cml治療課件

1、慢性髓細(xì)胞白血病(CML)治療概述,2,,1. Silver RT, et al. Blood 1999;94:1517–362. Baccarani M, et al. Blood 2006;108:1809–203. Baccarani M, et al. J Clin Oncol 2009;27:6041–51,CML 研究和治療的里程碑,,,,,ASH = American Society of HematologyBM

2、T = bone marrow transplant ELN = European LeukemiaNet; IFN = interferon,,,Virchow 和 Bennet 首次描述CML(“white blood”),發(fā)現(xiàn)Ph染色體 (Nowell/ Hungerford),揭示Ph染色體的機(jī)制 t(9;22) (Rowley),,發(fā)現(xiàn)C-Abl 酪氨酸激酶在Ph染色體易位中的作用,發(fā)現(xiàn)Bcr-Abl 融合蛋白,,Bcr-

3、Abl 酪氨酸激酶抑制劑的研發(fā),ASH 對(duì)CML治療推薦：白消安, 羥基脲, IFN-?, 或異基因骨髓移植,發(fā)現(xiàn)CML150年來，CML的治療并無革命性的進(jìn)展,3,TKI出現(xiàn)之前CML治療,干擾素 （ Interferon-? ）(+) 阿糖胞苷（ Ara-C ）,IFN-? 抑制STAT1和STAT2 轉(zhuǎn)錄因子抑制細(xì)胞增殖介導(dǎo)細(xì)胞生存IFN-? 在CML中的應(yīng)用療效： ~60%-80% 血液學(xué)緩解;

4、 少部分患者可達(dá)到遺傳學(xué)緩解。小劑量Ara-C可以抑制慢性期Ph+ 間期細(xì)胞,Robertson et al. Am J Hematol. 1993;43:95.Sokal et al. Leuk Res. 1988;12:453.,TKI出現(xiàn)之前CML治療,CHR = complete hematologic response; Ph = Philadelphia chromosome.,IFN-? 比白消安或羥基脲提高CML

5、慢性期患者生存期,Hehlmann et al. Blood. 1994;84:4064. Copyright American Society of Hematology, used with permission.,,Busulfan(n=186) 中位生存期45.4 月,INF-? vs busulfan: P=0.008,生存率比例,年,0,1,2,3,4,5,6,7,8,9,10,11,12,0,0.1,0.2,0.3,0

6、.4,0.5,0.6,0.7,0.8,0.9,1.0,INF-?(n=133) 中位生存期 63.2 月,Hydroxyurea(n=194) 中位生存期 56.0 月,,,,,,,,TKI出現(xiàn)之前CML治療,Allan et al. Lancet. 1995;345:1392; Guilhot et al. N Engl J Med. 1997;337:223. Hehlmann et al. Blood. 1994;84:406

7、4; Italian Cooperative Study Group on CML. N Engl J Med. 1994;330:820; Kantarjian et al. J Clin Oncol. 1999;17:284; Kantarjian et al. Ann Intern Med. 1995;122:254; Mahon et al. Blood. 1994;84:3592; Ohnishi et al. Blood.

8、1995;86:906; Ozer et al. Blood. 1993;82:2975; Silver et al. Blood. 1996;88(suppl 1):638a; Tura. Blood. 1998;92(suppl 1):317a.,IFN-?聯(lián)合Ara-C提高CML治療結(jié)果,CCR,百分比,CHR,MCR,3年 OS,IFN-? 單獨(dú) (數(shù)據(jù)由7個(gè)臨床實(shí)驗(yàn)匯總)IFN-? + Ara-C (數(shù)據(jù)由4個(gè)臨床實(shí)驗(yàn)匯總)

9、,P=0.02,,,31,80,92,64,58,50,41,74,38,6,10,50,CCR = complete cytogenetic response.,80,0,10,20,30,40,18,60,70,80,90,100,TKI出現(xiàn)之前CML治療,異基因造血干細(xì)胞移植Allogeneic Stem Cell Transplant（allo-SCT）,目前認(rèn)為能夠根治CML的唯一方法影響移植的因素：供者患者年齡合

