What is the Optimal Approach to CLL BR

What is the Optimal Approach to CLL, BR vs. FCR/FR? Michael J. Keating MD Anderson Cancer Center Presented by: Richard R. Furman Weill Cornell Medical College

Bendamustine Bifunctional Antineoplastic Agent CH 3 N Cl. H 2 C N N CO 2 H Alkylating Group Cl. H 2 C Purine-like Benzimidazole Ring Available in Germany, 1971 -1992 Unique in vitro anti-tumor profile Rummel M, J Clin Oncol. 2005; 23: 3383.

Fludarabine + Prednisone (1983 – 1993) Progression Free Survival Proportion Median PFS: 26 months

Survival Long Term Outcomes for FR: CALGB 9712 Months

Chlorambucil vs. Bendamustine in Untreated CLL: Progression-Free Survival Knauf WU. JCO. 2009; 27: 4378

GCLLSG CLL 2 M: BR in Untreated CLL Treatment: • Bendamustine 90 mg/m 2 days 1, 2 (cycles 1 -6) • Rituximab: 375 mg/m 2 (cycle 1) 500 mg/m 2 (cycles 2 -6) Study Characteristics: • 117 patients • No age limit (median=64; range 34 -78) • 73. 5% received all 6 cycles Fischer K. JCO 2012; 30: 3209.

CLL 2 M: BR in Untreated CLL: Event Free Survival median EFS = 33. 9 months Fischer K. JCO 2012; 30: 3209.

CLL 2 M: BR in Untreated CLL: Response Rates Response N=124 % ORR 103 88. 0 CR 27 23. 1 n. PR 2 1. 7 74 63. 2 SD 11 9. 4 PD - - PR Fischer K. JCO 2012; 30: 3209.

BR: Adverse Events, Grades 3+4 (pts) Adverse Event Hematologic Toxicities: Grade 3 (%) Grade 4 (%) 26. 5 25. 6 Leucopenia 15. 4 14. 5 Neutropenia 10. 3 9. 4 Thrombocytopenia 14. 5 7. 7 Anemia 15. 4 4. 3 Tumor lysis syndrome 2. 6 0 Allergic reaction 8. 5 0. 9 Infectious 6. 8 0. 9 Other non-hematologic 18. 8 0. 9

Phase III Trial of FC + / - Rituximab in Untreated CLL: GCLLSG CLL 8 Trial • Untreated • No age restriction • Active CLL requiring therapy R A N D O M I Z E (n = 817) Fludarabine 25 mg/m 2, d 1 -3 Cyclophosphamide 250 mg/m 2, d 1 -3 x 6 cycles Fludarabine 25 mg/m 2, d 1 -3 Cyclophosphamide 250 mg/m 2, d 1 -3 Rituximab 500 mg/m 2, d 1 (375 mg/m 2 initial dose) F O L L O W U P • Primary endpoint: PFS • No age limit • 74% of patients received all 6 courses of FCR Hallek M. Lancet 2010; 376: 1164

FCR vs. FC in Untreated CLL: GCLLSG CLL 8 Trial FCR FC p PFS 51. 8 m 32. 8 m <. 001 ORR 95. 1% 88. 4% . 001 CR 44. 1% 21. 8% <. 001 PR 51% 66. 6% <. 01 OS (3 yr) 87% 83% . 01 Hallek M. Lancet 2010; 376: 1164

GCLLSG CLL 8: FCR vs. FC Progression Free Survival Cumulative Survival 1. 0 Median PFS: FCR 57 months FC 33 months 0. 8 0. 6 Median follow-up: 5. 9 years 0. 4 0. 2 0. 0 Fischer K. ASH 2012.

CLL 8: Adverse Events (pts) Hallek M. Lancet 2010; 376: 1164

Response Comparison Response BR (%) FCR (%) 88. 0 95. 1 CR 23. 1 44. 1 PR 64. 9 51. 0 33. 9 mo 57. 0 mo ORR Median PFS

AE Comparison Adverse Event BR (%) FCR (%) Hematologic Toxicity 52. 1 96 Neutropenia 19. 7 55 Thrombocytopenia 22. 2 18 Anemia 19. 7 12 Infections 7. 7 46 Tumor Lysis Syndrome 2. 6 1

Patient Comparison Characteristic BR (%) FCR (%) Age > 65 48. 7 31 Binet Stage C 46. 2 31 Ig. VH unmutated 61. 8 63 Del 11 q / 17 p 26. 4 34 Zap-70+ 15. 7 42

FCR 300: First-line Outcomes Department of Leukemia UT MD Anderson Cancer Center Houston, TX

Response to FCR (NCI-WG: 300 Patients) Response ORR CR n. PR PR No response Early death # of Pts 285 217 31 (%) 95 72 10 37 13 2 12 4 1

Proportion Surviving FCR 300: PFS and OS P<. 0001 PFS OS Months

Proportion Progression-free FCR 300: PFS by IGHV Mutation Status Group IGHV-M Events Total 33 82 IGHV-UM 114 131 Unknown 39 87 P<. 0001 Months

FCR vs. BR: The Tally FCR Duration of follow up ORR CR PFS Toxicity Profile BR

CLL 10 GCLLSG: Randomized Trial of FCR vs. BR ASH 2013? fludarabine 25 mg/m 2 d 1 -3 cyclophosphamide 250 mg/m 2 d 1 -3 rituximab 375 mg/m 2 C 1, d 1 500 mg/m 2 C 2 -6, d 1 Untreated CLL (N = 564) Randomize bendamustine 90 mg/m 2 d 1, 2 rituximab 375 mg/m 2 C 1, d 1 500 mg/m 2 C 2 -6, d 1 Primary Endpoint: PFS @ 2 yr