1. 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

2. 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

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

4. Progress in follicular lymphoma
Bendamustine
Radioimmunotherapy
SCT
Novel agents 20 40
100 60 80
Chemo + R + maintenance R
Progression-Free Survival %
Chemo + R
After a median follow-up of 41 months, the actuarial PFS was significantly (P=0.007) superior for maintenance therapy vs re-treatment (31.7 vs 7.4 months, respectively).
However, the median duration of rituximab benefit was similar for maintenance and re-treatment groups (31.7 vs 27.4 months, respectively).
Thus the primary end point “duration of rituximab benefit” was not different between the 2 groups.
Chemo
Time

5. 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 ?

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

7. Rituximab maintenance
PRIMA: study design
INDUCTION
MAINTENANCE
Rituximab maintenance
375 mg/m2 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
Random 1:1*
Observation‡
PD/SD
off study
* 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

8. Primary endpoint (PFS): 36 months follow-up
1.0
0.8
75%
Rituximab maintenance
0.6
Progression-free rate
58%
0.4
Observation
Stratified HR = 0.55
95% CI: 0.44–0.68
p <
0.2
0.0 6 12 18 24 30 36 42 48 54 60
Time (months)
Patients at risk
505
472
445
423
404
307
207 84 17 –
513
469
415
367
334
247
161 70 16 –

9. Bendamustine-Rituximab (B-R) vs CHOP-R
StiL NHL
Bendamustine-Rituximab
Follicular
Waldenströms
Marginal zone
Small lymphocytic
Mantle cell R
CHOP-Rituximab
Bendamustine 90 mg/m2 day R day 1, max 6 cycles, q 4 wks.
CHOP-R, max 6 cycles, q 3 wks.
Rummel et al,
Lancet 2013

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

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

12. B-R vs R-CHOP for upfront FL Toxicity
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

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

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

15. 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

16. Frontline BR vs R-CVP or R-CHOP in Advanced Indolent NHL (BRIGHT)
Bendamustine 90 mg/m2 Day 1 and 2 Rituximab 375 mg/m2 on D1 q28d
(6-8 cycles)
Frontline advanced indolent NHL
(Preassignment of chemo arms by investigator)
Primary: Noninferiority of CR for BR vs standard treatment (IWG criteria; independent and investigator review)
R-CHOP and R-CVP: std dosing q21d
(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

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

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

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

21. 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