10、并癥等,HLA = human leukocyte antigen.Faderl et al. Oncology (Huntingt). 1999;13:169.Gale et al. Blood. 1998;91:1810.,TKI出現(xiàn)之前CML治療,,,,,,ELN推薦：HSCT為CML患者挽救性治療的策略二線TKI治療失敗后,,,National Marrow Donor Program overview slide pre

11、sentation. At: http://www.marrow.org/NMDP/SLIDESET/sld031.htm. Accessed November 2004.,移植后時(shí)間（年）,加速期和慢性期晚期 (n=744),不同疾病時(shí)期進(jìn)行SCT的生存率比較 (1987-2001),P=0.0001,100,90,70,60,50,40,30,20,10,0,80,生存率%,急變期 (n=159),慢性期早期 (n=1903),0

12、,1,2,3,4,5,TKI出現(xiàn)之前CML治療,BMS Privileged and Confidential Information. For Internal Purposes Only,10,TKI出現(xiàn)之前CML治療的生存率,CML 生存期 1965-1996 MDACC (N=2213),1. Kantarjian H. et al. Clin Cancer Res. 1997; 3: 2723-2733; 2. Goldm

13、an J, et al. N Engl J Med 2001;344:1084–6; 3. Hehlmann R, et al. Haematologica 2008;93:1765–1769; 4. Hehlmann R, et al. Leuk Lymphoma 1996;22:161–7; 5. Baccarani M, et al. Haematologica 2008;93:161–9; 6. Pavolvsky C,

14、 et al. Am J Hematol 2009;84:287–93; 7. Kantarjian HM, et al. Blood 2003;101:97–100,,Evolution of first-line drug therapy for CP-CML2-7,1.00.80.60.40.20.0,預(yù)期生存期,Figure 2 . Survival in CML by year of referral.,12

15、345678910,年,,,,,P<.0001,,,,,,,,,,,,,,,,,11,CML:治療方法決定生存率,,*主要改善癥狀，但不能延長(zhǎng)生存期**第一種治療可以延長(zhǎng)生存期,1. Silver RT, et al. Blood 1999;94:1517–362. Baccarani M, et al. Blood 2006;108:1809–20,12,CML 研究和治療的里程碑,,,,,,,Virchow

16、和 Bennet 首次描述CML(“white blood”),發(fā)現(xiàn)Ph染色體 (Nowell/ Hungerford),揭示Ph染色體的機(jī)制 t(9;22) (Rowley),,發(fā)現(xiàn)C-Abl 酪氨酸激酶在Ph染色體易位中的作用,發(fā)現(xiàn)Bcr-Abl 融合蛋白,,Bcr-Abl 酪氨酸激酶抑制劑的研發(fā),ASH 對(duì)CML治療推薦：白消安, 羥基脲, IFN-?, 或異基因骨髓移植,伊馬替尼被批準(zhǔn)用于治療IFN-α治療失敗的CML

17、患者,伊馬替尼被批準(zhǔn)用于治療新診斷CML患者,,,1. Silver RT, et al. Blood 1999;94:1517–362. Baccarani M, et al. Blood 2006;108:1809–203. Baccarani M, et al. J Clin Oncol 2009;27:6041–51,ASH = American Society of HematologyBMT = bone marrow

18、 transplant ELN = European LeukemiaNet; IFN = interferon,13,酪氨酸激酶抑制劑(TKI)治療CML,14,,,甲磺酸伊馬替尼（Imatinib）,一種選擇性的酪氨酸激酶抑制劑，可抑制KITBcr-AblPDGFR-A/B,C29H31N7O?CH4SO3 分子量 589.7,PDGFR = platelet-derived growth factor recepto

