1. Jonathan W. Friedberg M.D., M.M.Sc.
Should patients with advanced symptomatic FL responding to frontline chemoimmunotherapy receive maintenance rituximab?
NO!
Jonathan W. Friedberg M.D., M.M.Sc.
University of Rochester Medical Center

3. Follicular NHL: Concepts
Incurable disease with standard therapy
The addition of rituximab to induction chemotherapy dramatically improves PFS, and may impact OS.
Treatment of asymptomatic patients with chemotherapy or rituximab does not impact survival.

4. Follicular lymphoma: What are goals of treatment?
Change natural history of disease:
Decrease transformation
Improve survival
Remission:
How important is this in an asymptomatic indolent disease?
Improve quality of life
“Avoid chemotherapy”
We are now in a lenalidomide and ibrutinib era

5. Stratification Factor: β2M Level (Elevated or Not)
SWOG/CALGB Trial S0016
Advanced Stage Follicular NHL
CHOP x 6
CHOP x 6
+ Rituximab
CHOP x 6
+ 131I-Tositumomab
N =17
N =279
N =275
Stratification Factor: β2M Level (Elevated or Not)

6. S0016 Outcomes: No maintenance rituximab
PFS OS
No difference in PFS or OS between the arms.
Note excellent outcome in both groups.
Press et al JCO 31:314

7. PFS and OS by β2M and LDH Model Risk
Split at 150% of IULN
High risk group is very small.
Low risk group, more than half of patients, have outstanding outcome.
Strategies toward future clinical trial design are limited based upon this analysis.
Many patients are likely being overtreated….
Press et al, CCR 2013

8. “Updated 6 Year Follow-Up Of The PRIMA Study Confirms The Benefit Of 2-Year Rituximab Maintenance In Follicular Lymphoma Patients Responding To Frontline Immunochemotherapy”
Gilles Salles et al.
ASH 2013

9. Rituximab maintenance Five additional years of follow-up
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

10. PRIMA : Primary endpoint (PFS): 3 years Original publication
1.0
0.8
75%
Rituximab maintenance
0.6
Event-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 –
Salles et al., Lancet 2011

11. PRIMA 6 years follow-up Progression free survival from randomization
HR= 0.57
P<0001
Median follow-up since randomization : 73 months

12. PRIMA 6 years follow-up Time to next treatment
70 months = 51.0%
70 months = 63.5%
HR= 0.625
P<.0001
Median follow-up since randomization : 73 months

13. PRIMA 6 years follow-up Overall survival
HR= 1.027
P=.885
Median follow-up since randomization : 73 months

14. PRIMA = 6 years follow-up Rate of histological transformation
OBSERVATION
RITUXIMAB
MAINTENANCE
Progression
278
186
With morphology documentation
114 80
Transformed
histology
24 (21%)
16 (20%)

15. Long term follow-up of PRIMA: Data summary
A durable and significant benefit of rituximab maintenance for PFS and TNLT persists at 6 years
No survival benefit was observed, with similar numbers of patients dying from lymphoma in both arms
No differences in histological transformation
More than half of patients in control group (no maintenance) did not require any additional therapy at 70 months of follow-up.

16. Rituximab re-treatment at progression*
E4402 (RESORT) Schema R A N D O M I Z E
Rituximab
Maintenance*
375 mg/m2 q 3 months
Rituximab
375 mg/m2 qw  4
CR or PR
Rituximab re-treatment at progression*
375 mg/m2 qw  4
*Continue until treatment failure
No response to retreatment or PD within 6 months of R
Initiation of cytotoxic therapy or Inability to complete rx
Kahl et al, ASH 2011

17. Primary Endpoint: Time to Treatment Failure

18. Time to First Cytotoxic Therapy

19. Conclusions: RESORT
In this study of previously untreated low tumor burden FL:
Rituximab retreatment was as effective as maintenance rituximab for time to treatment failure
MR was superior to RR for time to cytotoxic therapy
At a cost of 3.5x more R
No benefit in QOL or anxiety at 12 months with MR

20. Is retreatment rituximab an option in advanced stage disease, rather than rituximab maintenance?

21. Impact of post-treatment PET on outcome: PRIMA study
Observation
Rituximab maintenance
Trotman et al JCO 29:3194

22. Bendamustine + Rituximab vs R-CHOP in First-Line Indolent and MCL
BR (× 6 cycles)
Bendamustine: 90 mg/m2: days 1-2, q4wk
+ Rituximab: 375 mg/m2 day 1, q4wk
FL patients R A N D O M I Z E
n = 139
Untreated pts with indolent and MCL (N = 514)
R-CHOP (× 6 cycles) Rituximab: 375 mg/m2 day 1, q3wk
+ CHOP (standard) day 1, q3wk
n = 140
Primary objective: To prove a noninferiority of BR vs R-CHOP in PFS (defined as a difference of less than 15% in PFS after 3 years)
Secondary objectives: ORR, OS, relapse-free survival, and safety
Rummel M, et al. Lancet Feb

23. PFS by arm in patients with follicular lymphomaBR
RCHOP
2 yr
Rummel M, et al. Lancet Feb

24. Based upon the STiL study, is BR the standard?
Poor outcome in RCHOP group, although different patient population
Long term safety and “life after bendamustine” still needs evaluation
Appears non-inferior, with less acute toxicity
ECOG trial using BR as standard in current randomized trial

25. No maintenance data with BR!

26. Summary: Just say No! to maintenance
No survival benefit
Does not impact transformation
In low tumor burden disease, retreatment rituximab is equivalent
No clear quality of life benefit
Costs more
No data of maintenance following bendamustine/rituximab
New treatment options (lenalidomide, ibrutinib) will likely further change treatment paradigm

27. Thank you!
Questions?