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
预测复发后生存模型 GOELAMS EPI CR 1 Duration > 12 Mo < 12 Mo 0 1 CR 1 Duration Cytogenetics Not High Risk 0 1 Cytogenetics FLT 3 ITD Neg Positive 0 1 Age > 18 Mo 7 -18 Mo < 6 Mo 0 3 5 Inv 16 T(8; 21) Other 0 3 5 0 1 2 <35 36 -45 >45 Points 2 Yr OS 2 Yr EFS 0 58% 45% Points % CR 2 1 Yr OS 5 Yr OS 1 37% 31% 0 -6 85% 70% 46% 2 -3 12% 7 -9 60% 49% 18% 10 -14 34% 16% 4% Chevallier Leukemia 2011; 25(6); 939 -44 Prior SCT? 2 Breems JCO 2005; 23(9): 1669 -78
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
FLT 3 -ITD: 复发时也是预后差的指标 N CR (p= 0. 09) Med Surv (p= 0. 001) FLT 3 -WT FLT 3 -ITD 69 34 41% 24% 37 weeks 13 weeks Overall Survival After Relapse 1 Diploid Cytogenteics Not Tx with anti FLT 3 agent CR#2 Remission Duration Overall Survival After CR#2 Ravandi Leuk. Res 2010: 34; 752 -756
预测2 nd 获得缓解的模型 CR 1 duration < 1 year or 1 o ref 1 -2 years >2 years # prior salvage attempts >1 0 0 0 N 58 160 30 15 CR Rate <1% 14% 47% 73% Estey & Kornblau Blood 1996; 88 : 756 CR 1 duration < 1 year or 1 o ref Prior Salvage Therapy? Prior Salvage Response # of Prior Salvage Yes CR rate Therapy choice No Yes No CR CR >1 1 Cytogenetics/AHD CR/N 1 -2 years >2 years No No Fav Unfav Fav 1/ 90 1/ 10 5/62 16/87 2/11 5/9 14/30 10/15 1% 10% 20% 40% 66% Phase I As an aside, perhaps Phase I and II studies should be sure to include patients form each category , or report what category they had Phase II Combination Chemo Estey & Kornblau unpublished 1998
目前常用的化疗联合: MEC Days 1 -2 -3: Mitoxantrone 12 mg/m 2/d & Ara-C 500 mg/m 2 /d Days 8 -9 -10: Etoposide 200 mg/m 2/d & Ara-C 500 mg/m 2 N=133 Age 15 -70 (22 >60) Cytogenetics ? but 7 M 4 Eos and 13 APL Median 1 st CR 11 mo CR Overall 60% – 1 st salvage for CR 1>6 mo =76% for CR 1 <6 mo =46% – >1 st CR 45% – Primary refractory 41% • Overall survival, not receiving SCT = 7 mo • • Archimbaud JCO 1995: 13; 11 -18
难治复发AML的随机临床结果: 没有什么是更好的 Median 2 nd CR Duration, Months ED, % Median OS, Months Treatment N CR Rate, % HDAra. C + Mit vs IDAC + Mit 186 52 vs 45 5. 3 vs 3. 3 32 vs 17 5 vs NA Martiat P, et al. 2 HDAra. C + Amsa vs HDAra. C + Mit 52 53 vs 60 11 vs 12 15 vs 8 8 vs 11 Larson R, et al. 3 HDAra. C vs HDAra. C + Amsa 36 14 vs 53 NA 25 vs 25 2 vs 6 Vogler W, et al. 4 HDAra. C vs HDAra. C + Eto 131 40 vs 45 12 vs 25 NA 5 vs 5 Ohno R, et al. 5 MAE vs MAE + G-CSF 58 42 vs 54 14 vs 12 8 vs 0 NA Study Kern W, et al. 1 2 nd Abbreviations: CR = complete remission; OS = overall survival; HDAra. C = high-dose cytarabine; Mit = mitoxantrone; IDAC = intermediate-dose Ara. C; NA = not available; Amsa = amsacrine; Eto = etoposide; MAE = Mit + Ara. C + Eto; G-CSF = granulocyte-colony stimulating factor; EMA = Eto + Mito + Ara. C; GM-CSF = granulocyte, macrophage–colony stimulating factor; ADE = Ara. C + daunorubicin + Eto; CSA = cyclosporine; seq ADE = sequential ADE; MEC = Mit + Eto + Ara. C. 1 Kern W, et al. Leukemia. 2000; 14: 226– 231; 2 Martiat P, et al. Eur J Haematol. 1990; 45: 164– 167; 3 Larson RA, et al. Br J Haematol. 1992; 82: 337– 346; 4 Vogler WR, Leukemia. 1994; 8: 1847– 1853; 5 Ohno R, et al. Blood. 1994; 83: 2086– 2092. 10 Slide Courtesy of Stefan Faderl