19、r; Ph = Philadelphia chromosome.Druker et al. Nat Med. 1996;2:561.,正常的Bcr-Abl 信號(hào)轉(zhuǎn)導(dǎo)途徑,P,P,P,P,P,ATP,Bcr-Abl,Savage and Antman. N Engl J Med. 2002;346:683Scheijen and Griffin. Oncogene. 2002;21:3314.,ADP = adenosine diph

20、osphate; ATP = adenosine triphosphate; P = phosphate.,TKI的作用機(jī)制,TKI,Bcr-Abl,Savage and Antman. N Engl J Med. 2002;346:683.,酪氨酸激酶的作用,18,參與CML形成的異常酪氨酸激酶BCR-ABL和酪氨酸底物結(jié)合的示意圖,19,20,1. Melo JV, et al. Cancer Lett 2007;249:121

21、–132.Figure: Reprinted from Cancer Cell, Volume 2, Shah NP, et al., Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast

22、 crisis chronic myeloid leukemia, 117–125, Copyright (2008), with permission from Elsevier.,伊馬替尼與ABL激酶區(qū)結(jié)合的3D結(jié)構(gòu)圖,21,BCR-ABL蛋白結(jié)構(gòu)示意圖,失活構(gòu)象,活化構(gòu)象,,,伊馬替尼只能與失活構(gòu)象BCR-ABL結(jié)合,BCR-ABL的構(gòu)象在不斷地進(jìn)行著從失活到活性的變換，而伊馬替尼只能結(jié)合失活構(gòu)象的BCR-ABL。伊馬替尼一旦與

23、BCR-ABL結(jié)合，BCR-ABL就會(huì)保持失活構(gòu)象不變，并可能出現(xiàn)下列情況：阻斷ATP與BCR-ABL激酶的結(jié)合，BCR-ABL一直保持失活狀態(tài)兩者的結(jié)合能防止底物磷酸化從而阻斷信號(hào)轉(zhuǎn)導(dǎo)通路，抑制CML細(xì)胞的生長(zhǎng)，促進(jìn)其凋亡伊馬替尼還能誘導(dǎo)P環(huán)的結(jié)構(gòu)發(fā)生改變，而P環(huán)能優(yōu)化結(jié)合時(shí)的親合力；P環(huán)還能影響失活構(gòu)象BCR-ABL的穩(wěn)定程度,22,BMS Privileged and Confidential Information. F

24、or Internal Purposes Only,23,伊馬替尼–CML治療的革命,imatinib,1. Kantarjian H. et al. Cancer 2008; 113(7): 1933-52; 2. Goldman J, et al. N Engl J Med 2001;344:1084–6; 3. Hehlmann R, et al. Haematologica 2008;93:1765–1769; 4. He

25、hlmann R, et al. Leuk Lymphoma 1996;22:161–7; 5. Baccarani M, et al. Haematologica 2008;93:161–9; 6. Pavolvsky C, et al. Am J Hematol 2009;84:287–93; 7. Kantarjian HM, et al. Blood 2003;101:97–100,CML survival over ti

26、me at MDACC (N=1736),Evolution of first-line drug therapy for CP-CML2-7,,Busulfan,Hydroxyurea,Interferon-?,2010,2000,1990,1980,1970,1950,1960,Proportion Alive,Years from referral,1.00.80.60.40.20.0,246810121

27、416,,,,,,85%,24,伊馬替尼治療CML,伊馬替尼的注冊(cè)劑量慢性期400mg/天加速期或急變期600mg/天一些醫(yī)生對(duì)慢性期采用 600mg/天的起始劑量或很快地從400 mg上升到600 mg,25,伊馬替尼注冊(cè)適應(yīng)癥,26,伊馬替尼相關(guān)臨床試驗(yàn),4 個(gè)開放標(biāo)簽、多中心的臨床試驗(yàn),1. Kantarjian H, et al. N Engl J Med. 2002;346:645-652.2. Talpaz

