Transcript Is there anything new for relapsed AML?

Is there anything new
for relapsed AML?
Steven M. Kornblau, M.D.
Department of Leukemia
Department of Stem Cell Transplantation and
Cellular Therapy
The Status Quo
• Most patients achieve remission
– 80% < age 60, no AHD
– 50% >60 or prior AHD
• Most relapse
– Cure rate 20-25% overall therefore 2/3rd relapse
• Cure after relapse without SCT very unlikely
– Exceptions: APL & those inadequately treated
• Conventional chemotherapy hasn’t advanced in a
long, long time.
• Strategy
– Get to SCT, Directly, or chemo to temporize
– No donor. Palliate, chemo or symptomatic care.
Allogeneic SCT
• Curative in
– ~35% subsequent CR
– 25% refractory relapse (IBMTR data)
• When to perform
– ASAP- but most can’t wait & will need something
– In CR2
• But most won’t achieve a second CR
• Toxicity and infections can close window of opportunity
Model for Predicting 2nd Remission Attainment
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Estey & Kornblau unpublished 1998
Models for Predicting Survival After Relapse
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
FLT3-ITD: Poor prognosis at relapse too
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
Combination
Chemotherapy Using
Approved Agents
Current Common Chemotherapy
Combinations: 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
Results of Randomized Trials In Patients With
Relapsed or Refractory AML:
Nothing Stands Out as Better
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.
9
Slide Courtesy of Stefan Faderl
Current Common Chemotherapy
Combinations: 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
Combinations of Purine Nucleotide Analogs With ARA-C
in Patients With Relapsed/Refractory 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
Fludarabine + Ara-C Effective After
Mitoxantrone + Etoposide Failure
•
•
•
•
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
Single Agents -Approved
•
•
•
•
Clofarabine
Hypomethylating agents
Immunomodulatory- Lenalidomide
Histone deacetylase inhibitors
– Vorinostat
• Gemtuzumab ozogamicin
Hypomethylating agents
Disappointing
Decitabine
ASH 2009 ASCO 2011 ASH 2010
Azacitidine ?
Ganetsky The Ann of Pharmacotherapy 2012;46: page?
Hypomethylating agents after HSCT
• 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
Clofarabine – Single Agent & 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
Clofarabine – Combinations
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
Clofarabine in the Elderly & Infirm
• 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
Lenalinomide
• 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
Can you spice up an old
recipe by adding a new
ingredient?
Adding Imatinib to MEC
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 7/7
– Fav & Int 8/9 Unfav 33%
• Response correlated with inhibition of AKT but not ERK
phosphorylation
Brandwein Leukemia 2011:25;945-952
Pravastatin + 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
Chemo + 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
Single Agents - Experimental
•
•
•
•
•
•
Tosedostat
mTOR inhibitors
Vosaroxin
Hypoxia Specific
Aptamers
Sapacitabine
• FLT3-inhibitors
–
–
–
–
Midostaurin
Lestaurtinib
Quizartinib (AC220)
Sorafenib
Tosedostat
• Aminopeptidase inhibitor
Proteosome
NH3-AA1-AAn….AAy-AAz-COOH
NH3-AA1-AAn….AAy-COOH + AAz
•
•
•
•
•
Amino Acid depravation
Inc Small peptides
UPR ?
Apoptosis
Synergizes with Bortezomib
MTD 120 mg 130 mg D x 28 D
DLT – Thrombocytopenia & ALT elevation
51 AML, 41 at MTD, all >60yrs, 7 CR, 7 PR
CR duration short 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
Trials with AKT/mTOR inhibitors
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
Targeting Tumor Hypoxia: Hypoxia-Selective Cytotoxins
•
•
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 inhibitors
• 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
AC220-002 : Phase II in AML salvage
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
Alphabet Soup Trials for Relapsed AML at MDACC
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
Conclusions
• Thus far nothing is better than old fashioned combo
chemo
– Clofarabine single agent has utility
• Many fascinating ideas :
– Hypoxia, cholesterol blockade, Imatinib
– Results of follow up studies required
• Lots of new agents
• FLT3 – Many drugs, unimpressive results
•
There is great chaos under (the relapsed AML ) heaven
– the situation is excellent (for new ideas and new
agents) - Mao Zedong
Overall Survival Using European Prognostic
Index & GOELAMS
Breems JCO 2005;23(9):1669-78
Giles Br J Haem 2006 ;134(1):58-61
GOELAMS
They are superimposable
Results of Randomized Trials In Patients With
Relapsed or Refractory AML
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
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
HDAraC vs
HDAraC + laromustine
178
19 vs 35
332 vs 275
2 vs 11
177 vs
128
Study
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
40
Current Common Chemotherapy
Combinations: Clofarabine +AraC
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
AC220-002 : Phase II in AML salvage
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 = Quizartinib: Phase 1 in AML salvage
• 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
Nucleolin targeting Aptamer 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
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