难治复发AML的随机临床结果 Treatment N 2 nd CR Rate, % Karanes C, et al. 1 HDAra. C vs HDAra. C + Mit 162 32 vs 44 9 vs 5 10 vs 16 8 vs 6 Thomas X, et al. 2 EMA vs EMA + GM-CSF 72 81 vs 89 4 vs 5 8 vs 5 9 vs 10 Liu Yin J, et al. 3 ADE +/-CSA vs Seq ADE +/- CSA 235 57 vs 38 NA 16 vs 24 NA List A, et al. 4 MEC vs MEC + PSC-833 226 33 vs 39 NA 15 vs 18 NA Greenberg P, et al. 5 MAE vs MAE + G-CSF 129 25 vs 17 9 vs 10 10 vs 16 5 vs 4 Feldmen E, et al. 6 MEC vs MEC + lintuzumab 191 23 vs 29 NA NA 8 vs 6 HDAra. C vs HDAra. C + laromustine 178 19 vs 35 332 vs 275 2 vs 11 177 vs 128 Study Giles FJ, et al. 7 1 Karanes Median 2 nd CR Duration, Mo ED, % Median OS, Mo C, et al. Leuk Res. 1999; 23: 787– 794; 2 Thomas X, , et al. Leukemia. 1999; 13: 1214– 1220; 3 Liu Yin JA, , et al. Br J Haematol. 2001; 113: 713– 726; 4 List AF, et al. Blood. 2001; 98: 3212– 3220; PL, et al. J Clin Oncol. 2004; 22: 1078– 1086; 6 Feldman EJ, et al. J Clin Oncol. 2005; 23: 4110– 4116; 7 Giles FJ, et al. Blood (ASH Annual Meeting Abstracts). 2006; 108: Abstract 1970. 5 Greenberg Slide Courtesy of Stefan Faderl 11
目前常用的化疗联合: FLAG Fludarabine 30 m g/m 2/d , Ara-C 2 g/m 2 /d 1 -5, G-CSF 300 day 1 -6 Group 1 N=21 Group 2 N=44 Since stopping TX >6 Mo < 6 mo or 1 o. Ref Age median 48 (18 -69) 47 (21 -74) Cytogenetics F/I/U % 19 /24 /10 48%? 2 / 61 / 18 19%? CR 81% 30% Median Survival 16 mo 3 ml Jackson Br J Haem 2001: 112; 127
嘌呤核苷类药物与阿糖胞苷联合 治疗难治/复发AML N Salvage Regimen Overall CR Rate, % OS and Time ED, % Wierzbowska A, et al. 1 118 CLAG-M 58 14% at 4 yrs 8 Steinmetz HT, et al. 2 36 FLAG-IDA 52 15% at 1 yrs 14 Jackson G, et al. 3 83 FLAG 81 50% at 2 yrs 18 de la Rubia J, et al. 4 32 FLAG-IDA 53 40% at 1 yrs 9 Clavio M, et al. 5 59 FLAG/FLANG 59 NA 10 Carella A, et al. 6 41 FLAG 56 20% at 2 yrs 7 Wrzesień-Kuśet A et al. 7 58 CLAG 50 42% at 1 yrs 17 Pastore D, et al. 8 46 FLAG-IDA 52 NA 7 Hänel M, et al. 9 29 Mit-FLAG 59 34% at 1 yrs 14 Huhmann I, et al. 10 22 FLAG 50 58% at 1 yrs 5 Camera A, et al. 11 61 FLAD 52 5. 8 months 12 Study 1 Wierzbowska A, et al. Eur J Haematol. 2008; 80: 115– 126; 2 Steinmetz HT, et al. Ann Hematol. 1999; 78: 418– 425; 3 Jackson G, et al. Br J Haematol. 2001; 112: 127– 137; 4 de la Rubia J, et al. Leuk Res. 2002; 26: 725– 730; 5 Clavio M, et al. Haematologica. 1996; 81: 513– 520; 6 Carella AM, et al. Leuk Lymphoma. 2001; 40: 295– 303; 7 Wrzesień-Kuśet A, et al. Eur J Haematol. 2003; 71: 155– 162; 8 Pastore D, et al. Ann Hematol. 2003; 82: 231– 235; 9 Hänel M, et al. Onkologie. 2001; 24: 356– 360; 10 Huhmann IM, et al. Ann Hematol. 1996; 73: 265– 271; 11 Camera A, et al. Ann Hematol. 2009; 88: 151– 158. Slide Courtesy of Stefan Faderl
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 (Flt 3 ? ) Prior CR with 3+7 alone (n=11) or with ME (n=7) Standard HDAC consolidation (most 4 cycles) Treated with – Mitoxantrone 10 mg/m 2 & – Etoposide 100 mg/m 2 x 5 days • CR in 7 (39%) • Median survival 4. 5 mo, 2 still alive ~ 1 yr • Mc. Laughlin Int J Hema 2012: 96; 743 -747
去甲基化药物 令人失望 Decitabine ASH 2009 ASCO 2011 ASH 2010 Azacitidine ? Ganetsky The Ann of Pharmacotherapy 2012; 46: page?