28、M, et al. Blood. 2002;99:1928-1937.3. Sawyers CL, et al. Blood. 2002;99:3530-3539.4. O’Brien SG, et al. N Engl J Med. 2003;348:994-1004.,27,IRIS 研究,IFN-a + Ara-C,伊馬替尼,交叉條件:不耐受失去主要血液學(xué)反應(yīng)(CHR) 失去主要遺傳學(xué)反應(yīng)(MCyR)6個(gè)月未達(dá)到

29、CHR 12個(gè)月未達(dá)到 MCyR,,,,,,,,,交叉,n= 1106,隨機(jī)分組,該研究確定了伊馬替尼400mg QD 成為新診斷CML的1線治療標(biāo)準(zhǔn),28,IRIS研究: 18個(gè)月的數(shù)據(jù)顯示與IFN相比IM顯著有效,Kaplan-Meier Estimates,O´Brien et al., NEJM 2003,不耐受,CHR,MCyR,CCyR,AP/BC,,,,,,,,,,,,,97,69,,,,,,,87,35,,,

30、,,,,76,14,,,,,,,3,8.5,,,,,,,3,31,,,,,,,0,20,40,60,80,100,患者百分率%,,,,,,,,各組比較p< 0.001,,29,IRIS研究---8年報(bào)告（總生存率）,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

31、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,0,10,20,30,40,50,60,70,80,90,100,0,12,24,36,48,60,72,84,96,,108,% Alive,從隨機(jī)分組開始的時(shí)間（月）,,生存: 只考慮CML相關(guān)死亡總生存,,,預(yù)估8年總生存率為

32、85% (僅考慮CML相關(guān)死亡，8年總生存率為93%),Deininger et al., ASH 2009 Poster presentation,30,預(yù)計(jì)8年EFS = 81%第8年1例進(jìn)展到 AP/BC和2例發(fā)生非CML相關(guān)的死亡 預(yù)計(jì)8年未進(jìn)展至AP/BC率 = 92%,Deininger et al., ASH 2009 Poster presentation,,,,,,,,,,,,,,,,,,,,,,,,3,.,3

33、,7,.,5,4,.,8,1,.,7,0,.,8,0,.,3,1,.,4,1,.,3,1,.,5,2,.,8,1,.,8,0,.,9,0,.,5,0,0,0,.,4,0,1,2,3,4,5,6,7,8,1,2,3,4,5,6,7,8,Year,事件失去CHR,失去MCyR,AP/BC, 治療過程中死亡AP/BC,,,,,,,,,,,,,,,事件百分率 %,IRIS研究---8年報(bào)告（每年事件發(fā)生率）,IRIS試驗(yàn)伊馬替尼中止治療

34、（8年數(shù)據(jù)）n=553,其他包括違背方案、政府行為、失訪或非正常程序；Deininger M 2009 poster ASH,32,伊馬替尼非血液學(xué)不良反應(yīng),新診斷CML患者中>20% 出現(xiàn)不良反應(yīng)(所有級(jí)別) (n=551)1,Gleevec® (imatinib mesylate) [package insert]. East Hanover, NJ: Novartis Pharmaceu

35、ticals Corp; March 2005.,不良反應(yīng),¾級(jí),所有級(jí)別,皮疹,腹瀉,體液潴留,骨骼肌肉疼痛,嘔吐,肌肉抽筋,疲乏,惡心,頭痛,關(guān)節(jié)痛,腹痛,鼻咽炎,出血,肌痛,33,伊馬替尼血液學(xué)毒性,1. Gleevec® (imatinib mesylate) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; March 20

36、05.,IM治療嚴(yán)重血液學(xué)毒性發(fā)生率1,不良反應(yīng),新診斷CML,慢性期IM治療失敗,加速期,髓系急變,¾級(jí),¾級(jí),¾級(jí),¾級(jí),中性粒細(xì)胞減少,貧血,血小板減少,34,CML的二線治療,盡管伊馬替尼徹底改變了CML的治療并顯示出作為一線治療具有顯著效果但仍有患者對(duì)伊馬替尼無效：不能耐受伊馬替尼治療對(duì)伊馬替尼治療耐藥獲得性（患者獲得了初始緩解，之后復(fù)發(fā)）原發(fā)性（從未獲得初始緩解）

