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Novel Strategies for the Treatment of AML: Tailoring Treatment For Specific Genetic Subtypes Martin S. Tallman, M.D. Northwestern University Feinberg School.

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Presentation on theme: "Novel Strategies for the Treatment of AML: Tailoring Treatment For Specific Genetic Subtypes Martin S. Tallman, M.D. Northwestern University Feinberg School."— Presentation transcript:

1 Novel Strategies for the Treatment of AML: Tailoring Treatment For Specific Genetic Subtypes Martin S. Tallman, M.D. Northwestern University Feinberg School of Medicine Robert H. Lurie Comprehensive Cancer Center Chicago, IL

2 Topics To Address Introduction and epidemiology Overview of current therapy Distinguishing genetic subtypes Novel strategies for specific genetic subtypes Future Directions

3 Introduction New patients/deaths in 2004: 12,000/9,000 Median age of AML: 68 years Heterogeneity in genetics and clinical manifestations Outcome varies by prognostic factors

4 Epidemiology Therapy-related (alkylating agent or topo II active agents) Evolving from MDS or MPD Congenital chromosomal instability syndromes Higher frequency of APL in Latin Americans 1 Higher frequency of t(8;21) in Japan 2 1 Douer Blood, 1996, Br J Haematol, 2003; 2 Nakase Leukemia, 2000

5 Current Treatment Results In Younger Adults STUDY N CR % ED %OS % (3-5 yr) CALGB GAMLCG HOVON ALFA

6 Current Treatment Results In Older Adults STUDY N CR % ED %OS % (2-7 yr) CALGB ECOG SWOG MRC 1,

7 Prognostic Factors Age Intensity of postremission therapy (younger adults) Cytogenetics (distinguish fav- intermed- and unfav-risk groups)

8 Overall Survival by Cytogenetic Group Slovak Blood, 2000 Years After Entering Study Cumulative Percent 846 Favorable % Intermediate % Unfavorable % Estimate At Risk Deaths at 5 Years Heterogeneity of 3 Groups: p<.0001

9 Prognostic Factors Molecular Markers Transmembrane transporter proteins which confer multidrug resistance (MDR1) Mutations in or overexpression of specific genes-unfav. prognosis: WT1, BAX, BCL- 2/BAX, BAALC, EVI1, KIT, FLT3, MLL, ERG; fav. prognosis: C/EBP , NMP1 Expressed in cells from pts with normal karyotype

10 Outcome For AML with Fav-risk Cytogenetics NCR %DFS %OS % CBF APL Castaigne Blood, 2002; 2 Appelbaum Proc ASCO, 2005; 3 Marcucci J Clin Oncol, 2005; 4 Sanz Pro ASCO, 2005; 5 Lo Coco Blood, 2004

11 Outcome For AML in Older Adults with Unfavorable Cytogenetics NCR%OS% (5-yr) MRC ECOG Grimwade Blood, 2004; 2 Rowe Blood, 2004

12 Current Therapeutic Strategies Induction with anthracycline mg/m2/day for 3 days + cytarabine 100 mg/m2/day for 7 days c.i. Multiple cycles of high-dose ara-C consolidation No maintenance (except APL)

13 Strategies To Improve Outcome Dose intensification (anthracyclines) Alternative chemotherapy Priming with growth factors New agents

14 Daunorubicin Dose Intensification 1 Appelbaum Ann Int Med, 1984; 2 Castaigne Blood, 2003; 3 Kolitz Blood, 1998 StudyDauno DoseCR% FHCRC 1 70 mg/m 2 80 ALFA 2 80 mg/m 2 76 CALGB mg/m 2 80

15 ECOG Priming Studies Recruiting Leukemic Cells into Cell Cycle GM-CSFPlacebo CR38%40% Induction mortality26%17% OS, median5.3 mo.8.5 mo. DFS, median6.9 mo.5.1 mo. Rowe Blood, 2004

16 Priming With Growth Factor (GF) in Younger Patients with Intermediate Cytogenetics StudyNCR %DFS %OS % GF/No GF HOVON /8645/33 (p=.006) 45/35 (p=.02) ALFA /87 50/35 (p=.05) 56/47 (p=.07) 1 Lowenberg NEJM, 2003; 2 Thomas Blood, 2005

