver D. Hantschel, PhDHormone-Conditional Activation of Bcr-Abl Kinase Highlights Stat5 Anti-Apoptotic

38、 Pathway Prior to Promoting Cell Growth-Ratanakanit HarnprasopwatAdaptor Protein Lnk Negatively Regulates Bcr-Abl-Induced Cell Proliferation through Inhibition of the Stat5 Signaling Pathway-Takayuki Tabayashi, MDPoster Session: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Thera

39、py: Poster I 1214Oral Session: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Therapy: NovelMolecular Mechanisms and Targets in CML 511Poster Session: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Therapy: Poster II 3380Poster Session: Chronic Myeloid Leukemia

40、- Biology and Pathophysiology, excluding Therapy: Poster II 3406STAT5信号Poster Session: ChronicSTAT5信号Stat5A在TKI耐药的CML细胞中异常激活，抑制Stat5A可逆转耐药；Stat5B在CML细胞生存和自我更新中起重要作用Bcr-Abl不依赖JAK2信号直接激活Stat5Bcr-Abl/Stat5通路通过整合多种效应分子(BCL-XL, HIF-1A, HSPA1A, WT1, PRAME)阻止细胞凋亡，成为治疗Ph+白血病的潜在分子靶点衔接蛋白Lnk通过抑制Stat5信号转导，负调控Bc

41、r-Abl诱导的细胞增殖，将为Ph+白血病的治疗提供靶点Poster Session: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Therapy: Poster I 1214Oral Session: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Therapy: NovelMolecular Mechanisms and Targets in CML 511Poster Session: Chronic Myeloid

42、 Leukemia - Biology and Pathophysiology, excluding Therapy: Poster II 3380Poster Session: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Therapy: Poster II 3406STAT5信号Poster Session: ChronicHedgehog信号通路Hedgehog Signaling Is Useful as a Novel Molecular Marker for Predicting Relapse

43、 and Resistance During Chronic Myeloid Leukemia Treatment-Michele Cea Inhibition of Chronic Myeloid Leukemia Stem Cells by the Combination of the Hedgehog Pathway Inhibitor LDE225 with Nilotinib-Bin Zhang Human Blast Crisis Leukemia Stem Cell Inhibition with a Novel Smoothened Antagonist -Alice Shih

44、, BS Poster Session: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Therapy: Poster I 1215Oral Session: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Therapy: Novel Molecular Mechanisms and Targets in CML 514Poster Session: Chronic Myeloid Leukemia - Biology an

45、d Pathophysiology, excluding Therapy: Poster I 1223Hedgehog信号通路Poster Session: ChHedgehog信号通路Hedgehog信号通路激活与BCR-ABL转录本升高直接正相关TKI耐药的CML患者存在Hedgehog信号通路异常激活，可预测复发和耐药阻断Hedgehog信号可抑制TKI耐药的CML细胞增殖Hedgehog抑制剂（LDE225）靶向白血病干细胞，与尼洛替尼联用可有效清除TKI治疗残留的白血病干细胞Hedgehog抑制剂（SMO拮抗剂）与达沙替尼联用抑制伊马替尼耐药的急变白血病干细胞自我更新Poster S

46、ession: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Therapy: Poster I 1215Oral Session: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Therapy: Novel Molecular Mechanisms and Targets in CML 514Poster Session: Chronic Myeloid Leukemia - Biology and Pathophysio

47、logy, excluding Therapy: Poster I 1223Hedgehog信号通路Poster Session: Ch其他信号通路NF-BDistinct Roles for the NF-B Pathway In Myeloid and Lymphoid Transformation and Leukemogenesis by BCR-ABL-Mo-Ying Hsieh, BS Syk-Lyn-AxlQuantitative Phosphoproteomics Identified a New Syk-Lyn-Axl Signalling Pathway Involved

48、In Resistance to Nilotinib In Chronic Myeloid Leukemia Cells-Romain Gioia, Ph, D Poster Session: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Therapy: Poster I 1225Poster Session: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Therapy: Poster II 3376其他信号通路Post

49、er Session: Chronic 其他信号通路NF-B在BCR-ABL表达的白血病细胞中，NF-B部分通过经典的IKK途径被激活NF-B信号在BCR-ABL表达的髓系及淋系白血病发病机制中扮演不同角色NF-B信号在产生和/或维持CML干细胞中发挥作用， IKKs将成为治疗Ph+白血病的新分子靶点Syk-Lyn-Axl定量磷酸蛋白质组学发现了一个新的Syk-Lyn-Axl信号通路其在尼洛替尼耐药中起重要作用Poster Session: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Therapy: Po

50、ster I 1225Poster Session: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Therapy: Poster II 3376其他信号通路Poster Session: Chronic Education Program探讨慢性期CML酪氨酸激酶抑制剂的优化治疗对于需要二线治疗的患者，我们应该做什么在2010年，CML还有哪些待解决的问题第三部分 继续医学教育CML 2010: Where Are We Now and Where Can We Go？Education Program第三部分 继续医学教育伊马替尼（400mg/d）是初诊CML慢性期患者的标准治疗IRIS 8年随访结果EFS、无加速/急变生存率分别是82%、92%TKI治疗大大降低CML死亡率部分患者仍存在耐药和疾病进展第二代TKI治疗伊马替尼耐药的CML-CP患者，仅50%获CCyR，加速期患者获得CCyR率更低CML治疗现状CML治疗现状TKI治疗CCyR比较