Spotlight on Chronic Lymphocytic Leukemia and Indolent Non-Hodgkin's Lymphoma: European and US Perspectives on the Evolving Standard of Care Bruce Cheson, MD Professor of Medicine, Head of Hematology Georgetown University Hospital The Lombardi Comprehensive Cancer Center Washington, DC Kanti Rai, MD Division of Hematology-Oncology The Long Island Jewish Medical Center New York, NY Mathias Rummel, MD, PhD Head, Department for Hematology and Medical Oncology The Justus-Liebig-University Hospital Giessen, Germany Clemens Wendtner, MD Professor of Medicine, Department of Internal Medicine and Head of Laboratory of Molecular Biology and Immunology of CLL The University Hospital of Cologne, Germany

GCLLSG CLL8 Phase 3 Trial FC vs FCR N = 817 (Age med : 61 yr; Binet stage A: 5%, B: 64%, C: 32%; -17p: 8%) Hallek M, et al. ASH Abstract 535. FC (n = 409) FCR (n = 408) P CR 21.8%44.1%<.001 Median PFS 32.8 mo51.8 mo<.001 OS 79.0%84.1%.01 Median Observation Time = 37.7 months The largest benefit for FCR was observed in Binet stage A and B FCR did not improve the PFS or OS of patients with a del(17p) FCR caused more neutropenia without increasing rate of severe infections

Progress in CLL Therapy F → FC/M → FCR Tam CS, et al. Blood. 2008;112: Historical Comparison From the M.D. Anderson Cancer Center Time, months Overall Survival

FC vs FCR Patients With Rai III/IV CLL Parikh SA, et al. ASCO Abstract Historical Comparison From the M.D. Anderson Cancer Center FC (n = 38) FCR (n = 102) P CR 29%66%.001 Median PFS 36 mo79 mo.000 Median OS 55 mo120 mo.004 Compared with historical patients treated with FC, FCR was associated with significantly improved response rates and survival

GCLLSG Phase 2 Trial in Advanced CLL Bendamustine and Rituximab as First-line Therapy N = 117 (Age med : 64 yr; Binet stage A: 11.1%, B: 41.0%, C: 47.9%) Fischer K, et al. ASH Abstract 205. Median Observation Time = 15.4 months BR ORR 90.9% CR 32.7% PR 55.5% SD 9.1% In patients with unmutated IgV H, ORR = 88.9% In patients with a del(17p), ORR = 42.9% Major side effects (myelosuppression and infections) were infrequent After 18 months, PFS med has not been reached B (90 mg/m² on days 1 and 2) + R (375 mg/m² for the first cycle and 500 mg/m² for subsequent cycles) BR administered every 28 days (6 courses max.)

Bendamustine-R vs R-CHOP (StiL Trial) Randomized Phase 3 Study N = 549 Rummel MJ, et al. ASH Abstract untreated patients randomized R (375 mg/m 2 ; day 1→every 28 days) + CHOP (standard regimen, every 21 days) 6 cycles max. FL=55%, MZL=12%, WM=8%, SLL=4%, MCL=19% Stage IV (77.5%), III (18.6%) Primary Endpoint: PFS

N = 549 (n = 513) Rummel MJ. ASCO 2010/ASH Joint Session. Bendamustine-R vs R-CHOP (StiL Trial) Safety: Final Results Adverse EventB-RR-CHOPP Neutropenia grade 3+4 (%) <.0001 Leukocytopenia grade 3+4 (%) <.0001 Alopecia (%) <.0001 Infectious complications (n) Paresthesia (n)1873<.0001 Stomatitis (n)1647<.0001 Urticaria and rash (n)

B-R (n=260) R-CHOP (n=253) P ORR92.7%91.3%NA CR39.6%30.0%.0262 N = 549 (n = 513) Rummel MJ. ASCO 2010/ASH Joint Session. Bendamustine-R vs R-CHOP (StiL Trial) Efficacy: Final Results B-R has the potential to become a new standard first-line treatment option for patients with FL, MCL, and other indolent lymphoma types PFS

Front-line Choices for Indolent NHL and CLL: FC, CHOP, or Bendamustine? Practicing physicians in the United States and Europe are likely to use more bendamustine in the future.

