1. Optimal use of rituximab in aggressive NHL
Professor Michael Pfreundschuh

2. International Prognostic Index (IPI)
Patients of all ages Risk factors Age >60 years PS 2–4 LDH level Elevated Extranodal involvement >1 site Stage (Ann Arbor) III-IV
Patients 60 years (age-adjusted) PS 2–4 LDH Elevated Stage III-IV
Shipp N Engl J Med 1993;329:987

3. DLBCL: overall survival
100 80
IPI 0–1 60
Patients (%) 40
IPI 2–3
IPI 4–5 20
p<0.001 1 2 3 4 5 6 7 8
Year
Adapted from Armitage and Weisenburger. J Clin Oncol. 1998;16:2780.

4. Rituximab in first-line treatment of aggressive NHL

5. Rituximab plus CHOP versus CHOP in elderly patients with DLBCL
GELA phase III trial (n=399)
Cyclophosphamide 750mg/m²
Doxorubicin 50mg/m²
Vincristine 1.4mg/m²
Prednisone 40mg/m²/day x 5 days
3 weeks cycles
R-CHOP 375mg/m²
Coiffier B, et al. N Engl J Med 2002;346:235–43
Feugier P, et al. J Clin Oncol :4117–26

6. GELA- LNH 98.5 trial planned interim analysis: initial data
R-CHOP CHOP p value (n=169) (n=159)
Median 1-year
EFS (%) <0.0005
OS (%) <0.01
Coiffier B, et al. Blood 2000;96:223a (Abstract 950)

7. GELA-LNH 98.5 5-year follow-up: overall survival
100 80 60 40 20
Rituximab plus
CHOP 58%
Overall survival (%)
CHOP 45%
p<0.007
Years
Feugier P, et al. J Clin Oncol 2005;23:4117–26

8. GELA-LNH 98.5 5-year follow-up: progression-free survival
100 80 60 40 20
PFS excludes late deaths not related to lymphoma or treatment
Rituximab plus
CHOP 54%
Progression-free survival (%)
CHOP 30%
p<
Years
Feugier P, et al. J Clin Oncol 2005;23:4117–26

9. GELA-LNH 98.5: 5-year EFS in low-aaIPI patients (aaIPI 0/1)
100 80 60 40 20
Rituximab plus
CHOP 63%
Event-free survival (%)
CHOP 34%
p=0.0008
Years
Feugier P, et al. J Clin Oncol 2005;23:4117–26

10. GELA-LNH 98.5: 5-year EFS in high-aaIPI patients (aaIPI 2/3)
100 80 60 40 20
Rituximab plus
CHOP 41%
Event-free survival (%)
CHOP 27%
p=0.004
Years
Feugier P, et al. J Clin Oncol 2005;23:4117–26

11. ECOG 4494 phase III trial: study design
Stratified by IPI
(0–1 vs 2–4)
Stratified by IPI
CR/PR; induction
Cycle 1 2 3 4 5 6 7 8 R A N D O M I S E R A N D O M I S E
MR every 6 months x 2 years
Rituximab
CHOP
Observation
Cycle 1 2 3 4 5 6 7 8
(n=632)
(n=415)
Habermann T, et al. Blood 2004;104:40a (Abstract 127)

12. Years from induction randomisation Years from induction randomisation
ECOG 4494: R-CHOP versus CHOP weighted analysis to remove the effect of maintenance
1.0
0.8
0.6
0.4
0.2
FFS
R-CHOP
Probability
CHOP
HR=0.64
p=0.003
Years from induction randomisation
1.0
0.8
0.6
0.4
0.2 OS
R-CHOP
Probability
Because the effects of maintenance confounded the analysis of induction, a
weighted analysis of induction was performed in patients in the observation
arm only
In this weighted analysis:
R-CHOP alone significantly decreased the risk of treatment failure as compared to CHOP alone with an estimated 3-year FFS of 52% for R-CHOP and 39% for CHOP
Overall survival was also longer after R-CHOP induction alone with an estimated 3-year overall survival of 67% for R-CHOP and 58% for CHOP.
HR=0.72
p=0.05
CHOP
Years from induction randomisation
Habermann T, et al. Blood 2004;104:40a (Abstract 127)

