1. First-line management of follicular lymphoma: Will induction and maintenance treatment prolong survival?
Robert Marcus Department of Haematology, Addenbrooke’s Hospital, Cambridge, UK

2. Trial 1: R-CVP versus CVP study design
Follicular NHL (IWF B, C, D)
Stage III−IV
 18 years
No prior Rx
Measurable disease
Central histology review R A N D O M I S E R E S T A G
R-CVP x 4 cycles (q3wk)
R-CVP x 4 cycles (q3wk)
CR, PR
CVP x 4 cycles
(q3wk)
CVP x 4 cycles
(q3wk)
SD PD
off study
Rituximab 375 mg/m2 iv day 1
Cyclophosphamide 750 mg/m2 iv day 1
Vincristine 1.4 mg/m2 iv day 1
Prednisolone 40 mg/m2 po days 1–5
Marcus R, et al. Blood 2005; 105:1417–1423.

3. Participating sites Australia Belgium Brazil Canada France Israel
K Bradstock, J Catalano, R Herrmann, J McKendrick, J Norman, D Rosenfeld, K Taylor
Belgium
M Bron, R De Bock, F Offner
Brazil
C Chiattone
Canada
A Belch, I Bence-Bruckler, M Crump, D Forrest, K Imrie, KS Robinson, C Shustik
France
S Castaigne, P Solal-Céligny
Israel
M Shaklai
Poland
A Dmoszynska, K Kuliczkowski, J Walewski
Portugal
F Placido, J Raposo, J Veiga
Spain
JN Batista, M Constenla, E Flores, J Gomez Codina, J Guma, A Rueda
Switzerland
T Cerny, R Zenhausern UK
D Cunningham, DJ Dunlop, E Fitzsimons, BW Hancock, C Hatton, P Johnson, R Marcus, G Morgan, A Pagliuca, R Pettengell, M Potter, C Poynton, S Proctor

4. Patient characteristics
R-CVP (n = 162)
CVP (n = 159)
Median age, years 52 53
Histology
Grade 3 FL, % 9 8
Bulky disease, % 39 46
FLIPI 3−5 (poor prognosis), % 40 47
FLIPI 2 (intermediate prognosis), % 41 37
FLIPI 0−1 (good prognosis), % 19 15
Central review of pathology performed on 90% of patients FL diagnosis confirmed in 95% of patients
Marcus R, et al. Blood 2005; 105:1417–1423.

5. Response rates* Response R-CVP (n = 162) CVP (n = 159) p-value
CR/CRu (%) 41 10
p <
PR (%) 40 47
ORR (%)
(CR+CRu+PR) 81 57
* Response up to 42 days after completion of treatment
Marcus R, et al. Blood 2005; 105:1417–1423.

6. Conclusions Rituximab plus CVP improved:
Overall and complete response rates
TTP, TTNLT, DFS
Overall survival
Addition of rituximab did not substantially increase regimen toxicity
8 cycles of R-CVP should be considered as standard treatment for previously untreated FL

7. Trial 2: R-CHOP versus CHOP study design
Patients < 60 years (< 65 years) R A N D O M I S T R A N D O M I S T
PBSCT
CR, PR
6–8 cycles x CHOP
6–8 cycles x CHOP plus
rituximab
Standard IFN-maintenance
Patients > 60 years (> 65 years)
Intensive IFN-maintenance
Standard IFN-maintenance
Hiddemann W, et al. Blood 2005; 106:3725–3732.

8. TTF is significantly improved with rituximab-based induction therapy
Patients aged > 60 years
1.0
0.8
R-CHOP (78/112)
Median 5 years
0.6
Probability
0.4
CHOP (37/109)
Median 2.1 years
0.2
p <
0.0 1 2 3 4 5 6
Years
Buske C, et al. Blood 2006; 108:Abstract 482.

9. Patients aged > 60 years
Overall survival is significantly improved with rituximab-based induction therapy
Patients aged > 60 years
1.0
R-CHOP (102/112)
0.8
CHOP (89/109)
0.6
Probability
4-year OS
R-CHOP: 90%
CHOP: 81%
0.4
0.2
p = 0.039
0.0 1 2 3 4 5 6
Years
Buske C, et al. Blood 2006; 108:Abstract 482.

