Immuno-chemotherapy

A new standard in the first-line treatment of advanced indolent (follicular) lymphoma?

Michael Herold

HELIOS – Klinikum Erfurt

Germany

Kuala-Lumpur, Malaysia 11.3.06

Non-Hodgkin‘s lymphoma: most frequent (important) entities

Entity Cases (%) 5-year survival (%)

DLBCL 30 46

Follic. lymphoma 22 72

Marginal-Zone B 8 74

(MALT-Type)

B-CLL 7 51

Mantle-Cell L. 6 27

Armitage, Blood 1997

Survival of patients with indolent lymphoma: the Stanford experience 1960–1996

Adapted from Horning. Semin Oncol 1993;20 (5 Suppl. 5):75–88

Pat

ien

ts (

%)

1987–1996

1976–1986

1960–1975

5-year 80%10-year 60%15-year 45%

Years

100

80

60

40

20

00 5 10 15 20 25 30

Median survival ~ 11y!

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

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

Rituximab + CHOP in low-grade NHL: efficacy

Czuczman M, et al. Blood 2003;102:411a (Abstract 1493),up date 2005

Previously untreated patients (n=29)

Previously treated patients (n=9)

CR (%) 59 56

PR (%) 41 44

TTP (range, months) 84.9+ (4.5–105.6+)

47.4 (6.8–95.5+)

Duration of response (range, months)

83.5+ (2.9–105.1+)

46.1 (4.1–94+)

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)

Chemotherapy +/- rituximab first-line

M 39021 CVP vs R-CVP

GLSG CHOP vs R-CHOP

FL 2000 GELA CHVP vs R-CHVP

M 39023 (OSHO) MCP vs R-MCP

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??

M39021: study design

•Follicular NHL (IWF B,C, D)•Stage III-IV•> 18 yrs.•No prior Rx•Measurable Dz•Central histology review

RANDOMIZE

CVP x 4 cycles(q 3 weeks)

R-CVP x 4 cycles (q 3 weeks)

RESTAGING

CVP x 4 cycles(q 3 weeks)

R-CVP x 4 cycles (q 3 weeks)

SD,PD off treatment

R. Marcus, 2005

CR, PR

rituximab 375 mg/m2 IV d1cyclophosphamide 750 mg/m2 IV d1vincristine 1.4 mg/m2 IV d1prednisone 40 mg/m2 PO d1–5

Patient characteristics Characteristic

CVP (n=159)

R-CVP

(n=162)

Median age (years) 53 52

Stage III−IV (%) 99 99

Histology − Follicular NHL (%)

Grade 1, 2 89 90

Grade 3 8 9

Elevated LDH level (%) 26 26

Bulky disease (%) 46 39

Extranodal sites > 1 (%) 17 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

CVP ± rituximab in previously untreated FL: response rates

Response

CVP (n=159)

Rituximab + CVP (n=162)

p value

ORR (%) 57.2 80.9 <0.0001

CR (%) 7.5 30.2

CRu (%) 2.5 10.5

CR/CRu (%) 10.0 40.7 <0.0001

PR (%) 47.2 40.1

159CVP

R–CVP

Patients at risk:Study month

162

Ev

en

t-fr

ee

pro

ba

bil

ity

06 12 18 24 30 36 42 48 540 60

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

86

123

51

113

34

98

30

93

21

76

16

66

5

36

1

15

0

5

0

0

Primary endpoint: time to treatment failuremedian FU 42 months

Primary endpoint: time to treatment failuremedian FU 42 months

R-CVP: median 27.0 months

CVP: median 6.6 monthsp <0.0001

Overall survival median FU 42 months

159CVP

R–CVP

Patients at risk:Study month

162

Ev

en

t-fr

ee

pro

ba

bil

ity

p = 0.0553

06 12 18 24 30 36 42 48 540 60

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

155

162

151

160

141

155

136

150

132

144

122

135

72

82

38

43

7

14

0

0

R-CVP: median not reached

CVP: median not reached

89 % vs 81 %

Summary of results

10 41

7 27

14 34

CVP

(n=159)

R-CVP

(n=162)

81

p-value

<0.0001

<0.0001

<0.0001

<0.0001

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 (%)

12

14

81

57

46

38

89

<0.0001

<0.0001

0.0553

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

R-CHOP versus CHOP in previously untreated follicular NHL and MCL: protocol

RANDOMISATION

CHOP x 4–6

CHOP x 4–6 +

rituximab

CR, PR

RANDOMISATION

Peripheral blood stem cell transplant

2 x CHOP (+ MabThera) +standard IFN-maintenance

2 x CHOP (+ MabThera) +intensive IFN-maintenance

2 x CHOP (+ MabThera) +standard IFN-maintenance

CR, PR

Hiddemann W, et al. Blood 2004;104:50a (Abstract 161)

<60 years

≥60 years

R-CHOP versus CHOP in previously untreated follicular NHL: response

CHOP (%) (n=272)

R-CHOP (%) (n=284)

ORR 91 97

CR 17 20

PR 74 77

MR 3 1

SD 2 1

PD 3 1

Excluded 1 1

Hiddemann W, et al. Blood 2005

p=0.005

0 1 2 3 4 5

100

80

60

40

20

0

Years

Pat

ien

ts (

%)

R-CHOP (231/285)

CHOP (164/272)

R-CHOP versus CHOP in previously untreated follicular NHL: TTF

Hiddemann W, et al. Blood 2005

p<0.0001

R-CHOP versus CHOP in previously untreated follicular NHL: overall survival

100

80

60

40

20

Years

Pat

ien

ts (

%)

