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对复发的 AML 有新方法吗 ?

对复发的 AML 有新方法吗 ?. Steven M. Kornblau, M.D. Department of Leukemia Department of Stem Cell Transplantation and Cellular Therapy. 现状. 多数患者获得缓解 80% < 60 岁 , 无既往血液病史 50% >60 岁或有既往血液病史 多数复发 治愈率 20-25% ，因此复发率 2/3 rd 复发后不做移植治愈几乎不可能 除了 : APL 和那些不适合移植的 传统化疗很长时间无进展了 . 策略

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对复发的 AML 有新方法吗 ?

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  1. 对复发的AML有新方法吗? Steven M. Kornblau, M.D. Department of Leukemia Department of Stem Cell Transplantation and Cellular Therapy

  2. 现状 • 多数患者获得缓解 • 80% < 60岁, 无既往血液病史 • 50% >60岁或有既往血液病史 • 多数复发 • 治愈率 20-25% ，因此复发率 2/3rd • 复发后不做移植治愈几乎不可能 • 除了: APL 和那些不适合移植的 • 传统化疗很长时间无进展了. • 策略 • 接受 SCT, 直接地, 或暂时化疗 • 无供者. 姑息, 化疗或对症治疗.

  3. 异基因 SCT • 治愈 • 约35% 后续获得 CR • 25% 难治复发 (IBMTR 资料) • 何时做 • ASAP- 但多数不能等 & 需要什么 • CR2 时 • 但多数不能获得第二次 CR • 毒性和感染导致没有机会

  4. 预测复发后生存模型 GOELAMS EPI 0 > 18 Mo 0 CR1 Duration > 12 Mo CR1 Duration < 12 Mo 1 7-18 Mo 3 < 6 Mo 5 0 0 Cytogenetics Cytogenetics Inv16 Not High T(8;21) 3 High Risk 1 Other 5 0 Age FLT3 ITD Neg 0 <35 1 Positive 36-45 1 2 >45 2 Prior SCT? Chevallier Leukemia 2011;25(6);939-44 Breems JCO 2005;23(9):1669-78

  5. 应用欧洲预后指数和GOELAMS 预测总生存 Breems JCO 2005;23(9):1669-78 Giles Br J Haem 2006 ;134(1):58-61 GOELAMS They are superimposable

  6. FLT3-ITD: 复发时也是预后差的指标 Diploid Cytogenteics Not Tx with anti FLT3 agent CR#2 Remission Duration Overall Survival After Relapse 1 Overall Survival After CR#2 RavandiLeukRes 2010:34;752-756

  7. 预测2nd获得缓解的模型 Estey & Kornblau Blood 1996;88 :756 As an aside, perhaps Phase I and II studies should be sure to include patients form each category , or report what category they had Estey & Kornblau unpublished 1998

  8. 化疗与获批的药物联合

  9. 目前常用的化疗联合: MEC • Days 1-2-3: Mitoxantrone 12mg/m2/d & Ara-C 500 mg/m2 /d • Days 8-9-10: Etoposide 200 mg/m2/d & Ara-C 500 mg/m2 • N=133 • Age 15-70 (22 >60) • Cytogenetics ? but 7 M4Eos and 13 APL • Median 1st CR 11 mo • CR Overall 60% • 1st salvage for CR1>6mo =76% for CR1 <6mo =46% • >1st CR 45% • Primary refractory 41% • Overall survival, not receiving SCT = 7 mo Archimbaud JCO 1995:13;11-18

  10. 难治复发AML的随机临床结果: 没有什么是更好的 Abbreviations: CR = complete remission; OS = overall survival; HDAraC = high-dose cytarabine; Mit = mitoxantrone; IDAC = intermediate-dose AraC; NA = not available; Amsa = amsacrine; Eto = etoposide; MAE = Mit + AraC + Eto; G-CSF = granulocyte-colony stimulating factor; EMA = Eto + Mito + AraC; GM-CSF = granulocyte, macrophage–colony stimulating factor; ADE = AraC + daunorubicin + Eto; CSA = cyclosporine; seq ADE = sequential ADE; MEC = Mit + Eto + AraC. 1Kern W, et al. Leukemia. 2000;14: 226–231; 2Martiat P, et al. Eur J Haematol. 1990;45:164–167; 3Larson RA, et al. Br J Haematol. 1992;82:337–346; 4Vogler WR, Leukemia. 1994;8:1847–1853; 5Ohno R, et al. Blood. 1994;83:2086–2092. Slide Courtesy of Stefan Faderl