17 Specific Genetic Subtypes of AML To Which Therapy Can Be Tailored APL CBF AML CD33 pos AML AML with FLT3 mutatations AML with c-kit mutations AML with MLL PTD

18 Curative Strategies in APL Induction:ATRA + anthracycline-based chemotherapy Consolidation:Anthracycline-based chemotherapy for 2-3 cycles to molecular negativity Intermediate-dose ara-C for high-risk Maintenance:ATRA +/- low-dose chemo for 1-2 years; ? Role in PCR neg after consol Mol. Monitoring: RT-PCR from PB every 3-6 months for 2-3 years, prob for high-risk only Relapse:Arsenic followed by ASCT (allo if PCR pos) (consider prophylactic IT therapy)

19 GIMEMA AIDA 2000 Years Survival N=338 3 years: 87% Overall Survival Courtesy of F. Lo Coco

20 Advances in Therapy in APL Paradigm for tailoring therapy to specific genetic subtype Study GroupContribution No. Am. IntergroupMaintenance PETHEMAElimination of ara-C PETH/GIMEMAATRA in consolidation No. Am. IntergroupATO in consolidation GIMEMAGemtuzumab ShanghaiATRA + ATO IranATO single agent Will chemotherapy be eliminated?

21 Arsenic Trioxide for Rel/Ref APL Pilot and US Multicenter Trial Overall and Relapse-Free Survival Years Probability (%) 14 OS - 1 st Relapse 23 OS - > 1 st Relapse RFS - 1 st Relapse RFS - > 1 st Relapse Soignet J Clin Oncol, 2001; Douer, Tallman J Clin Oncol, 2005

22 <.02* Relapse (%) (median follow- up 18 months) <  PML/RARα (fold) <  5 35  3 40  10 Time to CR (days) NS (%) CR —P 21 ATRA + ATO 20ATO 20ATRA N Induction/ maintenance therapy *All patients also treated with consolidation chemotherapy and 6-MP + MTX as maintenance Randomized Trial of Arsenic Trioxide and ATRA in Untreated APL Shen Proc Natl Acad Sci,U S A, 2004

23 Time of Follow-up (months) Probability ATRA + arsenic trioxide (n = 20) arsenic trioxide (n = 18) ATRA (n = 19) Shen PNAS, 2004 Disease-Free Survival by Treatment Group

24 1 Zhang J Biol Regul Homeost Agents, Ghavamzadeh ASCO, 2003[abst] 3 Ghavamzadeh EHA, 2004[abst] Induction With Single-Agent Arsenic Trioxide: Untreated APL N NR PCR neg (%) ATO  6 ATO  1 Chemotherapy Postremission therapy CR (%) Chandy – India 5,6,7 Ghavamzadeh – Iran 2,3,4 Zhang – China 1 Study 4 Ghavamzadeh Ann Oncol, George Haematologica, George European Hematol Assoc, Mathews Blood, 2005 (abstr)

25 North American Intergroup Trial C9710 Induction Consol #1 Consol #2Maint ATRA Dauno Ara-C ATO ATRA Dauno CR ATRA 6-MP MTX ATRA 7 days, QOW Untreated APL No ATO Tests arsenic as early consolidation and 2 maint regimens

26 Proposed North American Intergroup Study-Phase III Low- and Intermediate-Risk InductionConsol #1Consol #2Maint ATRA Daunorubicin Ara-C ATO ATRA Daunorubicin PCR ATRA 6-MP MTX neg pos OBS Gemtuzumab Ozogamicin HSCT Tests benefit of maint in PCR neg patients

27 Proposed North American Intergroup Study-Phase II High-Risk InductionConsol #1Consol #2Consol #3Maint ATRA ATO Gemtuzumab Ozogamicin ATO ATRA Daunorubicin Gemtuzumab Ozogamicin ATRA 6-MP MTX Tests benefits of 3 nonchemotherapy agents in induction

28 Incidence of CBF AML by Age AgeTotalinv(16)t(8;21)P-value %43%57% %55%45% %59%41% %50% %62%38% Appelbaum FR, Kopecky KJ, Tallman MS, et al (submitted)

