1. Making the Case for Maintenance Rituximab
Owen A. O’Connor, M.D., Ph.D.
Professor of Medicine and Experimental Therapeutics
Director, Center for Lymphoid Malignancies
Columbia University Medical Center – College of Physicians and Surgeons
The New York Presbyterian Hospital
New York, N.Y.

2. Making the Case for Maintenance Rituximab The Problem
The existing studies are almost as heterogeneous
as the disease in question:
- Are not consistent with regard to the kind of FL
enrolled
- Different doses and schedules of rituximab
- Molecular heterogeneity ignored
- Gender overlooked
- Varying endpoints
- Statistically never powered for OS

3. Heterogeneity of Follicular Lymphoma
Morphology Guides Grading with Poor Concordance : Berard Criteria
Grade 1
Grade 2
Grade 3
Small Cleaved
Mixed
Large Cell
Large Cells per high powered field
<5
5-15
>15%
Expert concordance
72%
61%
60%

4. Heterogeneity of Follicular Lymphoma Follicular Lymphoma Classification
Grade
Characteristic
Grade 1
0-5 centroblasts/hpf
Grade 2
6-15 centroblasts/hpf
Grade 3
> 15 centroblasts/hpf 3a
Centrocytes present 3b
Solid sheets of centroblasts
Expert Pathologist Agreement With Consensus Diagnosis (ILSG, n = 304)
Follicular Grade , %
Dx 1
Dx 2
Dx 3
Any grade, 93 94
Grade 1 72 73
Grade 2 61
Grade 3 60
Swerdlow SH, et al. WHO classification of tumors of haematopoietic and lymphoid tissues (4th ed). Lyon, France: IARC Press; 2008.

5. Gene Expression: Follicular NHL
Gene expression array demonstrates that the stromal microenvironment has profound prognostic influence
Expression Signature
Relative Risk of Death
P Value
Prognosis
Immune response 1
0.15
< .0001
Favorable
Immune response 2
9.35
Unfavorable
Expression Signature (Prognosis)
Relative Risk of Death
P Value
Immune response 1 (favorable)
0.15
< .0001
Immune response 2 (unfavorable)
9.35
Dave SS, et al. N Engl J Med. 2004;351:

6. Prognostic Factors in Follicular Lymphoma : Clinical Heterogeneity & FLIPI
Age >60
Ann Arbor Stage III-IV
LDH > Normal
Hemoglobin < 12
Number of nodal sites >5
100 1 12 24 36
Months 48 60 72 84 20 40 80
Poor
Intermediate
Good
Probability
# of Factors
Risk
% of Patients
5 Year OS
10 Year OS
0-1
Good 36
91%
71% 2
Intermediate 37
78%
51%
> 3
Poor
53%
36%

7. Monoclonal Antibodies Have Clearly Changed the Natural History of FL
100
CHOP + mAb 80
Pro-MACE 60
Patients (%) 40 N
Deaths, n
4-Yr Estimated OS, %
CHOP 20
179 18 91
425
189 79
356
226 69 2 4 6 8 10
Yr After Registration
Fisher RI, et al. J Clin Oncol. 2005;23:

8. Rationale for Maintenance Therapy in Indolent Lymphoma
Maintenance therapy applied in patients responding to induction treatment is effective in hematological malignancies
Maintenance therapy can deepen the response and lengthen remission
Need to have therapeutic agents with a good efficacy/toxicity ratio:
No cumulative toxicity (hematopoietic stem cells)
No long term side effects
Preserve quality of life
Do no compromise subsequent treatment(s) efficacy