10. Survival is significantly improved with R-CHOP in all FLIPI subgroups
1.0
1.0
Median NR
0.8
0.8
Median 4.1 years
Median NR
0.6
0.6
Survival probability
Survival probability
Median 3.0 years
Median 4.0 years
0.4
0.4
0.2
0.2
Median 2.0 years 1 2 3 4 5 6 1 2 3 4 5 6
Time (years)
Time (years)
FLIPI 0–1: Low risk p = FLIPI 2: Intermediate prognosis p < FLIPI 3–5: Poor prognosis p =
Buske C, et al. Blood 2006; 108:Abstract 482 and unpublished data.

11. Trial 3: R-MCP versus MCP study design
ESTAGING R A N D O M I S E
Advanced FL, IC and MCL
18–75 years
No prior rituximab
Central histology review
Written informed consent
R-MCP 6 cycles (q4wk)
R-MCP 2 cycles (q4wk)
CR, PR
MCP 6 cycles (q4wk)
MCP 2 cycles (q4wk)
IFN-maintenance for FL SD PD
off study
Rituximab 375mg/m2 iv d 1
Mitoxantrone 8 mg/m² iv d 3 and 4
Chlorambucil 3 x 3mg/m² po d 3–7
Prednisolone 25 mg/m² po d 3–7
Herold M, et al. J Clin Oncol 2007; April 9 (Epub).

12. Rituximab-based induction therapy significantly improves survival in patients with FL
ITT population: Median follow-up 47 months
1.00
R-MCP: Median NR
0.75
MCP: Median NR
Survival distribution function
0.50
4-year OS
R-MCP: 87%
MCP: 74%
0.25
p = 10 20 30 40 50 60
Time (months)
Herold M, et al. J Clin Oncol 2007; April 9 (Epub).

13. PFS is significantly improved with R-MCP in all FLIPI subgroups
Median NR 4-year PFS: 82%
1.0
1.0
Median 36 months
4-year PFS: 43%
0.8
0.8
Median NR 4-year PFS: 61%
0.6
0.6
Survival probability
Survival probability
0.4
0.4
Median 26.5 months 4-year PFS: 36%
0.2
0.2 10 20 30 40 50 60 10 20 30 40 50 60
Time (months)
Time (months)
FLIPI 2: Intermediate prognosis p = FLIPI 3–5: Poor prognosis p =
Herold M, et al. J Clin Oncol 2007; April 9 (Epub) and unpublished data.

14. Trial 4: R-CHVP-IFN vs CHVP-IFN study design
Arm A
6 months
12 months R
Staging including CT-scan and bone marrow biopsy
Arm B
d1 Cyclophosphamide 600 mg/m2
d1 Doxorubicin 25 mg/m2
d1 Etoposide 100 mg/m2
d1–5 Prednisolone 40 mg/m2
αIFN 2b, 4.5 MU
tiw for 18 months (3 MU if aged  70 yr)
Rituximab: 375 mg/m2
every month for 6 months (arm A & B) then every 2 months in arm A
Foussard C, et al. J Clin Oncol 2006; 24(18S):Abstract 7508.

15. EFS and OS are significantly increased with rituximab-based therapy
100
100
R-CHVP + IFN- (Arm B)
R-CHVP + IFN- (Arm B)
91%
Event-free survival 75
Ovarall survival 75
CHVP + IFN- (Arm A)
84%
67% 50 50
46%
CHVP + IFN- (Arm A) 25 25
p <
p = 0.029 10 20 30 40 50 60 70 10 20 30 40 50 60 70
Months
Months
Foussard C, et al. J Clin Oncol 2006; 24(18S):Abstract 7508.

16. First-line rituximab-based induction therapy improves overall survival
Induction regimen
Outcome (median)
Overall survival
CHVP  R + IFN-1
EFS
NR vs 3 yrs p <
3.5 yr
91% vs 84% p = 0.029
MCP  R2
PFS
NR vs 29 mo p <
4 yr
87% vs 74% p =
CHOP  R3
TTF
NR vs 31 mo p =
2 yr
95% vs 90% p = 0.016
CVP  R4
TTP
34 mo vs 15 mo p <
83% vs 77% p =
1. Foussard C, et al. J Clin Oncol 2006; 24:Abstract 7508.
2. Herold M, et al. J Clin Oncol 2007; April 9 (Epub).
3. Hiddemann W, et al. Blood 2005; 106:3725– Marcus R, et al. Blood 2006; 108:Abstract 481.