  11. 难治复发AML的随机临床结果 1Karanes C,et al. Leuk Res.1999;23:787–794; 2Thomas X,, et al. Leukemia. 1999;13:1214–1220; 3Liu Yin JA,, et al. Br J Haematol. 2001;113:713–726; 4List AF, et al. Blood. 2001;98:3212–3220; 5Greenberg PL, et al. J Clin Oncol. 2004;22:1078–1086; 6Feldman EJ, et al. J Clin Oncol. 2005;23:4110–4116; 7Giles FJ, et al. Blood (ASH Annual Meeting Abstracts). 2006;108:Abstract 1970. Slide Courtesy of Stefan Faderl

  12. 目前常用的化疗联合: FLAG Fludarabine 30m g/m2/d ,Ara-C 2 g/m2 /d 1-5, G-CSF 300 day 1-6 Jackson Br J Haem 2001:112; 127

  13. 嘌呤核苷类药物与阿糖胞苷联合治疗难治/复发AML嘌呤核苷类药物与阿糖胞苷联合治疗难治/复发AML 1Wierzbowska A, et al. Eur J Haematol. 2008;80:115–126; 2Steinmetz HT, et al. Ann Hematol. 1999;78: 418–425; 3Jackson G, et al. Br J Haematol. 2001;112:127–137; 4de la Rubia J, et al. Leuk Res. 2002;26:725–730; 5Clavio M, et al. Haematologica. 1996;81:513–520; 6Carella AM, et al. Leuk Lymphoma. 2001;40:295–303; 7Wrzesień-Kuśet A, et al. Eur J Haematol. 2003;71:155–162; 8Pastore D, et al. Ann Hematol. 2003;82:231–235; 9Hänel M, et al. Onkologie. 2001; 24:356–360; 10Huhmann IM, et al. Ann Hematol. 1996;73:265–271; 11Camera A, et al. Ann Hematol. 2009;88:151–158. Slide Courtesy of Stefan Faderl

  14. 米托蒽醌 + 依托胞苷失败后福达拉滨 +阿糖胞苷获效 • N = 18 Fav = 1, Int = 15 Unfav = 1 (Flt3 ?) • Prior CR with 3+7 alone (n=11) or with ME (n=7) • Standard HDAC consolidation (most 4 cycles) • Treated with • Mitoxantrone 10mg/m2 & • Etoposide 100mg/m2 x 5 days • CR in 7 (39%) • Median survival 4.5 mo, 2 still alive ~ 1 yr McLaughlin Int J Hema 2012:96;743-747

  15. 已批准的单药 • 氯法拉宾 • 去甲基化药物 • 免疫调节剂- 来那度胺 • 组蛋白去乙酰酶抑制剂 • Vorinostat • Gemtuzumab ozogamicin

  16. 去甲基化药物 令人失望 Decitabine ASH 2009 ASCO 2011 ASH 2010 Ganetsky The Ann of Pharmacotherapy 2012;46: page? Azacitidine ?

  17. HSCT 后去甲基化药物 • 10 of 37 Allo SCT relapses from 2007-2009 • BU-Cy/Flu Cy +TBI in 4 • 4 sib 2 haplo sib, 4 MUD • AML = 4 MDS = 6 Age 25-71 • Time from SCT to relapse: 0 0 5 6 14 18 18 36 36 132 months • Relapse = loss of donor chimerism + morphology/cytogenetics • Azacitidine 75mg/m2/d x 5 d (n=9) 40mg (n=1) • Best BM response = CR in 6, 3 progressed, 1 revert to MDS • 2 CR got DLI, 1 developed cGVHD • 4 CR lost all host chimerism 2 with MRD • 1 relapsed • Median survival = 422 Days Median FU of CR = 624 Days • 5 of 27 relapses not TX with aza from same period are alive. Bolanos-Meade Biol Blood Marrow Transplant 2011;17(5) 754-758

  18. 氯法拉宾 – 单药 & Combo • Purine analog • Inhibits DNA synthesis • Phase 1 40 mg/m2iv daily x 5 q4 wk. KantarjianBlood 2003 • Salvage N = 31 CR = 42% Table courtesy of Stefan Faderl