9. The Variability of Maintenance Rituximab Studies: Across Many Designs Same Conclusion
Study
Population
Treatment
Findings
SAKK 35/98
Blood 2004; 103(12)
JCO 2010; 28(29)
Heterogeneous. Prior chemo (n=138) and chemonaive (n=64); all grades; MAB naive
Rituximab 375 mg/m2 per week x 4 then randomize to observation vs 4 more doses (months 3, 5, 7 and 9)
Median F/U of 9.5 yrs EFS 13 vs 24 months
45% of untreated patients 8 yrs stage not prognostic; Fc-gamma RIIIA
Hainsworth
JCO 2005; 6(20)
FL Gr 1 or 2 and SLL (23 and 39% of patients); 1 prior chemotherapy
Rituximab 375 mg/m2 per week x 4 then randomize to retreatment on POD or maintenance weekly x 4 Q 6 months till POD or total of 4.
PFS was 31.3 vs 7.4 months (ORR and CR >> in maintenance arm)
EORTC 20981
(Van Oers)
JCO 2010; 28(17)
FL Gr 1-3; Stage 3-4 only; relapsed after max of 2 non-anthracycline regimens.
Randomized to CHOP vs R-CHOP then randomized maintenance rituximab 375 mg/m2 once Q 3 months
Rituximab maintenance PFS 3.7 vs 1.3 years. 5 yr OS 74% vs 64% (p=0.07). Increase in infections (9.7 vs 2.4%)
German Low Grade Lymphoma Study Group
Forstpointner
Blood 2006; 108(13)
FL all grades; relapsed after 1 prior;
FCM vs R-FCM; then randomize to maintenance weekly x 4 at 3 and 9 months or observation
PFS and response duration not met in maintenance arm vs 26 months in observation. (median observation of 26 months)
PRIMA
(Salles)
Lancet 2011; 377
Untreated FL, Grades 1-3a; high tumor burden (one lesion > 7 cm; 3 nodes > 3 cm; symptomatic splenomegaly; organ compression; effusions; increased LDH or b2 or ‘B’ symptoms)
R-Chemo (CVP/CHOP/FCM) followed by rituximab 375 mg/m2 every 8 weeks for two years.
PFS at 6 years 59% vs 42% favors maintenance, suggestion less transformation, no difference is OS.
Meta-Analysis
All studies
Variable
Highly statistically significant improvement in HR (0.005) for overall survival.

10. Arm B Rituximab induction Arm C Rituximab induction and maintenance
Preliminary Analysis of Rituximab vs Watch and Wait in Asymptomatic FL Patients
R A N D O M I Z A T N
Arm A Watch and wait
Clinic visits
R x 4
Patients with FL grades 1, 2, and 3a,
stage II, III, IV disease,
ECOG PS 0-1
(N = 462)
Arm B Rituximab induction
Continued follow-up
R x 4 R R R R R R R R R R R R
Arm C Rituximab induction and maintenance 1 3 5 7 9 11 13 15 17 19 21 23 25
Mos
Compulsory CT Scan
CT Scan only if clinical CR
Compulsory CT Scan
PD requiring therapy stops protocol treatment
Bone marrow for histology and MRD only if CT shows CR
Ardeshna K, et al. ASH Abstract 6.

11. Preliminary Analysis of Rituximab vs Watch and Wait in Asymptomatic FL Patients
Spontaneous remission observed in 3% of patients on watch and wait vs CR in 45% of patients on rituximab
93 patients required new therapy during follow-up period
84 patients (90%) had PD
78 patients (84%) received chemotherapy as new treatment
3-Yr PFS W + W: 33% R4: 60% R4 + RM: 81%
Progression Free Survival
1.0
0.8
Proportion of Patients Progression Free
0.6
0.4
Events
108 33
Totals
181 83
189
0.2
W + W R4 R4 + RM 1 2 3 4 5
Yrs From Randomization
HR (rituximab vs W + W): 0.46; 95% CI: ; P < .001 HR (rituximab + M vs W + W): 0.21; 95% CI:
; P < .001
HR (rituximab + M vs rituximab): 0.43; 95% CI: ; P = .001
Ardeshna K, et al. ASH Abstract 6.

12. Rituximab Maintenance Therapy in FL The First Study (SAKK Trial)
Observation
(n=78) R A N D O M I Z E
Rituximab
375 mg/m2 qw × 4
CR, PR, SD
maintenance
375 mg/m2 q8w  4
(n=73)
Untreated or relapsed/ refractory FL
grade I-III
(N=202)
ASSESS
Ghielmini et al. Blood. 2004;103:4416.

13. Rituximab Maintenance Therapy in FL (SAKK Trial): Event Free Survival
Time from 1st induction to POD, relapse, second CA or death
1.0
0.8
Prolonged: median 23.2 months
0.6
Probability
0.4
0.2
Standard: median 11.8 months
P=0.024 6 12 18 24 30 36 42 48
Months
Ghielmini et al. Blood. 2004;103:4416.