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 75 mg/m 2/d x 5 d (n=9) 40 mg (n=1) • Best BM response = CR in 6, 3 progressed, 1 revert to MDS – 2 CR got DLI, 1 developed c. GVHD – 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
氯法拉宾 – 单药 & Combo • Purine analog • Inhibits DNA synthesis • Phase 1 40 mg/m 2 iv daily x 5 q 4 wk. Kantarjian Blood 2003 – Salvage N = 31 CR = 42% Study N Faderl ASH 2005 29 30 (10 untr) Agura ASCO 2007 Powell 39 ASH 2008 Becker Regimen CR% ORR% Phase 1/2 CLO 40 mg/m 2/dx 5 + IDAC 1 g/m²/dx 5 24 41 Phase 2 CLO 40 mg/m 2/d x 5 + IDAC 1 g/m²/dx 5 56 68 Phase 2 38 43 49 61 27 39 25 31 29 42 CLO 40 mg/m 2/dx 5 + HDAC 2 g/m 2/dx 5 41 Phase 1 ASH 2009 CLO 15 -25 mg/m 2/dx 5 + HDAC 2 g/m 2/dx 5 with G -CSF priming (GCLAC) Faderl Phase 2 (R) EHA 2009 33 CLO 22. 5 mg/m 2/dx 5 + IDA 10 mg/m 2/dx 3 mg/m 2/dx 5 16 CLO 40 31 CLO 22. 5 mg/m 2/dx 5 + IDA 6 x 3 + AC 0. 75 x 5 Table courtesy of Stefan Faderl + IDAC 1 g/m 2/dx 5
氯法拉宾 – 联合 or Ara-C 1000 mg/m 2 over 2 hr 4 hrs after Clofarabine 40 mg/m 2 over 1 hr Placebo over 1 hr Day 1 2 3 4 5 P Ara-C 2 g/m 2 4 hrs after Clof 15 -25 mg/m 2 GCSF 5μ /kg Day 1 2 3 4 5 Ara-C Clof+ara-C Ara-C + Clofarabine + G-CSF N 163 Age 67 (55 -82) 67 (55 -86) Cyto F/I/P % 6/53/39 4/40/49 30 D Mortality 5% 16% Disease Status 1 o. Ref Rel % 44 56 46 54 N = 18 N =32 CR 18 18 33 38 0. 04 66% >6 mo 60%, < 6 mo 26% ORR 23 23 46* 49* <0. 01 Median Survival 5. 5 7. 2 5. 1 (Mo) Faderl JCO 2012: 28; 2492 -2499 8. 7 46 53 19 -69 6% 54% 40% <0. 01 61% 9 mo Becker Br J Haem 2011: 155; 182 -9
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: 30 mg/m 2/d over 1 hour days 1 -5 N Age CR median UWCM-001 40 71 BIOV-121 66 Total 106 CRi Fate of CR/CRi Median Survival 50% 5% Relapse =27 CR= 47 wks 71 21% 24% Toxicity =10 CRi = 30 71 32% 16% Unknown = 5 All =19 wks • Conclusion: Its better than LDAC Burnett JCO 2010: 282389 -2395
目前常用的联合化疗: 氯法拉宾 +阿糖胞苷 Clofarabine 40 mg/m 2 over 1 hr Ara-C 1000 mg/m 2 over 2 hr 4 hrs after Clof • • • 1 2 Day 3 1 2 3 4 5 N = 30, 18 Relapsed 13 with >1 prior salvage CR 1 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 & Int Cyto 5/7 =70%, Unfav 2/9 = 22% • Agura The Oncologist 2011; 16: 197 -206
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, tri 13 Post Allo, 4 as initial tx, 2 got GVHD and achieved CR. – ALL CR = 0 Blum JCO 2010: 28; 4919 -4925
MEC 中加入伊马替尼 Day Imatinib 200/300/400 Mitoxantrone 10 mg/m 2 Etoposide 100 mg/m 2 4 4 5 5 6 6 7 7 8 8 • MTD = 400 mg, N = 39, 21 @ MTD • Primary refractory 32, 14 @ MTD • CR 1 duration – <12 mo = 10, 3 @ MTD – 12 -24 mo 12, 4 @ MTD • Cytogenetics Fav: 1 Int: 27 Un. Fav; 21 ? = 4 • Response at MTD : 1 o. Ref 43% Relapse 100% – Fav & Int 8/9 Unfav 33% • Response correlated with inhibition of AKT but not ERK phosphorylation Brandwein Leukemia 2011: 25; 945 -952
