Transcript Is there anything new for relapsed AML?

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
• 多数患者获得缓解
现状
– 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
EPI
CR1 Duration
> 12 Mo
< 12 Mo
0
1
CR1 Duration
Cytogenetics
Not High
High Risk
0
1
Cytogenetics
FLT3 ITD
Neg
Positive
0
1
Age
> 18 Mo
7-18 Mo
< 6 Mo
0
3
5
Inv16
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
% CR2
1 Yr OS 5 Yr OS
1
37%
31%
0-6
85%
70%
46%
2-3
12%
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
FLT3-ITD: 复发时也是预后差的指标
N
CR (p= 0.09)
Med Surv (p= 0.001)
FLT3 -WT
FLT3-ITD
69
34
41%
24%
37 weeks
13 weeks
Overall Survival After Relapse 1
Diploid Cytogenteics
Not Tx with anti FLT3
agent
CR#2
Remission
Duration
Overall
Survival
After CR#2
Ravandi LeukRes 2010:34;752-756
预测2nd 获得缓解的模型
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%
Estey & Kornblau Blood 1996;88 :756
< 1 year or 1o ref
CR1 duration
Prior Salvage Therapy?
Prior Salvage Response
# of Prior Salvage
Yes
CR rate
Therapy choice
No
Yes
No CR
CR
No CR
CR
>1
1
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%
10%
20%
20%
40%
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Estey & Kornblau unpublished 1998
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
2nd
Median 2nd
CR Duration,
Months
ED, %
Median
OS,
Months
Treatment
N
CR
Rate, %
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
Study
Kern W, et al.1
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.
10
Slide Courtesy of Stefan Faderl
难治复发AML的随机临床结果
Treatment
N
2nd CR
Rate, %
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
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
HDAraC vs
HDAraC + laromustine
178
19 vs 35
332 vs 275
2 vs 11
177 vs
128
Study
List A, et al.4
Giles FJ, et al.7
1Karanes
Median 2nd
CR Duration, Mo
ED, %
Median
OS, Mo
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;
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.
5Greenberg
Slide Courtesy of Stefan Faderl
11
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
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
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
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
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
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 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
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
Faderl
ASH 2005
29
30
(10 untr)
Agura
ASCO 2007
Powell
39
CR%
ORR%
Phase 1/2
CLO 40 mg/m2/dx5 + IDAC 1 g/m²/dx5
24
41
Phase 2
CLO 40 mg/m2/d x5 + IDAC 1 g/m²/dx5
56
68
Phase 2
38
43
49
61
27
39
25
31
29
42
CLO 40 mg/m2/dx5 + HDAC 2 g/m2/dx5
ASH 2008
Becker
Regimen
41
Phase 1
ASH 2009
CLO 15-25 mg/m2/dx5 + HDAC 2 g/m2/dx5 with
G-CSF priming (GCLAC)
Faderl
Phase 2 (R)
EHA 2009
33
CLO 22.5 mg/m2/dx5 + IDA 10 mg/m2/dx3
mg/m2/dx5
16
CLO 40
31
CLO 22.5 mg/m2/dx5 + IDA 6x3 + AC 0.75x5
Table courtesy of Stefan Faderl
+ IDAC 1
g/m2/dx5
氯法拉宾 – 联合
Day
1 2 3 4 5
or
Ara-C 1000 mg/m2 over 2hr
4 hrs after Clof
Clofarabine 40 mg/m2 over 1 hr 1 2 3 4 5
1 2 3 4 5
Placebo over 1 hr
P
Ara-C 2g/m2
4 hrs after Clof
Clof 15-25 mg/m2
GCSF 5μ /kg
Day
1 2 3 4 5
1 2 3 4 5
1 2 3 4 5
Ara-C
Clof+ara-C
Ara-C + Clofarabine + G-CSF
N
163
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
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
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: 30mg/m2/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/m2 over 1 hr
Ara-C 1000 mg/m2 over 2hr
4 hrs after Clof
•
•
•
•
•
1
2
Day
3
1
2
3
4
5
4
5
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
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
Day
Imatinib 200/300/400
Mitoxantrone 10 mg/m2
Etoposide 100 mg/m2
1
2
3
4
4
4
5
5
5
6
6
6
7
7
7
8
8
8
9
10
• 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
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
Day
Pravastatin
Idarubicin 12 mg/m2/d
Ara-C 1.5g/m2/d CI
1
2
3
4
4
5
5
4
6
7
8
6
5
6
Doses:
40 …1680 mg/day
MTD =1280
DLT= too many
pills!