37、,35,不同分期CML伊馬替尼耐藥的發(fā)生率,總耐藥發(fā)生率隨疾病進(jìn)展而升高 1. Lahaye T, Riehm B, Berger U, et al. Cancer. 2005;103:1659-1669.,慢性期,加速期,髓系急變期,伊馬替尼耐藥%,36,伊馬替尼治療4年后，針對(duì)伊馬替尼耐藥增加1,1. Bran

38、ford S, Rudzki Z, Walsh S, et al. Blood. 2003;102:276-283.,與治療時(shí)間相關(guān)的伊馬替尼耐藥發(fā)生率,伊馬替尼耐藥患者%,IM治療<4年,IM治療>4年,37,已知的伊馬替尼耐藥機(jī)理,Branford S, Rudzki Z, Walsh S, et al. Blood. 2003;102:276-283.Weisberg E, Griffin JD. Blood. 20

39、00;95:3498-3505.Donato NJ, Wu JY, Stapley J, et al. Blood. 2003;101:690-698.,耐藥機(jī)制,BCR-ABL激酶域突變,BCR-ABL過表達(dá),其它癌性信號(hào)通路激活,獲得/原發(fā)突變P環(huán)活化環(huán)其它位點(diǎn),SRC通路激活,Lyn和HCK激活,IM無法結(jié)合,38,伊馬替尼的原發(fā)性耐藥和繼發(fā)性耐藥,原發(fā)性耐藥 未能達(dá)到有意義的血液學(xué)或細(xì)胞遺傳學(xué)緩解 繼發(fā)性耐藥

40、 在首度緩解后又進(jìn)行性出現(xiàn)白血病細(xì)胞，又稱為“獲得性”伊馬替尼耐藥,Melo JV, et al. Cancer Lett 2007;249:121–132.,39,中國(guó)CML患者的伊馬替尼耐藥情況,中國(guó)15家醫(yī)院慢性粒細(xì)胞白血病發(fā)病狀況及目前診斷治療模式調(diào)查分析，王建祥等，Chin J Hematol, 2009, vol.30,No.11,40,伊馬替尼耐藥機(jī)制,BCR-ABL激酶區(qū)突變1占耐藥患者的42-90%2BC

41、R-ABL過表達(dá)1占耐藥病例的18%左右BCR-ABL無關(guān)的機(jī)制1藥物流入和流出轉(zhuǎn)運(yùn)體α1酸性糖蛋白（AGP）結(jié)合Src家族激酶成員Lyn的過表達(dá)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.,41,Reprinted from Experimental Hema

42、tology, Volume 35(4 Supplement 1), Deininger MWN, Optimizing therapy of chronic myeloid leukemia, 144–154, Copyright (2007), with permission from Elsevier.,BCR-ABL激酶的突變頻率,42,1. Melo JV, et al. Cancer Lett 2007;249:121–1

43、32.Figure: Reprinted from Cancer Cell, Volume 2, Shah NP, et al., Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast c

44、risis chronic myeloid leukemia, 117–125, Copyright (2008), with permission from Elsevier.,伊馬替尼與ABL激酶區(qū)結(jié)合的3D結(jié)構(gòu)圖,43,BCR-ABL過表達(dá),BCR-ABL蛋白過表達(dá)是由于 BCR-ABL 基因的過度擴(kuò)增,,FISH,傳統(tǒng)染色體分析,1 個(gè)融合信號(hào),2個(gè)融合信號(hào),3個(gè)融合信號(hào),44,在耐藥病例中占 ~18%1耐藥機(jī)制:2伊馬