29 Outcome of t(8;21) AML StudyNCROSPostrem Palmeri1782%79%HiDACx3 Nishii8595%52%No I-or HDAC Baer2990%45%>/=1 HiDAC Marcucci13989%46%S-, I-, HiDAC Appelbaum Schlenk % 87% 45% 65% Variable HiDAC Palmeri Leuk Res, 2002; Nishii Leukemia, 2003; Baer Blood, 1997; Marcucci J Clin Oncol, 2005; Appelbaum (submitted); Schlenk J Clin Oncol, 2004

30 Outcome of inv16/t(16;16) AML StudyNCROSPostrem Marcucci16487%54%S-, I- HiDAC Delaunay11093%58%variable Appelbaum19689%50%variable Schlenk20189%60%HiDAC Marcucci J Clin Oncol, 2005; Delaunay Blood 2003; Appelbaum (submitted); Schlenk J Clin Oncol 2004

31 Overall Survival Years Percent Year N DeathsEstimate All Patients % Overall Survival by Abnormality Years Percent Year N EventsEstimate inv % t(8;21) % Disease-Free Survival by Treatement Years After Start of Post-CR Regimen Percent Year N EventsEstimate FA % HCT % HDAC % Other % Outcome for CBF Leukemias Appelbaum et al.(submitted)

32 CALGB Protocol 19808: Induction +/- MDR Modulation Followed by Cytogenetic Risk- Adapted Intensification in Younger Adults ADE ADEP Favorable Cytogenetics Unfavorable Cytogenetics HiDAC Consolidation Therapy x 3 If able to Receive PSCT If unable to Receive PSCT HiDAC G-CSF VP-16 Stem Cell Mobilize VP-16 HiDAC G-CSF BU/VP-16 PSCT HiDAC Consolidation Therapy x 2 Obs. IL-2 Tests HiDAC for fav. Cyto and IL-2 post-ASCT

33 Specific Genetic Subtypes Are Heterogeneous: t(8;21) CD56 expression may confer poor prognosis Associated trisomy 4 is a distinct subtype with poor prognosis Receptor tyrosine kinase pathway mutations in 49% and confer poor prognosis Baer Blood, 1997; Nishii Leukemia 2003; Nanri Leukemia 2005

34 New Agents ClassAgentTarget AntibodiesGemtuzumabCD33 MDR inhibitorsPSC833, ZosuquidarP-gp FT inhibitorsTipifamibLamin A, HJJ-2 FLT3 inhibitorsPKC-412, CEP-701, MLN518, SU11248 FLT3 ITD HDAC inhibitorsValproic acid, SAHA, depsipeptide HDAC Antiangio agentsBevacizumabVEGF Apoptosis inhibitorsGenasenseBCL-2 Deoxyadenosine analogs Nucleoside analogs Clofarabine Tiazofurin DNA IMPDH

35 S H HO O OCH 3 NH O O OCH 3 N Et O OH OCH 3 HO CH 3 O 3 HN HO O O OH CH 3 S 3 OCH 3 3 I O O O O O CH 3 S O NHN Me O O HN hP67.6 Gemtuzumab Ozogamicin Approved for adults > 60 in first relapse Induces CR + CRp in ~ 30% 1,2 Rare VOD/SOS if allo < 3.5 mo. 3 Structure hP humanized anti-CD33 antibody Blue- linker Periwinkle - calicheamicin 1 Sievers J Clin Oncol, 2001; 2 Larson Leukemia, 2002; 3 Wadleigh Blood, 2003

36 Gemtuzumab Ozogamicin CR MD Anderson 1 Single Agent8% With IL-1136% Northwestern 2 27% EORTC 3 Single Agent23% Followed by Chemo35% 1 Estey Blood, 2002; 2 Nabhan Leukemia Res, 2004; 3 Amadori Blood, 2004 [abstr]

37 Gemtuzumab Ozogamicin in Induction DeAngelo Blood, 2003 (abstr); Kell Blood, 2003 StudyChemotherapyGO DoseCR DeAngeloDauno/Ara-C6 mg/m 2 d483% KellDAT or FLAG-ida3 mg/m 2 d185% Prompts SWOG Phase III trial of chemotherapy +/- GO d4

