1. FDA ODAC AML in Older Individuals Frederick R. Appelbaum, MD May 5, 2005

2. Age-related Incidence of AML and ALL

3. Performance Status and Age in AML N = 437 AgePerformance Status 0123 56-60.28.49.11.8 61-65.27.42.17.12 66-70.26.48.19.13 71-75.23.49.16.11 76+.16.47.18

4. Age, Performance Status and Early Death in AML N = 437 Performance Status Death within 30 days 56-60 61-70 71+ 00%13%9% 10%14%21% 238%19%42% 317%24%62%

5. Performance Status Death within 30 days Age, Performance Status and Early Death in AML N = 437 Age

6. Age, Performance Status and Complete Response Rate in AML N = 437 PerformanceComplete Response Status56-6061-70+70 070%40%50% 160%49%38% 225%38%27% 350%41%29%

7. AML in Older Patients 1.More often preceded by myelodysplasia 2.Less proliferative 3.More frequently associated with unfavorable cytogenetics 4.Expresses multidrug resistance more often

8. Hematologic Values at Diagnosis Age < 5656-6566-75> 75 N38122224968 Hgb9.19 9.2 WBC17.713.710.012.7 PLT49 6158 % blasts39272426

9. Southwest Oncology Group Leukemia Committee Percentage of Patients in Cytogenetic Risk Groups by Age Category

10. Cytogenetics by Age Age < 5656-6566-75> 75p -5 or 5q (%)6151426<.0001 -7 or 7q8191822<.0001 17p29711=.0001 t(8;21)7420=.0087 inv(16)9247=.0011

11. MRK Staining Age < 5656-6566-75> 75 MRK+ (%)33626157

12. Complete Response in Older AML Patients 1 FeatureNCR%p (univariate) AML onset 2°2°5024.0005 1°1°16152 CD34 expression +13838.0027 -6659 MRK16 Bright10234.0019 Dim3345 Negative5467 Cytogenetics Unfavorable5221<.0001 Other11255 Functional Efflux Positive10135.0039 Negative7458 1 Leith et al. Blood, 89:3323-3329, 1997

13. Factors Associated with Lower CR Rates in Older AML Patients (multivariate) 1 N =211 Factorp value 2°AML.0035 Unfavorable cytogenetics.0031 MDR1 expression.0041 Patients with all three factors had a CR rate of 11% versus a CR rate of 81% in patients without all three. 1 Leith et al., Blood 89: 3323-3329, 1997

14. MCR AML 11 1 Induction – DAT vs. ADE vs. MAC ± G-CSF Consolidation – 2 cycles vs. 6 cycles 1 Goldstone et al., Blood 98: 1302, 2001

15. MRC AML 11 N1314 Age56-91 AML onset de novo81% 2°2°15% treatment related4%

16. MRC AML 11 Outcome CR62% Death in CR7% Relapse risk78% DFS at 5 years15%

17. Survival on MRC AML 11 by Induction Treatment

18. Factors Predictive of Outcome in Multivariate Analysis from MRC AML 11 ParameterEndpoint CROS Cytogenetics2 x 10 -14 8 x 10 -11 WBC4 x 10 -6 6 x 10 -13 Age2 x 10 -5 1 x 10 -4 2°2°5 x 10 -7 1 x 10 -6 Performance status3 x 10 -4 2 x 10 -6

19. Summary Using conventional chemotherapy, complete response rates of 50% and a median survival of 9 months can be expected in patients over age 55 with AML. However, patient and disease-related factors vary greatly and heavily influence treatment outcome. Particularly important are: Age Performance status 1° vs. 2° presentation Cytogenetics MDR status