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Is there anything new for relapsed AML?

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Presentation on theme: "Is there anything new for relapsed AML?"— Presentation transcript:

1 Is there anything new for relapsed AML?
Steven M. Kornblau, M.D. Department of Leukemia Department of Stem Cell Transplantation and Cellular Therapy

2 The Status Quo Most patients achieve remission Most relapse
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.

3 Allogeneic SCT Curative in When to perform ~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

4 Model for Predicting 2nd Remission Attainment
CR1 duration < 1 year or 1o ref 1-2 years >2 years # prior salvage attempts >1 N 58 160 30 15 CR Rate <1% 14% 47% 73% Estey & Kornblau Blood 1996;88 :756 CR1 duration < 1 year or 1o ref 1-2 years >2 years Prior Salvage Therapy? Yes No Prior Salvage Response No CR CR # of Prior Salvage > 1 1 Cytogenetics/AHD Fav Unfav CR/N 1/ 90 1/ 10 5/62 16/87 2/11 5/9 14/30 10/15 CR rate 1% 10% 20% 40% 66% Therapy choice Phase I Phase II Combination Chemo As an aside, perhaps Phase I and II studies should be sure to include patients form each category , or report what category they had Estey & Kornblau unpublished 1998

5 Models for Predicting Survival After Relapse
GOELAMS EPI CR1 Duration > 12 Mo CR1 Duration > 18 Mo < 12 Mo 1 7-18 Mo 3 < 6 Mo 5 Cytogenetics Not High Cytogenetics Inv16 High Risk 1 T(8;21) 3 Other 5 FLT3 ITD Neg Age <35 Positive 36-45 1 1 >45 2 Points 2 Yr OS 2 Yr EFS 58% 45% 1 37% 31% 2-3 12% 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% Chevallier Leukemia 2011;25(6);939-44 Breems JCO 2005;23(9):

6 FLT3-ITD: Poor prognosis at relapse too
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 Remission Duration Overall Survival After Relapse 1 Overall Survival After CR#2 Ravandi LeukRes 2010:34;

7 Combination Chemotherapy Using Approved Agents

8 Current Common Chemotherapy Combinations: MEC
Days 1-2-3: Mitoxantrone 12mg/m2/d & Ara-C 500 mg/m2 /d Days : Etoposide 200 mg/m2/d & Ara-C 500 mg/m2 N=133 Age (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

9 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, Months ED, % 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 + Eto 131 40 vs 45 12 vs 25 5 vs 5 Ohno R, et al.5 MAE vs MAE + G-CSF 58 42 vs 54 14 vs 12 8 vs 0 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

10 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

11 Combinations of Purine Nucleotide Analogs With ARA-C in Patients With Relapsed/Refractory AML
Study 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 53 40% at 1 yrs 9 Clavio M, et al.5 59 FLAG/FLANG NA 10 Carella A, et al.6 41 56 20% at 2 yrs 7 Wrzesień-Kuśet A et al.7 CLAG 50 42% at 1 yrs 17 Pastore D, et al.8 46 Hänel M, et al.9 29 Mit-FLAG 34% at 1 yrs Huhmann I, et al.10 22 58% at 1 yrs 5 Camera A, et al.11 61 FLAD 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

12 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;

13 Single Agents -Approved
Clofarabine Hypomethylating agents Immunomodulatory- Lenalidomide Histone deacetylase inhibitors Vorinostat Gemtuzumab ozogamicin

14 Hypomethylating agents
Disappointing Decitabine ASH ASCO 2011 ASH 2010 Ganetsky The Ann of Pharmacotherapy 2012;46: page? Azacitidine ?

15 Hypomethylating agents after HSCT
10 of 37 Allo SCT relapses from 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: 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)

16 Clofarabine – Single Agent & Combo
Purine analog Inhibits DNA synthesis Phase mg/m2 iv daily x 5 q4 wk Kantarjian Blood 2003 Salvage N = 31 CR = 42% Study N Regimen CR% ORR% Faderl ASH 2005 29 Phase 1/2 CLO 40 mg/m2/dx5 + IDAC 1 g/m²/dx5 24 41 Agura ASCO 2007 30 (10 untr) Phase 2 CLO 40 mg/m2/d x5 + IDAC 1 g/m²/dx5 56 68 Powell ASH 2008 39 CLO 40 mg/m2/dx5 + HDAC 2 g/m2/dx5 38 43 Becker ASH 2009 Phase 1 CLO mg/m2/dx5 + HDAC 2 g/m2/dx5 with G-CSF priming (GCLAC) 49 61 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 42 Table courtesy of Stefan Faderl

