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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

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Is there anything new for relapsed AML?

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  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 • 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 • ~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 Estey & Kornblau Blood 1996;88 :756 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II studies should be sure to include patients form each category , or report what category they had Estey & Kornblau unpublished 1998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 0 > 18 Mo 0 CR1 Duration > 12 Mo CR1 Duration < 12 Mo 1 7-18 Mo 3 < 6 Mo 5 0 0 Cytogenetics Cytogenetics Inv16 Not High T(8;21) 3 High Risk 1 Other 5 0 Age FLT3 ITD Neg 0 <35 1 Positive 36-45 1 2 >45 2 Prior SCT? Chevallier Leukemia 2011;25(6);939-44 Breems JCO 2005;23(9):1669-78

  6. FLT3-ITD: Poor prognosis at relapse too Diploid Cytogenteics Not Tx with anti FLT3 agent CR#2 Remission Duration Overall Survival After Relapse 1 Overall Survival After CR#2 RavandiLeukRes 2010:34;752-756

  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 8-9-10: Etoposide200 mg/m2/d & Ara-C500 mg/m2 • N=133 • Age 15-70 (22 >60) • Cytogenetics ? but 7 M4Eos and 13 APL • Median 1st CR 11 mo • CR Overall 60% • 1stsalvage 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 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

  11. Combinations of Purine Nucleotide Analogs With ARA-C in Patients With Relapsed/Refractory AML 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;743-747

  13. Single Agents -Approved • Clofarabine • Hypomethylating agents • Immunomodulatory- Lenalidomide • Histone deacetylase inhibitors • Vorinostat • Gemtuzumabozogamicin

  14. Hypomethylating agents Disappointing Decitabine ASH 2009 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 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

  16. Clofarabine – Single Agent & Combo • Purine analog • Inhibits DNA synthesis • Phase 1 40 mg/m2iv daily x 5 q4 wk. KantarjianBlood 2003 • Salvage N = 31 CR = 42% Table courtesy of Stefan Faderl

  17. Clofarabine – Combinations Day Day Ara-C 1000 mg/m2 over 2hr 4 hrs after Clof Ara-C 2g/m2 4 hrs after Clof 1 1 1 1 1 1 2 2 2 2 2 2 3 3 3 3 3 3 4 4 4 4 4 4 5 5 5 5 5 5 Clofarabine 40 mg/m2 over 1 hr or Clof 15-25 mg/m2 Placebo over 1 hr GCSF 5μ /kg Faderl JCO 2012:28;2492-2499 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 Burnett JCO 2010:282389-2395

  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 spice up an old recipe by adding a new ingredient?

  21. Adding Imatinib to MEC Day Imatinib 200/300/400 1 2 4 3 5 6 7 8 9 10 Mitoxantrone 10 mg/m2 4 5 6 7 8 • 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 Unfav33% • Response correlated with inhibition of AKT but not ERK phosphorylation 1 2 4 3 5 6 7 8 9 10 Etoposide 100 mg/m2 4 5 6 7 8 Brandwein Leukemia 2011:25;945-952

  22. Pravastatin + IA Doses: 40 …1680 mg/day MTD =1280 DLT= too many pills! • 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 CytoFav = 3% Int = 27% Unfav =70% Day Pravastatin 1 2 3 4 5 6 7 8 Idarubicin 12 mg/m2/d 4 5 6 Ara-C 1.5g/m2/d CI 4 5 6 7 SWOG Phase III trial stopped early in Nov 2012 for POSITIVE result Kornblau JCO 2007:109;2999-3006

  23. DAC + Gemtuzumab + Ozogamicin • 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. Day Decitabine20 mg/m2 1 2 3 4 5 12 6 9 GemtuzumabOzo 3 mg/m2 Chowdhur y Am J Hema 2009:84;599-600

  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 ? Middeldorf Am J Hema 2010:85;477-481

  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 Amino Acid depravation Inc Small peptides UPR ? Apoptosis Proteosome NH3-AA1-AAn….AAy-AAz-COOH NH3-AA1-AAn….AAy-COOH + AAz Lowenberg JCO 2010;28:4333-38

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

  29. Trials with AKT/mTOR inhibitors * Evidence of synergy with MEC not observed Table courtesy of Stefan Faderl

  30. VosaroxinneeVoreloxin neeSNS-595 • Quinolone derivative, intercalates DNA and poisons Topo II • Not a P-gpsubstrate, 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 Patterson., Clin Can Res 2007 Information Courtesy Marina Konopleva

  32. 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 SS-DNA 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%) 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 Kantarjian et al, JCO 2010

  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 moHiDAC +Lestaurtinib 80mg 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

  35. AC220-002 : Phase II in AML salvage Dose: Females 90 mg Males 135 mg continuously QTc25 % Grade 3-4 13% 26% Gr 3-4 10% Levis ASH 2012 Abstract # 673 Cortes ASH 2012 Abstract # 48

  36. Alphabet Soup Trials for Relapsed AML at MDACC

  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. 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

  39. Results of Randomized Trials In Patients With Relapsed or Refractory AML 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 ClinOncol. 2004;22:1078–1086; 6Feldman EJ, et al. J ClinOncol. 2005;23:4110–4116; 7Giles FJ, et al. Blood (ASH Annual Meeting Abstracts). 2006;108:Abstract 1970. Slide Courtesy of Stefan Faderl

  40. 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 & IntCyto 5/7 =70%, Unfav 2/9 = 22% Day Clofarabine 40 mg/m2 over 1 hr 1 2 4 3 5 Ara-C 1000 mg/m2 over 2hr 4 hrs after Clof 1 2 4 3 5 Agura The Oncologist 2011;16:197-206

  41. AC220-002 : Phase II in AML salvage 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

  42. 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

  43. 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 Why no update in 3 years? Stuart ASCO Proceedings 2009 #7019

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