  19. 氯法拉宾 – 联合 Day Day Ara-C 1000 mg/m2 over 2hr 4 hrs after Clof Ara-C 2g/m2 4 hrs after Clof 1 1 1 1 1 2 2 2 2 2 3 3 3 3 3 4 4 4 4 4 5 5 5 5 5 1 2 3 4 5 Clofarabine 40 mg/m2 over 1 hr or Clof 15-25 mg/m2 Placebo over 1 hr GCSF 5μ /kg Faderl JCO 2012:28;2492-2499 Becker Br J Haem 2011:155;182-9

  20. 氯法拉宾用于老年和体弱者 • Newly DX AML • UWCM-001 >70, >60 & poor PS (WHO >2) or with cardiac comorbidity • BIOV-121 >64 & unsuitable for intensive • Dose: 30mg/m2/d over 1 hour days 1-5 • Conclusion: Its better than LDAC Burnett JCO 2010:282389-2395

  21. 目前常用的联合化疗:氯法拉宾 +阿糖胞苷 • N = 30, 18 Relapsed 13 with >1 prior salvage • CR1 duration? • Age <60 30% > 60 70% • Cytogenetics Fav:1 Int: 13 Unfav 14 ? = 2 • Many comorbidities • CV history 43% • Karnofsky PS 80 or less in 53% • Early death rate = 28% in relapsed/refractory • CR=47% Relapsed 5 (27%) 60% first 23% >1 • Fav & IntCyto 5/7 =70%, Unfav 2/9 = 22% Day Clofarabine 40 mg/m2 over 1 hr 1 2 4 3 5 Ara-C 1000 mg/m2 over 2hr 4 hrs after Clof 1 2 4 3 5 Agura The Oncologist 2011;16:197-206

  22. 来那度胺 • AML N= 31 ALL = 4 , Median age 63 (22-80) • Primary refractory 8 • Relapsed & Refractory to last therapy = 23 • Post SCT n= 8 7 Allo, 1 Auto • Unfavorable cytogenetics = 17 • Median # prior therapies = 2 (1-4) • First therapy for this relapse n=12 • Response • MTD = 50 mg per day • DLT: fatigue • AML • CR = 5 (16%) at 25 35 50 50 50 mg/d • Duration 5.6-14 mo • all with WBC <3500 • Cyto complex, -7, tri13 • Post Allo, 4 as initial tx, 2 got GVHD and achieved CR. • ALL CR = 0 Blum JCO 2010:28; 4919-4925

  23. 你能在老药方中加入新成分吗？

  24. MEC 中加入伊马替尼 Day Imatinib 200/300/400 1 2 4 3 5 6 7 8 9 10 Mitoxantrone 10 mg/m2 4 5 6 7 8 • MTD = 400 mg, N = 39, 21 @ MTD • Primary refractory 32, 14 @ MTD • CR1 duration • <12 mo = 10, 3 @ MTD • 12-24mo 12, 4 @ MTD • Cytogenetics Fav:1 Int: 27 UnFav;21 ? = 4 • Response at MTD : 1oRef 43% Relapse 100% • Fav & Int 8/9 Unfav 33% • Response correlated with inhibition of AKT but not ERK phosphorylation 1 2 4 3 5 6 7 8 9 10 Etoposide 100 mg/m2 4 5 6 7 8 Brandwein Leukemia 2011:25;945-952

  25. 普伐他汀+ IA Doses: 40 …1680 mg/day MTD =1280 DLT= too many pills! • AML Blast make or eat a lot of cholesterol resistance • Blocking this with a statin reverses chemoresistance in vitro • N=37 1oRef=7 Relapse #1=11, Rel #2=4 • Age Median 55 Cyto Fav = 3% Int = 27% Unfav =70% Day Pravastatin 1 2 3 4 5 6 7 8 Idarubicin 12 mg/m2/d 4 5 6 Ara-C 1.5g/m2/d CI 4 5 6 7 SWOG Phase III trial stopped early in Nov 2012 for POSITIVE result Kornblau JCO 2007:109;2999-3006

