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Novel Strategies for the Treatment of AML: Tailoring Treatment For Specific Genetic Subtypes

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. Topics To Address. Introduction and epidemiology

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Novel Strategies for the Treatment of AML: Tailoring Treatment For Specific Genetic Subtypes

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  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 Americans1 • Higher frequency of t(8;21) in Japan2 1Douer Blood, 1996, Br J Haematol, 2003; 2Nakase Leukemia, 2000

  5. Current Treatment Results In Younger Adults

  6. Current Treatment Results In Older Adults

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

  8. Estimate At Risk Deaths at 5 Years Favorable 121 53 55% Intermediate 278 168 38% Unfavorable 184 162 11% Overall Survival by Cytogenetic Group 100 80 60 Cumulative Percent 40 20 Heterogeneity of 3 Groups: p<.0001 0 0 2 4 6 8 Years After Entering Study Slovak Blood, 2000

  9. Prognostic FactorsMolecular 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 1Castaigne Blood, 2002; 2Appelbaum Proc ASCO, 2005; 3Marcucci J Clin Oncol, 2005; 4Sanz Pro ASCO, 2005; 5Lo Coco Blood, 2004

  11. Outcome For AML in Older Adults with Unfavorable Cytogenetics 1Grimwade Blood, 2004; 2Rowe Blood, 2004

  12. Current Therapeutic Strategies • Induction with anthracycline 45-60 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 1Appelbaum Ann Int Med, 1984; 2Castaigne Blood, 2003; 3Kolitz Blood, 1998

  15. ECOG Priming StudiesRecruiting Leukemic Cells into Cell Cycle Rowe Blood, 2004

  16. Priming With Growth Factor (GF) in Younger Patients with Intermediate Cytogenetics 1Lowenberg NEJM, 2003; 2Thomas 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 Overall Survival 1.0 .75 N=338 3 years: 87% Survival .50 .25 0 0 .5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Years Courtesy of F. Lo Coco

  20. Advances in Therapy in APLParadigm for tailoring therapy to specific genetic subtype Will chemotherapy be eliminated?

  21. Arsenic Trioxide for Rel/Ref APL Pilot and US Multicenter Trial Overall and Relapse-Free Survival 100 80 60 Probability (%) 40 OS - 1st Relapse OS - > 1st Relapse 20 RFS - 1st Relapse RFS - > 1st Relapse 0 0 1 2 3 4 Years Soignet J Clin Oncol, 2001; Douer, Tallman J Clin Oncol, 2005

  22. Induction/ maintenance therapy N (%) CR Time to CR (days)  PML/RARα (fold) Relapse (%) (median follow-up 18 months) ATRA 20 95 40  10 6.7 26.3 ATO 20 90 35  3 32 11.1 ATRA + ATO 21 95 25  5 119 0 P — NS < .05 < .01 < .02* Randomized Trial of Arsenic Trioxide and ATRA in Untreated APL *All patients also treated with consolidation chemotherapy and 6-MP + MTX as maintenance Shen Proc Natl Acad Sci,U S A, 2004

  23. Disease-Free Survival by Treatment Group 1.0 0.8 0.6 Probability 0.4 ATRA + arsenic trioxide (n = 20) 0.2 arsenic trioxide (n = 18) ATRA (n = 19) 0 0 4 8 12 16 20 24 28 32 Time of Follow-up (months) Shen PNAS, 2004

  24. Induction With Single-Agent Arsenic Trioxide: Untreated APL Study N CR (%) PCR neg (%) Postremission therapy Zhang – China1 124 88 NR Chemotherapy Ghavamzadeh – Iran2,3,4 111 86 92 ATO  1 Chandy – India5,6,7 51 95 ATO  6 80 4Ghavamzadeh Ann Oncol, 2005 5George Haematologica, 2004 6George European Hematol Assoc, 2004 7Mathews Blood, 2005 (abstr) 1Zhang J Biol Regul Homeost Agents, 1999 2Ghavamzadeh ASCO, 2003[abst] 3Ghavamzadeh EHA, 2004[abst]

  25. North American Intergroup Trial C9710 Induction Consol #2 Maint Consol #1 ATRA6-MP MTX ATRA DaunoAra-C ATO ATRADauno UntreatedAPL CR No ATO ATRA7 days, QOW Tests arsenic as early consolidation and 2 maint regimens

  26. Proposed North American Intergroup Study-Phase IIILow- and Intermediate-Risk Induction Consol #1 Consol #2 Maint ATRA6-MP MTX neg ATRA DaunorubicinAra-C ATRADaunorubicin PCR OBS ATO pos GemtuzumabOzogamicin HSCT Tests benefit of maint in PCR neg patients

  27. Proposed North American Intergroup Study-Phase II High-Risk Induction Consol #1 Consol #2 Consol #3 Maint GemtuzumabOzogamicin ATRA6-MP MTX ATRAATOGemtuzumabOzogamicin ATRADaunorubicin ATO Tests benefits of 3 nonchemotherapy agents in induction