14. Updated EFS in SAKK 35/98: Rituximab Maintenance vs. Observation

15. Overall Survival: ASCO update of SAKK 2009
Probability
P = 0.09
Is this study powered for OS endpoint?
NO!
Years Since Start of Treatment

16. Rituximab 375 mg/m2 weekly × 4
Rituximab Maintenance Therapy vs Re-Treatment at Progression for Indolent NHL
114 rituximab-naive patients with previously treated indolent NHL
Rituximab 375 mg/m2 weekly × 4
Rituximab maintenance therapy (n=44)
Rituximab 375 mg/m2 weekly × 4
every 6 months for 4 courses R A N D O M I Z E
90 patients (70%) CR/PR/SD
Re-treatment at time of progression (n=46)
Rituximab 375 mg/m2 weekly × 4
Hainsworth et al. Blood. 2003;102(11). Abstract 231

17. LYM-5 - Maintenance vs Retreatment After Rituximab : Hainsworth Regimen
FL, SL rel/refr; R weekly x 4 + (repeat every 6 months x 4 max) or (treat at progression)
Progression Free Survival 20 40 60 80
100 24
Months 36 48
P=0.007
Maintenance
Retreatment 12
% Surviving w/o progression
Hainsworth et al. J Clin Oncol. 2005;23:1088

18. Phase III Trial of Rituximab Maintenance for Patients in Remission with Relapsed / Resistant Follicular NHL R A N D O M I Z E R A N D O M I Z E
CHOP every 21 days maximum 6 cycles
Observation
CR PR
Rituximab + CHOP every 21 days maximum 6 cycles
Rituximab maintenance*
*375mg/m2 q 3 months
x 2 yrs or until relapse
Van Oers et al. Blood. 2006;108:3295

19. Median PFS after CHOP (mo) Median PFS after R-CHOP (mo)
R-Maintenance in Patients With Relapsed/ Resistant FL After CHOP or R-CHOP: Progression Free Survival
Median PFS after CHOP (mo)
R-maintenance
Observation
Median PFS after R-CHOP (mo)
P=0.004 HR 0.54
P<0.001 HR 0.30
R-Maintenance
Observation 10 20 30 40 50 60 70 80 90
100 1 2 3 4 5
Years
Percent
Van Oers et al. Blood. 2006;108:3295.

20. Update of EORTC Intergroup Phase III Trial in R/R Follicular Lymphoma Patients: PFS from 2nd randomization
van Oers M, et al. J Clin Oncol. 2010;28(17):

21. EORTC 20981 Intergroup phase III trial: 5-year Overall Survival
Again, trends towards significance, despite being underpowered for this endpoint
Is it too early for this disease?
van Oers M, et al. J Clin Oncol. 2010;28(17):

22. PRIMA Study Design : High Tumor Burden
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
5 YEARS FOLLOW-UP
Salles G, et al. Lancet. 2011;377(9759):42-51.

23. Primary Endpoint (PFS) Met at the Planned Interim Analysis
Rituximab maintenance significantly reduced the risk of lymphoma progression by 50% (stratified by response and induction regimen, HR=0.50, 95% CI 0.39; 0.64)
1.0
82%
Rituximab maintenance
N=505
0.8
0.6
Observation
N=513
HR=0.50
p<0.0001
66%
Progression-free rate
0.4
0.2 6 12 18 24 30 36 42
Patients at risk
Time (months)
505
472
443
336
230
103 18
513
469
411
289
195 82 15
Salles G, et al. Lancet. 2011;377(9759):42-51.

24. Subgroup Analyses Results
Hazard ratio *
Category
Subgroup
Hazard ratio N
95% CIs
All
All
1018
0.49
0.38
0.64
Age
< 60
624
394
0.45
0.59
0.33
0.39
0.62
0.90
≥ 60
Sex
Female
485
533
485
533
0.58
0.43
0.40
0.31
0.85
0.61
Male
FLIPl Index (CRF)
FLIPl ≤ 1
216
370
431
0.38
0.39
0.61
0.19
0.25
0.43
0.77
0.61
0.87
FLIPl = 2
FLIPl ≥ 3
R-CHOP
Induction Chemotherapy
768
222 28
0.43
0.69
0.51
0.31
0.44
0.13
0.59
1.08
2.07
R-CVP
R-FCM
Response to Induction
CR/CRu
721
290
0.52
0.45
0.38
0.29
0.70
0.72 PR 1 2 3
Favors maintenance
Favors observation
* Non-stratified analysis
Salles G, et al. Lancet. 2011;377(9759):42-51.

25. Efficacy Across Secondary Endpoints
Substantial Improvement with R-Maintenance
Time to next anti-lymphoma treatment
Time to next chemotherapy treatment
Rituximab maintenance
Rituximab maintenance
1.0
1.0
0.8
0.8
0.6
0.6
Event-free rate
Event-free rate
HR = 0.61
p =
Observation
HR = 0.60
p =
Observation
0.4
0.4
0.2
0.2 6 12 18 24 30 36 42 6 12 18 24 30 36 42
Time (months)
Time (months)
Patients at risk
513
487
447
327
218 87 15
513
492
454
332
225 91 17
505
483
453
349
235
103 18
505
484
457
351
243
108 19
Salles G, et al. Lancet. 2011;377(9759):42-51.