45、替尼細(xì)胞內(nèi)濃度不足以抑制過表達(dá)的BCR-ABL蛋白,1. Melo JV, et al. Cancer Lett 2007;249:121–132.2. Shah NP, et al. Hematology Am Soc Hematol Educ Program 2005:183–187.,BCR-ABL過表達(dá),45,藥物轉(zhuǎn)運(yùn)蛋白缺陷,藥物溢入轉(zhuǎn)運(yùn)蛋白 – 有機(jī)陽離子轉(zhuǎn)運(yùn)蛋白 1 (OCT1),OCT1 介導(dǎo)伊馬替尼轉(zhuǎn)運(yùn)入細(xì)胞內(nèi)1O

46、CT1 抑制可降低伊馬替尼細(xì)胞內(nèi)濃度2在達(dá)到CCyR 患者中 OCT1 的表達(dá)比 > 65% Ph+ 的患者更高 (既具有低基線 OCT1 的患者由于伊馬替尼細(xì)胞內(nèi)濃度不充分可能達(dá)不到CCyR)1,2,Pre-imatinib OCT1 expression level in non-responders (NRs) and responders (Rs)1,1. This research was originally pu

47、blished in Blood. Crossman LC, et al. hOCT 1 and resistance to imatinib. Blood. 2005;106:1133–1134. © American Society of Hematology.2. Melo JV, et al. Cancer Lett 2007;249:121–132.,46,藥物轉(zhuǎn)運(yùn)蛋白缺陷,藥物溢出轉(zhuǎn)運(yùn)蛋白MDR1 (

48、P-糖蛋白)細(xì)胞表面能量依賴的溢出泵伊馬替尼是 P-糖蛋白 (Pgp)的底物在 Pgp-表達(dá)的細(xì)胞中伊馬替尼的細(xì)胞內(nèi)濃度更低在伊馬替尼耐藥的患者中并未報(bào)道 Pgp 過表達(dá)ABCG2 (乳腺癌耐藥蛋白)伊馬替尼是 ABCG2的底物和/或抑制劑在CML干細(xì)胞中功能性表達(dá),Melo JV, et al. Cancer Lett 2007;249:121–132.,47,致癌信號(hào)通路中BCR-ABL和Src 家族激酶,SG Li

49、. Leuk lymphoma. 2008;49(1):19-26.Rix U, et al. Blood. 2007;110:4055-4063,48,二代TKI的選擇,Mestan. Blood 2004;104（546a）: Abstract 1978Weisberg. Cancer Cell 2005;7（129）.,尼洛替尼抑制的激酶靶點(diǎn),,,,,尼洛替尼有效作用于一些伊馬替尼耐藥的BCR-ABL突變,,,,,,,,,,

50、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,F317C,G250V,M388L,E255D,S348L,F317V,E275K,M237I,E355A,M351T,L387F,E355G,E281K,E255R,K285N,G250A,Q252H,M244V,F486S,D276G,E292K,F317L,L248V,G250E,F311V,F359V,A380S,F3

51、59C,E255K,Y253H,E255V,T315I,,,0,,500,,1,000,,1,500,,,10,000,,,,尼洛替尼敏感性：范圍為19–791 nM,尼洛替尼 耐藥：>10,000 nM,對(duì)于33種突變中的32種突變，尼洛替尼400mg BID（1700nM）達(dá)到的血藥谷濃度超過IC50,,H396R,,BID：每日兩次Weisberg E et al. Cancer Cell. 2005;7:129-141

52、.,細(xì)胞增殖IC50 （nM）,51,尼洛替尼二線治療CML臨床注冊(cè)實(shí)驗(yàn),A2101全球注冊(cè)臨床研究 — CML慢性期/加速期,尼洛替尼A2101注冊(cè)性臨床研究設(shè)計(jì),II期、全球、多中心、開放性研究入組患者：伊馬替尼治療失敗的成人CML-CP/AP患者尼洛替尼給藥方案：每日2次，每次400mg研究目的：尼洛替尼安全性和有效性研究終點(diǎn)：,MCyR：主要細(xì)胞遺傳學(xué)反應(yīng) CCyR：完全細(xì)胞遺傳學(xué)反應(yīng)CHR：完

