RCHOP for Frontline Follicular Lymphoma John P Leonard

R-CHOP for Frontline Follicular Lymphoma John P. Leonard, M. D. Richard T. Silver Distinguished Professor of Hematology and Medical Oncology Associate Dean for Clinical Research Vice Chairman, Department of Medicine

Disclosures Consulting advice: Seattle Genetics, Abbott, Sanofi Aventis, Repligen, Johnson and Johnson, Pharmacyclics, Amgen, Biotest, Millenium, Celgene, Helsinn, GSK, Hospira, Boehringer Ingelheim, Genentech, Onyx, Teva, Medimmune, Gilead, Spectrum, Emergent, Cell Therapeutics

Issues to consider in selection of frontline therapy for FL l Indications for therapy l Bulk of disease l Comorbidities l Toxicity concerns l Interest in and availability of clinical trials l R/O transformation

Progress in follicular lymphoma Bendamustine Progression-Free Survival % 100 Radioimmunotherapy 80 SCT 60 Novel agents Chemo + R + maintenance R 40 Chemo + R 20 Chemo 0 0 Time

2 opposite FL management approaches: · Aggressive strategies – Objective of treatment – cure or extended survival – CHOP-R (B-R) + R maintenance or RIT or other – Hoping that more intensive strategy will pay off – Downside – more toxicity in short term · Gentler strategies – Objective of treatment – disease control, less toxicity – Rituximab + other biologics – Hoping that less intensity will improve QOL – Downside – is it less effective in long term ?

RELEVANCE study LYSA (France) + Celgene Previously Untreated Follicular NHL R A N D O M I Z E Lenalidomide + Rituximab Chemotherapy + Rituximab

PRIMA: study design INDUCTION MAINTENANCE Rituximab maintenance 375 mg/m 2 every 8 weeks for 2 years‡ Registration High tumor burden untreated follicular lymphoma Immunochemotherapy 8 x Rituximab + 8 x CVP or 6 x CHOP or 6 x FCM CR/CRu PR PD/SD off study Random 1: 1* Observation‡ * Stratified by response after induction, regimen of chemo, and geographic region ‡ Frequency of clinical, biological and CT-scan assessments identical in both arms Five additional years of follow-up

Primary endpoint (PFS): 36 months follow-up Progression-free rate 1. 0 0. 8 75% Rituximab maintenance 0. 6 58% 0. 4 Observation Stratified HR = 0. 55 95% CI: 0. 44– 0. 68 p < 0. 0001 0. 2 0. 0 0 6 12 18 24 30 36 42 48 54 60 84 70 17 16 0 0 – – Time (months) Patients at risk 505 513 472 469 445 415 423 367 404 334 307 247 207 161

Bendamustine-Rituximab (B-R) vs CHOP-R Sti. L NHL 1 -2003 Bendamustine-Rituximab Follicular Waldenströms Marginal zone Small lymphocytic Mantle cell R CHOP-Rituximab Bendamustine 90 mg/m 2 day 1+2 + R day 1, max 6 cycles, q 4 wks. CHOP-R, max 6 cycles, q 3 wks. Rummel et al, Lancet 2013

B-R vs R-CHOP for upfront FL • B-R – 261 subjects enrolled analyzed – 139 subjects with FL • CHOP-R – 253 subjects enrolled analyzed – 140 subjects with FL Rummel et al, Lancet 2013

B-R vs R-CHOP for upfront FL Toxicity • B-R – Less alopecia, heme tox, infection, neuropathy, stomatitis • CHOP-R – Less rash • Nausea – not reported Rummel et al, Lancet 2013

B-R vs R-CHOP for upfront FL Toxicity • B-R – 20 secondary malignancies – 1 MDS • CHOP-R – 22 secondary malignancies – 1 AML • No discussion of type and duration of toxicity followup after therapy Rummel et al, Lancet 2013

B-R vs R-CHOP for upfront FL PFS all subjects 261/253 enrolled analyzed Enrolled 2003 -2008, Data cutoff October 2011 Median f/u 45 months Rummel et al, Lancet 2013

B-R vs R-CHOP for upfront FL PFS /FLsubjects Enrolled 2003 -2008, Data cutoff October 2011 Rummel et al, Lancet 2013

B-R vs R-CHOP for upfront FL Followup • Median study f/u 45 months • Followup for efficacy/PFS after 2 years? • Followup for safety/long term toxicity after 2 years? Rummel et al, Lancet 2013

Frontline BR vs R-CVP or R-CHOP in Advanced Indolent NHL (BRIGHT) Bendamustine 90 mg/m 2 Day 1 and 2 Rituximab 375 mg/m 2 on D 1 q 28 d Frontline advanced indolent NHL (Preassignment of chemo arms by investigator) (6 -8 cycles) R-CHOP and R-CVP: std dosing q 21 d Primary: Noninferiority of CR for BR vs standard treatment (IWG criteria; independent and investigator review) (6 -8 cycles) More dose delays with B-R (35% vs 19%) Fewer dose reductions with B-R (22% vs 29%) More fatal AEs with BR (6 vs 1) CR rates similar in FL, PFS immature Flinn et al. ASH 2012, Abstract 902

CHOP-R vs CHOP-RIT Followup Press et al, JCO 2013

CHOP-R vs CHOP-RIT for upfront FL PFS Press et al, JCO 2013

CHOP-R vs CHOP-RIT for upfront FL Toxicity Press et al, JCO 2013

R-CHOP for upfront FL • Remains an appropriate option for many patients • Short term toxicity tradeoffs • Long term toxicity well established • Efficacy well established • Clearly treatment of choice where transformation is a concern