TREATMENT OPTIONS IN AML: A PRACTICAL CASED-BASED APPROACH

1. TREATMENT OPTIONS IN AML: A PRACTICAL CASED-BASED APPROACH

2. Current Status and Controversies in Acute Myeloid Leukemia Induction Therapy Edward A. Stadtmauer, MD University of Pennsylvania Health System

3. Acute Myeloid Leukemia (AML)

4. Acute Myeloid Leukemia • Uncontrolled proliferation of immature bone marrow cells • Transformed cells incapable of normal differentiation into mature myeloid cells • Leukemic cells prevent the maturation and differentiation of other bone marrow cells • Results in anemia, low platelets, and neutropenia • Mortality results primarily from infection, bleeding, or tumor lysis

5. Acute Myeloid Leukemia • Median age at diagnosis: 62 to 64 years • Incidence • <65 years of age: 1.8 cases per 100,000 • >65 years of age: 16.3 cases per 100,000 • Approximately 12,000 cases in 2004 • 1.2% of all cancer deaths • Most common cause of cancer death in young men and women • Public health problem in older adults

6. Age-Specific Incidence Rates for AML 1995-1998 35 Male Female 30 All persons 25 20 Average Annual Rate per 100,000 15 10 5 0 00-04 05-09 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+ Age (yrs) NCI SEER Program, 1995-1999.

7. Initial Therapy of AML • Complete remission (CR) must be attained to cure patient • CR defined as: • Clearance of peripheral blood & bone marrow of leukemic blasts • Reconstitution of normal hematopoiesis • Resolution of leukemic infiltrates Diagnosis Remission Induction Post-remission Therapy Consolidation Chemotherapy SCT

8. Remission Induction Total Leukemic Cell Number Induction Relapse Relapse Cure Clinically Detectable Disease Time

9. Post-remission Therapy Total Leukemic Cell Number Induction Consolidation Consolidation Clinically Detectable Disease Cure Time

10. Acute Myeloid Leukemia: Remission Induction • Cytarabine 100mg/m2/day x 7 days continuous infusion + anthracycline bolus x 3 days • Add ATRA if APL (may delete cytarabine) • Expect 60% to 80% complete remission rateif <60 years • One of the major cancer therapy success stories of the 20th century • But … not all AML has a good prognosis

11. Prognostic Factors in AML • Age • 60 years unfavorable • Cytogenetics • Favorable: t(8;21), inv16, t(15;17) • Intermediate: normal, -Y, +6, +8; others not considered favorable or unfavorable • Poor: Translocations or inversion of chromosome 3, monosomy 5 or 7, t(6;9), t(9;22), abn 11q23, or complex • Presenting white blood cell count • Hyperleukocytosis >100,000/μLunfavorable • Treatment-induced AML or history of myelodysplastic syndrome • Other unfavorable indicators • CD34 expression, MDR phenotype, FLT3-activating mutations, and Bcl-2 expression

12. SWOG/ECOG Adult AML; Age <56: Cytogenetics and Survival 100 At Risk Deaths Estimated (CI) at 5 Years Favorable 121 53 55% (45%-64%) Intermediate 278 168 38% (32%-44%) Unfavorable 184 162 11% (7%-16%) 80 60 Survival (%) 40 20 Heterogeneity of 3 groups: P<.0001 0 4 6 0 2 8 Years After Entering Study Slovak et al. Blood. 2000.

13. Comparison of Prognostic Factors: Older and Younger Adults With AML Characteristic <60 years 60 years #/100,000 in US 1.8 17.6 Cytogenetics Favorable 6%-12% 1%-4% Unfavorable 3%-7% 6%-18% MDR1 expression 35% 71% Secondary AML 8% 20%-50% Sekeres. Hematology. 2004.

14. ECOG AML Survival Data <60 years >60 years Study Year. 1989-1997, n=1044 Median Survival= 20.6 months 5-Year Survival =37% Study Year. 1989-1997, n=553 Median Survival= 3.2 months 5-Year Survival =12% 1.0 1.0 Study Year. 1983-1986, n=142 Median Survival= 6.3, months 5-Year Survival =13% Study Year. 1983-1986, n=499 Median Survival= 13.4 months 5-Year Survival =24% 0.8 0.8 0.6 0.6 Study Year. 1973-1979, n=454 Median Survival= 11.3 months 5-Year Survival =11% Study Year. 1973-1979, n=293 Median Survival= 3.5 months 5-Year Survival =6% Survival Survival 0.4 0.4 0.2 0.2 0.0 0.0 0 5 20 25 0 10 15 5 25 10 15 20 Years Years Appelbaum. Hematology. 2001.