普伐他汀+ IA • AML Blast make or eat a lot of cholesterol resistance • Blocking this with a statin reverses chemoresistance in vitro Pravastatin Idarubicin 12 mg/m 2/d Ara-C 1. 5 g/m 2/d CI 1 2 3 4 Day 4 5 5 4 6 7 8 6 5 6 Doses: 40 … 1680 mg/day MTD =1280 DLT= too many pills! 7 • N=37 1 o. Ref=7 Relapse #1=11, Rel #2=4 • Age Median 55 Cyto Fav = 3% Int = 27% Unfav =70% Salvage 9/22 41% New 11/15 73% Cytogenetics Exp Obs Ratio Intermediate 2. 88 3 1. 04 Unfavorable 4 8 2. 0 Status Exp Obs Ratio R 1 3. 96 7 1. 77 R 2 . 4 1 2. 5 4. 96 9 1. 81 All relapsed/Prim ref SWOG Phase III trial stopped early in Nov 2012 for POSITIVE result Kornblau JCO 2007: 109; 2999 -3006
DAC + Gemtuzumab + Ozogamicin Decitabine 20 mg/m 2 • • • Day 1 2 3 4 5 6 12 9 Gemtuzumab Ozo 3 mg/m 2 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, Tri 8, Diploid, T 9: 11 # Prior. Salvage 1 2 2 1 2 CR 1 duration? • Mild Grade 1 & 2 tansaminitis • Survival 4 still alive , median FU 1 yr. Chowdhur y Am J Hema 2009: 84; 599 -600
化疗 + Gemtuzumab + Ozogamicin • N = 23 with CD 33+ CR 1 duration? • Drs choice of chemo, then if CD 33+ Drs choice whether to give it a “GO”. • CR after chemo & before GO ? GO single GO Chemo GO N 3 5 16 Age 76 (70 -82) 62 (43 -74) 65 (43 -76) 1 o. Ref /R 1 /R>1 2/1/0 1 /2 / 2 9 /5 /2 GO 9 mg/m 2 D 1, 20 9 mg/m 2 D 1 9 mg/m 2 x 1 D 5 -17 CR 0 0 13 81% Inc 8/9 1 o. Ref Middeldorf Am J Hema 2010: 85; 477 -481
Vorinostat + IA • Does adding Histone deacetylase inhibitor add? – Vorinostat 600 mg t. i. d. Days 1 2 3 – Ida 12 mg/m 2 /d x 3 Days 4 5 6 – ara-C 1. 5 g/m 2 /d x 3 or 4 Days 4 5 6 (7) • N= 75 newly diagnosed • median age 52 (19 -65) • Cytogenetics – 29 diploid – FLT 3 -ITD =11 • Mortality 4% • CR = 76% (n=56) including 100% in FLT 3 53% in -5 -7 • Relapse in 27 • OS median all patients =82 weeks FLT 3 -ITD 91 weeks • Toxicity “ no excess” w. r. t. standard IA, Skin 38% Garcia-Manero JCO 2012; 30: 2204 -10
单药 – 试验 • • • Tosedostat m. TOR inhibitors Vosaroxin Hypoxia Specific Aptamers Sapacitabine • FLT 3 -inhibitors – – Midostaurin Lestaurtinib Quizartinib (AC 220) Sorafenib
Tosedostat • 氨肽酶抑制剂 Proteosome NH 3 -AA 1 -AAn…. AAy-AAz-COOH NH 3 -AA 1 -AAn…. AAy-COOH + AAz • • • Amino Acid depravation Inc Small peptides UPR ? Apoptosis 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 >60 yrs, 7 CR, 7 PR CR 期短 28 36 62 85 176 449 days Lowenberg JCO 2010; 28: 4333 -38