13. Rituximab plus CHOP for DLBCL in British Columbia (BC): study aim
March 1, 2001: BC Cancer Agency implemented a new policy recommending R-CHOP for all patients with advanced stage DLBCL in BC
Population-based retrospective analysis over a 3-year interval (1/9/99 – 31/8/02)
Compare outcomes
18 months prior to rituximab policy (pre-rituximab) versus
18 months following rituximab policy (post-rituximab)
Sehn LH, et al. J Clin Oncol 2005;23:5027–33

14. CHOP  rituximab in British Columbia: overall survival by treatment era and age (≥60 vs <60 years)
≥60 years (n=170)
<60 years (n=122)
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
Post-rituximab
Post-rituximab
Pre-rituximab
Probability of survival
Probability of survival
Pre-rituximab
p=0.0003
p=0.02
Years Years
Sehn LH, et al. J Clin Oncol 2005;23:5027–33

15. RICOVER 60: trial design 6 x CHOP-14 CD20+ DLBCL IPI I-V RANDOMISATION
61–80 years
IPI I-V
(n=828)
RANDOMISATION
2 x 2 factorial design
6 x CHOP-14
+ 36 Gy (Bulk, E)
8 x CHOP-14
+ 8 x rituximab
Pfreundschuh et al., Blood 2005;106 (Abstract 13)

16. RICOVER 60: response to therapy
6 Cycles 8 Cycles p
CR/CRu (%)
Progressive disease (%)
CHOP-14 R-CHOP p
CR/CRu (%)
Progressive disease (%)
Pfreundschuh et al., Blood 2005;106 (Abstract 13)

17. RICOVER 60 interim analysis: freedom from treatment failure (FFTF)
Regimen
No. of patients
FFTF*
6 x CHOP-14
203
53%
6 x CHOP x R
211
70%
8 x CHOP-14
210
58%
8 x CHOP x R
*Median 26 months follow-up
Pfreundschuh et al., Blood 2005;106 (Abstract 13)

18. RICOVER 60: time to treatment failure
6 cycles vs 8 cycles
CHOP-14 vs R-CHOP-14
100 80 60 40 20
100 80 60 40 20
p=0.23
p= -crit* = 0.031
70%
64%
62%
Failure-free survival (%)
Failure-free survival (%)
57%
8 x (R)-CHOP-14 (n=415)
6 x (R)-CHOP-14 (n=413)
6/8 x R-CHOP-14 (n=414)
6/8 x CHOP-14 (n=414)
Months
Months
Pfreundschuh et al., Blood 2005;106 (Abstract 13)

19. RICOVER 60: survival 6 cycles vs 8 cycles CHOP-14 vs R-CHOP-14 100 8040 20
p=0.284
100 80 60 40 20
p=0.088
78%
78%
77%
76%
Surviving (%)
Surviving (%)
6 x (R)-CHOP-14 (n=415)
8 x (R)-CHOP-14 (n=413)
6/8 x R-CHOP-14 (n=414)
6/8 x CHOP-14 (n=414)
Months
Months
Pfreundschuh et al., Blood 2005;106 (Abstract 13)

20. Elderly DLBCL: survival
Historical perspective (I): stages I–IV
100 80 60 40 20
78%
72%*
58%*
Surviving (%)
8 x R + 6/8 x CHOP-14 (n=414)
6 x CHOP-14* (n=172)
6 x CHOP-14* (n=176)
Months
*Pfreundschuh et al., Blood 2004;104:634–41
Pfreundschuh et al., Blood 2005;106 (Abstract 13)