53、全血液學(xué)反應(yīng) OS：總生存,Kantarjian HM, et al. 2009 ASCO Annual Meeting; Abstract #7029.,HR：血液學(xué)反應(yīng)；TTP：至疾病進(jìn)展時(shí)間；,尼洛替尼擴(kuò)大入組的實(shí)驗(yàn),53,12個(gè)月IM治療未達(dá)到CCyR的CML患者具有疾病進(jìn)展或死亡的風(fēng)險(xiǎn),Progression = AP/BP CML1. Druker BJ et al. N Engl J Med 2

54、006;355:2408-17 2. Saglio G, et al. ASH 2009, abstract LBA13. de Lavallade H, et al. J Clin Oncol 2008;26:3358–3363,31–43% 的患者在接受Imatinib治療后12個(gè)月不能達(dá)到CCyR1–3,,AP = accelerated phase; BP = blast phase; CP = chronic phase

55、; CCyR = complete cytogenetic response;OS = overall survival; PFS = progression-free survival,,12個(gè)月未達(dá)到CCyR患者，60個(gè)月評(píng)估：—6.5倍的疾病進(jìn)展或死亡率（PFS:74% VS 96%;p=0.007）—13倍的死亡率（OS：74% VS 98%；p=0.03),CCyR at 12 months (n=121)Optim

56、al responseNo CCyR at 12 months (n=72)Suboptimal response/failure,對(duì)IM治療應(yīng)答延遲的CML患者疾病進(jìn)展或死亡的風(fēng)險(xiǎn)增加,IM 治療12個(gè)月未達(dá)到CCyR的患者：將來達(dá)到CCyR的可能性減少應(yīng)答消失、疾病進(jìn)展、死亡的風(fēng)險(xiǎn)增加,Event = loss of CHR or MCyR, increasing white blood cell count (WBC),

57、progression to AP/BP CML, or deathAdapted from Quintas-Cardama A, et al. Blood 2009;113:6315-21,,,,高危患者應(yīng)用伊馬替尼療效不佳,Data from the IRIS trial1. Baccarani M. Relative Risk (Sokal & Hasford) Available at: http://www.le

58、ukemia-net.org/content/leukemias/cml/research/research/ 2. Hughes T, et al. N Engl J Med 2003;349:1423–32,12個(gè)月CCyR率(P<0.001)2低危: 76%中危: 67%高危: 49%,CCyR(%),P<0.001,100806040200,月,01224364860,低危 (n=201

59、),Sokal risk score1,中危 (n=111),高危 (n=71),高?；颊邞?yīng)用伊馬替尼長(zhǎng)期生存不佳,Data from the IRIS trial1. Hughes T, et al. N Engl J Med 2003;349:1423–322. Baccarani M. Relative Risk (Sokal & Hasford) Available at: http://www.leukemia-

60、net.org/content/leukemias/cml/research/research/,100806040200,01224364860,月,EFS(%),第二代TKI 1線治療CML,58,NCCN推薦的初發(fā)慢性期CML治療指導(dǎo),,60,ELN：治療建議,Baccarani et al. JCO 2009,1. IRIS研究對(duì)象是：新診斷慢性期Ph+ CML 患者 伊馬替尼與IFN-α+Ara-C療

61、效比較；伊馬替尼治療加速期Ph+CML患者；伊馬替尼治療急變期Ph+CML患者；伊馬替尼用于IFN-α 治療失敗或不耐受的慢性期Ph+CML患者；2 .伊馬替尼治療失敗的主要原因包括：不能耐受伊馬替尼治療；伊馬替尼治療原發(fā)性耐藥；伊馬替尼治療獲得性耐藥；以上都是；,61,,,,3. 對(duì)目前市面上TKI均表現(xiàn)出耐藥的BCR-ABL激酶突變是L248V；T315I；G321E；E352G；4. 以下英文縮寫本學(xué)科