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 2/3rd

• 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 .

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

预测复发后生存模型GOELAMS

CR1 Duration

EPI

> 12 Mo< 12 Mo

01

> 18 Mo7-18 Mo< 6 Mo

035

Cytogenetics Not HighHigh Risk

01

Inv16T(8;21)Other

FLT3 ITDNeg

Positive0

1

<3536-45>45

Age

035012

Prior SCT? 2

Points % CR2 1 Yr OS 5 Yr OS

0-6 85% 70% 46%

7-9 60% 49% 18%

10-14 34% 16% 4%

Points 2 Yr OS

2 YrEFS

0 58% 45%

1 37% 31%

2-3 12% 12%

Breems JCO 2005;23(9):1669-78

CR1 Duration

Cytogenetics

Chevallier Leukemia 2011;25(6);939-44

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

They are superimposable

GOELAMS

FLT3-ITD: 复发时也是预后差的指标Overall Survival After Relapse 1

Overall Survival After CR#2

Ravandi LeukRes 2010:34;752-756

FLT3 -WT FLT3-ITD

N 69 34

CR (p= 0.09) 41% 24%

Med Surv (p= 0.001) 37 weeks 13 weeks

Diploid Cytogenteics

Not Tx with anti FLT3 agent

CR#2 RemissionDuration

CR1 duration < 1 year or 1o ref < 1 year or 1o ref 1-2 years >2 years

# prior salvage attempts >1 0 0 0

N 58 160 30 15

CR Rate <1% 14% 47% 73%

预测 2nd 获得缓解的模型

CR1 duration < 1 year or 1o ref 1-2 years >2 years

Prior Salvage Therapy? Yes No Yes No No

Prior Salvage Response No CR CR No CR CR

# of Prior Salvage > 1 1 1 1

Cytogenetics/AHD Fav Unfav Fav

CR/N 1/ 90 1/ 10 5/62 16/87 2/11 5/9 14/30 10/15

CR rate 1% 10% 10% 20% 20% 40% 40% 66%

Therapy choice Phase I Phase II Combination Chemo

Estey & Kornblau Blood 1996;88 :756

Estey & Kornblau unpublished 1998As an aside, perhaps Phase I and II studies should be sure to include patients form each category , or report what category they had

化疗与获批的药物联合

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

难治复发 AML 的随机临床结果 : 没有什么是更好的Study Treatment N 2nd CR

Rate, %

Median 2nd CR Duration,

MonthsED, %

Median OS,

Months

Kern W, et al.1 HDAraC + Mit vs IDAC + Mit 186 52 vs 45 5.3 vs 3.3 32 vs 17 5 vs NA

Martiat P, et al.2 HDAraC + Amsa vs HDAraC + Mit 52 53 vs 60 11 vs 12 15 vs 8 8 vs 11

Larson R, et al.3 HDAraC vs HDAraC + Amsa 36 14 vs 53 NA 25 vs 25 2 vs 6

Vogler W, et al.4 HDAraC vs HDAraC + 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

10

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

难治复发 AML 的随机临床结果Study Treatment N 2nd CR

Rate, %Median 2nd

CR Duration, Mo ED, % Median OS, Mo

Karanes C, et al.1 HDAraC vs HDAraC + 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

Giles FJ, et al.7 HDAraC vs HDAraC + laromustine 178 19 vs 35 332 vs 275 2 vs 11 177 vs

128

11

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.


目前常用的化疗联合 : FLAGFludarabine 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

Group1 N=21 Group 2 N=44

Since stopping TX >6 Mo < 6 mo or 1oRef

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

嘌呤核苷类药物与阿糖胞苷联合治疗难治 / 复发 AMLStudy N Salvage

RegimenOverall

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 121Wierzbowska 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.


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

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

去甲基化药物Decitabine

ASH 2009 ASCO 2011 ASH 2010 Ganetsky The Ann of Pharmacotherapy 2012;46: page?

Azacitidine ?

令人失望

• 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.

HSCT 后去甲基化药物

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/m2 iv daily x 5 q4 wk. Kantarjian Blood 2003

– Salvage N = 31 CR = 42%

Study N Regimen CR% ORR%FaderlASH 2005

29 Phase 1/2 CLO 40 mg/m2/dx5 + IDAC 1 g/m²/dx5

24 41

AguraASCO 2007

30 (10 untr)

Phase 2CLO 40 mg/m2/d x5 + IDAC 1 g/m²/dx5

56 68

Powell

ASH 2008

39 Phase 2

CLO 40 mg/m2/dx5 + HDAC 2 g/m2/dx538 43

Becker

ASH 2009

41 Phase 1

CLO 15-25 mg/m2/dx5 + HDAC 2 g/m2/dx5 with G-CSF priming (GCLAC)

