1. HELIOS – Klinikum Erfurt
Immuno-chemotherapy
A new standard in the first-line treatment of advanced indolent (follicular) lymphoma?
Michael Herold
HELIOS – Klinikum Erfurt
Germany
Kuala-Lumpur, Malaysia

2. Increase of NHL – German data
2000
1.855
12.561
+ 40%

3. Non-Hodgkin‘s lymphoma: most frequent (important) entities
Entity Cases (%) year survival (%)
DLBCL
Follic. lymphoma
Marginal-Zone B
(MALT-Type)
B-CLL
Mantle-Cell L
Armitage, Blood 1997

4. Survival of patients with indolent lymphoma: the Stanford experience 1960–1996
1987–1996
1976–1986
1960–1975
100 80 60 40 20
Median survival ~ 11y!
Patients (%)
5-year 80%
10-year 60%
15-year 45%
Actuarial survival curves for patients with indolent NHL treated at Stanford University from 1960 to 1976, 1976 to 1987, and 1987 to 1996 are essentially indistinguishable, which shows that the widespread use of single-agent or multiagent chemotherapy or combined modality therapy has not had a significant impact on the natural course of the disease.54
Years
Adapted from Horning. Semin Oncol 1993;20 (5 Suppl. 5):75–88

5. Expanding treatment options in advanced follicular lymphoma
# Watch and wait
# Mono-chemotherapy
# Combination chemotherapy
# New cytotoxic drugs
# High-dose-chemotherapy +/- TBI + APBSCT
# Biological therapy: monoclonal antibodies
+/- chemotherapy

6. Rationale for combining chemotherapy and rituximab
Single agent activity
No cross resistance
No over-lapping toxicities
Synergistic effects in vitro
Sensitisation of NHL cell lines by rituximab against cytotoxic drugs in vitro

7. Rituximab + CHOP in low-grade NHL: efficacy
Czuczman M, et al. Blood 2003;102:411a (Abstract 1493),up date 2005

8. Rituximab + CHOP in low-grade NHL: conclusions from a phase II study
Rituximab plus CHOP results in an overall response rate of 100%
Time to progression is prolonged
Combination therapy is safe and does not cause significant added toxicity
Results have to be confirmed in large scale prospective randomized trials
Czuczman M, et al. Blood 2003;102:411a (Abstract 1493)

9. Chemotherapy +/- rituximab first-line
M CVP vs R-CVP
GLSG CHOP vs R-CHOP
FL 2000 GELA CHVP vs R-CHVP
M (OSHO) MCP vs R-MCP

10. Rationale/questions of all studies:
Can we improve the outcome of patients with advanced indolent NHL/follicular lymphoma by combining chemotherapy with rituximab?
End points :
# response rates, especially complete responses
# time to progression (PFS) and event-free survival (EFS), resp. time to next treatment
# is it even possible to prolong survival,
is cure possible??

11. R-CVP x 4 cycles (q 3 weeks) R-CVP x 4 cycles (q 3 weeks)
M39021: study design
Follicular NHL (IWF B,C, D)
Stage III-IV
> 18 yrs.
No prior Rx
Measurable Dz
Central histology review R E S T A G I N R A N D O M I Z E
CVP x 4 cycles
(q 3 weeks)
CVP x 4 cycles
(q 3 weeks)
CR, PR
R-CVP x 4 cycles (q 3 weeks)
R-CVP x 4 cycles (q 3 weeks)
Inclusion criteria
CD20+ follicular NHL; Ann Arbor stage III or IV (classes B, C and D)
No previous systemic antilymphoma treatment
WBC <25 x 109/L
No CNS involvement
Additional standard inclusion criteria
rituximab 375 mg/m2 IV d1
cyclophosphamide 750 mg/m2 IV d1
vincristine 1.4 mg/m2 IV d1
prednisone 40 mg/m2 PO d1–5
SD,PD off treatment
R. Marcus, 2005

12. Patient characteristics
CVP (n=159)
R-CVP (n=162)
Median age (years) 53 52
Stage III−IV (%) 99
Histology − Follicular NHL (%)
Grade 1, 2 89 90
Grade 3 8 9
Elevated LDH level (%) 26
Bulky disease (%) 46 39
Extranodal sites > 1 (%) 17
FLIPI 3−5 (poor prognosis) (%) 50 47
FLIPI 2 (intermediate prognosis) (%) 43 40
FLIPI 0−1 (good prognosis) (%) 7 13
Note: central review of pathology performed on 90% of patients, diagnosis of FL confirmed for 95% of patients