26. PRIMA 6-Years Follow-Up : PFS From Randomization
PFS according to maintenance (ITT patients)
With number of subjects at risk and 95% confidence intervals
1.0 –
0.8 –
0.6 –
0.4 –
0.2 –
0.0 –
Observation
Rituximab
Survival Probability
6 years = 59.2%
HR = 0.57
P<.0001
6 years = 42.7%
PFS Delay
Observation
Rituximab
No of Subjects
Event
Censored
Median Survival (95% CI)
Observation
513
56.5% (290)
43.5% (223)
8.5 ( )
Rituximab
505
39% (197)
61% (308)
NA ( NA)
Median follow-up since randomization: 73 months
Salles G, et al. Blood. 2013;122: Abstract 509.

27. PRIMA 6-Years Follow-Up : Overall Survival
OS according to maintenance (ITT patients)
With number of subjects at risk and 95% confidence intervals
1.0 –
0.8 –
0.6 –
0.4 –
0.2 –
0.0 –
6 years = 88.7%
Survival Probability
6 years = 87.4%
HR = 1.027
P = .885
Observation
Rituximab
OS Delay
Observation
Rituximab
No of Subjects
Event
Censored
Median Survival (95% CI)
Observation
513
11.3% (58)
88.7% (455)
NA (NA - NA)
Rituximab
505
11.7% (59)
88.3% (446)
Median follow-up since randomization: 73 months
Salles G, et al. Blood. 2013;122: Abstract 509.

28. Overall Survival: Meta-analysis R maintenance in FL Patients
In First Line:
Minimal effect on overall survival OR
Shorter follow-up and limited power of the studies
(low number of deaths ?)
Vidal et al. J Natl Cancer Inst Dec 7;103(23):

29. ECOG 4402 (RESORT) Primary End-point - Time to treatment failure
Accruing 389 patients with low-tumor-burden stage III/IV indolent NHL
Rituximab
maintenance
375 mg/m2 q12w R A N D O M I Z E
Rituximab
375 mg/m2 qw  4
CR or PR
Rituximab re-treatment at progression
375 mg/m2 qw  4
Primary End-point - Time to treatment failure
Secondary endpoint - Time to first cytotoxic therapy
Accessed May, 2005.

30. Is The Resort Study an Appropriate Comparator?
Population
Treatment
Findings
SAKK 35/98
Blood 2004; 103(12)
JCO 2010; 28(29)
Heterogeneous. Prior chemo (n=138) and chemonaive (n=64); all grades; MAB naive
Rituximab 375 mg/m2 per week x 4 then randomize to observation vs 4 more doses (months 3, 5, 7 and 9)
Median F/U of 9.5 yrs EFS 13 vs 24 months
45% of untreated patients 8 yrs stage not prognostic; Fc-gamma RIIIA
Hainsworth
JCO 2005; 6(20)
FL Gr 1 or 2 and SLL (23 and 39% of patients); 1 prior chemotherapy
Rituximab 375 mg/m2 per week x 4 then randomize to retreatment on POD or maintenance weekly x 4 Q 6 months till POD or total of 4.
PFS was 31.3 vs 7.4 months (ORR and CR >> in maintenance arm)
EORTC 20981
(Van Oers)
JCO 2010; 28(17)
FL Gr 1-3; Stage 3-4 only; relapsed after max of 2 non-anthracycline regimens.
Randomized to CHOP vs R-CHOP then randomized maintenance rituximab 375 mg/m2 once Q 3 months
Rituximab maintenance PFS 3.7 vs 1.3 years. 5 yr OS 74% vs 64% (p=0.07). Increase in infections (9.7 vs 2.4%)
German Low Grade Lymphoma Study Group
Forstpointner
Blood 2006; 108(13)
FL all grades; relapsed after 1 prior;
FCM vs R-FCM; then randomize to maintenance weekly x 4 at 3 and 9 months or observation
PFS and response duration not met in maintenance arm vs 26 months in observation. (median observation of 26 months)
PRIMA
(Salles)
Lancet 2011; 377
Untreated FL, Grades 1-3a; high tumor burden (one lesion > 7 cm; 3 nodes > 3 cm; symptomatic splenomegaly; organ compression; effusions; increased LDH or b2 or ‘B’ symptoms)
R-Chemo (CVP/CHOP/FCM) followed by rituximab 375 mg/m2 every 8 weeks for two years.
PFS at 6 years 59% vs 42% favors maintenance, suggestion less transformation, no difference is OS.
Meta-Analysis
All studies
Variable
Highly statistically significant improvement in HR (0.005) for overall survival.
RESORT
FL Gr 1-2 (+SLL, MZL); low tumor burden; Stage III-IV, no prior treatment
Rituximab 375 mg/m2 weekly x 4 then randomized to same with progression vs one dose Q 13 weeks.
TTTF equivalent in RR vs MR though time to next cytotoxic treatment favors MR