15. Current Common Clinical Questions • Should every patient with AML receive induction therapy? • How old is old? • What is the best anthracycline? • What is the best dose of cytarabine? • What is the best consolidation?

16. Older Adults Are Not as Responsive to or Tolerant of Treatment • Comorbid diseases • Slow metabolism of induction-regimen drugs • Particularly cytarabine • High drug levels • Hesitancy to give full doses • Biologically poor prognosis

17. Randomized Trials of Induction Therapy >60 Years • Only 2 studies have been reported • Lowenberg B, et al. J Clin Oncol. 1989;7:1268. • Survival advantage for induction chemotherapy but… • 21 weeks vs. 11 weeks • Median survival 16 days longer than the time spent in the hospital

18. Induction Therapy Decision-Making and Expectations of AML >60 years • Sekeres MA, et al. Leukemia. 2004;18:809. • 43 patients >60 years • Approx. 50% chose induction chemotherapy • 1-year mortality 63%, no difference in treatment groups • Induction chemotherapy: 79% of first 6 weeks in hospital • Supportive care: 14% of first 6 weeks in hospital • Older patients overestimate potential benefit from induction therapy • 74% patients rate chance of cure >50% • 90% patients rate 1-year survival >50% • 89% physicians rate chance of cure <10% • Most patients do not recall alternatives to therapy received; all were presented options

19. Treatment Options for Older Patient • Be realistic • Supportive care/Palliation • Blood and platelet transfusions • Antibiotics • Growth factors • Standard-dose induction chemotherapy • Low-dose chemotherapy • Hydrea • Low-dose cytarabine • Clinical trials!

20. Is There a Best Antracycline?(Age <60) • Comparisons • Idarubicin 12 mg/m2 vs. daunorubicin • Blood 1991, 1992; JCO 1992; EJC 1991 • Amsacrine vs daunorubicin • Leukemia 1999; JCO 1987 • Mitoxantrone vs. daunorubicin • Leukemia 1990; Ann Hematol 1994 • Summary: Similar outcomes • Current trials: • Daunorubicin 45 mg/m2 vs. daunorubicin 90 mg/m2

21. Is There a Best Antracycline?(Age >60) • No standard • Rowe JM, et al. Blood. 2004;103:479. • Cytarabine 100 mg/m2 intravenously continuous infusion for 7 days • Daunorubicin 45 mg/m2 or mitoxantrone 12 mg/m2 or idarubicin 12 mg/m2 bolus intravenously for 3 days • No difference in efficacy or toxicity (35%-50% CR) • SWOG. Blood. 2002;100:3869. • Mitoxantrone and etoposide vs. daunorubicin and cytarabine • No benefit of ME over DA • MRC. Blood. 2001;98:1302. • DAT best but not direct comparison at same cytarabine doses • Summary: Similar outcomes

22. Survival by Anthracycline Type 100 DA n=116 MA n=114 80 IA n=118 60 Survival (%) 40 20 0 1 2 3 4 5 0 Years Rowe JM, et al. Blood 2004;103:479.

23. Is There a Best Dose of Cytarabine in Induction? • No evidence for a dose escalation above 100 mg/m2 • 100–200 mg/m2 standard • Addition of high-dose cytarabine to the induction regimen has not yet been shown to increase efficacy, but does increase toxicity

24. Consolidation Therapy for AML • Age <60 years • At least 3 cycles of HiDAC (3g/m2 bid D1,3,5) • Superior to 1 cycle of HiDAC • Superior to low-dose cytarabine maintenance • Superior to no post-remission therapy • Role of stem cell transplant • Age >60 years • No randomized trial shows any post-remission therapy better than no therapy • But . . . all studies showing long term survival include consolidation • Single cycle of HiDAC • Repeated cycles of induction therapy • Low-dose cytarabine maintenance • IL-2 and histamine maintenance

25. Summary: AML Remission Induction Therapy • Combination therapy • Cytarabine plus an anthracycline (daunorubicin, idarubicin, or mitoxantrone) • “7+3” schedule • Remission induction rates • 70% to 80% in patients 18 to 40 years of age • 60% to 70% in patients 40 to 60 years of age • 40% to 50% in patients >60 years of age • Standard consolidation includes cycles of HiDAC • 30% to 45% long-term relapse-free survival <60 years • No clear benefit for age >60 years Stone RM. CA Cancer J Clin. 2002;52:363.