13. CVP ± rituximab in previously untreated FL: response rates
CVP R-CVP
Last Response
CR 12 (7.5 %) 49 (30.2%)
Cru 4 (2.5%) 17 (10.5%)
PR 75 (47.2%) 65 (40.1%)
SD 33 (20.8%) 12 (7.4%)
PD 30 (18.9%) 17(10.5%)
ORR 91 (57.1%) 131 (80.9%)
Not assessable 5 (3.1%) 2 (1.2%)
Best Response (either after cycle 4 or 8)
CR 13 (8.2%) 49 (30.2%)
Cru 5 (3.1%) 17 (10.5%)
PR 86 (54.1%) 71 (43.8%)
SD 37 (23.3%) 14 (8.6%)
PD 13 (8.2%) 9 (5.6%)
ORR 104 (65.4%) 137 (84.6%)

14. Primary endpoint: time to treatment failure median FU 42 months
1.0
0.9
0.8
0.7
0.6
Event-free probability
R-CVP: median 27.0 months
0.5
0.4
0.3
0.2
CVP: median 6.6 months
p <0.0001
0.1 6 12 18 24 30 36 42 48 54 60
Study month
Patients at risk:
CVP
159 86 51 34 30 21 16 5 1
R–CVP
162
123
113 98 93 76 66 36 15 5

15. Time to progression, relapse or death median FU 42 months
1.0
0.9
0.8
0.7
0.6
R-CVP: median 34 months
Event-free probability
0.5
0.4
0.3
CVP: median 15 months
0.2
p <
0.1 6 12 18 24 30 36 42 48 54 60
Study month
Patients at risk:
CVP
159
129 87 64 51 39 29 14 5
R–CVP
162
144
132
112
105 84 73 40 16 5

16. Duration of response median FU 42 months
1.0
0.9
0.8
0.7
R-CVP: median 38 months
0.6
Event-free probability
0.5
0.4
0.3
CVP: median 14 months
0.2
p <
0.1 6 12 18 24 30 36 42 48 54 60
Study month
Patients at risk:
CVP
104 78 53 41 29 25 13 2
R–CVP
137
128
110
100 87 75 54 28 12 1

17. Disease-free survival median FU 42 months
1.0
0.9
0.8
0.7
R-CVP: median 45 months
0.6
Event-free probability
0.5
0.4
0.3
CVP: median 21 months
0.2
p =
0.1 6 12 18 24 30 36 42 48 54 60
Study month
Patients at risk:
CVP 18 16 14 11 7 6 4
R–CVP 66 65 60 57 47 43 23 8 3

18. Overall survival median FU 42 months
R-CVP: median not reached
1.0
0.9
0.8
0.7
CVP: median not reached
0.6
Event-free probability
0.5
89 % vs 81 %
0.4
0.3
0.2
p =
0.1 6 12 18 24 30 36 42 48 54 60
Study month
Patients at risk:
CVP
159
155
151
141
136
132
122 72 38 7
R–CVP
162
162
160
155
150
144
135 82 43 14

19. Cox regression analysis: TTP by subgroup
0.5
0.1
0.9
1.2
1.6
Baseline parameter
Category n
Lower
95% CL
Estimate
All patients
Total
321
0.320
0.422
0.558
BNLI criteria
Yes No 91
230
0.202
0.315
0.347
0.440
0.596
0.613
Age (years)
≤60
>60
236 85
0.333
0.206
0.461
0.372
0.638
0.671
Extra-nodal sites
>1
0–1 56
265
0.351
0.292
0.686
0.399
1.341
0.545
BM involved (local)
205
112
0.332
0.469
0.662
0.547
Elevated LDH 78
226
0.240
0.264
0.431
0.375
0.773
0.532
Elevated B2M
140
148
0.279
0.255
0.420
0.397
0.630
0.617
IPI (CRF validated)
143
159
0.259
0.298
0.406
0.439
0.636
0.648
B-symptoms
116
0.314
0.263
0.505
0.377
0.812
0.541
Bulky disease
136
185
0.256
0.318
0.394
0.462
0.608
Nodal sites
<5 ≥5 54
267
0.297
0.459
0.401
1.040
0.543
Haemoglobin (g/dL)
>12
12
251 66
0.419
0.355
0.748
0.495
1.335
FLIP index
(prognosis)
0–2 (good)
3–5 (poor)
155
146
0.242
0.323
0.373
0.479
0.577
0.709
Upper
Note: CL = confidence limit. Vertical line = risk ratio estimate for all patients. Horizontal bars = 95% CLs for relevant category.
Model includes stratification by center pool.

