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

Age-related Incidence of AML and ALL

Performance Status and Age in AML N = 437 AgePerformance Status

Age, Performance Status and Early Death in AML N = 437 Performance Status Death within 30 days %13%9% 10%14%21% 238%19%42% 317%24%62%

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

Age, Performance Status and Complete Response Rate in AML N = 437 PerformanceComplete Response Status %40%50% 160%49%38% 225%38%27% 350%41%29%

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

Hematologic Values at Diagnosis Age < > 75 N Hgb WBC PLT % blasts

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

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

MRK Staining Age < > 75 MRK+ (%)

Complete Response in Older AML Patients 1 FeatureNCR%p (univariate) AML onset 2°2° °1°16152 CD34 expression MRK16 Bright Dim3345 Negative5467 Cytogenetics Unfavorable5221<.0001 Other11255 Functional Efflux Positive Negative Leith et al. Blood, 89: , 1997

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: , 1997

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

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

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

Survival on MRC AML 11 by Induction Treatment

Factors Predictive of Outcome in Multivariate Analysis from MRC AML 11 ParameterEndpoint CROS Cytogenetics2 x x WBC4 x x Age2 x x °2°5 x x Performance status3 x x 10 -6

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