26. New Approaches in AML Induction • Immunotherapeutic approaches • Gemtuzumab ozogamicin • IL-2 and histamine dihydrochloride • Cell-signaling modulation • FLT3 inhibitors (tyrosine kinase target) • Farnesyltransferase inhibitors • Drug-resistance modulation • PSC-833 • Bcl-2 antisense (oblimersen) • Zosquidar (LY335979) • Anti-angiogenic therapy • Proteosome inhibition (bortezomib)

27. IgG4 anti-CD33 Linker O O O Me Me NH O S NHN HO Me CH3 O NH O S CH3 I O S OCH3 CH3 O O O H HN OCH3 OH O HO O CH3 CH3 CH2 O OCH3 O HO OCH3 N OH OCH3 CH3 O Calicheamicin derivative DNA minor groove binding Gemtuzumab Ozogamicin (GO) • Recombinant, humanized murine monoclonal anti-CD33 antibody • CD33 expressed on 90% of blasts from patients with AML • Absent from normal hematopoietic stem cells • Calicheamicin derivative is a cytotoxic antibiotic • Linked by hydrolyzable linker • Shown to be active in AML in first relapse >60 years

28. GO + Chemotherapy in De Novo AML • Pilot study for MRC AML-15 trial • 64 patients aged 17 to 59 years treated with induction GO + chemotherapy • GO (3 or 6 mg/m2) with chemotherapy • DAT: daunorubicin, ara-C, thioguanine • DA: daunorubicin, ara-C • FLAG-Ida: fludarabine, ara-C, G-CSF, idarubicin • 86% achieved CR with course 1 of GO + chemotherapy • 78% of patients treated with GO + DA or FLAG-Ida are in continuous CR at median of 8 months • Combination with thioguanine increased hepatotoxicity Kell WJ, et al. Blood. 2003;102:4277.

29. Phase II Studies of GO + Chemotherapy for De Novo AML Age <60 years (n=53) 60 years (n=21) Dosing Daunomycin 45 mg/m2 Cytarabine 100mg/m2 Days 1,2,3 Days 1-7 Cytarabine 100 mg/m2 GO 6 mg/m2 Days 1 & 8 Days 1-7 GO 6 mg/m2 Day 4 Cyto- genetics Favorable 8% 0% Intermed 60% 72% Poor 32% 28% Unknown 6 3 DeAngelo. ASH 2003. Oral presentation.

30. GO + Chemotherapy: Efficacy <60 years 60 years Response Rates (n=53) (n=21) OR 81% 48% CR 79% 43% CRp 2% 5%* Median OS >15 months 13.4 months Median RFS 12.8 months 11.1 months *Platelet count 97,000/μL; patient lost to follow-up. DeAngelo. ASH 2003. Oral presentation.

31. GO + Chemotherapy: Toxicity <60 years 60 years (n=53) (n=21) Elevated bilirubin 17% 14% Elevated AST 19% 24% Elevated ALT 17% 14% VOD Induction induced 0% 0% HSCT associated >115 days after GO* 0%  <115 days after GO† 56%  *Includes 8 allogeneic, 2 mini-allogeneic, and 2 autologous HSCT †9 allogeneic HSCT DeAngelo. ASH 2003. Oral presentation.

32. GO for De Novo AML in Patients Age 65 Years or Older • Interim report on a Phase II trial of GO as induction, consolidation, and maintenance therapy in previously untreated patients with AML who were ≥65 years of age • n=12 (29 patients planned) • CR in 27% (3/11) evaluable patients • 7.6 months median duration of response • Generally well tolerated • No patient experienced grade 3 or 4 hepatic toxicity • No documented VOD or SOS • 5 patients developed transient LFT abnormalities Nabhan C, et al. Leuk Res. 2005;29:53.