Front-line Lenalidomide Elderly Patients With CLL N = 60 (Age med : 71 yr; Rai stage III-IV: 30%; -17p or -11q: 33%; unmutated IgV H : 60%) Badoux X, et al. ASCO Abstract ORR 60% CR 8% nPR 8% PR 43% 5 mg orally daily for the first 56 days → titrated ≤ 25 mg/day as tolerated in 5-mg increments Every cycle (28 days)

Front-line Lenalidomide and Rituximab Patients With CLL: Early Report N = 37 (n = 30) (Age med : 62 yr; Rai stage III-IV: 50%; -17p or -11q: 9%; unmutated IgV H : 50%) James DF, et al. ASCO Abstract Lenalidomide started at 2.5 mg/d → 5 mg and 10 mg on day 8, if tolerated (L 21/35 days [cycle 1] → 21/28 days [cycles 2-7]) Rituximab 50 mg/m 2 day 29, 325 mg/m 2 day 31, 375 mg/m 2 day 33 (cycle 1) → 375 mg/m 2 weekly x 4 (cycle 2) and on day 1 (cycles 3-7) Early results of the ongoing study suggest that lenalidomide/rituximab immunotherapy is tolerable

L-R ORR86% CR + CRu79% PR7% SD14% After 6 cycles of therapy, 1 patients with FL achieved CR The grade 3/4 AEs included rash (6 pts), neutropenia (7 pts), myalgia (4 pts), neuropathy (1 pt), infection (1 pt), and fatigue (1 pt), and thrombosis (1 pt) N = 30 (n = 28; age med : 56 yr) Fowler N, et al. ASCO Abstract Lenalidomide + Rituximab Front-line Therapy of Indolent B-Cell NHL

Ofatumumab-FC in Previously Untreated CLL Randomized, 2-Dose, Phase 2 Trial N = 61 (Age med : 56 yr; Rai stage III/IV: 39% [Gr. A], 53% [Gr. B]; -17p: 6% [Gr. A], 20% [Gr. B]; unmutated IgV H : 52% [Gr. A], 30% [Gr. B]) Wierda WG, et al. ASCO Abstract Ofatumumab Group A, 500 mg (n = 31) Group B, 1000 mg (n = 30) ORR 77%73% CR 32%50% O-FC is highly active at both ofatumumab doses investigated AEs were manageable with no unexpected toxicities After 8 months, PFS med has not been reached Ofatumumab (500 mg or 1000 mg)* on day 1 + Fludarabine (25 mg/m 2 IV daily; days 1-3) + Cyclophosphamide (250 mg/m 2 IV daily; days 1-3) Administered every 28 days (6 courses max.) *In both groups, the first dose of ofatumumab was 300 mg

Novel Options for Rituximab-Refractory Patients Another Anti-CD20 mAb Probably Not the Right Solution

O-CHOP in Previously Untreated FL Randomized, 2-Dose, Phase 2 Trial N = 59 (n = 58; age med : 55 yr [Gr. A], 54 yr [Gr. B}; FLIPI score 3-5: 34% [Gr. A], 38% [Gr. B]) Czuczman M, et al. ASCO Abstract Ofatumumab Group A, 1500 mg (n = 29) Group B, 1000 mg (n = 29) ORR90%100% CR + CRu69%55% At median follow-up of 9.7 months, high response rates achieved Effective across all FLIPI risk groups Well tolerated with no unexpected toxicities Ofatumumab (1500 mg or 1000 mg)* on day 1 + Cyclophosphamide (750 mg/m 2 ; day 3) + Doxorubicin (50 mg/m 2 ; day 3) + Vincristine (1.4 mg/m 2 ; day 3) + Prednisolone (100 mg; days 3-7) Administered every 3 weeks (6 courses max.) *In both groups, the first dose of ofatumumab was 300 mg

VBR Preliminary Results ORR84% CR47% PR37% The most common treatment-related AEs were primarily grade 1 and 2 and included nausea (79%), fatigue (65%), diarrhea (57%), and vomiting (44%) Of the 27% pts with treatment-related PN, only 6% had grade 3 (no grade 4) VBR is active in this heavily pretreated, high-risk population and is generally well tolerated N = 63 (≥ 4 doses of R, but no V or B; 39% refractory to R; 35% high FLIPI score) Fowler N, et al. ASH Abstract 933. Phase 2 VERTICAL Study VBR in Patients With Relapsed or Refractory FL V (1.6 mg/m 2 ; days 1, 8, 15, 22) + B (90 mg/m 2 ; days 1, 2) + R (375 mg/m 2 ; days 1, 8, 15, 22, cycle 1; day 1, cycles 2-5) 5 (35 days) cycles max.

N = 1217 Salles GA, et al. ASCO Abstract PRIMA Phase 3 Study Rituximab Maintenance Therapy in Untreated FL 2 years of rituximab maintenance therapy after induction immunochemotherapy in previously untreated FL significantly improves PFS with little additional toxicity

Cross-fertilization between the US and Europe –Europe → US: bendamustine –US → Europe: lenalidomide –Europe: large randomized trials –US: new drug development Strategic planning between European and US investigators –Avoid duplication of studies –Move toward the more efficient development of better treatment regimens –Improve patient outcomes Evolving Standard of Care European and US Perspectives