31. The Importance of Study Endpoints
Time to Treatment Failure Time to treatment failure (TTF) is defined as the time from randomization to treatment discontinuation for any reason, including disease progression, treatment toxicity, patient preference, or death. From a regulatory point of view, TTF is generally not accepted as a valid endpoint. TTF is a composite endpoint influenced by factors unrelated to efficacy. Discontinuation may be a result of toxicity, patient preference, or a physician's reluctance to continue therapy. These factors are not a direct assessment of the effectiveness of a drug

32. The Importance of Study Endpoints
Progression Free Survival
The progression-free survival (PFS) duration is defined as the time from randomization to objective tumor progression or death. Compared with other endpoints, PFS is a preferred regulatory endpoint because it includes death and may correlate better with OS. Assessment of either PFS or TTP needs to be conducted in randomized trials. To reduce bias, the same assessment technique should be used at each follow-up, and the same evaluation schedule should be consistently used.

33. Maintenance Rituximab (R): To Give or Not To Give?
Several different schedules of R maintenance have been or are being tested
Optimal dose/schedule and dosing is still unknown!
Men receiving RM do worse than women… PK study?
How important is it to determine the smallest amount of R & optimal time-points that is associated with improved PFS?

34. Maintenance Rituximab in Follicular Lymphoma : Where Do We Stand
Follicular lymphoma is a remarkably heterogeneous disease, and no study has addressed the value of MR as a function of this heterogeneity
There is enormous variability across all studies with regard to the study population, at least with respect to treatment, grade, stage, and little data on FLIPI, none on GEP
Every study consistently demonstrates compelling prolongation of PFS, some trending close to OS (not mature enough for the end-point)
No study ever powered for OS!
What’s the best end-point? Is TTTF a meaningful end-point in FL studies? I don’t think so, profoundly confounded.

35. Maintenance Rituximab in Follicular Lymphoma : Where Do We Stand
Gender differences are now emerging in clinical studies of rituximab, demonstrating substantial variability in PK between male and female. Would adjustment of dose based on gender make a difference?
PFS is a clinically meaningful end-point (per FDA) in FL.
Who wants to move to cytotoxic therapy sooner? RESORT demonstrates MR favors longer time to cytotoxic therapy
Building time between cytotoxic therapies may be an important determinant of chemotherapy sensitivity to future lines of treatment
Personally, I tailor the recommendation for maintenance rituximab based to the patient circumstances and their sensitivity to previous rituximab

36. Thank You

37. PRIMA: Statistical Assumptions
Sample size calculation:
Based on a 45% increase in median PFS, with a power of 80% to detect this difference (Type I alpha risk - 2-sided - of 5%)
1200 patients registered at induction, estimated response rate of 75%:
900 randomized to maintenance or observation (1:1)
Full analysis after 344 events
Interim analysis planned after 258 events:
Stopping rules for the IA: two-sided O’Brien-Fleming boundary of with type I of 5% (nominal p = )
Submitted to an independent Data Safety Monitoring Board

38. Maintenance Therapy for Indolent and Mantle Cell Lymphoma
Unanswered Questions
PK data support the scheme with one administration every 2 months
Benefit of longer duration of maintenance remains to be determined

39. PRIMA: Patient Disposition
Induction
Patients registered: N = 1217
* 3 sites closed prematurely (15 pts)
Patients evaluable (N = 1202) *
. 9 pts did not received chemo
pts withdraw during or at the end of induction (failure to respond; toxicity)
. 28 pts failed to be randomized
R-CHOP
N = 885
R-CVP
N = 272
R-FCM
N = 45
Randomized N = 769
Randomized
N = 222
Randomized N = 28
Maintenance
Patients randomized:
N = 1018 *
* 1 patient died during the randomization process
Observation
N = 513
Rituximab
N = 505
Salles G, et al. Lancet. 2011;377(9759):42-51.