33. Farnesyltransferase inhibitors in AML • ras mutations • Activating mutations of ras in 10% to 30% of AML patients • May lead to enhanced proliferation and survival • Inhibition of farnesyltransferase inhibits activation of ras protein • Inhibitors of farnesyltransferase in clinical development

34. Tipifarnib (R115777): Phase II Trial in De Novo AML • 104 patients with previously untreated high-risk AML and MDS • 94 patients with AML • 4 patients with MDS • 6 patients with CMML • High risk defined as: • Age >65 years • Age >18 years with poor cytogenetics • Secondary AML • Dosage: 600 mg p.o. BID for 21 days every2 to 4 weeks Lancet JE et al. Blood. 2003;102:176a. Abstract 613.

35. Tipifarnib: Clinical Activity in De Novo AML (n=92) • 21% CR • 33% OR (CR + PR) • 36% OR in patients >75 years • Median OS 5.8 months • Median OR in responding patients has not been reached, with 60% alive at 15 months • Toxicity • Grade 4 toxicity occurred in 13% of patients, mainly infection during neutropenia Lancet JE et al. Blood. 2003;102:176a. Abstract 613.

36. Trials of Drug Resistance Reversal in AML • Cyclosporine A is a potent inhibitor of p-glycoprotein (MDR1) • PSC-833 is a non-immunosuppressive cyclosporine analog • Randomized trials of PSC-833 in combination with chemotherapy in patients with relapsed/refractory disease did not show benefit • CALGB trial in older adults stopped early because of therapy-related deaths in PSC-833 group • A SWOG trial in relapsed/refractory AML with continuous infusion DnR/HiDAC +/– CyA showed no difference in CR rate but lower relapse rate resulting in survival advantage • CALGB trial of ADE +/– PSC-833 in patients aged 18-59 years recently closed Baer MR, et al. Blood. 2002;100:1224-1232.2. Kolitz JE, et al. Blood. 2001;98:461a.

37. Current Comparative Clinical Trials Investigating Induction Chemotherapy • Age <60 • ECOG: dauno (45mg/m2)/ara-C vs. dauno (90mg/m2) • SWOG: dauno/ara-C +/– GO • EORTC: ida/ara-C vs. ida/HiDAC • HOVON: ida/ara-C vs. ida/HiDAC +/– G-CSF • MRC: dauno/HiDAC vs. FLAG-ida +/– GO

38. Current Comparative Clinical Trials Investigating Induction Chemotherapy • Age >60 • CALGB: dauno/ara-C +/– oblimersen (Bcl-2 antisense) • ECOG: dauno/ara-C +/– zosquidar (MDR modulator) • SWOG: dauno/ara-C +/– cyclosporine A • EORTC: ida/ara-C +/– GO • HOVON: dauno (45mg/m2)/ara-C vs. dauno (90mg/m2) • MRC: dauno/ara-C vs. Hydrea/low-dose ara-C +/– ATRA

39. AML Induction Therapy Conclusions • AML remains a challenging disease to induce into complete remission, particularly for older patients • Many targeted approaches in combination with anthracycline and cytarabine hold promise for improved patient outcomes

40. TREATMENT OPTIONS IN AML: A PRACTICAL CASED-BASED APPROACH Corporate Friday Symposium Manchester Grand Hyatt Randle Ballroom C-E Friday, December 3, 2004 7:00am-11:00am

41. The Role of Transplantation in Acute Myelogenous Leukemia (AML) Michael W. Schuster, M.D.

42. Case Presentation • 45-year-old Wall Street investment banker presents to the ER with fevers and epistaxis. He is found to have a WBC count of 18,000 with 80% blasts and a platelet count of 4,000. A bone marrow aspirate and biopsy confirm the dx of M0 AML. Cytogenetics reveal monosomy 7, and he goes into prompt remission following “7&3” induction chemotherapy. A younger brother with a “wild lifestyle” is a perfect HLA match.

43. “We show that patients assigned to allo-SCT have a significantly better outcome…” • EORTC-LG/GIMEMA AML-10 “The number of relapses were substantially lower in the autologous BMT group” • MRC 10 “We conclude that intensive consolidation chemotherapy should be considered the standard post-remission therapy in adults with AML in CR1” • GOELAM

44. Mixed Results With Transplantation as Consolidation • EORTC/GIMEMA study showed benefit to both auto and allo transplant arms • MRC 10 trial showed benefit to auto transplant arm • American Cooperative Group study showed no benefit to either auto or allo arm • GOELAM study showed no benefit to auto transplant arm

45. Autologous or Allogeneic Bone Marrow Transplantation (BMT) Compared With Intensive Chemotherapy in AML • EORTC GIMEMA study • Randomized 623 patients in complete remission • Autologous as well as allogeneic bone marrow transplantationresults in better disease-free survival than intensive consolidationchemotherapy with high-dose cytarabine and daunorubicin Zittoun RA, et al.N Engl J Med. 1995; 332:217.