  26. DAC + Gemtuzumab + Ozogamicin • N = 12 A retrospective study? • Age 29-66 • All relapsed with a median 3 prior Tx (1-6) • Prior SCT Allo = 6, Auto = 1 • CR in 5 (42%) all SCT, 2 relapsed @ 2, 15 mo • Ages 41 44 44 48 66, • Cyto : Diploid, Diploid, Tri8, Diploid, T9:11 • # PriorSalvage 1 2 2 1 2 • CR1 duration? • Mild Grade 1 & 2 tansaminitis • Survival 4 still alive , median FU 1 yr. Day Decitabine20 mg/m2 1 2 3 4 5 12 6 9 GemtuzumabOzo 3 mg/m2 Chowdhur y Am J Hema 2009:84;599-600

  27. 化疗 + Gemtuzumab + Ozogamicin • N = 23 with CD33+ CR1 duration? • Drs choice of chemo, then if CD33+ Drs choice whether to give it a “GO”. • CR after chemo & before GO ? Middeldorf Am J Hema 2010:85;477-481

  28. Vorinostat + IA • Does adding Histone deacetylase inhibitor add? • Vorinostat 600 mg t.i.d. Days 1 2 3 • Ida 12mg/m2 /d x 3 Days 4 5 6 • ara-C 1.5 g/m2 /d x 3 or 4 Days 4 5 6 (7) • N= 75 newly diagnosed • median age 52 (19-65) • Cytogenetics • 29 diploid • FLT3-ITD =11 • Mortality 4% • CR = 76% (n=56) including 100% in FLT3 53% in -5 -7 • Relapse in 27 • OS median all patients =82 weeks FLT3-ITD 91 weeks • Toxicity “ no excess” w.r.t. standard IA, Skin 38% Garcia-Manero JCO 2012;30:2204-10

  29. 单药 – 试验 • Tosedostat • mTOR inhibitors • Vosaroxin • Hypoxia Specific • Aptamers • Sapacitabine • FLT3-inhibitors • Midostaurin • Lestaurtinib • Quizartinib (AC220) • Sorafenib

  30. Tosedostat • 氨肽酶抑制剂 • 与硼替佐米协调 • TD 120 mg 130 mg D x 28 D • DLT – 血小板减少& ALT 升高 • 51 AML, 41 at MTD, all >60yrs, 7 CR, 7 PR • CR 期短 28 36 62 85 175 176 449 days Amino Acid depravation Inc Small peptides UPR ? Apoptosis Proteosome NH3-AA1-AAn….AAy-AAz-COOH NH3-AA1-AAn….AAy-COOH + AAz Lowenberg JCO 2010;28:4333-38

  31. mTOR inhibition HGF, Cytokines PI3K/AKT/mTOR Pathway • Promotes growth and proliferation • Constitutively activated in the majority of AML but not in normal CD34+ cells • Important for the survival of AML cells, particularly after genotoxic stress • May be required by leukemic stem cells for survival • mTOR inhibition causes cell cycle arrest of AML cells and increases the pro-apoptotic effect of chemotherapy PI3K/AKT FLT3 mTOR RAPALOGS 4E-BP1 P70S6K Translation Cell cycle progression Proliferation & Survival Slide courtesy of Stefan Faderl

  32. AKT/mTOR 抑制剂的临床试验 * Evidence of synergy with MEC not observed Table courtesy of Stefan Faderl

  33. Vosaroxin neeVoreloxin neeSNS-595 • Quinolone derivative, intercalates DNA and poisons Topo II • Not a P-gp substrate, active in anthra-resistant settings • Non cardiotoxic • N=67; median age 65y (21-81) 84% AML (78% refract) • Weekly D 1 8 15. N=42 18-90 mg/m2/wk iv bolus (max 4 cycles) • Twice Weekly D 1, 4, 8, 11 N=31 9-50 mg/m2 iv bolus (max 4 cycles) • DLT: stomatitis (grade 3-4) • MTD: Weekly 72 mg/m2; Twice Weekly 40 mg/m2 • Complete remission CR or CRp • Weekly N=4 1) 1° Relapse, 3 refractory Duration 1.7 2.4 3.1 9.1 mo • Twice Weekly 1 CR refractory suartion 19.2 mo • Phase II trial «VALOR» of ara-C +/- V in untreated elderly AML Lancet Leukemia 2011:25;1808-14

  34. 靶向治疗缺氧: 低氧选择性细胞毒素 • Normal marrow is hypoxic 6%, Leukemic Marrow is 1% • Agents are converted to toxic moieties only under hypoxia • PR104 doses: 1100 (MTD in solid tumors), 1600, 2200, 3000 mg/m2 • Highly refractory population • BM Blasts cleared in many • CRp =4 CRi=2 • Relapse 2 • SCT 2, 2 pending Brown Nat Rev Ca 2004;4;437-447 Patterson., Clin Can Res 2007 Information Courtesy Marina Konopleva