49 61

Faderl

EHA 2009 33

16

31

Phase 2 (R)

CLO 22.5 mg/m2/dx5 + IDA 10 mg/m2/dx3

CLO 40 mg/m2/dx5 + IDAC 1 g/m2/dx5

CLO 22.5 mg/m2/dx5 + IDA 6x3 + AC 0.75x5

27

25

29

39

31

42Table courtesy of Stefan Faderl

氯法拉宾 – 联合Day

Ara-C 1000 mg/m2 over 2hr4 hrs after Clof 1 5432

Clofarabine 40 mg/m2 over 1 hrPlacebo over 1 hr

Ara-C Clof+ara-C P Ara-C + Clofarabine + G-CSF

N 163 163 46

Age 67 (55-82) 67 (55-86) 53 19-69

Cyto F/I/P % 6/53/39 4/40/49 6% 54% 40%

30 D Mortality 5% 16% <0.01

Disease Status 1oRef Rel 1oRef Rel 1oRef 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 61%

Median Survival (Mo)

5.5 7.2 5.1 8.7 9 mo

Faderl JCO 2012:28;2492-2499

Day Ara-C 2g/m2 4 hrs after Clof

1 5432

Clof 15-25 mg/m2 GCSF 5μ /kg

Becker Br J Haem 2011:155;182-9

or

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

N Age median

CR CRi

UWCM-001 40 71 50% 5%

BIOV-121 66 71 21% 24%

Total 106 71 32% 16%

Fate of CR/CRiRelapse =27

Toxicity =10

Unknown = 5

Median SurvivalCR= 47 wks

CRi = 30

All =19 wks

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 & Int Cyto 5/7 =70%, Unfav 2/9 = 22%•

Agura The Oncologist 2011;16:197-206

Day Clofarabine 40 mg/m2 over 1 hr

Ara-C 1000 mg/m2 over 2hr4 hrs after Clof

1 5432

1 5432

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

你能在老药方中加入新成分吗？

MEC 中加入伊马替尼• 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

Day Imatinib 200/300/400

Mitoxantrone 10 mg/m2Etoposide 100 mg/m2

8765487654

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

• N=37 1oRef=7 Relapse #1=11, Rel #2=4• Age Median 55 Cyto Fav = 3% Int = 27% Unfav =70%

Day

Idarubicin 12 mg/m2/dPravastatin 654321 7 8

654Ara-C 1.5g/m2/d CI 654 7

Doses: 40 …1680 mg/day

MTD =1280DLT= too many pills!

New New 11/15 73%11/15 73%

CytogeneticsCytogenetics Exp Obs Ratio

IntermediateIntermediate 2.88 3 1.04

UnfavorableUnfavorable 4 8 2.0

Salvage9/22 41%

Status Exp Obs Ratio

R1 3.96 7 1.77

R2 .4 1 2.5

All relapsed/Prim ref 4.96 9 1.81

SWOG Phase III trial stopped early in Nov 2012 for POSITIVE resultKornblau JCO 2007:109;2999-3006

DAC + Gemtuzumab + Ozogamicin

Chowdhur y Am J Hema 2009:84;599-600

Day

Gemtuzumab Ozo 3 mg/m2Decitabine20 mg/m2 129654321

• 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.

化疗 + Gemtuzumab + Ozogamicin

Middeldorf Am J Hema 2010:85;477-481

• 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 ?

GO single GO Chemo Chemo GO

N 3 5 16

Age 76 (70-82) 62 (43-74) 65 (43-76)

1oRef /R1 /R>1 2/1/0 1 /2 / 2 9 /5 /2

GO 9 mg/m2 D 1, 20 9 mg/m2 D 1 9 mg/m2 x1 D5-17

CR 0 0 13 81%Inc 8/9 1oRef

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

单药 – 试验

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

NH3-AA1-AAn….AAy-AAz-COOH

NH3-AA1-AAn….AAy-COOH + AAz

Proteosome Amino Acid depravationInc Small peptidesUPR ?Apoptosis

Lowenberg JCO 2010;28:4333-38

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

HGF, Cytokines

PI3K/AKT

mTOR

4E-BP1 P70S6K

TranslationCell cycle progressionProliferation & Survival

RAPALOGS

FLT3

mTOR inhibition

Slide courtesy of Stefan Faderl

AKT/mTOR 抑制剂的临床试验Study N Regimen Response

RecherBlood 2005

9(AML)

Phase 1 (Sirolimus) S: 6 mg/d1, 2 mg/d2-28

PR 4/9

PerlClin Cancer Res 2009

27(AML)

