1. Copyright © 2011 Research To Practice. All rights reserved. Interest in Topics Related to the Treatment of Patients with CLL (Percent Responding 9 or 10) 37% 35% 39% 44% 0%10%20%30%40%50% Initial therapy for patients >70 yo Cytogenetics and FISH Treatment of relapsed CLL Initial therapy for patients <70 yo New agents/ regimens

2. State of the Art Management of Chronic Lymphocytic Leukemia Michael Hallek University of Cologne

3. Professional Experience Required to “Tailor” CLL Therapy: Characteristics at Presentation Median age at diagnosis: 72 years 1 Elderly patients may be fit or have comorbidities 1 Ries LAG et al. SEER Cancer Statistics Review 1975–2005. 2 Yancik R. Cancer 1997; 80:1273–83. Age at CLL diagnosis (years) Patients 1 (%) Mean comorbidities 2 (all cancer types, n) ≤5411n/a 55–64192.9 65–74273.6 75+434.2 Mean no. of co-morbidities 2.9 3.6 4.2 n/a

4. Gribben JG. Blood 2009;114:3359-60; Balducci L, Extermann M. Oncologist 2000;5:224-37. Classification of Patients by a Comprehensive Geriatric Assessment (CGA) GO SLOW NO Suitable for standard treatment Suitable for reduced treatment Suitable for supportive care Cumulative Illness Rating Scale

5. Comparison of Fludarabine (F), Bendamustine (Ben), Alemtuzumab (Al) and Chlorambucil (Chl) as Single Agents Rai 2000 1 Hillmen 2007 2 Knauf 2009 3 Regimen N F Chl 179 193 Al 149 Chl 148 Ben 157 Chl 157 Median age, years646259606366 Rai Stage III-IV or Binet C, % 3941343329 Grade 3/4 ↓ ANC, % 271941252310.6 CR, %204242312 OR, %633783556831 Med. PFS (mo)201414.611.721.68.3 1 Rai KR et al. N Engl J Med 2000;343:1750–57. 2 Hillmen P et al. J Clin Oncol 2007;25:5616–23. 3 Knauf W et al. J Clin Oncol 2009;27:4378-84.

6. CLL5 Protocol, Patients >65 Years (Median 70) Eichhorst et al, Blood 114, 3382 (Oct 15, 2009) 193 patients were randomly assigned to receive fludarabine 25 mg/m 2 (5d IV q28d x 6 cycles) vs chlorambucil 0.4 mg/kg body weight (q15d x 12 mo) Overall survival, 46 mo vs 64 mo (p-value = 0.15) Eichhorst BF et al. Blood 2009;114(16):3382-91.

7. FC Improves Overall Survival in Non-High Risk CLL GCLLSG CLL4 protocol -375 patients (<66 years) with advanced CLL were randomly assigned to fludarabine 25 mg/m 2 x 5d IV q28d vs FC (fludarabine 30 mg/m 2 and cyclophosphamide 250 mg/m 2 x 3d IV q28d) -Complete remission rate, 24% vs 7% (p < 0.001) -Overall response rate, 94% vs 83% (p = 0.001) -Progression-free survival, 48 mo vs 20 mo (p = 0.001) -Treatment-free survival, 37 mo vs 25 mo (p < 0.001) Eichhorst BF et al. Blood 2006;107(3):885-91.

8. Outcomen6-year OSp-value F19054% F + (M or C)14059% R-FC30077% p = 0.37 p < 0.001 Improved Efficacy by Combining FC Chemotherapy with Rituximab (MD Anderson, historical comparison) Tam CS et al. Blood 2008;112:975–80. F = fludarabine; M = mitoxantrone; C = cyclophosphamide; R-FC = fludarabine, cyclophosphamide and rituximab

9. Median Progression-Free Survival N = 817 FCR, 57.9 mo vs FC, 32.9 mo Hazard ratio = 0.563 p < 0.0001 Hallek M et al. Lancet 2010;376:1164-74.

10. Median Overall Survival 408 patients were assigned to fludarabine, cyclophosphamide and rituximab (FCR) and 409 patients to fludarabine and cyclophosphamide (FC) FCR resulted in significant overall survival benefit: FC, 48.4 mo vs FCR, 60.7 mo Hazard ratio = 0.75 p = 0.039 At 4 years postrandomization: 75.5% alive on the FC arm 81.8% alive on the FCR arm Hallek M et al. Lancet 2010;376:1164-74.

