1. Best of ASH 2007 Acute Leukemias Charles Linker MD #439Tipifarnib for elderly AML #593Combination arsenic & ATRA for APL #297NPM predicts ATRA response in AML #7Dasatinib + Prednisone for Ph+ ALL #296Poor outcome of elderly AML

2. Tipifarnib (Zarnestra®) Induction for elderly AML Farnesyltransferase inhibitorFarnesyltransferase inhibitor Oral and well-toleratedOral and well-tolerated Conflicting results of prior trialsConflicting results of prior trials

3. French Tipifarnib Randomized Trial For elderly AML n = 457 n = 457 EligibilityEligibility Age > 70, not wishing aggressive chemo StratificationStratification Age 75, PS 0-1 vs 2 TreatmentTreatment Tipifarnib 600 mg BID for 21 of 28 days ResultsResults OS 3.6 vs 3.6 mo Tipifarnib CR 8%, MDCR 8 mo Harousseau, ASH 2007 #439

4. SWOG Tipifarnib Dose Trial For elderly AML n = 388 n = 388 EligibilityEligibility Age > 70, not wishing aggressive chemo WBC < 30,000 TreatmentTreatment Tipifarnib 4 different dose schedules ResultsResults No difference between doses CR 6% 1-year OS 20% Erba, ASH 2007 #440

5. CALGB 9710 Schema InductionInduction Daunorubicin, Ara-C, ATRA Experimental randomized armsExperimental randomized arms Arm A - observation Arm B - Arsenic trioxide 0.15 mg/kg IV x 50 doses 5 days/week x 5 weeks repeated twice with 2- week rest Consolidation x 2Consolidation x 2 Daunorubicin, ATRA MaintenanceMaintenance Powell, ASCO 2007

6. CALGB 9710 Results InductionInduction CR 427/480 (89%) Effect of arsenicEffect of arsenic 3-year EFS 81% vs. 66% (p = 0.0007) 3-year OS 86% vs. 79% (p = 0.035)

7. CALGB 9710 Results Low Int Int Hi Hi_p_ Complete Remission 94%93%75%<0.0001 Death during Induction 3%3%19% < 0.0001 Relapse < 1 year 2%3%9%0.01 Low WBC ≤ 10,000 and platelets > 40,000 Intermediate WBC ≤ 10,000 and platelets ≤ 40,000 High WBC > 10,000

8. EFS in Arsenic Arm Risk Groups 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 EFS 0102030405060708090 MONTHS Low Inter High p < 0.0001

9. ATRA alone, WBC >10K Survival DFS Time No Arsenic WBC <10K Arsenic WBC <10K Arsenic WBC >10K p = 0.0016, HR 2.24 No Arsenic WBC >10K DFS by Treatment Arm and Risk

10. Combination ATRA & Arsenic Shanghai, ASH 2006 InductionInduction ATRA + Arsenic to CR Consolidation Chemo x 3Consolidation Chemo x 3 Consolidation biologics x 5 coursesConsolidation biologics x 5 courses ATRA + Arsenic ResultsResults CR 93% (56/60) EFS 94% [FU 48mo (25-60)] OS 98% Liu, ASH 2006 #565

11. Oral Arsenic & ATRA Shanghai Arsenic tetra-sulfide is orally absorbedArsenic tetra-sulfide is orally absorbed As 4 S 4 InductionInduction Arsenic tetra-sulfide ATRA (if no leucocytosis) Chemotherapy if WBC > 4000/uL Consolidation chemo x 4-6 cyclesConsolidation chemo x 4-6 cycles MaintenanceMaintenance Arsenic tetra-sulfide & ATRA x 4 years Wu, ASH 2007 #591

12. Oral Arsenic & ATRA Induction ResultsInduction Results 68/68 CR Post-remission resultsPost-remission results 68 new CR + 46 previous CR = 114 patients median age 33 (10 - 73) median FU 36 mo (3 - 76) 4-year DFS 94%

13. RINGBBCoiled-CoilDNAHORMONE SUMO K160 D522 AF2 11S recruitment19S association NLS As 2 O 3 RA DEGRADATION (SUG-1) K490 Degradation of PML/RARA Zhu PNAS 1997 & 1999, Lallemand JEM 2001

