is there anything new for relapsed aml?
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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
CR1 duration < 1 year or 1o ref < 1 year or 1o ref 1-2 years >2 years
# prior salvage attempts >1 0 0 0N 58 160 30 15
CR Rate <1% 14% 47% 73%
Model for Predicting 2nd Remission Attainment
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 1Cytogenetics/AHD Fav Unfav FavCR/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Estey & Kornblau unpublished 1998As an aside, perhaps Phase I and II studies should be sure to include patients form each category , or report what category they had
Models for Predicting Survival After RelapseGOELAMS
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
FLT3-ITD: Poor prognosis at relapse too
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
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 moArchimbaud JCO 1995:13;11-18
Results of Randomized Trials In Patients With Relapsed or Refractory AML: Nothing Stands Out as Better
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
9
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
Current Common Chemotherapy Combinations: 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
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
Combinations of Purine Nucleotide Analogs With ARA-C in Patients With Relapsed/Refractory AML
Study N Salvage Regimen
OverallCR Rate, % OS and Time ED, %
Wierzbowska A, et al.1 118 CLAG-M 58 14% at 4 yrs 8Steinmetz HT, et al.2 36 FLAG-IDA 52 15% at 1 yrs 14Jackson G, et al.3 83 FLAG 81 50% at 2 yrs 18de la Rubia J, et al.4 32 FLAG-IDA 53 40% at 1 yrs 9Clavio M, et al.5 59 FLAG/FLANG 59 NA 10Carella A, et al.6 41 FLAG 56 20% at 2 yrs 7Wrzesień-Kuśet A et al.7 58 CLAG 50 42% at 1 yrs 17Pastore D, et al.8 46 FLAG-IDA 52 NA 7Hänel M, et al.9 29 Mit-FLAG 59 34% at 1 yrs 14Huhmann I, et al.10 22 FLAG 50 58% at 1 yrs 5Camera A, et al.11 61 FLAD 52 5.8 months 12
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
Decitabine
ASH 2009 ASCO 2011 ASH 2010 Ganetsky The Ann of Pharmacotherapy 2012;46: page?
Azacitidine ?
Disappointing
• 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.
Hypomethylating agents after HSCT
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 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
PowellASH 2008
39 Phase 2CLO 40 mg/m2/dx5 + HDAC 2 g/m2/dx5
38 43
BeckerASH 2009
41 Phase 1CLO 15-25 mg/m2/dx5 + HDAC 2 g/m2/dx5 with G-CSF priming (GCLAC)
49 61
FaderlEHA 2009 33
1631
Phase 2 (R)CLO 22.5 mg/m2/dx5 + IDA 10 mg/m2/dx3CLO 40 mg/m2/dx5 + IDAC 1 g/m2/dx5CLO 22.5 mg/m2/dx5 + IDA 6x3 + AC 0.75x5
272529
393142
Table courtesy of Stefan Faderl
Clofarabine – CombinationsDay
Ara-C 1000 mg/m2 over 2hr4 hrs after Clof 1 5432
Clofarabine 40 mg/m2 over 1 hrPlacebo over 1 hr
1 54321 5432
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
1 5432
1 5432
Becker Br J Haem 2011:155;182-9
or
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
• 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/CRi
Relapse =27
Toxicity =10
Unknown = 5
Median Survival
CR= 47 wks
CRi = 30
All =19 wks
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
• 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
Day Imatinib 200/300/400
Mitoxantrone 10 mg/m2Etoposide 100 mg/m2
1 98765432 108765487654
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
• 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 11/15 73%
Cytogenetics Exp Obs Ratio
Intermediate 2.88 3 1.04
Unfavorable 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.
Chemo + 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 GON 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
Single Agents - Experimental• Tosedostat• mTOR inhibitors• Vosaroxin• Hypoxia Specific• Aptamers• Sapacitabine
• FLT3-inhibitors– Midostaurin– Lestaurtinib– Quizartinib (AC220)– Sorafenib
Tosedostat• Aminopeptidase inhibitor
• 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
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
Trials with AKT/mTOR inhibitorsStudy 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)
YeeClin Cancer Res 2006
27various
Phase 1/2 (Everolimus)E: 5-10 mg daily
Modest activity (PB)
RavandiASH 2008
39(AML/MDS)
Phase 1 (Triciribine)T: MTD 55 mg/m2 d 1,8,15
Modest activity (PB)
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
Targeting Tumor Hypoxia: Hypoxia-Selective Cytotoxins • 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 inhibitors• 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
AC220-002 : Phase II in AML salvage
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 38Age 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
Alphabet Soup Trials for Relapsed AML at MDACCAgent MOA Phase Combo? Group
Lintuzumab AntiCD33 Ab 1 + LD araC > 60yrsOmacetaxine Protein Syn, histoneDAC 1 + LD araC > 60yrs
Pf-04449913 Hedgehog 1B + LD araC or DAC > 60yrs
SGI-110 Super DAC 1 > 60yrsTosedostat Aminopeptidase inhibitor I/II araC or Aza Post hypomethylatingVosaroxin Anthracycline III Ara-C +/- V Relapse1Plerixifor +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
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
They are superimposable
GOELAMS
Results of Randomized Trials In Patients With Relapsed or Refractory AML
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
40
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
Current Common Chemotherapy Combinations: Clofarabine +AraC
• 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
AC220-002 : Phase II in AML salvageCohort 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 = 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
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?