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Relapsed AML: Steve Kornblau

1) Current chemotherapy combinations for relapsed AML such as MEC (mitoxantrone, etoposide, cytarabine) and FLAG (fludarabine, cytarabine, G-CSF) produce overall response rates of 40-60% but have not been shown to be clearly superior to one another. 2) Single agent therapies approved for relapsed AML include hypomethylating agents, immunomodulatory drugs, and targeted therapies but have shown limited and disappointing efficacy as single agents. 3) Clofarabine has shown efficacy in combinations with cytarabine for relapsed AML, with complete response rates as high as 50% in some studies

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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 0 N 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 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20% 40% 40% 66% Therapy choice Phase I Phase II Combination Chemo Estey & Kornblau Blood 1996;88 :756 Estey & Kornblau unpublished 1998As an aside, perhaps Phase I and II studies should be sure to include patients form each category , or report what category they had
Models for Predicting Survival After Relapse GOELAMS CR1 Duration EPI > 12 Mo < 12 Mo 0 1 > 18 Mo 7-18 Mo < 6 Mo 0 3 5 Cytogenetics Not High High Risk 0 1 Inv16 T(8;21) Other FLT3 ITD Neg Positive 0 1 <35 36-45 >45 Age 0 3 5 0 1 2 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 Yr EFS 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 Remission Duration
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 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 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 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 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; 7Wrzesieo-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% 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 Phase 2 CLO 40 mg/m2/dx5 + HDAC 2 g/m2/dx5 38 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 42 Table courtesy of Stefan Faderl
Clofarabine – Combinations Day Ara-C 1000 mg/m2 over 2hr 4 hrs after Clof 1 5432 Clofarabine 40 mg/m2 over 1 hr Placebo over 1 hr 1 5432 1 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/m2 Etoposide 100 mg/m2 1 98765432 10 87654 87654 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/d Pravastatin 654321 7 8 654 Ara-C 1.5g/m2/d CI 654 7 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 2012 for POSITIVE result Kornblau JCO 2007:109;2999-3006
DAC + Gemtuzumab + Ozogamicin Chowdhur y Am J Hema 2009:84;599-600 Day Gemtuzumab Ozo 3 mg/m2 Decitabine20 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 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
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 depravation Inc Small peptides UPR ? 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 Translation Cell cycle progression Proliferation & Survival RAPALOGS FLT3 mTOR inhibition Slide courtesy of Stefan Faderl
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 (AML) 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) Yee Clin Cancer Res 2006 27 various Phase 1/2 (Everolimus) E: 5-10 mg daily Modest activity (PB) Ravandi ASH 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 0 10 20 30 40 50 60 70 80 90 100 0 20 40 60 80 100 Study Day Blasts(%) 183-1009 183-1010 183-1011 182-1014 182-1020 182-1023 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-ITD Many 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 80mg CR1 >6 mo HiDAC + Lestaurtinib 80mg Response correlates with target level inhibition Only 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-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 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 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 > 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
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 2hr 4 hrs after Clof 1 5432 1 5432
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 120 120 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 Stuart ASCO Proceedings 2009 #7019 HDAC HDAC +10 HDAC+40 Evaluable 14 21 9 Early Death 2 1 1 “Response” 0/13 3/19 4/7 Why no update in 3 years?

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Relapsed AML: Steve Kornblau