17 Clofarabine – Combinations
Day Ara-C mg/m2 over 2hr 4 hrs after Clof 1 5 4 3 2 Clofarabine 40 mg/m2 over 1 hr Placebo over 1 hr Day Ara-C 2g/m2 4 hrs after Clof 1 5 4 3 2 or Clof mg/m2 1 5 4 3 2 GCSF 5μ /kg 1 5 4 3 2 Ara-C Clof+ara-C P Ara-C + Clofarabine + G-CSF N 163 46 Age 67 (55-82) 67 (55-86) Cyto F/I/P % 6/53/39 4/40/49 6% 54% 40% 30 D Mortality 5% 16% <0.01 Disease Status 1oRef Rel % 44 56 54 N = 18 N =32 CR 18 33 38 0.04 66% >6 mo 60%, < 6 mo 26% ORR 23 46* 49* 61% Median Survival (Mo) 5.5 7.2 5.1 8.7 9 mo Faderl JCO 2012:28; Becker Br J Haem 2011:155;182-9

18 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 N Age median CR CRi UWCM-001 40 71 50% 5% BIOV-121 66 21% 24% Total 106 32% 16% Fate of CR/CRi Relapse =27 Toxicity =10 Unknown = 5 Median Survival CR= 47 wks CRi = 30 All =19 wks Burnett JCO 2010:

19 Lenalinomide AML N= 31 ALL = 4 , Median age 63 (22-80)
Primary refractory 8 Relapsed & Refractory to last therapy = 23 Post SCT n= 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 mg/d Duration 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;

20 Can you spice up an old recipe by adding a new ingredient?

21 Adding Imatinib to MEC MTD = 400 mg, N = 39, 21 @ MTD
8 7 6 5 4 3 2 10 Adding Imatinib to MEC Day Imatinib 200/300/400 Mitoxantrone 10 mg/m2 Etoposide 100 mg/m2 1 9 8 7 6 5 4 3 2 10 MTD = 400 mg, N = 39, MTD Primary refractory 32, MTD CR1 duration <12 mo = 10, MTD 12-24mo 12, 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;

22 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/d Pravastatin 6 5 4 3 2 1 7 8 Ara-C 1.5g/m2/d CI Doses: 40 …1680 mg/day MTD =1280 DLT= too many pills! New 11/15 73% Cytogenetics Exp Obs Ratio Intermediate 2.88 3 1.04 Unfavorable 4 8 2.0 Salvage 9/22 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 for POSITIVE result Kornblau JCO 2007:109;

23 DAC + Gemtuzumab + Ozogamicin
Day Gemtuzumab Ozo 3 mg/m2 Decitabine20 mg/m2 12 9 6 5 4 3 2 1 N = 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 2, 15 mo Ages , Cyto : Diploid, Diploid, Tri8, Diploid, T9:11 # PriorSalvage CR1 duration? Mild Grade 1 & 2 tansaminitis Survival 4 still alive , median FU 1 yr. Chowdhur y Am J Hema 2009:84;

24 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 81% Inc 8/9 1oRef Middeldorf Am J Hema 2010:85;

25 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 (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:

26 Single Agents - Experimental
Tosedostat FLT3-inhibitors mTOR inhibitors Midostaurin Lestaurtinib Vosaroxin Quizartinib (AC220) Hypoxia Specific Sorafenib Aptamers Sapacitabine

27 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 days Amino Acid depravation Inc Small peptides UPR ? Apoptosis NH3-AA1-AAn….AAy-AAz-COOH NH3-AA1-AAn….AAy-COOH + AAz Proteosome Lowenberg JCO 2010;28:

28 mTOR inhibition PI3K/AKT/mTOR Pathway PI3K/AKT
HGF, Cytokines PI3K/AKT 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 FLT3 mTOR RAPALOGS 4E-BP1 P70S6K Translation Cell cycle progression Proliferation & Survival Slide courtesy of Stefan Faderl

29 Trials with AKT/mTOR inhibitors
Study N Regimen Response Recher Blood 2005 9 (AML) Phase 1 (Sirolimus) S: 6 mg/d1, 2 mg/d2-28 PR 4/9 Perl Clin Cancer Res 2009 27 Phase 1 (MEC+Sirolimus) * S: MTD 12 mg/d1, 4 mg/d2-7 CR (n=4) =15% +PR (N=2) ORR= 22% Yee ASH 2004 7 (AML/ALL) Phase 2 (Temsirolimus) T: 25 mg weekly Modest activity (PB) Clin Cancer Res 2006 various Phase 1/2 (Everolimus) E: 5-10 mg daily Ravandi ASH 2008 39 (AML/MDS) Phase 1 (Triciribine) T: MTD 55 mg/m2 d 1,8,15 * Evidence of synergy with MEC not observed Table courtesy of Stefan Faderl