  28. Incidence of CBF AML by Age Appelbaum FR, Kopecky KJ, Tallman MS, et al (submitted)

  29. Outcome of t(8;21) AML 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 Marcucci J Clin Oncol, 2005; Delaunay Blood 2003; Appelbaum (submitted); Schlenk J Clin Oncol 2004

  31. 100 5Year N Events Estimate inv 16 196 97 50% t(8;21) 174 100 45% 80 60 Percent 40 20 0 0 5 10 15 20 25 Years Outcome for CBF Leukemias 100 Overall Survival 80 5Year N Deaths Estimate All Patients 370 197 48% 60 Percent 40 20 0 0 5 10 15 20 25 Years Overall Survival by Abnormality Disease-Free Survival by Treatement 5Year N Events Estimate FA 53 20 61% HCT 31 12 61% HDAC 44 23 50% Other 136 96 31% 100 80 60 Percent 40 20 0 0 5 10 15 20 25 Years After Start of Post-CR Regimen Appelbaum et al.(submitted)

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

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

  36. Gemtuzumab Ozogamicin 1Estey Blood, 2002; 2Nabhan Leukemia Res, 2004; 3Amadori Blood, 2004 [abstr]

  37. Gemtuzumab Ozogamicin in Induction Prompts SWOG Phase III trial of chemotherapy +/- GO d4 DeAngelo Blood, 2003 (abstr); Kell Blood, 2003

  38. ECOG ProtocolE1900: Dose Intensification in Induction and Gemtuzumab Ozogamicin (GO) pre-ASCT in Younger Adults with Untreated AML Daunorubicin45 mg/m2/day + Cytarabine High Risk Allogeneic HSCT CR Autologous ASCT HiDAC x 2 PBSH after 2nd course Daunorubicin90 mg/m2/day + Cytarabine GO 6 mg/m2 IV day 1 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-gp1 • Major limitation is alteration in pK of concomitant chemotherapy 1Leith Blood, 1994

  40. MDR Modulation Studies in AMLDe novo > 60 years 1Baer Blood, 1999; 2 Van der Holt Blood, 2004 (abstr)

  41. Inhibition of Multidrug Resistance LY335979 (Zosuquidar) • Selective P-gp inhibitor with high affinity1 • In vitro conc of 50-100nM circumvent P-gp-mediated resistance 2,3 • Does not alter PKs of co-administered drugs2 • Phase II trial in poor-risk AML CR or mCR 42%4 • ECOG phase III trial 1Sato Cancer Res, 1991; 2Dantzig Cancer Res, 1996; 3Green Biochem Pharmacol, 2001; 4Cripe Blood, 2001 (abstr)

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

  43. Ras • Ras mutations • Activating mutations in 10-30% of AML1,2 • Frequent in t(3;5) and inv(16)3 • Active inhibition of farnesyl transferase (FT), inhibits ras protein • Inhibitors of FT active in AML4,5 • Gene expression profiling may predict response to Tipifarnib6 1Radich Blood, 1990; 2Neubauer Blood, 1999; 3Bowen Blood, 2005; 4Karp Blood, 2001; 5Lancet Blood, 2002; 6Raponi 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. (1.5-11+) • 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 StudyZarnestra for Previously Untreated AML in Patients > Age 70

  46. AML With Mutant RAS and Cytarabine Intensification Neubauer ASCO, 2005

  47. Prognostic Significance of FLT3 ITD 100 80 60 Survival (%) ITD- n=627 44% 40 ITD+ n=227 32% 20 P<0.001 0 0 3 1 4 2 5 Years Kottaridis Blood, 2001

  48. Tyrosine Kinase Inhibitors PKC412 • Staurosporine-derived, targets PKC, KDR, VEGF-R2, PDGFR, c-KIT, FLT3 • Phase II study1 – 28 pts with FLT3 mutation, HI in 50%, but no CR or PR CEP-701 • Indolcarbazole alkyloid-targets TrkA, VEGFR, FLT3 • Phase I/II study2-14 pts with FLT3 mutation, biologic activity in 35%, but no CR or PR 1Estey Blood, 2003; Smith Blood, 2004

  49. FLT3 Inhibitors and Chemotherapy in AML • CEP-7011 • N=34 in first relapse • MEC or HiDAC +/- CEP-701 • 10/17 CR with CEP-701 • PKC4122 • N=19 de novo • Dauno + Ara-C + PKC412 • CR 71-75% • 100% FLT3 mut • 62% FLT3 wt 1Lewis, Blood, 2005 (abstr); 2Stone, 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 chemotherapy1, 2; Phase III US Intergroup trial planned (dauno + ara-C +/- PKC412) • Will combining agents with in vitro activity, but modest clinical activity, be effective? • 1Stone Blood, 2005; Levis, Blood 2005

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