21. Elderly DLBCL: survival
Historical perspective (II): stages II–IV
100 90 80 70 60 50 40 30 20 10
74%
64%*
Surviving (%)
55%*
8 x R + 6/8 x CHOP-14 n=414
8 x R-CHOP-21* n=202
8 x CHOP-21* n=197
Months
* Feugier P, et al. J Clin Oncol :4117–26
Pfreundschuh et al., Blood 2005;106 (Abstract 13)

22. RICOVER 60: conclusions R-CHOP-14 superior to CHOP-14
Trend in favour of 8 x CHOP-14 over 6 x CHOP-14
- disappears after rituximab
8 x R+ 6/8 x CHOP-14: best results in elderly to date
8 x R + 6 x CHOP-14: reference for future trials
Pfreundschuh et al., Blood 2005;106 (Abstract 13)

23. MInT: trial design 6 x CHOP-like CD20+ DLBCL 18–60 years IPI 0,1
+ 30–40 Gy (Bulk, E)
CD20+ DLBCL
18–60 years
IPI 0,1
Stages II–IV,
I with bulk
(n=823)
Randomisation
6 x CHOP-like
+ rituximab
+ 30–40 Gy (Bulk, E)
Pfreundschuh M, et al. Proc Am Soc Clin Oncol 2005 (Abstract 6529)

24. MInT: time to treatment failure
1.0
0.8
0.6
0.4
0.2
80%
R-Chemo
61%
Probability
Chemo p=
Months
Median observation time: 22 months
Pfreundschuh M, et al. Proc Am Soc Clin Oncol 2005 (Abstract 6529)

25. MInT: overall survival
1.0
0.8
0.6
0.4
0.2
95%
R-Chemo
86%
Chemo
Probability
Lymphoma-associated deaths:
Chemo: 42
R-Chemo: 13
p=0.0002
Months
Median observation time: 23 months
Pfreundschuh M, et al. Proc Am Soc Clin Oncol 2005 (Abstract 6529)

26. MInT: time to treatment failure
R-CHOP vs CHOP
R-CHOEP vs CHOEP
1.0
1.0
R-CHOEP (n = 181) .9
82.9% .9
80.4% .8
R-CHOP (n = 197) .8 .7 .7
65.1%
55.3% .6 .6
Probability .5
CHOP (n = 197)
Probability .5 .4 .4
CHOEP (n = 180) .3 .3 .2 .2 .1
P < .1
P =
0.0
0.0 5 10 15 20 25 30 35 40 45 50 5 10 15 20 25 30 35 40 45 50
Months
Months
Pfreundschuh M, et al. Proc Am Soc Clin Oncol 2005 (Abstract 6529)

27. MInT: time to treatment failure
CHOP vs CHOEP
R-CHOP vs R-CHOEP
1.0
1.0
R-CHOP
(n = 197)
82.9% .9 .9 .8
65.1% .8
80.4% .7
CHOEP
(n = 180) .7 .6
Probability .6
Probability .5
55.3%
CHOP
(n = 187) .5
R-CHOEP
(n = 181) .4 .4 .3 .3 .2 .2
P = 0.04
P = 0.67 .1 .1
0.0
0.0 5 10 15 20 25 30 35 40 45 50 5 10 15 20 25 30 35 40 45 50
Months
Months
Pfreundschuh M, et al. Proc Am Soc Clin Oncol 2005 (Abstract 6529)

28. MInT: overall survival for (R)-CHOP versus (R)-CHOEP
Very favourable (IPI=0, no bulk)
Less favourable (IPI=1 and/or bulk)
100%
R-CHOP
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
95.8%
R-CHOP
R-CHOEP
95.1%
R-CHOEP
92.8%
Probability
Probability
p=0.26
p=0.65
Months
Months
Pfreundschuh M, et al. Proc Am Soc Clin Oncol 2005 (Abstract 6529)

29. Rituximab in first-line treatment of aggressive NHL: conclusions
8 cycles of rituximab plus chemotherapy is the standard of care for DLBCL patients irrespective of age or risk factors
confirmed in a community-based study
Addition of 8 cycles of rituximab to dose intensified strategies allows a reduction in the number of cycles of CHOP
may reduce toxicity, particularly cardiotoxicity