7
• N=37 1oRef=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
R1
3.96
7
1.77
R2
.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
Day
Decitabine20 mg/m2
•
•
•
•
•
1
2
3
4
5
6
12
9
Gemtuzumab Ozo 3 mg/m2
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.
Chowdhur y Am J Hema 2009:84;599-600
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 ?
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
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 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
mTOR inhibitors
Vosaroxin
Hypoxia Specific
Aptamers
Sapacitabine
• FLT3-inhibitors
–
–
–
–
Midostaurin
Lestaurtinib
Quizartinib (AC220)
Sorafenib
Tosedostat
• 氨肽酶抑制剂
Proteosome
NH3-AA1-AAn….AAy-AAz-COOH
NH3-AA1-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 >60yrs, 7 CR, 7 PR
CR 期短 28 36 62 85 175 176 449 days
Lowenberg JCO 2010;28:4333-38
mTOR inhibition
HGF, Cytokines
FLT3
PI3K/AKT/mTOR Pathway
PI3K/AKT
• Promotes growth and proliferation
• Constitutively activated in the majority
RAPALOGS
of
AML but not in normal CD34+ cells
mTOR
• Important
for the survival of AML cells,
particularly after genotoxic stress
• May
4E-BP1
P70S6K
be required by leukemic stem cells
for survival
• mTOR
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/mTOR 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/d1, 2 mg/d2-28
27
(AML)
Phase 1 (MEC+Sirolimus)
7
(AML/ALL)
27
various
39
(AML/MDS)
Response
PR 4/9
*
S: MTD 12 mg/d1, 4 mg/d2-7
Phase 2 (Temsirolimus)
T: 25 mg weekly
Phase 1/2 (Everolimus)
E: 5-10 mg daily
Phase 1 (Triciribine)
T: MTD 55 mg/m2 d 1,8,15
CR (n=4) =15%
+PR (N=2) ORR= 22%
Modest activity (PB)
Modest activity (PB)
Modest activity (PB)
* Evidence of synergy with MEC not observed
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 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
Brown Nat Rev
Ca
2004;4;437-447
Patterson., Clin Can Res 2007
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
100
90
80
183-1009
183-1010
70
Blasts (%)
•
•
•
•
•
•
60
50
183-1011
182-1014
40
182-1020
30
182-1023
20
10
0
0
20
40
60
Study Day
Information Courtesy Marina Konopleva
80
100
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, 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%)
Kantarjian et al, JCO 2010
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-ITD
Many
available
inhibitors
Quizartinib
Lestaurtinib
Midostaurin
Specificity
of target
varies
greatly
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
FLT3 Mut
FLT3 WT
ALL FLT3 mut
Chemo
Chemo + L
Dose
50
100
50
100
N
112
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
0
0
CRp
9%
9%
PR
0
1
0
0
CR1 <6
11%
19%
Heme
improvement
50%
41%
43%
26%
CR1 >6
29%
32%
Survival
160D
160D
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
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 ITDR1 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 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
AC220-002 : AML 补救治疗的II期临床
Dose: Females 90 mg Males 135 mg continuously
>60, CR1 < 1 yr or 1oRef
Cohort
Mutation Status
>18 Rel/Ref to 2nd line or HSCT
ITD+
FLT3-WT
ITD+
FLT3-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 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
Evaluable
HDAC
14
Early Death 2
“Response” 0/13
Why no update in 3 years?
HDAC +10
21
HDAC+40
9
1
3/19
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
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
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
ABT348
Aurora Kinase
I
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
> 60yrs
Salvage
+ ara-C
+ Chemo
Salvage
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