46. Disease-free Survival After Autologous or Allogeneic BMT or a Second Course of Intensive Consolidation Therapy 100 90 Intensive therapy (n=126; 81 events) Autologous BMT (n=128; 64 events) 80 Allogeneic BMT (n=168; 70 events) 70 60 55%±4% 50 Disease-free Survival (%) 40 48%±5% 30 30%±4% 20 10 6 7 4 3 5 0 1 2 Years Intensive therapy 126 74 37 24 17 7 1 Autologous BMT 128 76 49 38 26 10 4 Allogeneic BMT 168 87 63 48 29 15 0 Zittoun R. A. et al. N Engl J Med. 1995;332:217.

47. Overall Survival After a First Complete Remission With Autologous or Allogeneic BMT or a Second Course of Intensive Consolidation Therapy 100 Intensive Therapy (n = 126; 57; events) Autologous BMT (n = 128; 50 events) Allogeneic BMT (n = 168; 61 events) 90 80 70 60 59%±4% 56%±5% 46%±5% 50 Overall Survival (%) 40 30 20 10 4 5 6 7 2 3 1 0 Year Patients at Risk Intensive Therapy 126 95 67 40 25 9 2 Autologous BMT 128 94 60 45 29 12 4 Allogeneic BMT 168 100 67 50 31 16 0 Zittoun R. A. et al. N Engl J Med. 1995;332:217.

48. Patients Younger than 46 Years with AML in First Complete Remission (CR1)EORTC/GIMEMAAML-10 trial • Of 1198 patients younger than 46 years of age,822 achieved CR • 734 patients received a single intensive consolidation (IC) course • 293 had a sibling donor and 441 did not • Allo-SCTand auto-SCT were performed in 68.9% and 55.8% • The DFS rates were 43.4% and 18.4%, respectively, in patients whose leukemia hadbad/very bad risk cytogenetics

49. DFS From CR According to Donor Availability 100 90 80 70 Relapse Death in CR 60 52.2% (±3.2%) 38.4% 17.41% 50 Percent Patients Alive in CR 42.2% (±2.6%) 52.2% 5.3% 40 30 20 P=.044 10 0 8 6 4 0 2 Years Events/Patients Number of patients at risk: • /441 171 91 28 No Donor • 126/293 336 80 33 Donor Suciu S, et al, Blood. 2003;102:1232.

50. DFS From CR According to Donor Availability in Four Cytogenetic Groups 100 100 Good Risk Intermediate Risk Relapse Death in CR Relapse Death in CR 80 65.7% (±5.9% 28.3% 6.0% 80 60 48.5% (±5.3%) 46.6% 5.0% 60 Percent Patients Alive in CR 62.1% (±7.2% 21.9% 26.9% 40 40 45.2% (±6.7%) 35.1% 19.7% 20 20 P=.51 P=.54 0 0 Years 0 2 4 6 8 0 2 4 6 8 Ev/Pt Number of patients at risk: Ev/Pt Number of patients at risk: 51/104 45 25 8 No Donor 32/61 25 11 3 Donor 23/73 45 25 9 No Donor 68/5 27 18 4 Donor 100 100 Bad/Very Bad Risk Unknown Risk Relapse Death in CR Relapse Death in CR 80 80 57.8% (±5.2%) 26.5% 15.7% 60 60 43.4% (±6.5%) 38.2% 38.4% Percent Patients Alive in CR 40 40 41.2% (±4.3%) 53.8% 5.0% 18.4% (±4.3%) 78.9% 3.2% 20 20 P=.0078 P=.0078 0 Years 0 6 8 0 2 4 2 6 0 4 8 Ev/Pt Number of patients at risk: Ev/Pt Number of patients at risk: 71/94 21 32 6 No Donor 32/61 28 39 8 Donor 84/170 60 29 5 No Donor 41/148 56 32 18 Donor