17. Rituximab-based induction therapy: Conclusions
R-Chemo yields superior results to chemotherapy in four prospective randomised trials
The FLIPI predicts outcome in all studies
Prognosis was worse with a high FLIPI score
Majority of patients with poor prognosis will relapse within 4–5 years
There does not seem to be a TTP/PFS ‘plateau’ of any subgroup in any trial yet

18. Overall survival improvement with rituximab in FL
1.0
GLSG study NHL 2000
0.8
0.6
GLSG study NHL 1996
Survival probability
0.4
0.2
p <
0.0 12 24 36 48 60 72 84 96
108
120
Time (months)
Number of patients at risk:
NHL 1996
538
485
457
419
386
332
242
125 46
NHL 2000
794
621
440
250
108 8
Hiddemann W, et al. Blood 2006; 108:Abstract 483.

19. Phase III trial of CVP ± rituximab maintenance
Rituximab maintenance after CVP in untreated indolent NHL: ECOG 1496 study design
Phase III trial of CVP ± rituximab maintenance
401 patients with previously untreated indolent NHL, 322 randomised R A N D O M I S E
Rituximab maintenance
375 mg/m2 q1wk  4
q6mo  4
CVP 6–8 cycles
PR, CR or SD
Observation

20. Rituximab maintenance therapy significantly prolongs PFS in FL
Median PFS from randomisation: 15 mo vs 61 mo
1.0
0.8
Rituximab maintenance (n = 120)
0.6
Probability
0.4
0.2
Observation (n = 117)
p =
0.0 1 2 3 4 5 6
Years from maintenance randomisation
Hochster H, et al. Blood 2005; 106:Abstract 349.

21. Median PFS/EFS (months)
Rituximab monotherapy induction and maintenance in first-line treatment of FL
Patients (n)
Median FU (months)
Induction regimen
Maintenance schedule
Median PFS/EFS (months)
Minnie Pearl Phase II1
38† 55
R-Mono*
q6mo x 4*
PFS: 52
SAKK 35/982 64 36
q2mo x 4
EFS: 19 vs 36 p = 0.009
* 375 mg/m2 rituximab once weekly x 4 † Follicular lymphoma patients only FU = follow-up
1. Hainsworth JD, et al. Blood 2003; 102:Abstract 1496.
2. Ghielmini M, et al. Blood 2004; 103:4416–4423.

22. SAKK 35/03 study: Efficacy of extended rituximab maintenance therapy in FL
Short maintenance
Rituximab maintenance q2mo x 4 R
Rituximab375 mg/m²
weekly x 4
PR, CR
Rituximab maintenance q2mo until relapse (maximum 5 years)
PD, SD off study
Long maintenance

23. Rituximab maintenance therapy
PRIMA study: Efficacy of rituximab-based induction and maintenance in first-line indolent NHL
Rituximab maintenance therapy
1 x q8wk
for 24 months R A N D O M I SE
8 x rituximab +
8 x CVP
or 6 x CHOP or 6 x FCM
Indolent NHL
stages III–IV,
untreated
CR, PR
Observation SD PD
off study

24. RiCHOP trial: Efficacy of ASCT followed by rituximab maintenance in indolent NHL
HDT ASCT R A N D O M I SE
Rituximab
maintenance 1 x q8wk
for 24 months
CR, PR
R-CHOP x 6 + R x 2 SD PD
off study
N > 600 patients with indolent FL (< 65 years old). Study start 2007

25. A note of caution! Incidence of hepatitis B reactivation with rituximab
Out of 456 patients, 32 were Hep B positive
14 received rituximab monotherapy
18 received rituximab plus chemotherapy
Group
Patients (n)
HBsAg
HBsAb
HBcAb
Liver event (%) A 12 – +
3 (25) B 6
2 (33) C 8
Not available
2 (25) D
Variable
4 (66)
A total of 5 patients developed liver failure (15%)
Hanbali A, et al. Blood 2006; 108:Abstract 2766.

26. But…prophylactic lamivudine can reduce the incidence of hepatitis during chemotherapy
Non-randomised comparison of lymphoma patients treated with prophylactic lamivudine during chemotherapy with historical controls
100 mg was administered daily for up to 64 weeks
% Control
(n = 116)
% Lamivudine
(n = 40)
p-value
Hepatitis incidence during chemo 52 18
0.000
Disruption in chemo administration 37 10
0.001
Lamivudine prophylaxis reduced the incidence of hepatitis
Li Y, et al. Cancer 2006; 106:1320–1325.

27. Outstanding questions in first-line therapy for FL
Do more intensive therapies yield superior results than R-CVP?
If so do ALL patients require such therapy, or only poor prognosis patients?
Which component provides superior results?
Anthracycline, interferon or both?
Does maintenance have a role in first-line FL?
PRIMA trial to provide evidence
Do PBSCT or other approaches have a role in first-line therapy?