Can Kinase Inhibitors and Immunomodulators Replace Chemotherapy? No Michael J. Keating MD Anderson Cancer Center Presented by: Susan O’Brien

Response to FC + Rituximab (NCI-WG: 300 Patients) Response* # Pts. ( % ) CR 217 (72%) Nodular PR 31 (10%) 95% PR 37 (12%) No Response 13 ( 4%) Early Death 2 ( 1%) * Evaluated 6 months after last course

CLL8 Study Design 6 courses FCR R FC Patients with untreated, active CLL, and good physical fitness (CIRS ≤6, creatinine clearance ≥70 mL/min) R FCR FC 6 courses Follow- up C1 C2 C3 C4 C5 C6 Updated results of the 2nd analysis Median observation time 37.7 months. Hallek et al. Lancet. 2010;376:1164-1174.

FC (%) FCR (%) P FC vs FCR: Response CR 23 45 <0.01 CRu 5 3 0.22 CRi 2 0.52 nPR 0.15 PR 50 40 OR 85 93 Hallek et al. Lancet. 2010;376:1164-1174.

CLL8 Update PFS N-817 Median PFS: FC: 32,9 months FCR: 57,9 months HR: 0,56 95%CI:0.465-0.673; P<0.0001 Fink, et al. ASH 2011, Abstract 977

CLL8 Trial: 1st Line FC vs. FCR Overall survival: HR= 0.68; p= .001 Median follow-up= 70 months Fischer et al. Updated, ASH 2012, Abstract 435

Are there any patients with CLL for whom FCR is NOT the Standard of Care?

CLL8 Genetic Analyses: PFS EHA Educational Talk 2013 21 September 2008 CLL8 Genetic Analyses: PFS FC FCR CLL8 Investigator Meeting 21 September 2008

CLL8 Study Design 6 courses FCR FC Follow R up Patients with untreated, active CLL and good physical fitness (CIRS  6, Creatinine clearance  70 ml/min) Updated results of the 2nd analysis Median observation time 37.7 months. Hallek et al Lancet 2010;376:1164-74

CLL8: Side Effects: the Effect of Age FC FCR < 70 yrs n = 359  70 yrs n = 37 p < 70 yrs n = 361  70 yrs n = 43 Total AEs gr 3/4 61.0% 78.4% 0.04 75.6% 83.7% 0.24 Anemia 6.7% 8.1% 0.74 5.5% 4.7% 0.81 AIHA 1.1% 0.0% 0.52 0.6% 2.3% 0.20 Leukocytopenia 12.0% 13.5% 0.79 24.9% 16.3% 0.21 Neutropenia 19.5% 35.1% 0.03 32.4% 44.2% 0.12 Thrombopenia 11.4% 5.4% 0.26 7.8% 0.46 Infections, unspecified 9.5% 13.0% 18.6% 0.31 Infections, bacterial 0.7% 0.02 1.9%

SOB’s Quick Survey All patients with CLL > 70 years seen by me in clinic last month: N = 14 Eligible for CLL8 trial? 3 too old, > 80 years, so N = 11 Meet creatinine clearance requirement? N = 4 So 4/14 = 29% eligible Not counting CIR score

FCR300: Progression-free & Overall Survival Median follow up time All - 9.8 yrs Alive - 11.5 yrs Proportion Surviving Events Total Median 186 300 6.5 yrs 113 300 11+ yrs Months

First-line FCR: NCI-WG Response & Bone Marrow MRD-free Status % of Patients % MRD- Negative* CR 153 65 75 nPR 29 12 4 PR 48 20 44 NR 7 3 Overall MRD 220 93 59 * Bone marrow evaluation by 4-color flow cytometry (sensitivity .01%)

First-line FCR: PFS & OS by MRD Status Progression-free Survival Overall Survival Proportion of Patients p<.0001 p=.0004 Months

First-line FCR: Multivariable Model for BM MRD-free Status (N=181) Pretreatment Characteristic p-value IGHV – Mutated .003 Rai Stage – 0-II .016 Trisomy 12 .02 No 17p del .04

FCR300: PFS by IGHV Mutation Status Group Events Total IGHV-M 33 82 IGHV-UM 114 131 Unknown 39 87 Proportion Progression-free P<.0001 Months

53rd ASH Annual Meeting, 10.-13. Dec. 2011, San Diego Prediction of Poor Outcome in CLL Patients Treated with FCR (Fludarabine, Cyclophosphamide, Rituximab) in the CLL8 Trial of the German CLL Study Group (GCLLSG) Anna Fink, MD1, Raymonde Busch2, Natali Pflug, MD1, Sebastian Boettcher, MD3, Dirk Winkler, MD4, Andreas Buehler, MD4, Matthias Ritgen, MD3, Kirsten Fischer, MD1, Barbara Eichhorst, MD1, Clemens-Martin Wendtner, MD1,5, Myriam Mendila, MD6, Michael K. Wenger, MD6, Hartmut Doehner, MD4, Michael Kneba, MD3, Stephan Stilgenbauer, MD4 and Michael Hallek, MD1 1Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital, Cologne, Germany; 2Institute for Medical Statistics and Epidemiology, Technical University Munich, Germany; 3Campus Kiel, 2nd Dept. of Internal Medicine, University of Schleswig-Holstein, Kiel, Germany; 4Internal Medicine III, University of Ulm, Germany; 5Department of Hematology, Oncology, Immunology, Palliative Care, Infectiology and Tropical Medicine, Hospital Munich-Schwabing, Munich, Germany; 6Pharmaceutical Division/Global Drug Dev., F. Hoffmann-La Roche Ltd., Basel, Switzerland; 53rd ASH Annual Meeting, 10.-13. Dec. 2011, San Diego Fink, et al. ASH 2011, Abstract 977

Defining High-risk for Early Progression in Patients Treated with First-line FCR (CLL8) Early progression defined as progression within 24 months of FCR MRD level of >10-2 OR MRD level of >10-4 to <10-2 plus at least one of the following three parameters (del(17p) OR TP53 mutation OR unmutated IGHV-status Fink, et al. ASH 2011, Abstract 977

PFS and OS in High-risk vs. Low-risk First-line FCR (CLL8) Progression Free Survival Low risk High risk Low risk High risk Proportion without progression Total n=143, HR n=40, LR n=103 OS High risk vs low risk Total n=143, HR n=40, LR n=103 Time since randomization in months Fink, et al. ASH 2011, Abstract 977

FCR300: Progression-free & Overall Survival Median follow up time All - 9.8 yrs Alive - 11.5 yrs Proportion Surviving Events Total Median 186 300 6.5 yrs 113 300 11+ yrs Months