30. Rituximab in relapsed/refractory aggressive NHL

31. Rituximab plus ICE for relapsed/refractory CD20+ DLBCL
Median days to complete three cycles R-ICE: 45 (35–59) vs 37 with ICE
10/34 (29%) patients completed R-ICE in 35 days
28/34 (83%) sufficient PBPC harvest vs 80/92 (87%) ICE
Kewalramani T, et al. Blood 2004;103:3684–8

32. R-ICE for relapsed/refractory CD20+ DLBCL
PFS
1.0
0.8
0.6
0.4
0.2
R-ICE (n=34)
Proportion progression-free
ICE (n=92; historical controls)
p=0.25
Months from ASCT
Kewalramani T, et al. Blood 2004;103:3684–8

33. Rituximab + EPOCH in relapsed aggressive NHL: protocol
MabThera 375 mg/m2 i.v. day 1 Doxorubicin 15 mg/m2 c.i.v. days 2–4
Etoposide 65 mg/m2 c.i.v. days 2–4 Vincristine 0.5 mg c.i.v. days 2–4
Cyclophosphamide 750 mg/m2 i.v. day 5 Prednisone 60 mg/m2 p.o. days 1–14
MabThera
Doxorubicin
Etoposide
Vincristine
Cyclophosphamide
Prednisone
Days
Updated from Jost et al. Proc Am Soc Clin Oncol. 2001;21:290a. Abstract 1157.

34. Rituximab + EPOCH in relapsed aggressive NHL: response
Patients (%)
(n=50)
ORR 64
CR 26
PR 38
Stem cell harvest in 18 of 27 patients (67%) under 60 years
Updated from Jost et al. Proc Am Soc Clin Oncol. 2001;21:290a. Abstract 1157.

35. CORAL trial of R-ICE versus R-DHAP
SD/PD Off R A N D O M I S E
R-ICE x 3 R A N D O M I S E
R x 6
CD20+ DLBCL
Relapsed/ refractory
BEAM +
ASCT
PR/CR
Stratification:
rituximab-naive
versus previous
rituximab
R-DHAP x 3
Obs
400 patients needed

36. Rationale for rituximab in vivo purging and consolidation
Rituximab in vivo purging can eliminate residual lymphoma cells, a major cause of relapse, from stem cell harvests, without adversely affecting the yield or function of stem cells
Rituximab can also be used as consolidation therapy post-transplant to eliminate residual malignant cells and reduce the likelihood of relapse

37. In vivo purging with rituximab prior to ASCT
B-NHL patients (n=27) received rituximab plus DexaBEAM therapy prior to ASCT
Patients (%)
Remission rate
25 (96)
Complete remission
24 (92)
Partial remission
1 (4)
16 months post HDT:
95% overall survival
77% progression-free survival
Flohr T, et al. Bone Marrow Transplant 2002;29:796–75

38. Rituximab after HDT/ASCTCY
BCNU/VP/CY
Rituximab*
Rituximab*
Harvest†
ASCT
42 days
6 months
Time
*375mg/m2 weekly x 4 †CD34-enriched and in-vitro antibody purged
Horwitz SM, et al. Blood 2004;103:777–83

39. Rituximab after autologous transplantation: event-free survival
120
100 80 60 40 20
All patients
120
100 80 60 40 20
Recurrent DLBCL
Event-free survival (%)
Event-free survival (%)
n=35
n=21
Years
Years
Horwitz S, et al. Blood 2004;103:777–83

40. Rituximab for treatment of relapsed/refractory aggressive NHL: conclusions
Adding rituximab to salvage chemotherapy improves the response to chemotherapy and therefore can improve patient outcome
In vivo purging with rituximab prior to ASCT may impact progression-free and overall survival
Rituximab consolidation post-ASCT may impact event-free survival providing further patient benefit