  35. Sapacitabine (CS-682) • Orally bioavailable (fatty-acid modified) cyanocytosine analog with a unique mechanism of action • Converts in vivo to CNDAC, incorporates into DNA, causes SS-DNA breaks, G2 arrest and apoptosis PHASE 1 • N=47; median age 65y; 42 R/R AML • 75-375 mg BID x 7d q3-4 wks (N=35) 375-475 mg BID d1-3, d8-10 q3-4 wks (N=12) • DLT: GI • MTD 375 mg BID x 7 days; 425 mg BID d1-3, d8-10 • ORR: 13/47 (28%): 4 CRs, 2 CRp, 7 CRi • 30-d mortality (4%) PHASE 2 • N= 51 Untreated • Median age 77y, 35% ≥80y • Median 3 cycles • ORR: A 45% (CR 10%); B 25% (CR/CRp 10%); C 35% (CR/CRp 25%) • 30-d mortality 8/60 (13%) • 400 Mg BID D1-3 8-10 q 3-4 wk selected for further testing Kantarjian et al, ASH 2009 Kantarjian et al, JCO 2010

  36. FLT3-ITD Many available inhibitors Specificity of target varies greatly Quizartinib Lestaurtinib Midostaurin

  37. FLT3 抑制剂 • As single agents very few CRs • Better at reducing PB than BM blasts • Will addition to Chemotherapy improve results ? Midostaurin 50 or 100 mg twice daily CR1 <6mo MEC +Lestaurtinib 80mg CR1 >6 mo HiDAC +Lestaurtinib 80mg Response correlates with target level inhibition Only 58% got inhibited at D 15 Fischer JCO 2010:28;4239-45 Levis Blood 2011:117;3294-3301

  38. AC220 = Quizartinib:AML 补救治疗的I期临床 • N=76; median age 60y; 24% FLT3/ITD+ • Dosing (oral solution) • 12-450 mg once daily x 14d, q4wks (ID regimen) • 200 and 300 mg/d x 28d (CD regimen) • MTD 200 mg CD • DLT at 300 mg CD (QTc prolongation) • ORR 30%: CR+CRp+CRi 13%, PR 17% • Most responses @1 cycle; median DOR 14 wks • Higher ORR in FLT3/ITD+ (56% vs 20%) • Phase 2 study in FLT3/ITD+ AML (advanced) ongoing • Phase 1 combo trials planned Cortes et al, ASH 2009

  39. AC220-002 : AML 补救治疗的II期临床 Dose 200 mg If QTc 135 males 90 females Opened 11/09 100 Sites Planned Interim Analysis N=62 2/22/2011 QTc 34% Females > Males http://www.ambitbio.com/pdf/AC220-002_EHA%202011_06_08_11.pdf

  40. AC220-002 : AML 补救治疗的II期临床 Dose: Females 90 mg Males 135 mg continuously QTc 25 % Grade 3-4 13% 26% Gr 3-4 10% Levis ASH 2012 Abstract # 673 Cortes ASH 2012 Abstract # 48

  41. 核仁素靶向的核酸适体 AS1411 + HDAC • Aptamers are “chemical antibodies” bind with specificity. • AS1411 binds Nucleolin on cell surface apoptosis • Phase II trial N =71 Relapsed/refractory up to 3 prior TX • HDAC 1.5g/m2 q 12 hr x 8 doses Days 4-7 Alone N=23 • With AS1411 10mg CI Days 1-7 N= 22 • or with AS1411 40mg/kg.d CI Days 1-7 N=26 Why no update in 3 years? Stuart ASCO Proceedings 2009 #7019

  42. MDACC 应用Alphabet Soup 治疗复发 AML 的试验

  43. 总结 • 迄今尚无优于古老的联合化疗的方法 • 氯法拉宾单药有用 • 许多好的想法 : • 低氧, 阻断胆固醇, 伊马替尼 • 追踪期有限 • 许多新药 • FLT3 – 许多药物, 结果不好 • 天堂有很大的混乱 (复发 AML ) – 这样极好 (对新的想法和新药) - 毛泽东

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