m. TOR inhibition HGF, Cytokines FLT 3 PI 3 K/AKT/m. TOR Pathway PI 3 K/AKT • Promotes growth and proliferation • Constitutively activated in the majority of RAPALOGS AML but not in normal CD 34+ cells m. TOR • Important for the survival of AML cells, particularly after genotoxic stress • May 4 E-BP 1 P 70 S 6 K be required by leukemic stem cells for survival • m. TOR inhibition causes cell cycle arrest of AML cells and increases the proapoptotic effect of chemotherapy Translation Cell cycle progression Proliferation & Survival Slide courtesy of Stefan Faderl
AKT/m. TOR 抑制剂的临床试验 Study Recher Blood 2005 Perl Clin Cancer Res 2009 Yee ASH 2004 Yee Clin Cancer Res 2006 Ravandi ASH 2008 N Regimen 9 (AML) Phase 1 (Sirolimus) S: 6 mg/d 1, 2 mg/d 2 -28 27 (AML) Phase 1 (MEC+Sirolimus) * 7 (AML/ALL) 27 various 39 (AML/MDS) S: MTD 12 mg/d 1, 4 mg/d 2 -7 Phase 2 (Temsirolimus) T: 25 mg weekly Phase 1/2 (Everolimus) E: 5 -10 mg daily Phase 1 (Triciribine) T: MTD 55 mg/m 2 d 1, 8, 15 * Evidence of synergy with MEC not observed Response PR 4/9 CR (n=4) =15% +PR (N=2) ORR= 22% Modest activity (PB) Table courtesy of Stefan Faderl
Vosaroxin nee Voreloxin nee SNS-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 65 y (21 -81) 84% AML (78% refract) – Weekly D 1 8 15. N=42 18 -90 mg/m 2/wk iv bolus (max 4 cycles) – Twice Weekly D 1, 4, 8, 11 N=31 9 -50 mg/m 2 iv bolus (max 4 cycles) • DLT: stomatitis (grade 3 -4) • MTD: Weekly 72 mg/m 2; Twice Weekly 40 mg/m 2 • 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
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 Brown Nat Rev Ca 2004; 4; 437 -447 Patterson. , Clin Can Res 2007 • • • PR 104 doses: 1100 (MTD in solid tumors), 1600, 2200, 3000 mg/m 2 Highly refractory population BM Blasts cleared in many CRp =4 CRi=2 Relapse 2 SCT 2, 2 pending Information Courtesy Marina Konopleva
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 SSDNA breaks, G 2 arrest and apoptosis PHASE 1 • N=47; median age 65 y; 42 R/R AML • 75 -375 mg BID x 7 d q 3 -4 wks (N=35) 375 -475 mg BID d 1 -3, d 8 -10 q 3 -4 wks (N=12) • DLT: GI • MTD 375 mg BID x 7 days; 425 mg BID d 1 -3, d 8 -10 • ORR: 13/47 (28%): 4 CRs, 2 CRp, 7 CRi – 30 -d mortality (4%) Kantarjian et al, JCO 2010 PHASE 2 • N= 51 Untreated • Median age 77 y, 35% ≥ 80 y • 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 D 1 -3 8 -10 q 3 -4 wk selected for further testing Kantarjian et al, ASH 2009
FLT 3 -ITD Quizartinib Lestaurtinib Midostaurin Many available inhibitors Specificity of target varies greatly
FLT 3 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 CR 1 <6 mo MEC + Lestaurtinib 80 mg CR 1 >6 mo Hi. DAC + Lestaurtinib 80 mg FLT 3 Mut FLT 3 WT ALL FLT 3 mut Chemo + L Dose 50 100 N 112 N 18 17 31 29 Age 54 (21 -79) 59 (20 -81) Age>64 39% 53% 77% 72% CR 12% 17% CR 0 0 CRp 9% 9% PR 0 1 0 0 CR 1 <6 11% 19% Heme improvement 50% 41% 43% 26% CR 1 >6 29% 32% Survival 160 D 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
