4. Historical Control(HC) CCG-1800s/1922 series vs. Current CCG-1950/60s(1956s) series EFS Outcome by Day 7 Marrow (Remission at End of Induction) 5 Year EFS: HC Current M1 80.4% 82.6% M2 74.0% 74.6% M3 67.9% 69.0% Probability Years Followed

5. CCG-1882: Augmented Therapy Improves EFS for Patients with an SER (M3 Marrow at day 7) Probability Years Followed (from Randomization) 8-Year EFS RHR BFM 52.3%(s.d. 6.5%) 1.9 Augmented BFM 70.2%(s.d. 6.7%) Baseline Augmented BFM (n=155) BFM (n=156) Log Rank p=.0006 Nachman et al., NEJM 338: 1663-1671, 1998 DATA UPDATED DEC 2004

11. MRD-SR .97, SE=.03 (N= 39, 1 event) MRD-MR .77, SE=.05 (N=160, 23 events) MRD-HR .38, SE=.06 (N=114, 57 events) AIEOP + ALL-BFM 2000, EFS (4 years) Risk Group HR 95 by MRD Risk Groups Pts enrolled Sep/Jul 00–Oct 04 (Status April 05) Data courtesy of Valentino Conter and Martin Schrappe years p: 1-2 .05 1-3 .0001 2-3 .0001 dsmc0405.tab 13APR05 P 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 1 2 3 4 5

12. Reducing Disease Burden Pre-Transplant Improves Outcomes Uzunel et al. Blood 2001

13. Residual Disease Monitoring at End Induction: Flow Cytometry Tumor Tumor Dx d29 POG ALinC17 to Date : > 2,000 samples received 95% compliance MRD Sensitivity 1/1000 - 1/10,000 24 hr turn around 28.6% of patients positive; Median .069%

14. End Induction Marrow 534/1937 (28%) of Cases Positive Overall No. of cases + <.01 .01-.1 .1-1.0 1.0-10 >10 Percent Leukemic Cells Michael Borowitz

15. Day 29 Flow MRD Correlates with NCI Risk Group % MRD + MRD level Median .043% LR Median .14% HR Michael Borowitz

16. Day 29 Flow MRD Correlates with Day 8 Morphologic Assessment of Response Day 8 Marrow Blasts % MRD + (n=1879) MRD level p<.001 Michael Borowitz

17. Prognostic Significance of MRD - 9906 n=79 n=156 EVENT-FREE SURVIVAL 0 20 40 60 80 100 0 1 2 3 4 5 Years Probability (%) MRD>.01% MRD Negative p-value=0.00304

18. Minimal Residual Disease 9906 169 21 33 24 p=.0054

21. Remission Re-induction Rates Remission induction/re-induction rates ~ 75% Early marrow relapse > 90% Late marrow relapse > 98% Newly diagnosed ALL

23. Higher Risk Relapse: Common Therapeutic Approaches Early Marrow/T-cell Late Marrow/Early EM Chemotherapy Alt Donor SCT Matched Related Donor Transplant Common Re-induction Block 1 Block 2 Block 3 Early Marrow Late Marrow Early CNS Early Testicular

24. Introduction of New Agents in Patients with Very High Risk of Treatment Failure Re-induction Block 1 Re-induction Block 2 Reduction Phase VCR, Pred, PEG, Adr Re-induction Block 3 ARA-C, ASP CTX, VP-16, MTX VCR, Pred, PEG, Adr ARA-C, ASP CTX, VP-16, MTX MRD Time MRD MRD Epratuzumab Pilot I New Agent Pilot Correlate with 4 month EFS

26. AALL01P2 Study Design Continuation Therapy MRD ARM A MRD MRD Block 2 MRD MRD ARM B Block 2 MRD Block 1 Block 1 Block 3 Block 3 On Study Randomization CNS + patients non-randomly assigned to ARM B DNA Arrays DNA Arrays

28. Correlation of MRD with Time of First Relapse: AALL01P2 Borowitz, et al. ASH 2004 .01 3/19 (16%) 9/15 (60%) 3 .009 9/21 (43%) 18/22 (82%) 2 .018 14/29 (48%) 31/41 (76%) 1 p value MRD+ Late Relapse MRD+ Early Relapse Time Point

29. Kinetics of MRD Response: Good Responders (34/46) (n=15) (n=8) (n=11)

31. New Agent Initiatives: Epratuzumab ADVL04P2 (Early Relapse) Block 1 Block 2 Block 3 Triple Induction Phase 2 Block 1 Block 2 Block 3 Triple Induction Reduction Phase 6 dose levels Phase 1 E-mab MRD Response

34. Acknowledgements Steve Hunger Naomi Winick Elizabeth Raetz Michael Borowitz