38 ECOG Protocol E1900: Dose Intensification in Induction and Gemtuzumab Ozogamicin (GO) pre-ASCT in Younger Adults with Untreated AML Daunorubicin 45 mg/m 2 /day + Cytarabine Allogeneic HSCT CR Daunorubicin 90 mg/m 2 /day + Cytarabine High Risk HiDAC x 2 PBSH after 2nd course GO 6 mg/m 2 IV day 1 Autologous ASCT Tests anthracycline dose intens and GO as in vitro purge pre- ASCT

39 Inhibition of Multidrug Resistance P-gp-mediated MDR plays major role in clinical resistance to chemotherapy P-gp correlates inversely with CR 71% of patients > age 60 express moderate to high P-gp 1 Major limitation is alteration in pK of concomitant chemotherapy 1 Leith Blood, 1994

40 GroupModulatorRegimenOutcome CALGB 1 PSC-833ADE+PSC-833Closed due to toxicity HOVON 2 PSC-833DA+PSC-833DFS, OS not improved 1 Baer Blood, 1999; 2 Van der Holt Blood, 2004 (abstr) MDR Modulation Studies in AML De novo > 60 years

41 Inhibition of Multidrug Resistance Selective P-gp inhibitor with high affinity 1 In vitro conc of nM circumvent P-gp-mediated resistance 2,3 Does not alter PKs of co- administered drugs 2 Phase II trial in poor-risk AML CR or mCR 42% 4 ECOG phase III trial LY (Zosuquidar) 1 Sato Cancer Res, 1991; 2 Dantzig Cancer Res, 1996; 3 Green Biochem Pharmacol, 2001; 4 Cripe Blood, 2001 (abstr)

42 ECOG Protocol E3999: Dauno + Cytarabine +/- Zosuquidar in Older Adults Daunorubicin Cytarabine Zosuquidar Induction Consolidation I Daunorubicin Cytarabine Placebo V A L U A T E E CR or MR Cytarabine Consolidation II Daunorubicin Cytarabine Zosuquidar Daunorubicin Cytarabine Placebo Tests novel MDR modulator

43 Ras Ras mutations –Activating mutations in 10-30% of AML 1,2 –Frequent in t(3;5) and inv(16) 3 Active inhibition of farnesyl transferase (FT), inhibits ras protein Inhibitors of FT active in AML 4,5 Gene expression profiling may predict response to Tipifarnib 6 1 Radich Blood, 1990; 2 Neubauer Blood, 1999; 3 Bowen Blood, 2005; 4 Karp Blood, 2001; 5 Lancet Blood, 2002; 6 Raponi Blood, 2005

44 Tipifarnib-Phase II Trial in Untreated High-risk AML/MDS Med age 74 yrs (46-85) CR in 21% Med CR dur 5-8 mo. ( ) Gr. 4 neutropenia 13% Inhibition of FT in 74% of samples Encouraged US Intergr Phase II trial of 2 different doses/schedules in older adults Lancet Blood, 2003 (abstr)

45 S0432: US Intergroup Phase II Study Zarnestra for Previously Untreated AML in Patients > Age 70 Randomization Arm 1Arm 2Arm 3Arm 4 Zarnestra 600 mg bid x 21 days q 28 days Zarnestra 600 mg bid x 7 days every other week q 28 days Zarnestra 300 mg bid x 21 days q 28 days Zarnestra 300 mg bid x 7 days every other week q 28 days

46 AML With Mutant RAS and Cytarabine Intensification wtRASmutRAS LoDACHDACLoDACHDAC Yrs to relapse NR RR82%71%100%45% Neubauer ASCO, 2005

47 Survival (%) Years % 32% ITD- n=627 ITD+ n=227 P<0.001 Kottaridis Blood, 2001 Prognostic Significance of FLT3 ITD

48 Tyrosine Kinase Inhibitors PKC412 Staurosporine-derived, targets PKC, KDR, VEGF-R2, PDGFR, c-KIT, FLT3 Phase II study 1 – 28 pts with FLT3 mutation, HI in 50%, but no CR or PR CEP-701 Indolcarbazole alkyloid-targets TrkA, VEGFR, FLT3 Phase I/II study pts with FLT3 mutation, biologic activity in 35%, but no CR or PR 1 Estey Blood, 2003; Smith Blood, 2004