14. Lallemand JEM 1999, Rego PNAS 2000 Mouse Model of APL Synergy of ATRA and Arsenic

15. Prognostic factors in AML Treatment of AML CR1, age < 60 is risk- adapted, by cytogeneticsTreatment of AML CR1, age < 60 is risk- adapted, by cytogenetics Favorable10% Intermediate risk 75%(50-60% normal cyto) High risk15% Molecular mutation analysis can better define prognostic subgroups within the large group of normal cytogeneticsMolecular mutation analysis can better define prognostic subgroups within the large group of normal cytogenetics

16. German AML Trials Role of NPM and FLT3 872 AML normal cyto NPM1 mut 53% FLT3-ITD mut31% FLT3-TKD11% CEBPA14% 666 CR1 (76%) NPM1+/ITD- prognostic for CR (p < 0.0001) Schlenk, ASH 2006 #4

17. German AML Trials 666 CR1  171 sib donor495 no donor  143 Allo SCT (84%)chemo vs ASCT

18. German AML Trials Role of NPM and FLT3 ITT analysis of donor vs no donor 4-year DFS and OS, Median FU 4.1 yrs NPM+/FLT3 ITD- DFS 61% (donor) vs 57%, p = NS DFS 61% (donor) vs 57%, p = NS HR for DFS 0.89, for OS.93 HR for DFS 0.89, for OS.93Others DFS 47% (donor) vs 23% *** HR.56 (.39 -.81) for DFS;.69 (.48 -.98) for OS

19. ATRA Trial AML Age > 60 German Study Group TrialGerman Study Group Trial AML age > 60AML age > 60 Explore role of ATRA in addition to chemoExplore role of ATRA in addition to chemo InductionInduction Ida, cytarabine, etoposide Consolidation x 1Consolidation x 1 Intermediate dose cytarabine Schlenk ASH 2007 # 297

20. ATRA Trial - 2 372 enrolled372 enrolled Age 67 (61 - 83) 67% de-novo, 33% secondary Standard Risk groupsStandard Risk groups Low 7%APL and inv16q Standard58%normal, non-complex High35%complex **

21. ATRA Trial - 3 242 randomized to ATRA vs none242 randomized to ATRA vs none Randomization stopped for no difference 130 others allocated to non-ATRA arm130 others allocated to non-ATRA arm

22. ATRA Trial Results NPM1+/ITD- is prognostic for CRNPM1+/ITD- is prognostic for CR HR 2.6 (1.2 - 5.5) ITT analysis of randomized patientsITT analysis of randomized patients Median FU 5.7 yrs 5-year OS5-year OS NPM1+/ITD-57% (ATRA) vs 6%, p= 0.002 *** Others 2% (ATRA) vs 2%

23. Molecular Subgroups of AML with normal cyto NPM1+/ITD- group is less frequent in older AMLNPM1+/ITD- group is less frequent in older AML NPM1+/ITD- group is more favorableNPM1+/ITD- group is more favorable NPM1+/ITD- group benefits from ATRANPM1+/ITD- group benefits from ATRA

24. Prednisone + Dasatinib for Ph+ ALL GIMEMA Study 1 week pre-phase with prednisone 60 mg/m21 week pre-phase with prednisone 60 mg/m2 Continue for 1 month Dasatinib 70 mg bid x 12 weeksDasatinib 70 mg bid x 12 weeks Patient FeaturesPatient Features Median age 56 (30 - 73) ResultsResults 27/27 CR With FU of 7 mo, 7/22 completing therapy relapsed Foa, ASH 2007 #7

25. Post-remission therapy AML CR1, age > 60 Background CALGB AML age > 60 with cytogeneticsCALGB AML age > 60 with cytogenetics n = 600 CR 50% 5-year OS 7% Cytogenetics predictive of outcome No signs of progress in chemotherapyNo signs of progress in chemotherapy New approaches are warrantedNew approaches are warranted Baer, ASH 2007 #296

26. OS by Cytogenetics

27. OS by Age

28. AML CR1 age > 60 Background - 2 Results in best group are still poor (n = 276)Results in best group are still poor (n = 276) Age 60-75 Receive first consolidation on randomized trial 2-year DFS 24%2-year DFS 24% 3-year DFS 17%3-year DFS 17%

29. CALGB 100103 mini-allo for AML CR1, age > 60 AML CR1AML CR1 Prior MDS, t-AML allowed Age 60-74Age 60-74 Sibling or unrelated donorSibling or unrelated donor ObjectiveObjective 2-year DFS > 35%