Phase 1 (MEC+Sirolimus) *S: MTD 12 mg/d1, 4 mg/d2-7

CR (n=4) =15%+PR (N=2) ORR= 22%

YeeASH 2004

7(AML/ALL)

Phase 2 (Temsirolimus)T: 25 mg weekly

Modest activity (PB)

Yee

Clin Cancer Res 2006

27various

Phase 1/2 (Everolimus)E: 5-10 mg daily


RavandiASH 2008

39(AML/MDS)

Phase 1 (Triciribine)T: MTD 55 mg/m2 d 1,8,15


Table courtesy of Stefan Faderl* Evidence of synergy with MEC not observed

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 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

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

01020304050

60708090

100

0 20 40 60 80 100

Study Day

Bla

sts

(%)

183-1009183-1010183-1011182-1014182-1020182-1023

Information Courtesy Marina Konopleva

Patterson., Clin Can Res 2007

Sapacitabine (CS-682)

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%)

Kantarjian et al, JCO 2010

• 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 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

FLT3-ITDMany available inhibitors

Specificity of target varies greatly

Lestaurtinib Midostaurin

Quizartinib

FLT3 抑制剂• As single agents very few CRs

– Better at reducing PB than BM blasts• Will addition to Chemotherapy improve results ?

ALL FLT3 mut Chemo Chemo + L

N 112 112

Age 54 (21-79) 59 (20-81)

CR 12% 17%

CRp 9% 9%

CR1 <6 11% 19%

CR1 >6 29% 32%

Survival 160D 160D

CR1 <6mo MEC + Lestaurtinib 80mgCR1 >6 mo HiDAC + Lestaurtinib 80mg

Response correlates with target level inhibitionOnly 58% got inhibited at D 15

Levis Blood 2011:117;3294-3301

FLT3 Mut FLT3 WT

Dose 50 100 50 100

N 18 17 31 29

Age>64 39% 53% 77% 72%

CR 0 0 0 0

PR 0 1 0 0

Heme improvement

50% 41% 43% 26%

Midostaurin 50 or 100 mg twice daily

Fischer JCO 2010:28;4239-45

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

AC220-002 : AML 补救治疗的 II 期临床Cohort 1 2 3

Features >60 ITD+ R1

>18 ITD+ R2 or Post SCT

>18 ITD- R1 R2

Planned N 120 120 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 mgIf QTc 135 males

90 femalesOpened 11/09100 Sites

Planned Interim AnalysisN=62 2/22/2011

QTc 34%Females > Males

http://www.ambitbio.com/pdf/AC220-002_EHA%202011_06_08_11.pdf

AC220-002 : AML 补救治疗的 II 期临床Cohort >60, CR1 < 1 yr or 1oRef >18 Rel/Ref to 2nd line or HSCT

Mutation Status ITD+ FLT3-WT ITD+ FLT3-WTN 92 41 99 38

Age 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%

Median CRc duration

12.7 wks 22.1 wks 11.3 5

Median Survival 25 19 23.1 25.6

Cortes ASH 2012 Abstract # 48

Dose: Females 90 mg Males 135 mg continuously

QTc 25 % Grade 3-4 13% 26% Gr 3-4 10%

Levis ASH 2012 Abstract # 673

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

Stuart ASCO Proceedings 2009 #7019

HDAC HDAC +10 HDAC+40Evaluable 14 21 9Early Death 2 1 1“Response” 0/13 3/19 4/7

Why no update in 3 years?

MDACC 应用 Alphabet Soup 治疗复发 AML 的试验 Agent MOA Phase Combo? Group

Lintuzumab AntiCD33 Ab 1 + LD araC > 60yrs

Omacetaxine Protein Syn, histoneDAC 1 + LD araC > 60yrs

Pf-04449913 Hedgehog 1B + LD araC or DAC > 60yrs

SGI-110 Super DAC 1 > 60yrs

Tosedostat Aminopeptidase inhibitor I/II araC or Aza Post hypomethylating

Vosaroxin Anthracycline III Ara-C +/- V Relapse1

Plerixifor +G-CSF CXCR4 inhibitor I /II +MEC Relapse1

BP-100-1.01 L-GRB2 AS I Salvage

ABT348 Aurora Kinase I + ara-C Salvage

AMG 900 Aurora Kinase I Salvage

KB004 Anti EphrinA3 I Salvage

BKM120 PI3K inhibitor I Salvage

Lurbinectedin Ds-DNA breaks I Salvage

CWP232291 WNT inhibitor I Salvage

PRI-724 B-Catenin inhibitor I /II Salvage

AZD1208 PIM Kinase inhibitor 1A/!B Salvage

DFP-10917 Purine analog-Sapacitabine I /II

MK-8242 HDM2 inhibitor I + Chemo Salvage

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

对复发的 aml 有新方法吗 ?

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