AC 220 = Quizartinib: AML 补救治疗的I期临床 • N=76; median age 60 y; 24% FLT 3/ITD+ • Dosing (oral solution) – 12 -450 mg once daily x 14 d, q 4 wks (ID regimen) – 200 and 300 mg/d x 28 d (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 FLT 3/ITD+ (56% vs 20%) • Phase 2 study in FLT 3/ITD+ AML (advanced) ongoing • Phase 1 combo trials planned Cortes et al, ASH 2009
AC 220 -002 : AML 补救治疗的II期临床 Cohort 1 2 3 Features >60 ITD+ R 1 >18 ITD+ R 2 or Post SCT >18 ITDR 1 R 2 Planned N 120 60 Analyzed 25 37 CR 0 0 CRp or CRi 9 (41%) 15 (48%) PR 7 (32%) 6 (19% ) Median Survival Not Reached 24 wks 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/AC 220 -002_EHA%202011_06_08_11. pdf
AC 220 -002 : AML 补救治疗的II期临床 Dose: Females 90 mg Males 135 mg continuously Cohort >60, CR 1 < 1 yr or 1 o. Ref Mutation Status >18 Rel/Ref to 2 nd line or HSCT ITD+ FLT 3 -WT 92 41 99 38 70 (54 -85) 69 (60 -78) 50 (19 -77) 55 (30 -73) CR composite 54% 32% 44% (4% CR) 34% (3% CR) PR 18% 9% 24% 13% 12. 7 wks 22. 1 wks 11. 3 5 25 19 23. 1 25. 6 N Age Median CRc duration Median Survival QTc 25 % Grade 3 -4 13% Cortes ASH 2012 Abstract # 48 26% Gr 3 -4 10% Levis ASH 2012 Abstract # 673
核仁素靶向的核酸适体 AS 1411 + HDAC • Aptamers are “chemical antibodies” bind with specificity. • AS 1411 binds Nucleolin on cell surface apoptosis • Phase II trial N =71 Relapsed/refractory up to 3 prior TX – HDAC 1. 5 g/m 2 q 12 hr x 8 doses Days 4 -7 Alone N=23 – With AS 1411 10 mg CI Days 1 -7 N= 22 – or with AS 1411 40 mg/kg. d CI Days 1 -7 N=26 HDAC Evaluable 14 Early Death 2 “Response” 0/13 Why no update in 3 years? HDAC +10 21 1 3/19 HDAC+40 9 1 4/7 Stuart ASCO Proceedings 2009 #7019
MDACC 应用Alphabet Soup 治疗复发 AML 的试验 Agent MOA Phase Combo? Group Lintuzumab Anti. CD 33 Ab 1 + LD ara. C > 60 yrs Omacetaxine Protein Syn, histone. DAC 1 + LD ara. C > 60 yrs Pf-04449913 Hedgehog 1 B + LD ara. C or DAC > 60 yrs SGI-110 Super DAC 1 Tosedostat Aminopeptidase inhibitor I/II ara. C or Aza Post hypomethylating Vosaroxin Anthracycline III Ara-C +/- V Relapse 1 Plerixifor +G-CSF CXCR 4 inhibitor I /II +MEC Relapse 1 BP-100 -1. 01 L-GRB 2 AS I ABT 348 Aurora Kinase I AMG 900 Aurora Kinase I Salvage KB 004 Anti Ephrin. A 3 I Salvage BKM 120 PI 3 K inhibitor I Salvage Lurbinectedin Ds-DNA breaks I Salvage CWP 232291 WNT inhibitor I Salvage PRI-724 B-Catenin inhibitor I /II Salvage AZD 1208 PIM Kinase inhibitor 1 A/!B Salvage DFP-10917 Purine analog-Sapacitabine I /II MK-8242 HDM 2 inhibitor I > 60 yrs Salvage + ara-C + Chemo Salvage