49 FLT3 Inhibitors and Chemotherapy in AML CEP N=34 in first relapse MEC or HiDAC +/- CEP /17 CR with CEP-701 PKC412 2 N=19 de novo Dauno + Ara-C + PKC412 CR 71-75% 100% FLT3 mut 62% FLT3 wt 1 Lewis, Blood, 2005 (abstr ); 2 Stone, Blood, 2005 (abstr)

50 FLT3 Inhibitors In vitro data strong Modest clinical activity-few, if any, CRs How best to develop? Focus on combinations with chemotherapy 1, 2 ; Phase III US Intergroup trial planned (dauno + ara-C +/- PKC412) Will combining agents with in vitro activity, but modest clinical activity, be effective? 1 Stone Blood, 2005; Levis, Blood 2005

51 Genasense (Oblimersen Sodium) Bcl-2 associated with poor outcome in AML Phosphorothioate 18-mer antisense oligonucleotide directed at first 6 codons of Bcl-2 Genasense + dauno/cytarabine in high-risk de novo pts –26 pts, med. age 67 –CR in 45.4%; no unexpected toxicity CALGB phase III trial underway Marcucci Blood, 2003

52 G Cytarabine + Daunorubicin Cytarabine + Daunorubicin High-Dose Cytarabine G High-Dose Cytarabine CALGB 10201: Daunorubicin + Cytarabine +/- G3139 (Genasense) in Older Adults CR Remission Induction Consol I & II CR Tests bcl-2 antisense strategy

53 Clofarabine Intentionally designed to incorporate the favorable properties of fludarabine/cladribine Multiple mechanisms of action –Inhibits DNA replication and repair –Disrupts mitochondrial function leading to apoptosis Active in both dividing and non- dividing cells

54 Clofarabine Trials in AML RegimenN PopulationCR/OR % Clo31Rel/Ref0101 Clo28Untreated59/75 2 Clo +IDAC25Rel/Ref22/38 3 Clo + IDAC60Untreated52/60 4 Clo + LoDAC32Untreated59/ Kantarjian Blood, 2003; 2 Faderl Blood, 2005; 3 Burnett Blood, 2005; 4 Faderl Blood, 2005; 5 Faderl Blood, 2005

55  CClofarabine Low-dose cytarabine  DDaunorubicin Cytarabine Clofarabine  CClofarabine Low-dose cytarabine  CCytarabine 1.5 mg/m 2 IV Q12 d1-6  CCytarabine 1.5 g/m 2 IV Q12 d1-3  CClofarabine Age R R No CR Off Study Age HLA-iden siblingMini-MUD alloSCT Proposed ECOG Trial CRCR Can we eliminate conventional chemotherapy in older adults?

56 Specific Genetic Subtypes Of AML To Target In The Very Near Future C-KIT AML: Imatinib, Dasatinib, FLT3 inhibitors MLL PTD AML: HDAC and DMT inhibitors Bcr-abl pos AML: IMP dehydrogenous inhibitor (Tiazofurin ) Whitman Blood, 2005; Malek Leuk Res, 2004

57 Other Active Agents Awaiting Assignement To Specific Genetic Subtypes Choretazine (VNP40101M): sulfonylhydrazine alkylating agent 1 Tandutinib: small molecule inhibitor or type II receptor tyrosine kinases 2 XL99: inhibits multiple receptor kinases(VEGFR- 2, PDGFR-alpha, PDGFR-beta, c-KIT, SRC, FGFR1, FLT4, FLT3) Low-dose decitabine 3 Arsenic plus low-dose ara-C 4 1 Giles Blood 2005 (abstr); 2 Deangelo Blood, 2004 (abstr); 3 Lubbat Blood, 2005 (abtsr); 4 Robosz Blood, 2005(abstr)

58 Future Directions Gene expression profiling to determine signatures characteristic of specific genetic subtypes, identify cooperating mutations and perturbed pathways and predict treatment response Further characterization of normal karyotype AML and adverse karyotype AML Increased collaboration among cooperative groups to study myriad of new agents to tailor to specific genetic subtypes

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