11. FCRFC 3-yr OS* None: 83.8% 12q+: 95.8% 11q-: 93.7% 13q-: 94.9% 17p-: 38.1% 3-yr OS* None: 86.9% 12q+: 85.8% 11q-: 82.6% 13q-: 89.1% 17p-: 36.5% Overall Survival and Cytogenetic Abnormalities According to the Hierarchical Model * p < 0.05 Hallek M et al. Lancet 2010;376:1164-74.

12. N = 110 (7 pts not yet evaluable) Bendamustine plus Rituximab Fischer et al, ASH 2009;Abstract 205. ResponseN% ORR10090.9 CR 3632.7 nPR 3 2.7 PR 6155.5 SD 10 9.1 PD - -

13. Chlorambucil (Chl) plus Rituximab (R) in Older CLL Patients Hillmen et al, ASH 2010 Foa et al, ASH 2010 Trial Therapy n Response CRORSD/PD Chl-R (Foa) A54 (of 98)16.7%81.4%7.4% Chl-R (Hillmen) B1009 (9%)82 (82%)15 (15%) UK CLL4 (Chl only) C20012 (6%)132 (66%)60 (30%) A)CLB 8 mg/m 2 d1-7 q28d up to 8x + R 375 mg/m 2 c1-2, 500 mg/m 2 c3-8, followed by R-maintenance 375 mg/m 2 q 2 m for 2 yrs B)CLB 10 mg/m 2 d1-7 q28d up to 6x + R 375 mg/m 2 c1, 500 mg/m 2 c2-6 C)CLB like B without R

14. CD20 Targeting RITUXIMABOFATUMUMABGA101 STATUSLicensed Phase III TYPEChimericHumanized EPITOPEType I Type II ADCC+++++ CDC+++– CELL DEATH+±+++ Adapted from Lim et al, Haematologica 2010

15. CLL11 Protocol for Unfit, Slow Go Patients Chlorambucil combined with GA101 GChl Randomization Chlorambucil Chl Chlorambucil combined with rituximab RChl

16. Summary: Translation into Clinical Practice

17. Therapy of CLL 2011 StageFitness del(17p) p53mut Therapy Binet A-B, Rai 0-II, inactive Irrelevant None Active disease or Binet C or Rai III-IV Go go NoFCR YesAlloSCT Slow go NoCLB YesAl, HD R or O

18. CLL 2011: Second-Line Therapy Response to First-Line Therapy FitnessTherapy StandardAlternatives (trials) Refractory or progress within 2 years Go go Al, FA, FCR  Allo SCT Flavopiridol, lenalidomide, BR Slow go Change therapy (if possible, include in trial) Al for del(17p), FCRlite, BR, bendamustine, lenalidomide, ofatumumab, HD rituximab Progress after 2 years All Repeat first-line therapy

19. W&W Inactive Binet AActive disease + all Binet C, not del(17p) CLL12CLL10CLL11 Go goSlow go Which is the best score to define high risk? yesno CLBCLB + R BR FCR treatW&W Disease (MRD) eradication Longer survival Symptom control Longer disease-free survival CLB + GA101 Third Generation of Trials of the GCLLSG: Risk, Stage and Fitness Adapted

20. CD20 Targeting RITUXIMABOFATUMUMABGA101 STATUSLicensed Phase III TYPEChimericHumanized EPITOPEType I Type II ADCC+++++ CDC+++– CELL DEATH+±+++ Adapted from Lim et al, Haematologica 2010

21. Copyright © 2011 Research To Practice. All rights reserved. What is your usual preferred induction systemic regimen in a younger patient (60 years old) requiring treatment for CLL?

22. Copyright © 2011 Research To Practice. All rights reserved. What is your usual preferred induction systemic regimen in an older patient (age 75) requiring treatment for CLL?

23. Copyright © 2011 Research To Practice. All rights reserved. What Clinicians Want to Know A Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical Management of Select Hematologic Cancers Sunday, June 5, 2011 7:00 PM – 9:30 PM Chicago, Illinois Faculty Sergio Giralt, MD John P Leonard, MD Lauren C Pinter-Brown, MD Moderator Neil Love, MD Antonio Palumbo, MD Susan M O’Brien, MD Professor Michael Hallek