30 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 N= mg/m2/wk iv bolus (max 4 cycles) Twice Weekly D 1, 4, 8, 11 N= 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 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;

31 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; Patterson., Clin Can Res 2007 Information Courtesy Marina Konopleva

32 Sapacitabine (CS-682) PHASE 2 PHASE 1 N=47; median age 65y; 42 R/R AML
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 D q 3-4 wk selected for further testing PHASE 1 N=47; median age 65y; 42 R/R AML mg BID x 7d q3-4 wks (N=35) 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 Kantarjian et al, ASH 2009

33 FLT3-ITD Many available inhibitors
Specificity of target varies greatly Quizartinib Lestaurtinib Midostaurin

34 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 Dose 50 100 N 18 17 31 29 Age>64 39% 53% 77% 72% CR PR 1 Heme improvement 50% 41% 43% 26% ALL FLT3 mut Chemo Chemo + L N 112 Age 54 (21-79) 59 (20-81) CR 12% 17% CRp 9% CR1 <6 11% 19% CR1 >6 29% 32% Survival 160D Response correlates with target level inhibition Only 58% got inhibited at D 15 Fischer JCO 2010:28; Levis Blood 2011:117;

35 AC220-002 : Phase II in AML salvage
Dose: Females 90 mg Males 135 mg continuously Cohort >60, CR1 < 1 yr or 1oRef >18 Rel/Ref to 2nd line or HSCT Mutation Status ITD+ FLT3-WT N 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 QTc 25 % Grade % % Gr % Cortes ASH 2012 Abstract # 48 Levis ASH 2012 Abstract # 673

36 Alphabet Soup Trials for Relapsed AML at MDACC
Agent MOA Phase Combo? Group Lintuzumab AntiCD33 Ab 1 + LD araC > 60yrs Omacetaxine Protein Syn, histoneDAC Pf Hedgehog 1B + LD araC or DAC SGI-110 Super DAC 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 BP L-GRB2 AS I Salvage ABT348 Aurora Kinase + ara-C AMG 900 KB004 Anti EphrinA3 BKM120 PI3K inhibitor Lurbinectedin Ds-DNA breaks CWP232291 WNT inhibitor PRI-724 B-Catenin inhibitor AZD1208 PIM Kinase inhibitor 1A/!B DFP-10917 Purine analog-Sapacitabine MK-8242 HDM2 inhibitor + Chemo

37 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

38

39 Overall Survival Using European Prognostic Index & GOELAMS
Breems JCO 2005;23(9): Giles Br J Haem 2006 ;134(1):58-61 GOELAMS They are superimposable

40 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 List A, et al.4 MEC vs MEC + PSC-833 226 33 vs 39 15 vs 18 Greenberg P, et al.5 MAE vs MAE + G-CSF 129 25 vs 17 5 vs 4 Feldmen E, et al.6 MEC + lintuzumab 191 23 vs 29 Giles FJ, et al.7 HDAraC + laromustine 178 19 vs 35 332 vs 275 2 vs 11 177 vs 128 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

41 Current Common Chemotherapy Combinations: Clofarabine +AraC
Day Clofarabine 40 mg/m2 over 1 hr Ara-C mg/m2 over 2hr 4 hrs after Clof 1 5 4 3 2 N = 30, 18 Relapsed with >1 prior salvage CR1 duration? Age < % > % 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 % >1 Fav & Int Cyto 5/7 =70%, Unfav 2/9 = 22% Agura The Oncologist 2011;16:

42 AC220-002 : Phase II in AML salvage
Cohort 1 2 3 Features >60 ITD+ R1 >18 ITD+ R2 or Post SCT >18 ITD- R1 R2 Planned N 120 60 Analyzed 25 37 CR CRp or CRi 9 (41%) 15 (48%) PR 7 (32%) 6 (19% ) Median Survival Not Reached 24 wks Dose 200 mg If QTc males 90 females Opened 11/09 100 Sites Planned Interim Analysis N=62 2/22/2011 QTc 34% Females > Males

43 AC220 = Quizartinib: Phase 1 in AML salvage
N=76; median age 60y; 24% FLT3/ITD+ Dosing (oral solution) 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 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

44 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 AS mg CI Days N= 22 or with AS mg/kg.d CI Days N=26 HDAC HDAC +10 HDAC+40 Evaluable 14 21 9 Early Death 2 1 “Response” 0/13 3/19 4/7 Why no update in 3 years? Stuart ASCO Proceedings 2009 #7019


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