20. Summary of results CVP R-CVP p-value (n=159) (n=162)
Median time to treatment failure (months)
Median time to progression (months)
Median time to new
antilymphoma treatment (months)
Overall response (%)
Median duration of response (months)
Estimated 3-year overall survival (%)
Complete response (%) 57 81
<0.0001 10 41
<0.0001 7 27
<0.0001 14 34
<0.0001 12 46
<0.0001 14 38
<0.0001 81 89
0.0553

21. Conclusions
The addition of rituximab to each of 8 courses of CVP demonstrates major improvement in all clinical endpoints
R-CVP is an effective, short and very low toxicity regimen
R-CVP shows superior efficacy to any other chemotherapy regimen published in a large scale clinical trial

22. R-CHOP versus CHOP in previously untreated follicular NHL and MCL: protocol
Peripheral blood stem cell transplant
CHOP x 4–6 +
rituximab
CR, PR
<60 years
2 x CHOP (+ MabThera) +
standard IFN-maintenance
2 x CHOP (+ MabThera) +
intensive IFN-maintenance
CHOP x 4–6
CR, PR
≥60 years
2 x CHOP (+ MabThera) +
standard IFN-maintenance
Hiddemann W, et al. Blood 2004;104:50a (Abstract 161)

23. R-CHOP versus CHOP in previously untreated follicular NHL: response
Hiddemann W, et al. Blood 2005

24. R-CHOP versus CHOP in previously untreated follicular NHL: TTF
100 80 60 40 20
R-CHOP (231/285)
Patients (%)
CHOP (164/272)
p<0.0001
Years
Hiddemann W, et al. Blood 2005

25. R-CHOP versus CHOP in previously untreated follicular NHL: overall survival
100 80 60 40 20
R-CHOP (272/285)
CHOP (249/272)
Patients (%)
P=0,016
Years
Hiddemann W, et al. Blood 2005

26. Staging including CT-scan and bone marrow biopsy
FL2000 study design R
Arm A
Arm B
Staging including CT-scan and bone marrow biopsy
12 months
6 months
D1 Cyclophosphamide mg/m2
D1 Doxorubicin mg/m2
D1 Etoposide mg/m2
D1-D5 Prednisone mg/m2
α-IFN 2b (Roferon) : 4.5 MU
t. i. w for 18 months (3MU if aged > 70)
Rituximab : 375 mg/m2
every month for 6 months (arm A & B) then every 2 months in arm A

27. FL2000: response at the end of planned therapy (18 months - 358 patients)
Arm A
(n= 183)
Arm B
(n=175) p
CR + CRu
109 (60%)
132 (75%)
.0046
Partial Response
22 (12%)
10 (6%)
Stable/PD/Death
52 (28%)
33 (19%)
Cheson criteria
G. Salles - December 2004 ASH Meeting

28. FL2000 : event-free survival GS - December 2004 ASH Meeting
Median follow-up 31 months
Log-Rank P=
63%
78%
Arm B
Arm A
Arm B
Arm A
GS - December 2004 ASH Meeting

29. R-MCP x 6 cycles (q 4 weeks) R-MCP x 2 cycles (q 4 weeks)
M 39023: study design
Advanced FL, IC and MCL
18–75 years
No prior Rx
Central histology review
Written informed consent R
ESTAGING R A N D O M I Z E
MCP x 6 cycles
(q 4 weeks)
MCP x 2 cycles
(q 4 weeks)
CR, PR
R-MCP x 6 cycles (q 4 weeks)
R-MCP x 2 cycles (q 4 weeks)
Inclusion criteria
CD20+ follicular NHL; Ann Arbor stage III or IV (classes B, C and D)
No previous systemic antilymphoma treatment
WBC <25 x 109/L
No CNS involvement
Additional standard inclusion criteria
IFN-maintenance for FL
SD, PD off treatment
MCP ± rituximab
Rituximab 375mg/m2 IV d 1
Mitoxantrone 8 mg/m² IV d 3 + 4
Chlorambucil 3 x 3mg/m² PO d 3–7
Prednisolone 25 mg/m² PO d 3–7
ASH, San Diego 12/04
9. ICML, Lugano 6/05

30. M 39023: rituximab + MCP vs MCP (n=358 ITT)
Other (n=29) 8% IC
(n=34) 10%
R-MCP (n=181) 50.6% FL
(n=201)
57%
MCL (n=90) 25%

31. M 39023: demographic characteristics follicular lymphoma
R-MCP (105)
MCP (96)
Age median
60 (33–78)
57 (31–76)
Sex m/f
53/52
36/60
FLIPI (low/interm./high)
8/38/59
6/37/53
Median f/u 7/05
(37)
31 mo.
ECOG (0/1/2/3)
68/29/7/1
54/36/6/0
Stage III/IV
30/75
22/74
Bone marrow 73 71

32. M 39023 toxicity (all SP patients)
R-MCP(n = 183) events/pt.
AE total /180 (98%)
SAE total /34 (19%)
AB-inf.reaction /1 (0,5%)
(CTC 3)
WBC CTC /130 (71%)
PLT CTC /19 (11%)
Infection CTC /9 (5%)
FUO CTC /14 (8%)
MCP(n = 177) events/pt.
1.589/157 (89%)
69/41 (23%)
0/0 (0%)
342/96 (54%)
32/18 (10%)
16/14 (8%)
2/2 (1%)