  • 1.
    Is there anythingnew 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 – 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 • Curativein – ~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.
    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% 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 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
  • 5.
    Models for PredictingSurvival After Relapse GOELAMS CR1 Duration EPI > 12 Mo < 12 Mo 0 1 > 18 Mo 7-18 Mo < 6 Mo 0 3 5 Cytogenetics Not High High Risk 0 1 Inv16 T(8;21) Other FLT3 ITD Neg Positive 0 1 <35 36-45 >45 Age 0 3 5 0 1 2 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 Yr EFS 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
  • 6.
    FLT3-ITD: Poor prognosisat 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 Remission Duration
  • 7.
  • 8.
    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
  • 9.
    Results of RandomizedTrials 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 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
  • 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 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
  • 11.
    Combinations of PurineNucleotide 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 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 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; 7Wrzesieo-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-CEffective 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
  • 13.
    Single Agents -Approved •Clofarabine • Hypomethylating agents • Immunomodulatory- Lenalidomide • Histone deacetylase inhibitors – Vorinostat • Gemtuzumab ozogamicin
  • 14.
    Hypomethylating agents Decitabine ASH 2009ASCO 2011 ASH 2010 Ganetsky The Ann of Pharmacotherapy 2012;46: page? Azacitidine ? Disappointing
  • 15.
    • 10 of37 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
  • 16.
    Clofarabine – SingleAgent & 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% 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 Phase 2 CLO 40 mg/m2/dx5 + HDAC 2 g/m2/dx5 38 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 42 Table courtesy of Stefan Faderl
  • 17.
    Clofarabine – Combinations Day Ara-C1000 mg/m2 over 2hr 4 hrs after Clof 1 5432 Clofarabine 40 mg/m2 over 1 hr Placebo over 1 hr 1 5432 1 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
  • 18.
    Clofarabine in theElderly & 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
  • 19.
    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
  • 20.
    Can you spiceup an old recipe by adding a new ingredient?
  • 21.
    Adding Imatinib toMEC • 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/m2 Etoposide 100 mg/m2 1 98765432 10 87654 87654 Brandwein Leukemia 2011:25;945-952
  • 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 654321 7 8 654 Ara-C 1.5g/m2/d CI 654 7 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 2012 for POSITIVE result Kornblau JCO 2007:109;2999-3006
  • 23.
    DAC + Gemtuzumab+ Ozogamicin Chowdhur y Am J Hema 2009:84;599-600 Day Gemtuzumab Ozo 3 mg/m2 Decitabine20 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.
  • 24.
    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 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
  • 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 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
  • 26.
    Single Agents -Experimental • Tosedostat • mTOR inhibitors • Vosaroxin • Hypoxia Specific • Aptamers • Sapacitabine • FLT3-inhibitors – Midostaurin – Lestaurtinib – Quizartinib (AC220) – Sorafenib
  • 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 28 36 62 85 175 176 449 days NH3-AA1-AAn….AAy-AAz-COOH NH3-AA1-AAn….AAy-COOH + AAz Proteosome Amino Acid depravation Inc Small peptides UPR ? Apoptosis Lowenberg JCO 2010;28:4333-38
  • 28.
    PI3K/AKT/mTOR Pathway • Promotesgrowth 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 Translation Cell cycle progression Proliferation & Survival RAPALOGS FLT3 mTOR inhibition Slide courtesy of Stefan Faderl
  • 29.
    Trials with AKT/mTORinhibitors 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 (AML) 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) Yee Clin Cancer Res 2006 27 various Phase 1/2 (Everolimus) E: 5-10 mg daily Modest activity (PB) Ravandi ASH 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
  • 30.
    Vosaroxin nee Voreloxinnee 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
  • 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;437-447 0 10 20 30 40 50 60 70 80 90 100 0 20 40 60 80 100 Study Day Blasts(%) 183-1009 183-1010 183-1011 182-1014 182-1020 182-1023 Information Courtesy Marina Konopleva Patterson., Clin Can Res 2007
  • 32.
    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
  • 33.
  • 34.
    FLT3 inhibitors • Assingle 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 80mg CR1 >6 mo HiDAC + Lestaurtinib 80mg Response correlates with target level inhibition Only 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
  • 35.
    AC220-002 : PhaseII 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-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 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
  • 36.
    Alphabet Soup Trialsfor 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 > 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
  • 37.
    Conclusions • Thus farnothing 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
  • 39.
    Overall Survival UsingEuropean Prognostic Index & GOELAMS Breems JCO 2005;23(9):1669-78 Giles Br J Haem 2006 ;134(1):58-61 They are superimposable GOELAMS
  • 40.
    Results of RandomizedTrials 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
  • 41.
    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 2hr 4 hrs after Clof 1 5432 1 5432
  • 42.
    AC220-002 : PhaseII in AML salvage 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 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
  • 43.
    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
  • 44.
    Nucleolin targeting AptamerAS1411 + 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+40 Evaluable 14 21 9 Early Death 2 1 1 “Response” 0/13 3/19 4/7 Why no update in 3 years?

Editor's Notes