R-CHOP (272/285)

CHOP (249/272)

0 1 2 3 4 5

Hiddemann W, et al. Blood 2005

P=0,016

FL2000 study design

D1 Cyclophosphamide 600 mg/m2

D1 Doxorubicin 25 mg/m2 D1 Etoposide 100 mg/m2 D1-D5 Prednisone 40 mg/m2

α-IFN 2b (Roferon) : 4.5 MU t. i. w for 18 months (3MU if aged > 70)

Rituximab : 375 mg/m2every month for 6 months (arm A &

B) then every 2 months in arm A

R

Arm A

Arm B

Staging including CT-scan and bone marrow biopsy

12 months6 months

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%)

FL2000: response at the end of planned therapy

(18 months - 358 patients)

G. Salles - December 2004 ASH Meeting

Cheson criteria

FL2000 : event-free survivalMedian follow-up 31 months

Arm B

Arm A

GS - December 2004 ASH Meeting

Log-Rank P= 0.0031

63%

78%Arm B

Arm A

MCP ± rituximab Rituximab 375mg/m2 IV d 1Mitoxantrone 8 mg/m² IV d 3 + 4Chlorambucil 3 x 3mg/m² PO d 3–7Prednisolone 25 mg/m² PO d 3–7

• Advanced FL, IC and MCL

• 18–75 years• No prior Rx• Central

histology review

• Written informed consent

RANDOMIZE

MCP x 6 cycles(q 4 weeks)

R-MCP x 6 cycles (q 4 weeks)

RESTAGING

MCP x 2 cycles(q 4 weeks)

R-MCP x 2 cycles (q 4 weeks)

SD, PD off treatment

CR, PR

IFN-maintenance for FL

M 39023: study design

ASH, San Diego 12/049. ICML, Lugano 6/05

MCP(n=177) 49.4 %

R-MCP(n=181) 50.6%

MCL(n=90) 25%

IC(n=34) 10%

Other(n=29) 8%

M 39023: rituximab + MCP vs MCP(n=358 ITT)(n=358 ITT)

FL(n=201)

57%

M 39023: demographic characteristics follicular lymphoma

R-MCP (105) MCP (96)

Age median 60 (33–78) 57 (31–76)

Sex m/f 53/52 36/60FLIPI (low/interm./high)

8/38/59 6/37/53

Median f/u 7/05 43 (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

M 39023 toxicity (all SP patients)

R-MCP(n = 183) events/pt.

AE total 1.839/180 (98%)

SAE total 58/34 (19%)

AB-inf.reaction 1/1 (0,5%) (CTC 3)

WBC CTC 3+4 457/130 (71%)

PLT CTC 3+4 20/19 (11%)

Infection CTC 3+4 9/9 (5%)

FUO CTC 3 9/14 (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%)

M 39023: remission rates FL patients (ITT population)

RR (%)

CR (%)

92.4 75 0.0009

49.5 25 0.0004

R-MCP MCP pn = 105 n = 96

M39023: progression-free survivalFL patients (ITT population)

median f/u 37 months

Pro

gre

ssio

n-f

ree

surv

ival

1.00

0.75

0.50

0.25

00 10 20 30 40 50 60

Time (months)

3y PFS 77.4%

3y PFS 44%R-MCP: median 54.3 months

MCP: median 27.8 months

p<0.0001CensoredEvents 27 vs 54

M39023: overall survivalFL patients (ITT population)

median f/u 37 months

Ove

rall

su

rviv

al

1.00

0.75

0.50

0.25

0 0 10 20 30 40 50 60 Time (months)

3y OS 88%

3y OS 74%

R-MCP: median not reachedMCP: median not reached

P=0.0140CensoredEvents 14 vs 24

Cause specific deaths: R-MCP 7 vs MCP 16 p=0.0261

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

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

Treatment costs M 39023

* Active treatment includes the cost of managing adverse events.† Observation includes the costs associated with disease progression, complications, new therapies and other costs.

Type MCP R-MCP p-value

Active treatment*

€ 21,500 € 35,600 < 0.01

Observation† € 30,700 € 17,900 < 0.01

Total € 52,200 € 53,500 0.6

Cumulative treatment costs – per period analyses M 39023

0

10,000

20,000

30,000

40,000

50,000

60,000

70,000

80,000

90,000

the

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1o

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2o

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3o

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4o

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5o

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6o

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7o

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8o

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9o

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10

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s 1

1o

bs

12

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MCP

R-MCP

21 months after end of initial therapyC

um

ula

tive

tre

atm

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t c

ost

s (

€)

Unpublished data

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

R – MCP x 6 + 2 R

R – CHOP x 6 + 2 R

R – FCM x 6 + 2 RCR+PR

RANDOMIZE

Observation

R–maintenance (SAKK):375 mg/m² q 2 mo. x 2 y

OSHO # 70 Study (>65)

PRIMA = Primary Rituximab and Maintenance

ChRx x 6-8Rituximab x 8

European CooperationOSHO # 70 (only G) + PRIMA Study (EU)

RANDOMIZE

Advanced FL (<65 J.)RI-CHOP

R-CHOP x 6 +

2 x R

CR, PR

RANDOMISATION

HD-ChRx + APBSCT+

Rituximab–maintenance375 mg/m² q 2 months/2y.

Rituximab–maintenance375 mg/m² q 2 months/2 y.

P

atie

nts

(%

)

1987–1996

1976–1986

1960–1975

Years

100

80

60

40

20

00 5 10 15 20 25 30

2000 – 2010??

Perspectives for follicular lymphoma?