33. M 39023: remission rates FL patients (ITT population)
R-MCP MCP p
n = n = 96
RR (%)
CR (%)
92.4 75
0.0009
49.5 25
0.0004

34. Progression-free survival
M39023: progression-free survival FL patients (ITT population) median f/u 37 months
1.00
0.75
0.50
0.25
3y PFS 77.4%
Progression-free survival
R-MCP: median 54.3 months
3y PFS 44%
MCP: median 27.8 months
Censored
Events 27 vs 54
p<0.0001
Time (months)

35. M39023: overall survival FL patients (ITT population) median f/u 37 months
3y OS 88%
1.00
0.75
0.50
0.25
3y OS 74%
Overall survival
R-MCP: median not reached
MCP: median not reached
Censored
Events 14 vs 24
P=0.0140
Time (months)
Cause specific deaths: R-MCP 7 vs MCP 16 p=0.0261

36. Phase III trials of chemo versus R-chemo in previously untreated advanced follicular NHL
Study
Treatment, n
median FU (mos)
ORR (%)
CR (%)
TTP
(median, mos) OS
Solal-Celigny et al. [2005]
CVP, 159
R-CVP, 162 42 57 81 10 41 14 34
(p<0.0001)
81%
89%
(est. 3-yr; p=0.0553)
Hiddemann et al. [2005]
CHOP, 205
R-CHOP, 223 18 90 96
17*
20* 29 NR
(TTF; p<0.001)
90%
95%
(est. 2-yr; p=0.016)
Herold et al. [2005]
MCP, 96
R-MCP, 105 37 75 92
25*
50* 25 54
(TTF;p<0.0001)
74%
88%
(36 mos; p=0.014)
Salles et al. [2004]
CHVP-IFN, 175
R-CHVP-IFN, 184 30 73 84 63 79
62%
78%
(EFS; p=0.003)
N/A
*patients who fulfilled CR criteria but had no evaluable negative BM biopsy defined as PR, not CRu

37. Antibody based therapy - conclusions
New and promising treatment option for NHL including follicular lymphoma,
# effective
# very well tolerated
# but expensive!! ?  
Combination of AB with chemotherapy improves the outcome significantly and is a new standard in 2005
Curative potential ??
More, and new, moAB and AB-conjugates will be introduced soon

38. Treatment costs M 39023 Type MCP R-MCP p-value Active treatment*
€ 21,500
€ 35,600
< 0.01
Observation†
€ 30,700
€ 17,900
Total
€ 52,200
€ 53,500
0.6
* Active treatment includes the cost of managing adverse events.
† Observation includes the costs associated with disease progression, complications, new therapies and other costs.

39. Cumulative treatment costs – per period analyses M 39023
90,000
80,000
MCP
70,000
60,000
Cumulative treatment costs (€)
R-MCP
50,000
40,000
30,000
20,000
21 months after end of initial therapy
10,000
obs 1
obs 2
obs 3
obs 4
obs 5
obs 6
obs 7
obs 8
obs 9
obs 10
obs 11
obs 12
obs 13
obs 14
therapy
Unpublished data

40. Antibody based therapy - conclusions
New and promising treatment option for NHL including follicular lymphoma,
# effective
# very well tolerated
# but expensive !! ?
Combination of AB with chemotherapy improves the outcome significantly and is a new standard in 2006
Curative potential ??
More, and new, moAB and AB-conjugates will be introduced soon
European study perspectives   

41. OSHO # 70 (only G) + PRIMA Study (EU)
European Cooperation
OSHO # 70 (only G) + PRIMA Study (EU) R A N D O M I Z E
OSHO # 70 Study (>65)
R–maintenance
(SAKK):
375 mg/m²
q 2 mo. x 2 y
R – MCP x R
R – CHOP x R
R – FCM x R R A N D O M I Z E
CR+PR 
ChRx x 6-8
Rituximab x 8
Observation
PRIMA
= Primary Rituximab and Maintenance

42. Advanced FL (<65 J.) RI-CHOPM I S T
HD-ChRx + APBSCT +
Rituximab–maintenance
375 mg/m² q 2 months/2y.
R-CHOP x 6 +
2 x R
CR, PR
Rituximab–maintenance
375 mg/m² q 2 months/2 y.

43. Perspectives for follicular lymphoma?
1987–1996
1976–1986
1960–1975
100 80 60 40 20
2000 – 2010??
Patients (%)
Actuarial survival curves for patients with indolent NHL treated at Stanford University from 1960 to 1976, 1976 to 1987, and 1987 to 1996 are essentially indistinguishable, which shows that the widespread use of single-agent or multiagent chemotherapy or combined modality therapy has not had a significant impact on the natural course of the disease.54
Years